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| __NOTOC__
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| {{CMG}}; {{AE}} {{HMHJ}}a
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| ==Overview==
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| {| class="wikitable"
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| |+
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| ! colspan="5" |Vascular Anomalies
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| |-
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| !Vascular Tumors
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| ! colspan="4" |Vascular Malformations
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| |-
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| | rowspan="2" |Benign
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|
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| Locally aggressive or
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|
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| Borderline
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|
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| Malignant
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| |Simple
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| |Combined°
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| |of major named vessels
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| |associated with other anomalies
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| |-
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| |Capillary malformations
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| Lymphatic malformations
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|
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| Venous malformations
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|
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| Arteriovenous malformations*
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|
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| Arteriovenous fistula*
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| |Capillary venous malformation , Capillary lymphatic malformation
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| Lymphatic venous malformation, Capillary lymphatic venous malformation
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|
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| Capillary arteriovenous malformation
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|
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| Capillary lymphatic arteriovenous malformation
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|
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| others
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| |See details
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| |See list
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| |}
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|
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| ° defined as two or more vascular malformations found in one lesion
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|
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| <nowiki>*</nowiki> high flow lesions
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|
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| ==Classification==
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|
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| ===Classification of Vascular Malformations===
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|
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| ===Tables===
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| {| class="wikitable" style="text-align:left"
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| !Anomalies of major named vessels
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| (also known as "channel type" or "truncal" vascular malformations)
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| |-
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| |Affect
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| lymphatics
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| veins
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| arteries
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|
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| Anomalies of
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| origin
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| course
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| number
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| length
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| diameter (aplasia, hypoplasia, stenosis, ectasia / aneurysm)
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| valves
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| communication (AVF)
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| persistence (of embryonal vessel)
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| |}
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|
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| {|class="wikitable"
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| ! colspan="3" |Combined vascular malformations*
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| |-
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| |CM + VM
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| |capillary-venous malformation
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| |CVM
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| |-
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| |CM + LM
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| |capillary-lymphatic malformation
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| |CLM
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| |-
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| |CM + AVM
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| |capillary-arteriovenous malformation
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| |CAVM
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| |-
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| |LM + VM
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| |lymphatic-venous malformation
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| |LVM
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| |-
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| |CM + LM + VM
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| |capillary-lymphatic-venous malformation
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| |CLVM
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| |-
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| |CM + LM + AVM
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| |capillary-lymphatic-arteriovenous malformation
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| |CLAVM
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| |-
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| |CM + VM + AVM
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| |capillary-venous-arteriovenous malformation
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| |CVAVM
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| |-
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| |CM + LM + VM + AVM
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| |capillary-lymphatic-venous-arteriovenous m.
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| |CLVAVM
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| |}
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|
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|
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| {| class="wikitable" style="text-align:center"
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| ! colspan="3" |Vascular malformations associated with other anomalies
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| |-
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| | colspan="2" |Klippel-Trenaunay syndrome *
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| |CM + VM +/-LM + limb overgrowth
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| |-
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| | colspan="2" |Parkes Weber syndrome
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| |CM + AVF + limb overgrowth
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| |-
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| | colspan="2" |Servelle-Martorell syndrome
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| |limb VM + bone undergrowth
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| |-
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| | colspan="2" |Sturge-Weber syndrome
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| |facial + leptomeningeal CM + eye anomalies
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| +/-bone and/or soft tissue overgrowth
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| |-
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| | colspan="2" |Limb CM + congenital non-progressive limb overgrowth
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| |-
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| | colspan="2" |Maffucci syndrome
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| |VM +/-spindle-cell hemangioma + enchondroma
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| |-
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| | colspan="2" |Macrocephaly-CM (M-CM / MCAP) *
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| |-
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| | colspan="2" |Microcephaly-CM (MICCAP)
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| |-
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| | colspan="2" |CLOVES syndrome *
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| |LM + VM + CM +/-AVM+ lipomatous overgrowth
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| |-
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| | colspan="2" |Proteus syndrome
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| |CM, VM and/or LM + asymmetrical somatic overgrowth
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| |-
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| |Bannayan-Riley-Ruvalcaba sd
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| | colspan="2" |lower lip CM + face and neck LM + asymmetry and partial/generalized overgrowth
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| |}
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|
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| ==Vascular Tumors==
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| ===Benign vascular tumors 1===
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| ====Infantile hemangioma / Hemangioma of infancy====
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| {| class="wikitable"
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| !Pattern
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| * focal
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|
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| * multifocal
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|
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| * segmental
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|
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| * indeterminate
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| |}
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| {| class="wikitable"
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| |+
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| !Different types
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| |-
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| * superficial
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|
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| * deep
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|
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| * mixed (superficial + deep)
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|
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| * reticular / abortive / minimal growth
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|
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| * others
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| |}
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| {| class="wikitable"
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| |+
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| ! colspan="2" |Association with other lesions
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| |-
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| |PHACE association /
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| syndrome
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| | rowspan="2" |Posterior fossa malformations, Hemangioma, Arterial
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| anomalies, Cardiovascular anomalies, Eye anomalies ,
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|
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| sternal clefting and ⁄ or supraumbilical raphe
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| |-
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| | rowspan="2" |LUMBAR (SACRAL,
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| PELVIS) association /
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|
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| syndrome
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| |-
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| |Lower body hemangioma, Urogenital anomalies,
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| Ulceration, Myelopathy, Bony deformities, Anorectal
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|
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| malformations, Arterial anomalies, and Renal anomalies
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| |}
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| * Most common tumor of infancy. Usually appearing after birth, infantile hemangiomas undergo a period of proliferation in few weeks after birth followed by regression and involution in first year of life. Superficial lesions appear as red or “strawberry” colored nodules, papules, or plaques while deeper hemangiomas are typically bluish or skin colored. Mixed tumors, involving both epidermis and deeper structures, may display characteristics of both. They may also be classified as focal, that appear in a specific anatomical area, and segmental that shows varied pattern of growth following developmental growth regions. Segmental type is often associated with other developmental abnormalities.<ref name="pmid28402073">{{cite journal |vauthors=Smith CJF, Friedlander SF, Guma M, Kavanaugh A, Chambers CD |title=Infantile Hemangiomas: An Updated Review on Risk Factors, Pathogenesis, and Treatment |journal=Birth Defects Res |volume=109 |issue=11 |pages=809–815 |date=July 2017 |pmid=28402073 |pmc=5839165 |doi=10.1002/bdr2.1023 |url=}}</ref><ref name="pmid12472344">{{cite journal |vauthors=Chiller KG, Passaro D, Frieden IJ |title=Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex |journal=Arch Dermatol |volume=138 |issue=12 |pages=1567–76 |date=December 2002 |pmid=12472344 |doi= |url=}}</ref><ref name="pmid22229118">{{cite journal |vauthors=Greenberger S, Bischoff J |title=Infantile hemangioma-mechanism(s) of drug action on a vascular tumor |journal=Cold Spring Harb Perspect Med |volume=1 |issue=1 |pages=a006460 |date=September 2011 |pmid=22229118 |pmc=3234458 |doi=10.1101/cshperspect.a006460 |url=}}</ref>
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| * Rarely, infantile hemangioms can cause life-threatening complications such as congestive cardiac failure, respiratory difficulty and respiratory compromise, and loss of vision. There may also be long-term sequela including permanent disfigurement and scarring. If lesions are multiple, there is an increased risk of visceral involvement. There may be an association with certain syndromes such as PHACE syndrome.<ref name="pmid28402073">{{cite journal |vauthors=Smith CJF, Friedlander SF, Guma M, Kavanaugh A, Chambers CD |title=Infantile Hemangiomas: An Updated Review on Risk Factors, Pathogenesis, and Treatment |journal=Birth Defects Res |volume=109 |issue=11 |pages=809–815 |date=July 2017 |pmid=28402073 |pmc=5839165 |doi=10.1002/bdr2.1023 |url=}}</ref><ref name="pmid29924216">{{cite journal |vauthors=Rotter A, Samorano LP, Rivitti-Machado MC, Oliveira ZNP, Gontijo B |title=PHACE syndrome: clinical manifestations, diagnostic criteria, and management |journal=An Bras Dermatol |volume=93 |issue=3 |pages=405–411 |date=June 2018 |pmid=29924216 |pmc=6001075 |doi=10.1590/abd1806-4841.20187693 |url=}}</ref>
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| * Some studies have indicated autosomal-dominant and maternal patterns of inheritance. Some studies suggest that environmental factors play the key role. Some risk factors that have been identified in association with infantile hemangioma include female gender, preterm birth, low weight at birth, increasing maternal age ta birth, placenta previa, pre-eclampsia, progesterone use by mother, and Caucasian race.<ref name="pmid27940781">{{cite journal |vauthors=Castrén E, Salminen P, Vikkula M, Pitkäranta A, Klockars T |title=Inheritance Patterns of Infantile Hemangioma |journal=Pediatrics |volume=138 |issue=5 |pages= |date=November 2016 |pmid=27940781 |doi=10.1542/peds.2016-1623 |url=}}</ref><ref name="pmid28402073">{{cite journal |vauthors=Smith CJF, Friedlander SF, Guma M, Kavanaugh A, Chambers CD |title=Infantile Hemangiomas: An Updated Review on Risk Factors, Pathogenesis, and Treatment |journal=Birth Defects Res |volume=109 |issue=11 |pages=809–815 |date=July 2017 |pmid=28402073 |pmc=5839165 |doi=10.1002/bdr2.1023 |url=}}</ref><ref name="pmid17307549">{{cite journal |vauthors=Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry DW, Newell B, Nopper AJ, Frieden IJ |title=Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics |journal=J. Pediatr. |volume=150 |issue=3 |pages=291–4 |date=March 2007 |pmid=17307549 |doi=10.1016/j.jpeds.2006.12.003 |url=}}</ref><ref name="pmid18940356">{{cite journal |vauthors=Drolet BA, Swanson EA, Frieden IJ |title=Infantile hemangiomas: an emerging health issue linked to an increased rate of low birth weight infants |journal=J. Pediatr. |volume=153 |issue=5 |pages=712–5, 715.e1 |date=November 2008 |pmid=18940356 |doi=10.1016/j.jpeds.2008.05.043 |url=}}</ref>
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| * THE diagnosis is made clinically and a thorough investigation should be carried out for visceral hemangiomas and other associative abnormalities if suspicion arises. Majority of these lesions do not require any treatment but treatment is indicated if there is risk for complications such as visual or respiratory involvement. Elective treatment is also offered to prevent disfigurement or scarring. Recently there have been an increased usage of oral beta-blockers such as timolol over systemic glucocorticoids because of higher efficacy. Vincristine and interferon alpha have been used in some high risk hemangiomas but carry the risk of severe complications. Visceral hemangioms may require embolization or surgery if they do not respond to systemic therapy. Laser therapy especially PDL is another modality used in cases of hemangioms unresponsive to medication.<ref name="pmid28402073">{{cite journal |vauthors=Smith CJF, Friedlander SF, Guma M, Kavanaugh A, Chambers CD |title=Infantile Hemangiomas: An Updated Review on Risk Factors, Pathogenesis, and Treatment |journal=Birth Defects Res |volume=109 |issue=11 |pages=809–815 |date=July 2017 |pmid=28402073 |pmc=5839165 |doi=10.1002/bdr2.1023 |url=}}</ref><ref name="pmid26416928">{{cite journal |vauthors=Darrow DH, Greene AK, Mancini AJ, Nopper AJ |title=Diagnosis and Management of Infantile Hemangioma: Executive Summary |journal=Pediatrics |volume=136 |issue=4 |pages=786–91 |date=October 2015 |pmid=26416928 |doi=10.1542/peds.2015-2482 |url=}}</ref><ref name="pmid14871317">{{cite journal |vauthors=Ceisler EJ, Santos L, Blei F |title=Periocular hemangiomas: what every physician should know |journal=Pediatr Dermatol |volume=21 |issue=1 |pages=1–9 |date=2004 |pmid=14871317 |doi= |url=}}</ref><ref name="pmid26859502">{{cite journal |vauthors=Tal R, Dotan M, Lorber A |title=Approach to haemangiomatosis causing congestive heart failure |journal=Acta Paediatr. |volume=105 |issue=6 |pages=600–4 |date=June 2016 |pmid=26859502 |doi=10.1111/apa.13359 |url=}}</ref><ref name="pmid21788220">{{cite journal |vauthors=Hogeling M, Adams S, Wargon O |title=A randomized controlled trial of propranolol for infantile hemangiomas |journal=Pediatrics |volume=128 |issue=2 |pages=e259–66 |date=August 2011 |pmid=21788220 |doi=10.1542/peds.2010-0029 |url=}}</ref><ref name="pmid11559219">{{cite journal |vauthors=Bennett ML, Fleischer AB, Chamlin SL, Frieden IJ |title=Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation |journal=Arch Dermatol |volume=137 |issue=9 |pages=1208–13 |date=September 2001 |pmid=11559219 |doi= |url=}}</ref><ref name="pmid12102167">{{cite journal |vauthors=Perez J, Pardo J, Gomez C |title=Vincristine--an effective treatment of corticoid-resistant life-threatening infantile hemangiomas |journal=Acta Oncol |volume=41 |issue=2 |pages=197–9 |date=2002 |pmid=12102167 |doi= |url=}}</ref><ref name="pmid20936416">{{cite journal |vauthors=Schiestl C, Neuhaus K, Zoller S, Subotic U, Forster-Kuebler I, Michels R, Balmer C, Weibel L |title=Efficacy and safety of propranolol as first-line treatment for infantile hemangiomas |journal=Eur. J. Pediatr. |volume=170 |issue=4 |pages=493–501 |date=April 2011 |pmid=20936416 |doi=10.1007/s00431-010-1324-2 |url=}}</ref><ref name="pmid26711436">{{cite journal |vauthors=Chinnadurai S, Sathe NA, Surawicz T |title=Laser treatment of infantile hemangioma: A systematic review |journal=Lasers Surg Med |volume=48 |issue=3 |pages=221–33 |date=March 2016 |pmid=26711436 |doi=10.1002/lsm.22455 |url=}}</ref>
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| * To learn more about infantile hemagioma click here.
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|
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| ====Congenital hemangioma====
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| * Rare tumor that arises in utero and presents as fully developed lesion at birth. Following birth they can regress completely, partially or not at all. So they can be classified as Rapidly involuting (RICH), Non-involuting (NICH), Partially involuting (PICH).<ref name="urlwww.issva.org">{{cite web |url=http://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf |title=www.issva.org |format= |work= |accessdate=}}</ref><ref name="pmid27058448">{{cite journal |vauthors=Ayturk UM, Couto JA, Hann S, Mulliken JB, Williams KL, Huang AY, Fishman SJ, Boyd TK, Kozakewich HP, Bischoff J, Greene AK, Warman ML |title=Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma |journal=Am. J. Hum. Genet. |volume=98 |issue=4 |pages=789–95 |date=April 2016 |pmid=27058448 |pmc=4833432 |doi=10.1016/j.ajhg.2016.03.009 |url=}}</ref>
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| *# '''Rapidly involuting (RICH)'''
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| *#* This fast flow tumor can be detected in utero and appears as raised gray single lesions with dilated veins, telangiectasias and a halo at birth. This tumor may be complicated by thrombocytopenia and congestive cardiac failure due to its high-flow nature. Tumor typically regresses spontaneously in 1 to 2 years of life. Sometimes it can occur in liver where it follows the same pattern of involution as that of skin.<ref name="pmid27058448">{{cite journal |vauthors=Ayturk UM, Couto JA, Hann S, Mulliken JB, Williams KL, Huang AY, Fishman SJ, Boyd TK, Kozakewich HP, Bischoff J, Greene AK, Warman ML |title=Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma |journal=Am. J. Hum. Genet. |volume=98 |issue=4 |pages=789–95 |date=April 2016 |pmid=27058448 |pmc=4833432 |doi=10.1016/j.ajhg.2016.03.009 |url=}}</ref><ref name="pmid15018449">{{cite journal |vauthors=Berenguer B, Mulliken JB, Enjolras O, Boon LM, Wassef M, Josset P, Burrows PE, Perez-Atayde AR, Kozakewich HP |title=Rapidly involuting congenital hemangioma: clinical and histopathologic features |journal=Pediatr. Dev. Pathol. |volume=6 |issue=6 |pages=495–510 |date=2003 |pmid=15018449 |doi= |url=}}</ref>
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| *# '''Non-involuting (NICH)'''
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| *#* Fast flow tumor that presents as well defined, plaque like lesion with pink to purple color, telangiectasias and pale borders. Typically remains stable but there have been some reports of growth and expansion.<ref name="pmid27058448">{{cite journal |vauthors=Ayturk UM, Couto JA, Hann S, Mulliken JB, Williams KL, Huang AY, Fishman SJ, Boyd TK, Kozakewich HP, Bischoff J, Greene AK, Warman ML |title=Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma |journal=Am. J. Hum. Genet. |volume=98 |issue=4 |pages=789–95 |date=April 2016 |pmid=27058448 |pmc=4833432 |doi=10.1016/j.ajhg.2016.03.009 |url=}}</ref>
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| *# '''Partially involuting (PICH)'''
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| *#* These lesions start involution as RICH but become stable over time and persist as NICH.<ref name="pmid24176519">{{cite journal |vauthors=Nasseri E, Piram M, McCuaig CC, Kokta V, Dubois J, Powell J |title=Partially involuting congenital hemangiomas: a report of 8 cases and review of the literature |journal=J. Am. Acad. Dermatol. |volume=70 |issue=1 |pages=75–9 |date=January 2014 |pmid=24176519 |doi=10.1016/j.jaad.2013.09.018 |url=}}</ref>
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| * Somatic mutations in GNAQ/GNA11 are thought to cause the congenital hemangioma. GNAQ and its paralogue GNA11 function in intracellular signaling pathways as Gq alpha subunit.<ref name="pmid27058448">{{cite journal |vauthors=Ayturk UM, Couto JA, Hann S, Mulliken JB, Williams KL, Huang AY, Fishman SJ, Boyd TK, Kozakewich HP, Bischoff J, Greene AK, Warman ML |title=Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma |journal=Am. J. Hum. Genet. |volume=98 |issue=4 |pages=789–95 |date=April 2016 |pmid=27058448 |pmc=4833432 |doi=10.1016/j.ajhg.2016.03.009 |url=}}</ref><ref name="urlError 403">{{cite web |url=https://www.omim.org/entry/139313 |title=Error 403 |format= |work= |accessdate=}}</ref>
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| * Diagnosis is usually clinical but imaging techniques such as MRI, CT scan, contrast-enhanced ultrasound and later biopsy can be considered if required. Surgical excision should be considered in case of complications, NICH and PICH.<ref name="pmid29922526">{{cite journal |vauthors=Ramphul K, Mejias SG, Ramphul-Sicharam Y, Sonaye R |title=Congenital Hemangioma: A Case Report of a Finding Every Physician Should Know |journal=Cureus |volume=10 |issue=4 |pages=e2485 |date=April 2018 |pmid=29922526 |pmc=6003795 |doi=10.7759/cureus.2485 |url=}}</ref><ref name="pmid29971555">{{cite journal |vauthors=Thimm MA, Rhee D, Takemoto CM, Karnsakul W, Cuffari C, Guerrerio AL, Garcia A, Gearhart J, Huisman TAGM, Hwang M |title=Diagnosis of congenital and acquired focal lesions in the neck, abdomen, and pelvis with contrast-enhanced ultrasound: a pictorial essay |journal=Eur. J. Pediatr. |volume=177 |issue=10 |pages=1459–1470 |date=October 2018 |pmid=29971555 |doi=10.1007/s00431-018-3197-8 |url=}}</ref>
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| ====Tufted angioma====
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| * Benign tumor that is characterized by dense clumps of endothelial cells and capillaries located in dermis. Most lesions appear in adolescence but some can manifest at birth or late in adulthood. Clinical presentation varies but majority of lesions appear as solitary stained area or elevation that later forms red-purple or dusky red plaque while some lesions appear as firm nodules. Lesions are usually solitary, asymptomatic but tender with occasional painful episodes and located on trunk and neck in majority of the cases. Some cases of multi-focal tufted angiomas have also been reported.<ref name="pmid26225332">{{cite journal |vauthors=Prasuna A, Rao PN |title=A tufted angioma |journal=Indian Dermatol Online J |volume=6 |issue=4 |pages=266–8 |date=2015 |pmid=26225332 |pmc=4513407 |doi=10.4103/2229-5178.160259 |url=}}</ref><ref name="pmid2644316">{{cite journal |vauthors=Jones EW, Orkin M |title=Tufted angioma (angioblastoma). A benign progressive angioma, not to be confused with Kaposi's sarcoma or low-grade angiosarcoma |journal=J. Am. Acad. Dermatol. |volume=20 |issue=2 Pt 1 |pages=214–25 |date=February 1989 |pmid=2644316 |doi= |url=}}</ref><ref name="pmid26312663">{{cite journal |vauthors=Pesapane F, Nazzaro G, Alberti-Violetti S, Gianotti R |title=A case of acquired tufted angioma in adulthood |journal=An Bras Dermatol |volume=90 |issue=3 Suppl 1 |pages=16–8 |date=2015 |pmid=26312663 |pmc=4540497 |doi=10.1590/abd1806-4841.20153733 |url=}}</ref><ref name="pmid26288441">{{cite journal |vauthors=Bandyopadhyay D, Saha A |title=Multifocal Annular Tufted Angioma: An Uncommon Clinical Entity |journal=Indian J Dermatol |volume=60 |issue=4 |pages=422 |date=2015 |pmid=26288441 |pmc=4533571 |doi=10.4103/0019-5154.160528 |url=}}</ref>
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| * Tufted angioma can be associated with Kasabach-Merritt phenomenon.<ref name="pmid26288441">{{cite journal |vauthors=Bandyopadhyay D, Saha A |title=Multifocal Annular Tufted Angioma: An Uncommon Clinical Entity |journal=Indian J Dermatol |volume=60 |issue=4 |pages=422 |date=2015 |pmid=26288441 |pmc=4533571 |doi=10.4103/0019-5154.160528 |url=}}</ref><ref name="urlwww.issva.org">{{cite web |url=http://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf |title=www.issva.org |format= |work= |accessdate=}}</ref><ref name="pmid26225332">{{cite journal |vauthors=Prasuna A, Rao PN |title=A tufted angioma |journal=Indian Dermatol Online J |volume=6 |issue=4 |pages=266–8 |date=2015 |pmid=26225332 |pmc=4513407 |doi=10.4103/2229-5178.160259 |url=}}</ref>
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| * Somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations have been found in some tufted angiomas. These mutations may cause the cell growth to be growth-factor independent by up-regulating the MAPK pathway.<ref name="pmid27476652">{{cite journal |vauthors=Lim YH, Bacchiocchi A, Qiu J, Straub R, Bruckner A, Bercovitch L, Narayan D, McNiff J, Ko C, Robinson-Bostom L, Antaya R, Halaban R, Choate KA |title=GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation |journal=Am. J. Hum. Genet. |volume=99 |issue=2 |pages=443–50 |date=August 2016 |pmid=27476652 |pmc=4974082 |doi=10.1016/j.ajhg.2016.06.010 |url=}}</ref><ref name="urlGNA14 G protein subunit alpha 14 [Homo sapiens (human)] - Gene - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/gene/9630 |title=GNA14 G protein subunit alpha 14 [Homo sapiens (human)] - Gene - NCBI |format= |work= |accessdate=}}</ref>
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| * Imaging such as MRI and ultrasound can add into clinical diagnosis to differentiate tufted angioma from similar lesions such as Kaposi sarcoma, kaposiform hemangioendothelioma and infantile hemangioma. Biopsy and histopathological studies are sometimes required for accurate diagnosis. Surgical excision is the treatment modality but some recommend to only observe the lesions due to its slow growth and possible remission. Other therapies include radiation beam therapy, cryosurgery, corticosteroids and pulsed laser therapy. Vincristine and embolization has been used with success in angiomas associated with Kasabach-Merritt phenomenon.<ref name="pmid26288441">{{cite journal |vauthors=Bandyopadhyay D, Saha A |title=Multifocal Annular Tufted Angioma: An Uncommon Clinical Entity |journal=Indian J Dermatol |volume=60 |issue=4 |pages=422 |date=2015 |pmid=26288441 |pmc=4533571 |doi=10.4103/0019-5154.160528 |url=}}</ref><ref name="pmid21965850">{{cite journal |vauthors=Ghosh SK, Bandyopadhyay D, Ghosh A, Biswas SK, Barma KD |title=Acquired multifocal tufted angiomas in an immunocompetent young adult |journal=Indian J Dermatol |volume=56 |issue=4 |pages=412–4 |date=July 2011 |pmid=21965850 |pmc=3179005 |doi=10.4103/0019-5154.84741 |url=}}</ref><ref name="pmid20644037">{{cite journal |vauthors=Osio A, Fraitag S, Hadj-Rabia S, Bodemer C, de Prost Y, Hamel-Teillac D |title=Clinical spectrum of tufted angiomas in childhood: a report of 13 cases and a review of the literature |journal=Arch Dermatol |volume=146 |issue=7 |pages=758–63 |date=July 2010 |pmid=20644037 |doi=10.1001/archdermatol.2010.135 |url=}}</ref><ref name="pmid17520468">{{cite journal |vauthors=Chiu CS, Yang LC, Hong HS, Kuan YZ |title=Treatment of a tufted angioma with intense pulsed light |journal=J Dermatolog Treat |volume=18 |issue=2 |pages=109–11 |date=2007 |pmid=17520468 |doi=10.1080/09546630601028752 |url=}}</ref><ref name="pmid18301012">{{cite journal |vauthors=Yesudian PD, Parslew R, Klafowski J, Gould D, Pizer B |title=Tufted angioma-associated Kasabach-Merritt syndrome treated with embolization and vincristine |journal=Plast. Reconstr. Surg. |volume=121 |issue=2 |pages=692–3 |date=February 2008 |pmid=18301012 |doi=10.1097/01.prs.0000298541.92722.5d |url=}}</ref><ref name="pmid29166525">{{cite journal |vauthors=Silva CMD, Schettini APM, Santos M, Chirano CAR |title=Tufted angioma |journal=An Bras Dermatol |volume=92 |issue=5 |pages=742–743 |date=2017 |pmid=29166525 |pmc=5674719 |doi=10.1590/abd1806-4841.20175896 |url=}}</ref><ref name="pmid28623854">{{cite journal |vauthors=Kimura R, Yoshida Y, Wakumoto K, Yamada N, Yamamoto O |title=Successful treatment of tufted angioma with low-dose electron beam radiation therapy: Report of two cases |journal=J. Dermatol. |volume=44 |issue=10 |pages=e262–e263 |date=October 2017 |pmid=28623854 |doi=10.1111/1346-8138.13936 |url=}}</ref>
| |
| ====Spindle-cell hemangioma====
| |
| * Rare benign tumor that manifests as solitary or multiple nodules confined to dermis and subcutaneous tissues in almost all of the cases. Histopathologically it appears as solid areas that are cellular and consist of spindle cells seen attached to vessel walls, and cavernous spaces that can be thrombosed. Size may increase over time and patient usually complains of swelling and pain. The nodules or masses can be mobile and elastic or can be firm and immobile.<ref name="pmid29780644">{{cite journal |vauthors=Murakami K, Yamamoto K, Sugiura T, Kirita T |title=Spindle Cell Hemangioma in the Mucosa of the Upper Lip: A Case Report and Review of the Literature |journal=Case Rep Dent |volume=2018 |issue= |pages=1370701 |date=2018 |pmid=29780644 |pmc=5892276 |doi=10.1155/2018/1370701 |url=}}</ref><ref name="pmid26266229">{{cite journal |vauthors=Chavva S, Priya MH, Garlapati K, Reddy GS, Gannepalli A |title=Rare Case of Spindle Cell Haemangioma |journal=J Clin Diagn Res |volume=9 |issue=6 |pages=ZD19–21 |date=June 2015 |pmid=26266229 |pmc=4525619 |doi=10.7860/JCDR/2015/11998.6080 |url=}}</ref><ref name="pmid22606579">{{cite journal |vauthors=Minagawa T, Yamao T, Shioya R |title=Spindle cell hemangioendothelioma of the temporal muscle resected with zygomatic osteotomy: a case report of an unusual intramuscular lesion mimicking sarcoma |journal=Case Rep Surg |volume=2011 |issue= |pages=481654 |date=2011 |pmid=22606579 |pmc=3350060 |doi=10.1155/2011/481654 |url=}}</ref>
| |
| * Somatic mutations in IDH1 and IDH2 have been found to be present in 70% of spindle-cell hemangiomas. IDH1 and IDH2 are important enzymes in cell energy cycles (α-ketoglutarate and NADPH generation).<ref name="pmid22057234">{{cite journal |vauthors=Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, Sangiorgi L, Toker B, Liegl-Atzwanger B, San-Julian M, Sciot R, Limaye N, Kindblom LG, Daugaard S, Godfraind C, Boon LM, Vikkula M, Kurek KC, Szuhai K, French PJ, Bovée JV |title=Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome |journal=Nat. Genet. |volume=43 |issue=12 |pages=1256–61 |date=November 2011 |pmid=22057234 |pmc=3427908 |doi=10.1038/ng.1004 |url=}}</ref><ref name="pmid22343901">{{cite journal |vauthors=Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O'Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, Thompson CB |title=IDH mutation impairs histone demethylation and results in a block to cell differentiation |journal=Nature |volume=483 |issue=7390 |pages=474–8 |date=February 2012 |pmid=22343901 |pmc=3478770 |doi=10.1038/nature10860 |url=}}</ref>
| |
| * Diagnosis often requires biopsy and imaging studies such as MRI to ascertain the extent of the tumor. Local excision is the treatment modality of choice with excellent prognosis in majority of the cases although recurrence is very common.<ref name="pmid29780644">{{cite journal |vauthors=Murakami K, Yamamoto K, Sugiura T, Kirita T |title=Spindle Cell Hemangioma in the Mucosa of the Upper Lip: A Case Report and Review of the Literature |journal=Case Rep Dent |volume=2018 |issue= |pages=1370701 |date=2018 |pmid=29780644 |pmc=5892276 |doi=10.1155/2018/1370701 |url=}}</ref><ref name="pmid26266229">{{cite journal |vauthors=Chavva S, Priya MH, Garlapati K, Reddy GS, Gannepalli A |title=Rare Case of Spindle Cell Haemangioma |journal=J Clin Diagn Res |volume=9 |issue=6 |pages=ZD19–21 |date=June 2015 |pmid=26266229 |pmc=4525619 |doi=10.7860/JCDR/2015/11998.6080 |url=}}</ref><ref name="pmid22606579">{{cite journal |vauthors=Minagawa T, Yamao T, Shioya R |title=Spindle cell hemangioendothelioma of the temporal muscle resected with zygomatic osteotomy: a case report of an unusual intramuscular lesion mimicking sarcoma |journal=Case Rep Surg |volume=2011 |issue= |pages=481654 |date=2011 |pmid=22606579 |pmc=3350060 |doi=10.1155/2011/481654 |url=}}</ref><ref name="pmid23730241">{{cite journal |vauthors=Gray SS, Eltorky MA, Riascos RF, Montilla RD |title=Spindle cell hemangioma reoccurrence in the hand: case report |journal=Hand (N Y) |volume=7 |issue=2 |pages=194–9 |date=June 2012 |pmid=23730241 |pmc=3351523 |doi=10.1007/s11552-012-9397-1 |url=}}</ref><ref name="pmid8827025">{{cite journal |vauthors=Perkins P, Weiss SW |title=Spindle cell hemangioendothelioma. An analysis of 78 cases with reassessment of its pathogenesis and biologic behavior |journal=Am. J. Surg. Pathol. |volume=20 |issue=10 |pages=1196–204 |date=October 1996 |pmid=8827025 |doi= |url=}}</ref>
| |
| ====Epithelioid hemangioma====
| |
| * Rare benign tumor that typically presents as solitary painful nodule on head and neck. Penis is an atypical location. They can involve skin, bone and soft tissues. Histopathologically these lesions are characterized by presence of endothelial cells that resemble epithelial cells with evidence of proliferation such as large nuclei and prominent nucleoli, and often inflammatory infiltrates. Vessels are typically well-formed. Nuclear atypia is absent.<ref name="pmid25295139">{{cite journal |vauthors=Barber E, Domes T |title=Painful erections secondary to rare epithelioid hemangioma of the penis |journal=Can Urol Assoc J |volume=8 |issue=9-10 |pages=E647–9 |date=September 2014 |pmid=25295139 |pmc=4164556 |doi=10.5489/cuaj.1833 |url=}}</ref><ref name="pmid28159479">{{cite journal |vauthors=Tsikopoulos K, Perdikakis E, Georgiannos D, Bisbinas I |title=Epithelioid hemangioma of the scapula treated with chemoembolization and microwave ablation: Α case report |journal=Acta Orthop Traumatol Turc |volume=52 |issue=2 |pages=157–161 |date=March 2018 |pmid=28159479 |pmc=6136344 |doi=10.1016/j.aott.2017.01.003 |url=}}</ref><ref name="pmid24314244">{{cite journal |vauthors=Gong QX, Fan QH, Xie J, Su ZL, Zhang MH, Zhang ZH |title=[Epithelioid hemangioma: a clinicopathologic analysis of 7 cases] |language=Chinese |journal=Zhonghua Bing Li Xue Za Zhi |volume=42 |issue=9 |pages=593–8 |date=September 2013 |pmid=24314244 |doi= |url=}}</ref>
| |
| * FOS gene rearrangements such as ZFP36-FOSB fusions are found to be present in one third of epithelioid hemangioma in a study. It encodes a transcription factors that causes over-expression of vascular endothelial growth factor-D (VEGF-D).<ref name="pmid16199154">{{cite journal |vauthors=Milde-Langosch K |title=The Fos family of transcription factors and their role in tumourigenesis |journal=Eur. J. Cancer |volume=41 |issue=16 |pages=2449–61 |date=November 2005 |pmid=16199154 |doi=10.1016/j.ejca.2005.08.008 |url=}}</ref><ref name="pmid19760594">{{cite journal |vauthors=Durchdewald M, Angel P, Hess J |title=The transcription factor Fos: a Janus-type regulator in health and disease |journal=Histol. Histopathol. |volume=24 |issue=11 |pages=1451–61 |date=November 2009 |pmid=19760594 |doi=10.14670/HH-24.1451 |url=}}</ref><ref name="pmid10449752">{{cite journal |vauthors=Marconcini L, Marchio S, Morbidelli L, Cartocci E, Albini A, Ziche M, Bussolino F, Oliviero S |title=c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue=17 |pages=9671–6 |date=August 1999 |pmid=10449752 |pmc=22268 |doi= |url=}}</ref><ref name="pmid26135557">{{cite journal |vauthors=Huang SC, Zhang L, Sung YS, Chen CL, Krausz T, Dickson BC, Kao YC, Agaram NP, Fletcher CD, Antonescu CR |title=Frequent FOS Gene Rearrangements in Epithelioid Hemangioma: A Molecular Study of 58 Cases With Morphologic Reappraisal |journal=Am. J. Surg. Pathol. |volume=39 |issue=10 |pages=1313–21 |date=October 2015 |pmid=26135557 |pmc=4567921 |doi=10.1097/PAS.0000000000000469 |url=}}</ref>
| |
| * Diagnosis requires biopsy to determine characteristic histopathological features. Imaging techniques such as MRI can useful. Bone tumors often require surgery for accurate diagnosis. Surgical excision has been used in majority of cases. Other treatment modalities include radiotherapy and embolization. Recently chemoembolization and microwave ablation in combination have been used with success.<ref name="pmid25295139">{{cite journal |vauthors=Barber E, Domes T |title=Painful erections secondary to rare epithelioid hemangioma of the penis |journal=Can Urol Assoc J |volume=8 |issue=9-10 |pages=E647–9 |date=September 2014 |pmid=25295139 |pmc=4164556 |doi=10.5489/cuaj.1833 |url=}}</ref><ref name="pmid28159479">{{cite journal |vauthors=Tsikopoulos K, Perdikakis E, Georgiannos D, Bisbinas I |title=Epithelioid hemangioma of the scapula treated with chemoembolization and microwave ablation: Α case report |journal=Acta Orthop Traumatol Turc |volume=52 |issue=2 |pages=157–161 |date=March 2018 |pmid=28159479 |pmc=6136344 |doi=10.1016/j.aott.2017.01.003 |url=}}</ref><ref name="pmid26054166">{{cite journal |vauthors=Gérard V, Tomasella M, Kurth W, Brands G, Lognard M |title=[Epithelioid hemangioma, a rare bone tumor] |language=French |journal=Rev Med Liege |volume=70 |issue=4 |pages=169–71 |date=April 2015 |pmid=26054166 |doi= |url=}}</ref>
| |
| ====Pyogenic granuloma====
| |
| * Also called as lobular capillary hemangioma, this common vascular lesion typically manifests as single, localized nodules on gingiva with sessile base but large lesions often present as lobulated or pediculated . Majority of the lesions are <2 cm in diameter and color of the lesion depending on vascularity varies from pink to purple. It can found anywhere on skin and mucous membranes such as lips, tongues, palate, and on atypical locations such asperiungual or gastrointestinal tract but gingiva is the typical location. Majority of the patients present with profuse bleeding. Others complain of painless mass, swelling, obstructive or interference related symptoms.<ref name="pmid27382492">{{cite journal |vauthors=Marla V, Shrestha A, Goel K, Shrestha S |title=The Histopathological Spectrum of Pyogenic Granuloma: A Case Series |journal=Case Rep Dent |volume=2016 |issue= |pages=1323798 |date=2016 |pmid=27382492 |pmc=4921146 |doi=10.1155/2016/1323798 |url=}}</ref><ref name="pmid24859551">{{cite journal |vauthors=Thada SR, Pai KM, Agarwal P |title=A huge oral pyogenic granuloma with extensive alveolar bone loss and 'sun-ray' appearance mimicking a malignant tumour |journal=BMJ Case Rep |volume=2014 |issue= |pages= |date=May 2014 |pmid=24859551 |pmc=4039851 |doi=10.1136/bcr-2013-202367 |url=}}</ref><ref name="pmid28785323">{{cite journal |vauthors=Wollina U, Langner D, França K, Gianfaldoni S, Lotti T, Tchernev G |title=Pyogenic Granuloma - A Common Benign Vascular Tumor with Variable Clinical Presentation: New Findings and Treatment Options |journal=Open Access Maced J Med Sci |volume=5 |issue=4 |pages=423–426 |date=July 2017 |pmid=28785323 |pmc=5535648 |doi=10.3889/oamjms.2017.111 |url=}}</ref><ref name="pmid22434943">{{cite journal |vauthors=Kamal R, Dahiya P, Puri A |title=Oral pyogenic granuloma: Various concepts of etiopathogenesis |journal=J Oral Maxillofac Pathol |volume=16 |issue=1 |pages=79–82 |date=January 2012 |pmid=22434943 |pmc=3303528 |doi=10.4103/0973-029X.92978 |url=}}</ref>
| |
| * Trauma or chronic irritation have been cited as the most common causes but it can arise due to multiple other factors such as medications, viral infections such as herpes virus type 1, Orf virus and/or human papilloma virus type 2, and BRAF mutations or use of BRAF inhibitors that can cause multiple, disseminated lesions. Medications that have been implicated in development of this lesion include oral contraceptives, retinoids, gefitinib, cabecitabine, and afatinib, BRAF inhibitors such as vemurafenib or encorafenib, and rituximab. Mutations in BRAF/RAS/GNA14 have all been associated with pyogenic granuloma, BRAF c.1799T>A has been recently described as one of the major mutations associated.<ref name="pmid24859551">{{cite journal |vauthors=Thada SR, Pai KM, Agarwal P |title=A huge oral pyogenic granuloma with extensive alveolar bone loss and 'sun-ray' appearance mimicking a malignant tumour |journal=BMJ Case Rep |volume=2014 |issue= |pages= |date=May 2014 |pmid=24859551 |pmc=4039851 |doi=10.1136/bcr-2013-202367 |url=}}</ref><ref name="pmid28785323">{{cite journal |vauthors=Wollina U, Langner D, França K, Gianfaldoni S, Lotti T, Tchernev G |title=Pyogenic Granuloma - A Common Benign Vascular Tumor with Variable Clinical Presentation: New Findings and Treatment Options |journal=Open Access Maced J Med Sci |volume=5 |issue=4 |pages=423–426 |date=July 2017 |pmid=28785323 |pmc=5535648 |doi=10.3889/oamjms.2017.111 |url=}}</ref><ref name="pmid22434943">{{cite journal |vauthors=Kamal R, Dahiya P, Puri A |title=Oral pyogenic granuloma: Various concepts of etiopathogenesis |journal=J Oral Maxillofac Pathol |volume=16 |issue=1 |pages=79–82 |date=January 2012 |pmid=22434943 |pmc=3303528 |doi=10.4103/0973-029X.92978 |url=}}</ref><ref name="pmid27885661">{{cite journal |vauthors=Simmons BJ, Chen L, Hu S |title=Pyogenic granuloma association with isotretinoin treatment for acne |journal=Australas. J. Dermatol. |volume=57 |issue=4 |pages=e144–e145 |date=November 2016 |pmid=27885661 |doi=10.1111/ajd.12418 |url=}}</ref><ref name="pmid26603180">{{cite journal |vauthors=Inoue A, Sawada Y, Nishio D, Nakamura M |title=Pyogenic granuloma caused by afatinib: Case report and review of the literature |journal=Australas. J. Dermatol. |volume=58 |issue=1 |pages=61–62 |date=February 2017 |pmid=26603180 |doi=10.1111/ajd.12423 |url=}}</ref><ref name="pmid27116335">{{cite journal |vauthors=Henning B, Stieger P, Kamarachev J, Dummer R, Goldinger SM |title=Pyogenic granuloma in patients treated with selective BRAF inhibitors: another manifestation of paradoxical pathway activation |journal=Melanoma Res. |volume=26 |issue=3 |pages=304–7 |date=June 2016 |pmid=27116335 |doi=10.1097/CMR.0000000000000248 |url=}}</ref><ref name="pmid26802240">{{cite journal |vauthors=Groesser L, Peterhof E, Evert M, Landthaler M, Berneburg M, Hafner C |title=BRAF and RAS Mutations in Sporadic and Secondary Pyogenic Granuloma |journal=J. Invest. Dermatol. |volume=136 |issue=2 |pages=481–6 |date=February 2016 |pmid=26802240 |doi=10.1038/JID.2015.376 |url=}}</ref>
| |
| * The diagnosis is made by clinical features and then confirmed by histopatholgical features. Current standard of care is surgical excision. Other treatment modalities include curettage, electrocautery, radiosurgery, cryosurgery, sclerotherapy, or laser treatment. Topical or oral beta-blockers timolol or propranolol and topical imiquimod have also been successful.<ref name="pmid24859551">{{cite journal |vauthors=Thada SR, Pai KM, Agarwal P |title=A huge oral pyogenic granuloma with extensive alveolar bone loss and 'sun-ray' appearance mimicking a malignant tumour |journal=BMJ Case Rep |volume=2014 |issue= |pages= |date=May 2014 |pmid=24859551 |pmc=4039851 |doi=10.1136/bcr-2013-202367 |url=}}</ref><ref name="pmid28785323">{{cite journal |vauthors=Wollina U, Langner D, França K, Gianfaldoni S, Lotti T, Tchernev G |title=Pyogenic Granuloma - A Common Benign Vascular Tumor with Variable Clinical Presentation: New Findings and Treatment Options |journal=Open Access Maced J Med Sci |volume=5 |issue=4 |pages=423–426 |date=July 2017 |pmid=28785323 |pmc=5535648 |doi=10.3889/oamjms.2017.111 |url=}}</ref><ref name="pmid17478135">{{cite journal |vauthors=Giblin AV, Clover AJ, Athanassopoulos A, Budny PG |title=Pyogenic granuloma - the quest for optimum treatment: audit of treatment of 408 cases |journal=J Plast Reconstr Aesthet Surg |volume=60 |issue=9 |pages=1030–5 |date=2007 |pmid=17478135 |doi=10.1016/j.bjps.2006.10.018 |url=}}</ref><ref name="pmid27874157">{{cite journal |vauthors=Al-Mohaya MA, Al-Malik AM |title=Excision of oral pyogenic granuloma in a diabetic patient with 940nm diode laser |journal=Saudi Med J |volume=37 |issue=12 |pages=1395–1400 |date=December 2016 |pmid=27874157 |pmc=5303780 |doi=10.15537/smj.2016.12.15941 |url=}}</ref><ref name="pmid24836966">{{cite journal |vauthors=Malik M, Murphy R |title=A pyogenic granuloma treated with topical timolol |journal=Br. J. Dermatol. |volume=171 |issue=6 |pages=1537–8 |date=December 2014 |pmid=24836966 |doi=10.1111/bjd.13116 |url=}}</ref><ref name="pmid24656264">{{cite journal |vauthors=Millsop JW, Trinh N, Winterfield L, Berrios R, Hutchens KA, Tung R |title=Resolution of recalcitrant pyogenic granuloma with laser, corticosteroid, and timolol therapy |journal=Dermatol. Online J. |volume=20 |issue=3 |pages= |date=March 2014 |pmid=24656264 |doi= |url=}}</ref>
| |
| ====Hobnail hemangioma====
| |
| * Benign tumor that typically presents as solitary growth with often, but not always, tagetoid appearance of a central papule and peripheral brown ring that may or may not disappear over time. Characteristic histopathological feature include plump endothelial cells that line ectatic and irregular vessels, and project into lumina like hobnails. Deeper dermis shows vessels dissecting collagen fibers. Majority of the lesions are fund on trunk and extremities with head and neck, and oral cavity as uncommon locations. Patient may present with pain, or an asymptomatic growing lesion.<ref name="pmid23808782">{{cite journal |vauthors=Hiremath SK, Charantimath S, Byakodi S, Bijjal S, Byakodi R, Sapra G |title=Oral hobnail hemangioma: a case report |journal=Arch Iran Med |volume=16 |issue=7 |pages=428–30 |date=July 2013 |pmid=23808782 |doi=013167/AIM.0013 |url=}}</ref><ref name="pmid22148030">{{cite journal |vauthors=Yoon SY, Kwon HH, Jeon HC, Lee JH, Cho S |title=Congenital and multiple hobnail hemangiomas |journal=Ann Dermatol |volume=23 |issue=4 |pages=539–43 |date=November 2011 |pmid=22148030 |pmc=3229956 |doi=10.5021/ad.2011.23.4.539 |url=}}</ref><ref name="pmid26156669">{{cite journal |vauthors=Takayama R, Ueno T, Futagami A, Ansai S, Fukumoto T, Saeki H |title=Hobnail Hemangioma: A Case Report |journal=J Nippon Med Sch |volume=82 |issue=3 |pages=151–5 |date=2015 |pmid=26156669 |doi=10.1272/jnms.82.151 |url=}}</ref>
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|
| |
| ===Locally aggressive or borderline vascular tumors===
| |
| ====Kaposiform hemangioendothelioma====
| |
| * Locally Aggressive tumor that originates on skin and occurs primarily in childhood.<ref name="pmid29536769">{{cite journal |vauthors=Hu PA, Zhou ZR |title=Clinical and imaging features of Kaposiform Hemangioendothelioma |journal=Br J Radiol |volume=91 |issue=1086 |pages=20170798 |date=June 2018 |pmid=29536769 |doi=10.1259/bjr.20170798 |url=}}</ref> It is characterized by a single or multiple masses with following characteristics:
| |
| ** Deep reddish-purple color
| |
| ** Shiny, firm texture
| |
| ** Warm to the touch
| |
| ** Swollen and painful
| |
| * May be complicated by Kasabach-Merritt phenomenon (KMP), characterized by consumption coagulopathy, thrombocytopenia, and hemolytic anemia.<ref name="pmid59885">{{cite journal |vauthors= |title=Letter: Prevention of coronary heart-disease |journal=Lancet |volume=2 |issue=7980 |pages=313–4 |date=August 1976 |pmid=59885 |doi= |url=}}</ref> Typical features also include low fibrinogen and elevated D-dimers.
| |
| * Somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations have been found in some KHE.<ref name="pmid27476652">{{cite journal |vauthors=Lim YH, Bacchiocchi A, Qiu J, Straub R, Bruckner A, Bercovitch L, Narayan D, McNiff J, Ko C, Robinson-Bostom L, Antaya R, Halaban R, Choate KA |title=GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation |journal=Am. J. Hum. Genet. |volume=99 |issue=2 |pages=443–50 |date=August 2016 |pmid=27476652 |pmc=4974082 |doi=10.1016/j.ajhg.2016.06.010 |url=}}</ref>
| |
| * Invasion of bone, retroperitoneum, and mediastinum has occured in some cases but no case of metastasis has been reported yet. <ref name="pmid59885">{{cite journal |vauthors= |title=Letter: Prevention of coronary heart-disease |journal=Lancet |volume=2 |issue=7980 |pages=313–4 |date=August 1976 |pmid=59885 |doi= |url=}}</ref>
| |
| * Diagnostic work up may include blood tests, biopsy, contrast enhanced ultrasound and MRI or CT scan imaging.
| |
| * Treatment Options include steroid, vincristine, interferon alpha, anti-platelet agents, sirolimus-containing therapies and surgery.<ref name="pmid30054848">{{cite journal| author=Schmid I, Klenk AK, Sparber-Sauer M, Koscielniak E, Maxwell R, Häberle B| title=Kaposiform hemangioendothelioma in children: a benign vascular tumor with multiple treatment options. | journal=World J Pediatr | year= 2018 | volume= 14 | issue= 4 | pages= 322-329 | pmid=30054848 | doi=10.1007/s12519-018-0171-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30054848 }} </ref>
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|
| |
| ====Retiform hemangioendothelioma====
| |
| * First described in 1994 as a form of low grade angiosarcoma, Retiform hemangioendothelioma commonly presents as a slow growing asymptomatic solitary nodule or plaque on distal extremities in 2nd-4th decade of life.<ref name="pmid25484427">{{cite journal |vauthors=Ranga SM, Kuchangi NC, Shankar VS, Amita K, Haleuoor BB, Belagola SD |title=Retiform hemangioendothelioma: an uncommon pediatric vascular neoplasm |journal=Indian J Dermatol |volume=59 |issue=6 |pages=633 |date=November 2014 |pmid=25484427 |pmc=4248535 |doi=10.4103/0019-5154.143583 |url=}}</ref>
| |
| * Must be differentiated from Angiosarcoma.
| |
| * High level of local recurrence but very low potential for metastasis.
| |
| * Diagnostic work up includes histopathological studies, that shows arborizing blood vessels are arranged in retiform pattern <ref name="pmid25484427">{{cite journal |vauthors=Ranga SM, Kuchangi NC, Shankar VS, Amita K, Haleuoor BB, Belagola SD |title=Retiform hemangioendothelioma: an uncommon pediatric vascular neoplasm |journal=Indian J Dermatol |volume=59 |issue=6 |pages=633 |date=November 2014 |pmid=25484427 |pmc=4248535 |doi=10.4103/0019-5154.143583 |url=}}</ref>, and MRI.
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| * Surgery is the treatment of choice, though 2/3rd cases recur. Adjuvant radiotherapy and ddjuvant chemotherapy with recombinant interferon alpha and low dose cisplatin have also been reported in selected cases. <ref name="pmid25484427">{{cite journal |vauthors=Ranga SM, Kuchangi NC, Shankar VS, Amita K, Haleuoor BB, Belagola SD |title=Retiform hemangioendothelioma: an uncommon pediatric vascular neoplasm |journal=Indian J Dermatol |volume=59 |issue=6 |pages=633 |date=November 2014 |pmid=25484427 |pmc=4248535 |doi=10.4103/0019-5154.143583 |url=}}</ref>
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| ====Papillary intralymphatic angioendothelioma (PILA), Dabska tumor====
| |
| * First described in 1969 by Dabska,this rare vascular neoplasm generally occurs in soft tissues but can also occur in bone. They usually appear as painless inflammatory irregular or nodular lesions below the skin surface.
| |
| * The distinctive feature on histopathology is the intravascular growth of well-differentiated endothelial cells presenting as a matchstick columnar configuration.<ref>© 1999 Lippincott Williams & Wilkins, Inc.</ref>
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| * They are locally aggressive but rarely metastasize. Locally recurrence after surgery is very common.
| |
| * Diagnostic studies may include histopathological studies, fine needle aspiration, MRI and Ct scan.<ref>https://www.dovemed.com/diseases-conditions/papillary-intralymphatic-angioendothelioma-pila/</ref>
| |
| * Wide local excision is the treatment of choice. However any combination of steroids, chemotherapy, radiation therapy, and invasive procedures can be used to treat this tumor.<ref>https://www.dovemed.com/diseases-conditions/papillary-intralymphatic-angioendothelioma-pila/</ref>
| |
| ====Composite hemangioendothelioma====
| |
| * A rare vascular neoplasms, characterized by an admixture of benign, low-grade malignant, and malignant vascular components, the ratio of each component can vary. They can occur in any age group.<ref name="pmid29233122">{{cite journal |vauthors=Rokni GR, Montazer F, Sharifian M, Goldust M |title=Composite hemangioendothelioma of the forehead and right eye; a case report |journal=BMC Dermatol. |volume=17 |issue=1 |pages=15 |date=December 2017 |pmid=29233122 |pmc=5727897 |doi=10.1186/s12895-017-0067-4 |url=}}</ref>
| |
| * They occur predominantly as long-standing lesions in the dermis and subcutis of the extremities, but can also occur at other sites, including the oral cavity and in viscera such as kidney and spleen.<ref name="pmid26050262">{{cite journal |vauthors=Shang Leen SL, Fisher C, Thway K |title=Composite hemangioendothelioma: clinical and histologic features of an enigmatic entity |journal=Adv Anat Pathol |volume=22 |issue=4 |pages=254–9 |date=July 2015 |pmid=26050262 |doi=10.1097/PAP.0000000000000079 |url=}}</ref>
| |
| * It may recur locally and has the potential to metastasize. Recurrence was found to be in 8/10 cases in some studies. <ref>https://www.jpatholtm.org/upload/pdf/kjp-40-2-142.pdf</ref>
| |
| * Diagnostic work up must include biopsy because of heterogeneity of lesions and it must be differentiated from other vascular tumors.<ref name="pmid29233122">{{cite journal |vauthors=Rokni GR, Montazer F, Sharifian M, Goldust M |title=Composite hemangioendothelioma of the forehead and right eye; a case report |journal=BMC Dermatol. |volume=17 |issue=1 |pages=15 |date=December 2017 |pmid=29233122 |pmc=5727897 |doi=10.1186/s12895-017-0067-4 |url=}}</ref>
| |
| * Surgical excision is the treatment of choice although some patients have been treated with interferon and electron beams.<ref name="pmid29233122">{{cite journal |vauthors=Rokni GR, Montazer F, Sharifian M, Goldust M |title=Composite hemangioendothelioma of the forehead and right eye; a case report |journal=BMC Dermatol. |volume=17 |issue=1 |pages=15 |date=December 2017 |pmid=29233122 |pmc=5727897 |doi=10.1186/s12895-017-0067-4 |url=}}</ref>
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|
| |
| ====Pseudomyogenic hemangioendothelioma====
| |
| * A locally aggressive tumor with endothelial differentiation that usually presents as multiple asymptomatic discontinuous lesions, often at extremities.<ref name="pmid29511030">{{cite journal |vauthors=van IJzendoorn DGP, Sleijfer S, Gelderblom H, Eskens FALM, van Leenders GJLH, Szuhai K, Bovée JVMG |title=Telatinib Is an Effective Targeted Therapy for Pseudomyogenic Hemangioendothelioma |journal=Clin. Cancer Res. |volume=24 |issue=11 |pages=2678–2687 |date=June 2018 |pmid=29511030 |doi=10.1158/1078-0432.CCR-17-3512 |url=}}</ref><ref name="pmid29406432">{{cite journal |vauthors=Raftopoulos E, Royer M, Warren M, Zhao J, Rush W |title=Pseudomyogenic Hemangioendothelioma: Case Report and Review of the Literature |journal=Am J Dermatopathol |volume=40 |issue=8 |pages=597–601 |date=August 2018 |pmid=29406432 |doi=10.1097/DAD.0000000000001104 |url=}}</ref>
| |
| * SERPINE1-FOSB fusions are characteristic that result in over-expression of truncated form of FOSB.<ref name="pmid29511030">{{cite journal |vauthors=van IJzendoorn DGP, Sleijfer S, Gelderblom H, Eskens FALM, van Leenders GJLH, Szuhai K, Bovée JVMG |title=Telatinib Is an Effective Targeted Therapy for Pseudomyogenic Hemangioendothelioma |journal=Clin. Cancer Res. |volume=24 |issue=11 |pages=2678–2687 |date=June 2018 |pmid=29511030 |doi=10.1158/1078-0432.CCR-17-3512 |url=}}</ref> FBJ murine osteosarcoma viral oncogene homolog B, also known as Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B, FOSB or FosB, is a protein that, in humans have been implicated as regulators of cell proliferation, differentiation, and transformation.<ref>https://en.wikipedia.org/wiki/FOSB</ref>
| |
| * It may mimic epithelioid sarcoma on histology but metastasis is very rare and prognosis is excellent.<ref name="pmid29406432">{{cite journal |vauthors=Raftopoulos E, Royer M, Warren M, Zhao J, Rush W |title=Pseudomyogenic Hemangioendothelioma: Case Report and Review of the Literature |journal=Am J Dermatopathol |volume=40 |issue=8 |pages=597–601 |date=August 2018 |pmid=29406432 |doi=10.1097/DAD.0000000000001104 |url=}}</ref>
| |
| * Diagnostic work up includes X-ray, MRI, CT scan and biopsy of the lesion.
| |
| * Excision is the typical treatment but chemotherapeutic agents including gemcitabine/taxane and mammalian target of rapamycin inhibitor <ref name="pmid26500758">{{cite journal |vauthors=Joseph J, Wang WL, Patnana M, Ramesh N, Benjamin R, Patel S, Ravi V |title=Cytotoxic and targeted therapy for treatment of pseudomyogenic hemangioendothelioma |journal=Clin Sarcoma Res |volume=5 |issue= |pages=22 |date=2015 |pmid=26500758 |pmc=4615364 |doi=10.1186/s13569-015-0037-8 |url=}}</ref>, mTOR inhibitors such as sirolimus <ref name="pmid28843050">{{cite journal |vauthors=Gabor KM, Sapi Z, Tiszlavicz LG, Fige A, Bereczki C, Bartyik K |title=Sirolimus therapy in the treatment of pseudomyogenic hemangioendothelioma |journal=Pediatr Blood Cancer |volume=65 |issue=2 |pages= |date=February 2018 |pmid=28843050 |doi=10.1002/pbc.26781 |url=}}</ref>, VEGFR1-4/PDGFRA inhibitors such as telatinib <ref name="pmid29511030">{{cite journal |vauthors=van IJzendoorn DGP, Sleijfer S, Gelderblom H, Eskens FALM, van Leenders GJLH, Szuhai K, Bovée JVMG |title=Telatinib Is an Effective Targeted Therapy for Pseudomyogenic Hemangioendothelioma |journal=Clin. Cancer Res. |volume=24 |issue=11 |pages=2678–2687 |date=June 2018 |pmid=29511030 |doi=10.1158/1078-0432.CCR-17-3512 |url=}}</ref> have been used with success in various studies.
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|
| |
| ====Polymorphous hemangioendothelioma====
| |
| * A rare vascular neoplasm, Polymorphous hemangioendothelioma occurs in lymph nodes, but a few cases have been found in extra-nodal sites such as the mediastinum, spinal cord, and liver. It is a very rare cause of persistent lymphadenopathy. The data on natural history and clinical presentation is limited due to very few number of cases reported. <ref name="pmid27913780">{{cite journal |vauthors=El Hussein S, Omarzai Y |title=Multifocal Polymorphous Hemangioendothelioma of the Liver: Case Report and Review of Literature |journal=Int. J. Surg. Pathol. |volume=25 |issue=3 |pages=266–270 |date=May 2017 |pmid=27913780 |doi=10.1177/1066896916679517 |url=}}</ref>
| |
| * Characterized by a polymorphous blend of solid, primitive vascular and angiomatous areas in varied proportions on microscopic examination.<ref name="pmid27913780">{{cite journal |vauthors=El Hussein S, Omarzai Y |title=Multifocal Polymorphous Hemangioendothelioma of the Liver: Case Report and Review of Literature |journal=Int. J. Surg. Pathol. |volume=25 |issue=3 |pages=266–270 |date=May 2017 |pmid=27913780 |doi=10.1177/1066896916679517 |url=}}</ref>
| |
| * Diagnotic work up includes histopathological examination, MRI and Ct scan.
| |
| * Wide local excision<ref name="pmid12808568">{{cite journal |vauthors=Tadros M, Rizk SS, Opher E, Thompson LD |title=Polymorphous hemangioendothelioma of the neck |journal=Ann Diagn Pathol |volume=7 |issue=3 |pages=165–8 |date=June 2003 |pmid=12808568 |doi= |url=}}</ref> has been used for treatment, with radiation therapy in case of recurrence.<ref name="pmid19366064">{{cite journal |vauthors=Falleti J, Siano M, De Cecio R, Somma A, Pettinato G, Insabato L |title=Nodal and extranodal soft tissue polymorphous hemangioendothelioma: a case report and review of the literature |journal=Tumori |volume=95 |issue=1 |pages=94–7 |date=2009 |pmid=19366064 |doi= |url=}}</ref>
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|
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| ====Kaposi sarcoma====
| |
| * An AIDS-associated vascular malignancy that usually presents as mucocutaneous lesions <ref name="pmid30191128">{{cite journal |vauthors=Khan S, Guevara J, Barbosa A, Ayuby A, Bien-Aime F, Verda L, Glick N, Mehta V |title=Primary pulmonary Kaposi Sarcoma in a newly diagnosed cisgender heterosexual HIV positive patient presenting before cutaneous manifestations |journal=IDCases |volume=14 |issue= |pages=e00420 |date=2018 |pmid=30191128 |pmc=6125769 |doi=10.1016/j.idcr.2018.e00420 |url=}}</ref> but can also occur in viscera such as lungs. It can remain confined to skin but widespread visceral involvement may occur.
| |
| * There are three known variants
| |
| ** One variant occurs spontaneously in Jewish and Italian males in Europe and the United States.
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| ** Another more aggressive variant is endemic in young children is endemic in Africa.
| |
| ** A third form occurs in about 0.04% of kidney transplant patients. There is also a high incidence in AIDS patients.<ref>From Dorland, 27th ed and Holland et al., Cancer Medicine, 3d ed, pp2105-7</ref> HHV-8 is the suspected cause.<ref name="pmid30201148">{{cite journal |vauthors=Piccolo V, Russo T, Moscarella E, Brancaccio G, Alfano R, Argenziano G |title=Dermatoscopy of Vascular Lesions |journal=Dermatol Clin |volume=36 |issue=4 |pages=389–395 |date=October 2018 |pmid=30201148 |doi=10.1016/j.det.2018.05.006 |url=}}</ref>
| |
| * To learn more about KS, click here.
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|
| |
| ===Malignant vascular tumors===
| |
| ====Angiosarcoma====
| |
| * Angiosarcoma(AS) is malignancy that presents with a very heterogeneous distribution in the human body with aggressive clinical course, and may appear in multiple locations, from breast to liver or skin.<ref name="pmid30217704">{{cite journal |vauthors=Villaescusa Catalan JM, Martín IG, Cagigal Cobo ML |title=Popliteal Angiosarcoma After Bypass With Autologous Saphenous Vein |journal=Ann Vasc Surg |volume= |issue= |pages= |date=September 2018 |pmid=30217704 |doi=10.1016/j.avsg.2018.06.034 |url=}}</ref>
| |
| * Associated with MYC gene amplification and protein overexpression.<ref name="pmid27780597">{{cite journal |vauthors=Udager AM, Ishikawa MK, Lucas DR, McHugh JB, Patel RM |title=MYC immunohistochemistry in angiosarcoma and atypical vascular lesions: practical considerations based on a single institutional experience |journal=Pathology |volume=48 |issue=7 |pages=697–704 |date=December 2016 |pmid=27780597 |doi=10.1016/j.pathol.2016.08.007 |url=}}</ref> Myc is a family of regulator genes and proto-oncogenes that code for transcription factors.
| |
| * Complete surgical excision and radiotherapy are the main treatments, with a minor role of chemotherapy.<ref name="pmid30179666">{{cite journal |vauthors=Priyakumari T, Chandar R, Jayasree K, Ramachandran K |title=Pediatric Primary Ovarian Angiosarcoma: From rarity to a realization |journal=J Pediatr Adolesc Gynecol |volume= |issue= |pages= |date=September 2018 |pmid=30179666 |doi=10.1016/j.jpag.2018.08.008 |url=}}</ref>
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| * To learn more about angiosarcoma click here.
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|
| |
| ====Epithelioid hemangioendothelioma====
| |
| * A rare vascular tumor, described for the first time in 1975 by Dail and Liebow,that usually affects lung, liver and bones, although may occur many other sites in body including head and neck, breasts and lymph nodes.<ref name="pmid25992243">{{cite journal |vauthors=Sardaro A, Bardoscia L, Petruzzelli MF, Portaluri M |title=Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor |journal=Oncol Rev |volume=8 |issue=2 |pages=259 |date=September 2014 |pmid=25992243 |pmc=4419652 |doi=10.4081/oncol.2014.259 |url=}}</ref>
| |
| * Usually Asymptomatic but patient may present with respiratory symptoms, bone pains or other symptoms depending on the site of the tumor.
| |
| * Majority are characterized by a reciprocal t(1;3)(p36;q25) translocation. The t(1;3) results in fusion of a gene known as WWTR1 (or TAZ) to CAMTA1. These genes code for transcription factors.<ref name="pmid21584898">{{cite journal |vauthors=Errani C, Zhang L, Sung YS, Hajdu M, Singer S, Maki RG, Healey JH, Antonescu CR |title=A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites |journal=Genes Chromosomes Cancer |volume=50 |issue=8 |pages=644–53 |date=August 2011 |pmid=21584898 |pmc=3264678 |doi=10.1002/gcc.20886 |url=}}</ref><ref name="pmid21885404">{{cite journal |vauthors=Tanas MR, Sboner A, Oliveira AM, Erickson-Johnson MR, Hespelt J, Hanwright PJ, Flanagan J, Luo Y, Fenwick K, Natrajan R, Mitsopoulos C, Zvelebil M, Hoch BL, Weiss SW, Debiec-Rychter M, Sciot R, West RB, Lazar AJ, Ashworth A, Reis-Filho JS, Lord CJ, Gerstein MB, Rubin MA, Rubin BP |title=Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma |journal=Sci Transl Med |volume=3 |issue=98 |pages=98ra82 |date=August 2011 |pmid=21885404 |doi=10.1126/scitranslmed.3002409 |url=}}</ref>
| |
| * Imaging is crucial in forming both diagnosis and management plan. Recognition of the expression of vascular markers (Fli-1 and CD31 are endothelial-specific markers), and the microscopic evidence of vascular differentiation is of primary importance as well.<ref name="pmid25992243">{{cite journal |vauthors=Sardaro A, Bardoscia L, Petruzzelli MF, Portaluri M |title=Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor |journal=Oncol Rev |volume=8 |issue=2 |pages=259 |date=September 2014 |pmid=25992243 |pmc=4419652 |doi=10.4081/oncol.2014.259 |url=}}</ref>
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| * Surgery has been used as primary treatment modality depending upon the location of the tumor, with radiotherapy being used in some cases.
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|
| |
| ==Vascular malformations==
| |
| ===Simple vascular malformations===
| |
| ====Capillary malformations (CM)====
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| =====Nevus simplex=====
| |
| * Also called "salmon patch" , “angel kiss”, “stork bite”, this common anomaly presents as single or multiple blanchable, pink-red patches with poorly defined borders in newborn infants. It may affect up to 60% of new born infants.<ref name="pmid20728246">{{cite journal |vauthors=Juern AM, Glick ZR, Drolet BA, Frieden IJ |title=Nevus simplex: a reconsideration of nomenclature, sites of involvement, and disease associations |journal=J. Am. Acad. Dermatol. |volume=63 |issue=5 |pages=805–14 |date=November 2010 |pmid=20728246 |doi=10.1016/j.jaad.2009.08.066 |url=}}</ref>
| |
| * Typically are found at the nape of the neck , on the forehead between the eyebrows or on the eyelids. Although asymptomatic, they often become more noticeable during crying or temperature changes.
| |
| * Fades within one to two years, though some lesions can persist on the back of the neck.<ref name="pmid3562091">{{cite journal |vauthors=Cohen BA |title=Hemangiomas in infancy and childhood |journal=Pediatr Ann |volume=16 |issue=1 |pages=17–26 |date=January 1987 |pmid=3562091 |doi= |url=}}</ref> No treatment is needed except when asked by the patient.
| |
| * Imaging studies are recommended to evaluate for underlying spinal dysraphism if lumbosacral nevus simplex is present with another lumbosacral abnormality such as dermal sinus or pit, lipoma, patch of hypertrichosis, or deviated gluteal cleft.<ref name="pmid20728246">{{cite journal |vauthors=Juern AM, Glick ZR, Drolet BA, Frieden IJ |title=Nevus simplex: a reconsideration of nomenclature, sites of involvement, and disease associations |journal=J. Am. Acad. Dermatol. |volume=63 |issue=5 |pages=805–14 |date=November 2010 |pmid=20728246 |doi=10.1016/j.jaad.2009.08.066 |url=}}</ref>
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|
| |
| =====Cutaneous and/or mucosal CM (“port-wine” stain)=====
| |
| * "A vascular malformation of developmental origin characterized pathologically by ectasia of superficial dermal capillaries, and clinically by persistent macular erythema." They occur on face for majority of times and may vary from pale pink to deep red or purple, ranging from few millimeters to centimeters in diameter.<ref name="urlPort-Wine Stain - MeSH - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/mesh/68019339 |title=Port-Wine Stain - MeSH - NCBI |format= |work= |accessdate=}}</ref> Lesions are usually flat, are not painful and do not regress spontaneously.
| |
| * Can be classified as follows:
| |
| ** Nonsyndromic CM
| |
| ** CM with CNS and/or ocular anomalies (Sturge-Weber syndrome)
| |
| ** CM with bone and/or soft tissues overgrowth
| |
| ** Diffuse CM with overgrowth (DCMO)
| |
| * Usually occur as sporadic isolated lesions, following the embryonic vasculature of the face.<ref name="pmid26192947">{{cite journal |vauthors=Frigerio A, Wright K, Wooderchak-Donahue W, Tan OT, Margraf R, Stevenson DA, Grimmer JF, Bayrak-Toydemir P |title=Genetic Variants Associated with Port-Wine Stains |journal=PLoS ONE |volume=10 |issue=7 |pages=e0133158 |date=2015 |pmid=26192947 |pmc=4508108 |doi=10.1371/journal.pone.0133158 |url=}}</ref> Majority of lesions are caused by somatic mutations in GNAQ (Guanine nucleotide-binding protein G(q) subunit alpha) and its paralogue GNA 11. Somatic activating mutation in GNAQ c.548G>A, p.Arg183Gln has been demonstrated in majority of lesions. A novel GNAQ, c.547C>G, p.Arg183Gly variant has also been found to be associated with some lesions.<ref name="pmid26192947">{{cite journal |vauthors=Frigerio A, Wright K, Wooderchak-Donahue W, Tan OT, Margraf R, Stevenson DA, Grimmer JF, Bayrak-Toydemir P |title=Genetic Variants Associated with Port-Wine Stains |journal=PLoS ONE |volume=10 |issue=7 |pages=e0133158 |date=2015 |pmid=26192947 |pmc=4508108 |doi=10.1371/journal.pone.0133158 |url=}}</ref>
| |
| * May be associated with other abnormalities including glaucoma, and soft tissue and bone overgrowth and with various syndromes including Sturge-Weber syndrome, Klippel-Trenaunay syndrome, Parkes-Weber syndrome, Servelle-Martorell syndrome, Proteus syndrome, CLOVES syndrome, Bannayan-Riley-Ruvalcaba syndrome, Capillary malformation-arteriovenous malformation syndrome, Macrocephaly-capillary malformation syndrome, Microcephaly-capillary malformation syndrome, Beckwith-Wiedemann syndrome.
| |
| * Diagnosis is mainly clinical depending upon history and examination. New born screening for other congenital and genetic anomalies may be indicated including urgent ophthalmology review and a brain MRI.<ref name="pmid24976116">{{cite journal |vauthors=Waelchli R, Aylett SE, Robinson K, Chong WK, Martinez AE, Kinsler VA |title=New vascular classification of port-wine stains: improving prediction of Sturge-Weber risk |journal=Br. J. Dermatol. |volume=171 |issue=4 |pages=861–7 |date=October 2014 |pmid=24976116 |pmc=4284033 |doi=10.1111/bjd.13203 |url=}}</ref>
| |
| * The pulsed dye laser (PDL) treatment is considered to be the gold standard. Surgery is considered when PWS is associated with bone and soft tissues overgrowth.<ref name="pmid29217063">{{cite journal |vauthors=Lee JW, Chung HY |title=Capillary Malformations (Portwine Stains) of the Head and Neck: Natural History, , Laser, and Surgical Management |journal=Otolaryngol. Clin. North Am. |volume=51 |issue=1 |pages=197–211 |date=FebInvestigationsruary 2018 |pmid=29217063 |doi=10.1016/j.otc.2017.09.004 |url=}}</ref>
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| * To learn more about PWS click here.
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|
| |
| =====Reticulate CM=====
| |
| * Cutaneous capillary malformations which are reticulated, widespread on body ranging from few to hundreds of oval/circular macules or patches varying in size from few mm to several cm. These anomalies are found in two syndromes:
| |
| ** CM of MIC-CAP (microcephaly-capillary malformation)
| |
| ** CM of MCAP (megalencephaly-capillary malformation-polymicrogyria)
| |
|
| |
| =====CM of CM-AVM=====
| |
| * Usually multiple, these malformations can be round to oval, can vary from pink-red to tan,and are found in patches of 1 to 2 cm in size. These patches are scattered throughout the body and new ones may continue to appear throughout childhood. Sometimes a high flow murmur can be heard using Doppler device.<ref name="pmid18446851">{{cite journal |vauthors=Revencu N, Boon LM, Mulliken JB, Enjolras O, Cordisco MR, Burrows PE, Clapuyt P, Hammer F, Dubois J, Baselga E, Brancati F, Carder R, Quintal JM, Dallapiccola B, Fischer G, Frieden IJ, Garzon M, Harper J, Johnson-Patel J, Labrèze C, Martorell L, Paltiel HJ, Pohl A, Prendiville J, Quere I, Siegel DH, Valente EM, Van Hagen A, Van Hest L, Vaux KK, Vicente A, Weibel L, Chitayat D, Vikkula M |title=Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations |journal=Hum. Mutat. |volume=29 |issue=7 |pages=959–65 |date=July 2008 |pmid=18446851 |doi=10.1002/humu.20746 |url=}}</ref>
| |
| * These are found in Capillary malformation-arteriovenous malformation syndrome, an autosomal dominant syndrome associated with mutations in RASA1.<ref name="pmid20007727">{{cite journal |vauthors=Thiex R, Mulliken JB, Revencu N, Boon LM, Burrows PE, Cordisco M, Dwight Y, Smith ER, Vikkula M, Orbach DB |title=A novel association between RASA1 mutations and spinal arteriovenous anomalies |journal=AJNR Am J Neuroradiol |volume=31 |issue=4 |pages=775–9 |date=April 2010 |pmid=20007727 |doi=10.3174/ajnr.A1907 |url=}}</ref>
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|
| |
| =====Cutis marmorata telangiectatica congenita (CMTC)=====
| |
| * A congenital, vascular malformation consisting of capillary and venous sized vessels. Presentation is similar to physiologic cutis marmorata with a fixed reticulate erythema but unlike physiologic cutis marmorata, the erythema does not resolve with warming and may be associated with skin ulceration, atrophy of the skin, and undergrowth of the involved extremity. <ref name="pmid10792796">{{cite journal |vauthors=Amitai DB, Fichman S, Merlob P, Morad Y, Lapidoth M, Metzker A |title=Cutis marmorata telangiectatica congenita: clinical findings in 85 patients |journal=Pediatr Dermatol |volume=17 |issue=2 |pages=100–4 |date=2000 |pmid=10792796 |doi= |url=}}</ref> <ref>Ponnurangam VN, Paramasivam V. Cutis marmorata telangiectatica congenita. Indian Dermatol Online J [serial online] 2014 [cited 2018 Sep 25];5:80-2. Available from: http://www.idoj.in/text.asp?2014/5/1/80/126042</ref>
| |
| * Findings may include prominent veins, telangiectasias, cutaneous atrophy, ulceration, and hyperkeratosis. May have localized or generalized appearance. In localized pattern, the lesions are confined to one side of the body, not crossing midline with or without sharp demarcation. <ref>Ponnurangam VN, Paramasivam V. Cutis marmorata telangiectatica congenita. Indian Dermatol Online J [serial online] 2014 [cited 2018 Sep 25];5:80-2. Available from: http://www.idoj.in/text.asp?2014/5/1/80/126042</ref>
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| * May be associated with a number of other abnormalities, of which limb asymmetry is the most common. Others may include glaucoma, port wine stains, angiokeratomas, hemangiomas. It may also be associated with Sturge-Weber syndrome.<ref>Ponnurangam VN, Paramasivam V. Cutis marmorata telangiectatica congenita. Indian Dermatol Online J [serial online] 2014 [cited 2018 Sep 25];5:80-2. Available from: http://www.idoj.in/text.asp?2014/5/1/80/126042</ref> Most cases tend be sporadic but autosomal recessive pattern has been observed in familial cases.<ref name="urlCutis marmorata telangiectatica congenita - MeSH - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/mesh/?term=C536226 |title=Cutis marmorata telangiectatica congenita - MeSH - NCBI |format= |work= |accessdate=}}</ref>
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| * Diagnosis is clinical and depends on history and examination. Management depends on the systemic involvement. Skin lesions tend to improve spontaneously.<ref name="pmid19196300">{{cite journal |vauthors=Kienast AK, Hoeger PH |title=Cutis marmorata telangiectatica congenita: a prospective study of 27 cases and review of the literature with proposal of diagnostic criteria |journal=Clin. Exp. Dermatol. |volume=34 |issue=3 |pages=319–23 |date=April 2009 |pmid=19196300 |doi=10.1111/j.1365-2230.2008.03074.x |url=}}</ref><ref name="pmid10943257">{{cite journal |vauthors=Dohil MA, Baugh WP, Eichenfield LF |title=Vascular and pigmented birthmarks |journal=Pediatr. Clin. North Am. |volume=47 |issue=4 |pages=783–812, v–vi |date=August 2000 |pmid=10943257 |doi= |url=}}</ref>
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|
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| =====Telangiectasia=====
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| * "Permanent dilation of preexisting blood vessels creating small focal red lesions, most commonly in the skin or mucous membranes. It is characterized by the prominence of skin blood vessels, such as vascular spiders."<ref name="urlTelangiectasis - MeSH - NCBI">{{cite web |url=+++++https://www.ncbi.nlm.nih.gov/mesh/?term=D013684 |title=Telangiectasis - MeSH - NCBI |format= |work= |accessdate=}}</ref> To learn about Hereditary hemorrhagic telangiectasia (HHT) click here.
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|
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| ====Lymphatic malformations (LM)====
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| =====Common (cystic) LM=====
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| * benign lesions consisting of dilated lymphatic channels or cysts lined by cells of endothelial origin with lymphatic differentiation.<ref name="pmid26055853">{{cite journal |vauthors=Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, Burrows P, Frieden IJ, Garzon MC, Lopez-Gutierrez JC, Lord DJ, Mitchel S, Powell J, Prendiville J, Vikkula M |title=Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies |journal=Pediatrics |volume=136 |issue=1 |pages=e203–14 |date=July 2015 |pmid=26055853 |doi=10.1542/peds.2014-3673 |url=}}</ref> If these lesions are associated with overgrowth then some of these lesions belong to the PIK3CA-related overgrowth spectrum. <ref>http://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf</ref>
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| * These are classified as follows:
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| ** Macrocystic LM
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| ** Microcystic LM
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| ** Mixed cystic LM
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| *# '''Macrocystic LM'''
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| *#* Also called cystic hygroma, and cystic lymphangioma. A cystic growth consisting of large, interconnected lymphatic cysts lined by a thin endothelium. Usually found in neck, axilla and groin. Presents as a large, poorly delineated, translucent, soft cystic mass covered by normal skin.
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| *#* May be associated with chromosomal abnormalities such as Down syndrome, Turner syndrome. To learn more click here.
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| *# '''Microcystic LM'''
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| *#* Also known as 'lymphangioma circumscriptum', these lymphatic anomalies may be present at birth or may develop in first few years of life. Usual presentation is as a cluster of clear, translucent or hemorrhagic vesicles that may cause pressure symptoms as they grow in size.
| |
| *#* Usually affect deep seated structures and frequent locations are proximal extremities, trunk, axilla, and the oral cavity.
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| *#* Diagnosis is clinical and treatment options include surgery, sclerotherapy, radiotherapy, and laser therapy. Recently topical sirolimus has also been used.<ref name="pmid30133999">{{cite journal |vauthors=Çalışkan E, Altunel CT, Özkan CK, Tunca M |title=A case of microcystic lymphatic malformation successfully treated with topical sirolimus |journal=Dermatol Ther |volume= |issue= |pages=e12673 |date=August 2018 |pmid=30133999 |doi=10.1111/dth.12673 |url=}}</ref> To learn more click here.
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|
| |
| =====Generalized lymphatic anomaly (GLA)=====
| |
| * Diffuse or multicentric proliferation of dilated lymphatic vessels that may involve skin, bones, and internal organs. The proliferating vessels resemble common lymphatic malformations but the disease involvement is multi-system.<ref name="pmid29871646">{{cite journal |vauthors=Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C |title=Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report |journal=J Cardiothorac Surg |volume=13 |issue=1 |pages=59 |date=June 2018 |pmid=29871646 |pmc=5989411 |doi=10.1186/s13019-018-0752-3 |url=}}</ref><ref name="pmid29397482">{{cite journal |vauthors=Manevitz-Mendelson E, Leichner GS, Barel O, Davidi-Avrahami I, Ziv-Strasser L, Eyal E, Pessach I, Rimon U, Barzilai A, Hirshberg A, Chechekes K, Amariglio N, Rechavi G, Yaniv K, Greenberger S |title=Somatic NRAS mutation in patient with generalized lymphatic anomaly |journal=Angiogenesis |volume=21 |issue=2 |pages=287–298 |date=May 2018 |pmid=29397482 |doi=10.1007/s10456-018-9595-8 |url=}}</ref> Lungs, bones and mediastinum are most commonly affected but skin, liver and spleen are commonly affected as well. Liver, spleen, and thoracic duct involvement typically indicates worse prognosis.<ref name="pmid2709285">{{cite journal |vauthors=Levine C |title=Primary disorders of the lymphatic vessels--a unified concept |journal=J. Pediatr. Surg. |volume=24 |issue=3 |pages=233–40 |date=March 1989 |pmid=2709285 |doi= |url=}}</ref>
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| * Considered to b sporadic and non-hereditary, it may present in childhood or can be diagnosed later in life.<ref name="pmid10712360">{{cite journal |vauthors=Faul JL, Berry GJ, Colby TV, Ruoss SJ, Walter MB, Rosen GD, Raffin TA |title=Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome |journal=Am. J. Respir. Crit. Care Med. |volume=161 |issue=3 Pt 1 |pages=1037–46 |date=March 2000 |pmid=10712360 |doi=10.1164/ajrccm.161.3.9904056 |url=}}</ref><ref name="pmid23457676">{{cite journal |vauthors=Kadakia KC, Patel SM, Yi ES, Limper AH |title=Diffuse pulmonary lymphangiomatosis |journal=Can. Respir. J. |volume=20 |issue=1 |pages=52–4 |date=2013 |pmid=23457676 |pmc=3628648 |doi=10.1155/2013/971350 |url=}}</ref> Etiology is unknown but high levels of VEGFR-3 have been reported in patient population.
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| * Chylothorax due to leakage of lymphtic fluid is commonly encountered and is difficult to treat.<ref name="pmid29906363">{{cite journal |vauthors=Ludwig KF, Slone T, Cederberg KB, Silva AT, Dellinger M |title=A New Case and Review of Chylothorax in Generalized Lymphatic Anomaly and Gorham-Stout Disease |journal=Lymphology |volume=49 |issue=2 |pages=73–84 |date=June 2016 |pmid=29906363 |doi= |url=}}</ref> Patient may present with respiratory symptoms such as chest pain, wheezing, SOB, cough, repeated infections or symptoms due to involvement of other organs such as bone pain, pathological fractures, pelvic or abdominal pain, swelling, fever, internal bleeding, skin lesions.<ref name="pmid29871646">{{cite journal |vauthors=Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C |title=Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report |journal=J Cardiothorac Surg |volume=13 |issue=1 |pages=59 |date=June 2018 |pmid=29871646 |pmc=5989411 |doi=10.1186/s13019-018-0752-3 |url=}}</ref><ref name="pmid11247693">{{cite journal |vauthors=Aviv RI, McHugh K, Hunt J |title=Angiomatosis of bone and soft tissue: a spectrum of disease from diffuse lymphangiomatosis to vanishing bone disease in young patients |journal=Clin Radiol |volume=56 |issue=3 |pages=184–90 |date=March 2001 |pmid=11247693 |doi=10.1053/crad.2000.0606 |url=}}</ref><ref name="pmid22196284">{{cite journal |vauthors=Satria MN, Pacheco-Rodriguez G, Moss J |title=Pulmonary lymphangiomatosis |journal=Lymphat Res Biol |volume=9 |issue=4 |pages=191–3 |date=2011 |pmid=22196284 |pmc=3246407 |doi=10.1089/lrb.2011.0023 |url=}}</ref><ref name="pmid23457676">{{cite journal |vauthors=Kadakia KC, Patel SM, Yi ES, Limper AH |title=Diffuse pulmonary lymphangiomatosis |journal=Can. Respir. J. |volume=20 |issue=1 |pages=52–4 |date=2013 |pmid=23457676 |pmc=3628648 |doi=10.1155/2013/971350 |url=}}</ref>
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| * Diagnosis of GLA is very challenging and requires multidisciplinary input. It depends on history, examination, imaging studies such as MRI, contrast ultrasound, magnetic resonance lymphangiogram, CXR,near-infrared fluorescence lymphatic imaging, nanotechnology-based MRI agents and biopsy.<ref name="pmid29871646">{{cite journal |vauthors=Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C |title=Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report |journal=J Cardiothorac Surg |volume=13 |issue=1 |pages=59 |date=June 2018 |pmid=29871646 |pmc=5989411 |doi=10.1186/s13019-018-0752-3 |url=}}</ref><ref name="pmid24590275">{{cite journal |vauthors=Sevick-Muraca EM, Kwon S, Rasmussen JC |title=Emerging lymphatic imaging technologies for mouse and man |journal=J. Clin. Invest. |volume=124 |issue=3 |pages=905–14 |date=March 2014 |pmid=24590275 |pmc=3938259 |doi=10.1172/JCI71612 |url=}}</ref><ref name="pmid19913379">{{cite journal |vauthors=Lohrmann C, Foeldi E, Langer M |title=Assessment of the lymphatic system in patients with diffuse lymphangiomatosis by magnetic resonance imaging |journal=Eur J Radiol |volume=80 |issue=2 |pages=576–81 |date=November 2011 |pmid=19913379 |doi=10.1016/j.ejrad.2009.10.021 |url=}}</ref> Sometimes surgery is required that can be both diagnostic and therapeutic.<ref name="pmid29871646">{{cite journal |vauthors=Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C |title=Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report |journal=J Cardiothorac Surg |volume=13 |issue=1 |pages=59 |date=June 2018 |pmid=29871646 |pmc=5989411 |doi=10.1186/s13019-018-0752-3 |url=}}</ref>
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| * Management is usually focused on symptomatic improvement. Options include chest drainage, open thorax surgery, sclerotherapy, surgical removal (debulking), lymphatic anastomosis and medical therapies such as sirolimus and interferon.<ref name="pmid29871646">{{cite journal |vauthors=Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C |title=Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report |journal=J Cardiothorac Surg |volume=13 |issue=1 |pages=59 |date=June 2018 |pmid=29871646 |pmc=5989411 |doi=10.1186/s13019-018-0752-3 |url=}}</ref>
| |
| *# '''Kaposiform lymphangiomatosis (KLA)'''
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| *#* A rare subtype with worse pronosis.<ref name="pmid25598153">{{cite journal |vauthors=Wang Z, Li K, Yao W, Dong K, Xiao X, Zheng S |title=Successful treatment of kaposiform lymphangiomatosis with sirolimus |journal=Pediatr Blood Cancer |volume=62 |issue=7 |pages=1291–3 |date=July 2015 |pmid=25598153 |doi=10.1002/pbc.25422 |url=}}</ref> Malformed vessels occur with cluster and sheets of spindle lymphatic endothelial cells.<ref name="pmid24252784">{{cite journal |vauthors=Croteau SE, Kozakewich HP, Perez-Atayde AR, Fishman SJ, Alomari AI, Chaudry G, Mulliken JB, Trenor CC |title=Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly |journal=J. Pediatr. |volume=164 |issue=2 |pages=383–8 |date=February 2014 |pmid=24252784 |pmc=3946828 |doi=10.1016/j.jpeds.2013.10.013 |url=}}</ref> Consumptive coagulopathy is also a feature.<ref name="pmid25307772">{{cite journal |vauthors=Fernandes VM, Fargo JH, Saini S, Guerrera MF, Marcus L, Luchtman-Jones L, Adams D, Meier ER |title=Kaposiform lymphangiomatosis: unifying features of a heterogeneous disorder |journal=Pediatr Blood Cancer |volume=62 |issue=5 |pages=901–4 |date=May 2015 |pmid=25307772 |doi=10.1002/pbc.25278 |url=}}</ref>
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| *#* Intra-thoracic component is often the cause of mortality.<ref name="pmid24252784">{{cite journal |vauthors=Croteau SE, Kozakewich HP, Perez-Atayde AR, Fishman SJ, Alomari AI, Chaudry G, Mulliken JB, Trenor CC |title=Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly |journal=J. Pediatr. |volume=164 |issue=2 |pages=383–8 |date=February 2014 |pmid=24252784 |pmc=3946828 |doi=10.1016/j.jpeds.2013.10.013 |url=}}</ref> Currently there are no treatment guidelines.<ref name="pmid25598153">{{cite journal |vauthors=Wang Z, Li K, Yao W, Dong K, Xiao X, Zheng S |title=Successful treatment of kaposiform lymphangiomatosis with sirolimus |journal=Pediatr Blood Cancer |volume=62 |issue=7 |pages=1291–3 |date=July 2015 |pmid=25598153 |doi=10.1002/pbc.25422 |url=}}</ref>
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|
| |
| =====LM in Gorham-Stout disease=====
| |
| * Lymphatic malformation in Gorham-Stout disease affect a single or multiple bones and adjacent soft tissues, leading to progressive osteolysis and invasion of the bone cortex.<ref name="pmid8961021">{{cite journal |vauthors=Klein M, Metelmann HR, Gross U |title=Massive osteolysis (Gorham-Stout syndrome) in the maxillofacial region: an unusual manifestation |journal=Int J Oral Maxillofac Surg |volume=25 |issue=5 |pages=376–8 |date=October 1996 |pmid=8961021 |doi= |url=}}</ref><ref name="pmid18519969">{{cite journal |vauthors=Radhakrishnan K, Rockson SG |title=The clinical spectrum of lymphatic disease |journal=Ann. N. Y. Acad. Sci. |volume=1131 |issue= |pages=155–84 |date=2008 |pmid=18519969 |doi=10.1196/annals.1413.015 |url=}}</ref><ref name="pmid23371338">{{cite journal |vauthors=Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G |title=Gorham-Stout disease and generalized lymphatic anomaly--clinical, radiologic, and histologic differentiation |journal=Skeletal Radiol. |volume=42 |issue=7 |pages=917–24 |date=July 2013 |pmid=23371338 |doi=10.1007/s00256-012-1565-4 |url=}}</ref> Was originally described as disappearing or vanishing bone disease. GSD progression often leads to visceral, abdominal and thoracic involvement that may cause effusion and ascites<ref name="pmid23371338">{{cite journal |vauthors=Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G |title=Gorham-Stout disease and generalized lymphatic anomaly--clinical, radiologic, and histologic differentiation |journal=Skeletal Radiol. |volume=42 |issue=7 |pages=917–24 |date=July 2013 |pmid=23371338 |doi=10.1007/s00256-012-1565-4 |url=}}</ref> The osteolysis is progressive in GSD as compared to non-progressive osteolysis in GLA.<ref name="pmid23371338">{{cite journal |vauthors=Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G |title=Gorham-Stout disease and generalized lymphatic anomaly--clinical, radiologic, and histologic differentiation |journal=Skeletal Radiol. |volume=42 |issue=7 |pages=917–24 |date=July 2013 |pmid=23371338 |doi=10.1007/s00256-012-1565-4 |url=}}</ref>
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| * There are two distinct forms of GSD. Primary form involves multiple bones and tissues with multi-focal lesions as described above versus trauma induced GSD that typically involves one or closely adjacent one and is usually self limited.<ref name="pmid30248728">{{cite journal |vauthors=Tanoue N, Moedano L, Witte M, Montague M, Lukefahr A, Bernas M |title=Primary versus trauma-induced Gorham-Stout disease |journal=Lymphology |volume=51 |issue=1 |pages=18–27 |date=2018 |pmid=30248728 |doi= |url=}}</ref>
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| * The etiology has not been established and gender, genetic inheritance, or race seem to play no role but inflammation, trauma and puberty have been thought to pay a role. Activation of platelet derived growth factor pathway and up regulation of lymphangiogenesis stimulating pathways may play a role in pathogenesis.<ref name="pmid16816171">{{cite journal |vauthors=Meijer-Jorna LB, van der Loos CM, de Boer OJ, van der Horst CM, van der Wal AC |title=Microvascular proliferation in congenital vascular malformations of skin and soft tissue |journal=J. Clin. Pathol. |volume=60 |issue=7 |pages=798–803 |date=July 2007 |pmid=16816171 |pmc=1995770 |doi=10.1136/jcp.2006.038885 |url=}}</ref><ref name="pmid18519972">{{cite journal |vauthors=Radhakrishnan K, Rockson SG |title=Gorham's disease: an osseous disease of lymphangiogenesis? |journal=Ann. N. Y. Acad. Sci. |volume=1131 |issue= |pages=203–5 |date=2008 |pmid=18519972 |doi=10.1196/annals.1413.022 |url=}}</ref><ref name="pmid17139320">{{cite journal |vauthors=Hagendoorn J, Padera TP, Yock TI, Nielsen GP, di Tomaso E, Duda DG, Delaney TF, Gaissert HA, Pearce J, Rosenberg AE, Jain RK, Ebb DH |title=Platelet-derived growth factor receptor-beta in Gorham's disease |journal=Nat Clin Pract Oncol |volume=3 |issue=12 |pages=693–7 |date=December 2006 |pmid=17139320 |pmc=2693369 |doi=10.1038/ncponc0660 |url=}}</ref> IL-6 has been found to be elevated in some patients.<ref name="pmid8626854">{{cite journal |vauthors=Devlin RD, Bone HG, Roodman GD |title=Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease |journal=J. Clin. Endocrinol. Metab. |volume=81 |issue=5 |pages=1893–7 |date=May 1996 |pmid=8626854 |doi=10.1210/jcem.81.5.8626854 |url=}}</ref>
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| * Symptoms depend on the bone involved and extent of involvement. Patient can experience chest pain, dyspnea, tachypnea, wheezing, SOB, dull ache, back pain, paralysis, loose teeth and facial deformation.<ref name="pmid22937447">{{cite journal |vauthors=Garbers E, Reuther F, Delling G |title=Report of a rare case of gorham-stout disease of both shoulders: bisphosphonate treatment and shoulder replacement |journal=Case Rep Rheumatol |volume=2011 |issue= |pages=565142 |date=2011 |pmid=22937447 |pmc=3420766 |doi=10.1155/2011/565142 |url=}}</ref><ref name="pmid16012125">{{cite journal |vauthors=Duffy BM, Manon R, Patel RR, Welsh JS |title=A case of Gorham's disease with chylothorax treated curatively with radiation therapy |journal=Clin Med Res |volume=3 |issue=2 |pages=83–6 |date=May 2005 |pmid=16012125 |pmc=1183437 |doi= |url=}}</ref> The involvement of thorax and development of chylothorax indicate poor prognosis.<ref name="pmid16012125">{{cite journal |vauthors=Duffy BM, Manon R, Patel RR, Welsh JS |title=A case of Gorham's disease with chylothorax treated curatively with radiation therapy |journal=Clin Med Res |volume=3 |issue=2 |pages=83–6 |date=May 2005 |pmid=16012125 |pmc=1183437 |doi= |url=}}</ref>
| |
| * Diagnosis often requires clinical, radiological and histopathological evidence. Imaging studies including MRI and CT scan are often crucial. Management is often symptomatic and encompasses anti-osteoclastic medication and radiotherapy.<ref name="pmid16012125">{{cite journal |vauthors=Duffy BM, Manon R, Patel RR, Welsh JS |title=A case of Gorham's disease with chylothorax treated curatively with radiation therapy |journal=Clin Med Res |volume=3 |issue=2 |pages=83–6 |date=May 2005 |pmid=16012125 |pmc=1183437 |doi= |url=}}</ref><ref name="pmid14528108">{{cite journal |vauthors=Fontanesi J |title=Radiation therapy in the treatment of Gorham disease |journal=J. Pediatr. Hematol. Oncol. |volume=25 |issue=10 |pages=816–7 |date=October 2003 |pmid=14528108 |doi= |url=}}</ref> If disease affects neuro-vascular structures then surgery is indicated.<ref name="pmid29363434">{{cite journal |vauthors=Mulvihill D, Kumar RS, Muzaffar J, Irving R |title=Gorham-Stout disease of the temporal bone involving the temporomandibular joint |journal=J Laryngol Otol |volume=132 |issue=3 |pages=279–281 |date=March 2018 |pmid=29363434 |doi=10.1017/S0022215118000099 |url=}}</ref><ref name="pmid22865280">{{cite journal |vauthors=Noda M, Endo C, Hoshikawa Y, Ishibashi N, Suzuki T, Okada Y, Kondo T |title=Successful management of intractable chylothorax in Gorham-Stout disease by awake thoracoscopic surgery |journal=Gen Thorac Cardiovasc Surg |volume=61 |issue=6 |pages=356–8 |date=June 2013 |pmid=22865280 |doi=10.1007/s11748-012-0130-3 |url=}}</ref>
| |
| =====“Acquired” progressive lymphatic anomaly=====
| |
| * Also called acquired progressive lymphangioma, this vascular anomaly usually presents as asymptomatic, slow growing, reddish brown or violaceous papule, plaque, macule or erythema. Histological studies show numerous, dilated, thin-walled vessels that are lined by flat endothelial cells and are proliferating. No nuclear atypia has been demonstrated in this locally aggressive tumor. The cells appear to dissect between the collagen fibers.<ref name="pmid25246470">{{cite journal |vauthors=Alkhalili E, Ayoubieh H, O'Brien W, Billings SD |title=Acquired progressive lymphangioma of the nipple |journal=BMJ Case Rep |volume=2014 |issue= |pages= |date=September 2014 |pmid=25246470 |pmc=4173197 |doi=10.1136/bcr-2014-205966 |url=}}</ref><ref name="pmid21034710">{{cite journal |vauthors=Messeguer F, Sanmartín O, Martorell-Calatayud A, Nagore E, Requena C, Guillén-Barona C |title=[Acquired progressive lymphangioma (benign lymphangioendothelioma)] |language=Spanish; Castilian |journal=Actas Dermosifiliogr |volume=101 |issue=9 |pages=792–7 |date=November 2010 |pmid=21034710 |doi= |url=}}</ref><ref name="pmid7999605">{{cite journal |vauthors=Meunier L, Barneon G, Meynadier J |title=Acquired progressive lymphangioma |journal=Br. J. Dermatol. |volume=131 |issue=5 |pages=706–8 |date=November 1994 |pmid=7999605 |doi= |url=}}</ref><ref name="pmid12601956">{{cite journal |vauthors=Paredes Esteban RM, Velasco Sánchez B, Martínez-Victoria Muñoz JM, Cuevas C, García Ruiz M |title=[Progressive acquired lymphangioma: report of a case and review of the literature] |language=Spanish; Castilian |journal=Cir Pediatr |volume=13 |issue=4 |pages=170–1 |date=October 2000 |pmid=12601956 |doi= |url=}}</ref>
| |
| * Excision is usually the treatment of choice but some other therapies such as Imiquimod 5% cream have been tried.<ref name="pmid29633311">{{cite journal |vauthors=Larkin SC, Wentworth AB, Lehman JS, Tollefson MM |title=A case of extensive acquired progressive lymphangioma |journal=Pediatr Dermatol |volume=35 |issue=4 |pages=486–489 |date=July 2018 |pmid=29633311 |doi=10.1111/pde.13486 |url=}}</ref><ref name="pmid28940760">{{cite journal |vauthors=Salman A, Sarac G, Can Kuru B, Cinel L, Yucelten AD, Ergun T |title=Acquired progressive lymphangioma: Case report with partial response to imiquimod 5% cream |journal=Pediatr Dermatol |volume=34 |issue=6 |pages=e302–e304 |date=November 2017 |pmid=28940760 |doi=10.1111/pde.13283 |url=}}</ref>
| |
| =====Primary lymphedema=====
| |
| * Edema due to obstruction or disorder of lymphatic vessels and lymph nodes. Can present at any stage of life but majority of he cases present at puberty.<ref name="pmid9796078">{{cite journal |vauthors=Szuba A, Rockson SG |title=Lymphedema: classification, diagnosis and therapy |journal=Vasc Med |volume=3 |issue=2 |pages=145–56 |date=1998 |pmid=9796078 |doi=10.1177/1358836X9800300209 |url=}}</ref>
| |
| * Treatment is usually conservative by compression therapy that may include complex physical therapy, pneumatic pumps and compressive garments. Some cases may require volume reducing surgery. Lymphatic microsurgery is being tried in some experimental studies.<ref name="pmid9796078">{{cite journal |vauthors=Szuba A, Rockson SG |title=Lymphedema: classification, diagnosis and therapy |journal=Vasc Med |volume=3 |issue=2 |pages=145–56 |date=1998 |pmid=9796078 |doi=10.1177/1358836X9800300209 |url=}}</ref>
| |
| *# '''Nonne-Milroy syndrome'''
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| *#* A hereditary disorder that usually presents as bilateral edema of lower limbs that may involve the whole extremity or may be limited to legs, feet or toes. This may or may not be accompanied by toenail changes such as upslanting toenails and deep creases in the toes, papillomatosis, hydrocele, hydrothorax, lung hypoplasia and prominent leg veins. A case of unilateral phenotype have also been reported. Swellings may be complicated by recurrent episodes of cellulitis.<ref name="pmid12528167">{{cite journal |vauthors=Lev-Sagie A, Hamani Y, Raas-Rothschild A, Yagel S, Anteby EY |title=Prenatal ultrasonographic diagnosis of atypical Nonne-Milroy lymphedema |journal=Ultrasound Obstet Gynecol |volume=21 |issue=1 |pages=72–4 |date=January 2003 |pmid=12528167 |doi=10.1002/uog.16 |url=}}</ref><ref name="pmid2075326">{{cite journal |vauthors=Zbranca V, Aramă A, Mihăescu T, Covic M |title=[Hereditary lymphedema (Nonne-Milroy-Meige syndrome) associated with chylothorax. Comments on 2 cases] |language=Romanian |journal=Rev Med Chir Soc Med Nat Iasi |volume=94 |issue=1 |pages=189–92 |date=1990 |pmid=2075326 |doi= |url=}}</ref><ref name="urlMilroy disease - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/condition/milroy-disease#inheritance |title=Milroy disease - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref><ref name="pmid16924388">{{cite journal |vauthors=Spiegel R, Ghalamkarpour A, Daniel-Spiegel E, Vikkula M, Shalev SA |title=Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3 |journal=J. Hum. Genet. |volume=51 |issue=10 |pages=846–50 |date=2006 |pmid=16924388 |doi=10.1007/s10038-006-0031-3 |url=}}</ref>
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| *#* The disease typically follows autosomal-dominant pattern though cases of autosomal-recessive inheritance and variable expression has also been reported. The defect thought to be responsible has been located on VEGFR3 (FLT4) gene that codes for vascular endothelial growth factor receptor 3 (VEGFR3).<ref name="urlMilroy disease - Genetics Home Reference - NIH">{{cite web |url=+https://ghr.nlm.nih.gov/condition/milroy-disease#inheritance |title=Milroy disease - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref><ref name="pmid16924388">{{cite journal |vauthors=Spiegel R, Ghalamkarpour A, Daniel-Spiegel E, Vikkula M, Shalev SA |title=Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3 |journal=J. Hum. Genet. |volume=51 |issue=10 |pages=846–50 |date=2006 |pmid=16924388 |doi=10.1007/s10038-006-0031-3 |url=}}</ref><ref name="pmid2075326">{{cite journal |vauthors=Zbranca V, Aramă A, Mihăescu T, Covic M |title=[Hereditary lymphedema (Nonne-Milroy-Meige syndrome) associated with chylothorax. Comments on 2 cases] |language=Romanian |journal=Rev Med Chir Soc Med Nat Iasi |volume=94 |issue=1 |pages=189–92 |date=1990 |pmid=2075326 |doi= |url=}}</ref>
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| *# '''Primary hereditary lymphedema'''
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| *#* Chronic edema that can appear in any body part due to blockage or malfunctioning of lymphatic channels that may lead to recurrent infections and impairment.<ref name="pmid30071673">{{cite journal |vauthors=Nadarajah N, Schulte D, McConnell V, Martin-Almedina S, Karapouliou C, Mortimer PS, Jeffery S, Schulte-Merker S, Gordon K, Mansour S, Ostergaard P |title=A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon |journal=Int J Mol Sci |volume=19 |issue=8 |pages= |date=August 2018 |pmid=30071673 |pmc=6121331 |doi=10.3390/ijms19082259 |url=}}</ref><ref name="urlVEGFC gene - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/gene/VEGFC#conditions |title=VEGFC gene - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref>
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| *#* Results from mutations in VEGFC gene that encodes the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4). This gene plays an important role in lymphangiogenesis.<ref name="urlVEGFC gene - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/gene/VEGFC#conditions |title=VEGFC gene - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref><ref name="pmid30071673">{{cite journal |vauthors=Nadarajah N, Schulte D, McConnell V, Martin-Almedina S, Karapouliou C, Mortimer PS, Jeffery S, Schulte-Merker S, Gordon K, Mansour S, Ostergaard P |title=A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon |journal=Int J Mol Sci |volume=19 |issue=8 |pages= |date=August 2018 |pmid=30071673 |pmc=6121331 |doi=10.3390/ijms19082259 |url=}}</ref>
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| *# '''Primary hereditary lymphedema'''
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| *#* Edema typically first appears in legs and then progresses to involve the arms.<ref name="urlGJC2 gene - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/gene/GJC2#conditions |title=GJC2 gene - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref>
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| *#* Thought to be associated with muatation in GJC2 gene that encodes for connexin-47, a member of the gap junction connecxin family. Mutation in this gene has also been linked to Pelizaeus-Merzbacher-like disease type 1 and spastic paraplegia type 44.<ref name="urlGJC2 gene - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/gene/GJC2#conditions |title=GJC2 gene - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref><ref name="pmid23550541">{{cite journal |vauthors=Brice G, Ostergaard P, Jeffery S, Gordon K, Mortimer PS, Mansour S |title=A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family |journal=Clin. Genet. |volume=84 |issue=4 |pages=378–81 |date=October 2013 |pmid=23550541 |doi=10.1111/cge.12158 |url=}}</ref>
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| *# '''Lymphedema-distichiasis'''
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| *#* A syndrome that is characterized by edema that typically manifests in lower limb and distichiasis that is an anomaly of eyelashes. Distichiasis appears earlier in life than lymphedema and manifests as extra eyelashes that typically arise from meibomian glands. This syndrome has been associated with congenital heart disease, varicose veins, cleft palate, ptosis, strabismus, renal abnormalities, spinal extradural cysts, and neck webbing.<ref name="pmid26759405">{{cite journal |vauthors=Marques NS, Miranda A, Barros S, Parreira S |title=Lymphoedema-distichiasis syndrome |journal=BMJ Case Rep |volume=2016 |issue= |pages= |date=January 2016 |pmid=26759405 |pmc=4716369 |doi=10.1136/bcr-2015-213651 |url=}}</ref><ref name="pmid17366583">{{cite journal |vauthors=Yabuki S, Kikuchi S, Ikegawa S |title=Spinal extradural arachnoid cysts associated with distichiasis and lymphedema |journal=Am. J. Med. Genet. A |volume=143A |issue=8 |pages=884–7 |date=April 2007 |pmid=17366583 |doi=10.1002/ajmg.a.31669 |url=}}</ref><ref name="pmid12114478">{{cite journal |vauthors=Brice G, Mansour S, Bell R, Collin JR, Child AH, Brady AF, Sarfarazi M, Burnand KG, Jeffery S, Mortimer P, Murday VA |title=Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24 |journal=J. Med. Genet. |volume=39 |issue=7 |pages=478–83 |date=July 2002 |pmid=12114478 |pmc=1735188 |doi= |url=}}</ref><ref name="pmid23806988">{{cite journal |vauthors=Sardesai VR, Mhatre MA, Patil RM |title=Lymphoedema - distichiasis syndrome with recurrent abortions |journal=Indian J Med Sci |volume=66 |issue=5-6 |pages=141–3 |date=2012 |pmid=23806988 |doi=10.4103/0019-5359.114202 |url=}}</ref><ref name="pmid28959174">{{cite journal |vauthors=Planinsek Rucigaj T, Rijavec M, Miljkovic J, Selb J, Korosec P |title=A Novel Mutation in the FOXC2 Gene: A Heterozygous Insertion of Adenosine (c.867insA) in a Family with Lymphoedema of Lower Limbs without Distichiasis |journal=Radiol Oncol |volume=51 |issue=3 |pages=363–368 |date=September 2017 |pmid=28959174 |pmc=5612002 |doi=10.1515/raon-2017-0026 |url=}}</ref><ref name="pmid29406328">{{cite journal |vauthors=De Niear MA, Breazzano MP, Mawn LA |title=Novel FOXC2 Mutation and Distichiasis in a Patient With Lymphedema-Distichiasis Syndrome |journal=Ophthalmic Plast Reconstr Surg |volume=34 |issue=3 |pages=e88–e90 |date=2018 |pmid=29406328 |doi=10.1097/IOP.0000000000001079 |url=}}</ref>
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| *#* Inherited in autosomal dominant pattern mutation in FOXC2 gene that encodes for transcription factors. Inheritance also shows variable expression.<ref name="pmid24984567">{{cite journal |vauthors=Zhu LL, Lv YN, Chen HD, Gao XH |title=A Chinese pedigree of lymphoedema-distichiasis syndrome with a novel mutation in the FOXC2 gene |journal=Clin. Exp. Dermatol. |volume=39 |issue=6 |pages=731–3 |date=August 2014 |pmid=24984567 |doi=10.1111/ced.12389 |url=}}</ref><ref name="pmid27570485">{{cite journal |vauthors=Zhang L, He J, Han B, Lu L, Fan J, Zhang H, Ge S, Zhou Y, Jia R, Fan X |title=Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation |journal=Int. J. Biol. Sci. |volume=12 |issue=9 |pages=1114–20 |date=2016 |pmid=27570485 |pmc=4997055 |doi=10.7150/ijbs.13774 |url=}}</ref><ref name="pmid28959174">{{cite journal |vauthors=Planinsek Rucigaj T, Rijavec M, Miljkovic J, Selb J, Korosec P |title=A Novel Mutation in the FOXC2 Gene: A Heterozygous Insertion of Adenosine (c.867insA) in a Family with Lymphoedema of Lower Limbs without Distichiasis |journal=Radiol Oncol |volume=51 |issue=3 |pages=363–368 |date=September 2017 |pmid=28959174 |pmc=5612002 |doi=10.1515/raon-2017-0026 |url=}}</ref>
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| *#* Diagnosis is clinical. Treatment for lymphedema is mainly conservative with management of complications such as cellulitis. Treatment for distichiasis consists of symptomatic management such as lubrication or definitive management such as surgery, cryotherapy, or electrolysis.<ref name="pmid26759405">{{cite journal |vauthors=Marques NS, Miranda A, Barros S, Parreira S |title=Lymphoedema-distichiasis syndrome |journal=BMJ Case Rep |volume=2016 |issue= |pages= |date=January 2016 |pmid=26759405 |pmc=4716369 |doi=10.1136/bcr-2015-213651 |url=}}</ref><ref name="pmid20301630">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Mansour S, Brice GW, Jeffery S, Mortimer P |title= |journal= |volume= |issue= |pages= |date= |pmid=20301630 |doi= |url=}}</ref>
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| *# '''Hypotrichosis-lymphedema-telangiectasia'''
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| *#* Characterized by less than normal body hair (hypotrichosis), chronic swelling of the body (lymphedema), and dilated blood vessels (telangiectasia). These usually appear at birth or early in life and then progressively worsen over time. Hypotrichosis may present as absent eyebrows, eyelashes and alopecia or may manifest as sparse body hair. Lymphedema typically has predilection for lower limbs and telangiectasia are more commonly seen on palms although plantar telangiectasia are also seen. This syndrome has also been associated with cutis marmorata, hydrocele, palpebral edema, ascites, dermal atrophy, small cutaneous papular vascular lesions, skin degeneration, hydrops fetalis, pleural effusion, renal defects, aortic dilation and abnormal nails.<ref>{{cite web |url=https://rarediseases.info.nih.gov/diseases/12827/hypotrichosis-lymphedema-telangiectasia-syndrome |title=Hypotrichosis-lymphedema-telangiectasia syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |format= |work= |accessdate=}}</ref><ref>{{cite journal |vauthors=Wünnemann F, Kokta V, Leclerc S, Thibeault M, McCuaig C, Hatami A, Stheneur C, Grenier JC, Awadalla P, Mitchell GA, Andelfinger G, Preuss C |title=Aortic Dilatation Associated With a De Novo Mutation in the SOX18 Gene: Expanding the Clinical Spectrum of Hypotrichosis-Lymphedema-Telangiectasia Syndrome |journal=Can J Cardiol |volume=32 |issue=1 |pages=135.e1–7 |date=January 2016 |pmid=26148450 |doi=10.1016/j.cjca.2015.04.004 |url=}}</ref><ref>{{cite journal |vauthors=Moalem S, Brouillard P, Kuypers D, Legius E, Harvey E, Taylor G, Francois M, Vikkula M, Chitayat D |title=Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene |journal=Clin. Genet. |volume=87 |issue=4 |pages=378–82 |date=April 2015 |pmid=24697860 |doi=10.1111/cge.12388 |url=}}</ref><ref>{{cite journal |vauthors=Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M |title=Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia |journal=Am. J. Hum. Genet. |volume=72 |issue=6 |pages=1470–8 |date=June 2003 |pmid=12740761 |pmc=1180307 |doi=10.1086/375614 |url=}}</ref>
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| *#* Mutation in SOX18 gene that encodes for transcription factor SOX18 is thought to be the cause of this syndrome. This transcription factor is expressed widely in body tissues and that may explain the wide ranging manifestations of this syndrome. Inheritance can both be autosomal-dominant and autosomal-recessive.<ref>{{cite journal |vauthors=Valenzuela I, Fernández-Alvarez P, Plaja A, Ariceta G, Sabaté-Rotés A, García-Arumí E, Vendrell T, Tizzano E |title=Further delineation of the SOX18-related Hypotrichosis, Lymphedema, Telangiectasia syndrome (HTLS) |journal=Eur J Med Genet |volume=61 |issue=5 |pages=269–272 |date=May 2018 |pmid=29307792 |doi=10.1016/j.ejmg.2018.01.001 |url=}}</ref><ref>{{cite journal |vauthors=Bastaki F, Mohamed M, Nair P, Saif F, Tawfiq N, Al-Ali MT, Brandau O, Hamzeh AR |title=A novel SOX18 mutation uncovered in Jordanian patient with hypotrichosis-lymphedema-telangiectasia syndrome by Whole Exome Sequencing |journal=Mol. Cell. Probes |volume=30 |issue=1 |pages=18–21 |date=February 2016 |pmid=26631803 |doi=10.1016/j.mcp.2015.11.005 |url=}}</ref><ref>{{cite journal |vauthors=Wünnemann F, Kokta V, Leclerc S, Thibeault M, McCuaig C, Hatami A, Stheneur C, Grenier JC, Awadalla P, Mitchell GA, Andelfinger G, Preuss C |title=Aortic Dilatation Associated With a De Novo Mutation in the SOX18 Gene: Expanding the Clinical Spectrum of Hypotrichosis-Lymphedema-Telangiectasia Syndrome |journal=Can J Cardiol |volume=32 |issue=1 |pages=135.e1–7 |date=January 2016 |pmid=26148450 |doi=10.1016/j.cjca.2015.04.004 |url=}}</ref><ref>{{cite journal |vauthors=Moalem S, Brouillard P, Kuypers D, Legius E, Harvey E, Taylor G, Francois M, Vikkula M, Chitayat D |title=Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene |journal=Clin. Genet. |volume=87 |issue=4 |pages=378–82 |date=April 2015 |pmid=24697860 |doi=10.1111/cge.12388 |url=}}{{cite journal |vauthors=Downes M, François M, Ferguson C, Parton RG, Koopman P |title=Vascular defects in a mouse model of hypotrichosis-lymphedema-telangiectasia syndrome indicate a role for SOX18 in blood vessel maturation |journal=Hum. Mol. Genet. |volume=18 |issue=15 |pages=2839–50 |date=August 2009 |pmid=19429912 |doi=10.1093/hmg/ddp219 |url=}}</ref><ref>{{cite journal |vauthors=François M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C, Paavonen K, Karnezis T, Shayan R, Downes M, Davidson T, Tutt D, Cheah KS, Stacker SA, Muscat GE, Achen MG, Dejana E, Koopman P |title=Sox18 induces development of the lymphatic vasculature in mice |journal=Nature |volume=456 |issue=7222 |pages=643–7 |date=December 2008 |pmid=18931657 |doi=10.1038/nature07391 |url=}}</ref><ref>{{cite journal |vauthors=Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M |title=Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia |journal=Am. J. Hum. Genet. |volume=72 |issue=6 |pages=1470–8 |date=June 2003 |pmid=12740761 |pmc=1180307 |doi=10.1086/375614 |url=}}</ref><ref>{{cite web |url=https://rarediseases.info.nih.gov/diseases/12827/hypotrichosis-lymphedema-telangiectasia-syndrome |title=Hypotrichosis-lymphedema-telangiectasia syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |format= |work= |accessdate=}}</ref>
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| *#* There is no definitive treatment for this syndrome. Management is based on genetic counseling and symptomatic treatment.<ref>{{cite web |url=https://rarediseases.info.nih.gov/diseases/12827/hypotrichosis-lymphedema-telangiectasia-syndrome |title=Hypotrichosis-lymphedema-telangiectasia syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |format= |work= |accessdate=}}</ref><ref>{{cite journal |vauthors=Valenzuela I, Fernández-Alvarez P, Plaja A, Ariceta G, Sabaté-Rotés A, García-Arumí E, Vendrell T, Tizzano E |title=Further delineation of the SOX18-related Hypotrichosis, Lymphedema, Telangiectasia syndrome (HTLS) |journal=Eur J Med Genet |volume=61 |issue=5 |pages=269–272 |date=May 2018 |pmid=29307792 |doi=10.1016/j.ejmg.2018.01.001 |url=}}</ref>
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| *# '''Primary lymphedema with myelodysplasia'''
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| *#* Also called Emberger syndrome, this anomaly presents with wide variety of phenotypes including congenital sensorineural deafness, lymphedema, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), hypotelorism, epicanthic folds, long tapering fingers and/or neck webbing, and generalized warts.. Lymphedema has predisposition for lower limbs. Patient may present with complication of these phenotypes such as infections, bleeding and recurrent cellulitis.<ref name="pmid26767875">{{cite journal |vauthors=Seo SK, Kim KY, Han SA, Yoon JS, Shin SY, Sohn SK, Moon JH |title=First Korean case of Emberger syndrome (primary lymphedema with myelodysplasia) with a novel GATA2 gene mutation |journal=Korean J. Intern. Med. |volume=31 |issue=1 |pages=188–90 |date=January 2016 |pmid=26767875 |pmc=4712426 |doi=10.3904/kjim.2016.31.1.188 |url=}}</ref><ref name="pmid21892158">{{cite journal |vauthors=Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, Dafou D, Kilo T, Smithson S, Lunt P, Murday VA, Hodgson S, Keenan R, Pilz DT, Martinez-Corral I, Makinen T, Mortimer PS, Jeffery S, Trembath RC, Mansour S |title=Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome) |journal=Nat. Genet. |volume=43 |issue=10 |pages=929–31 |date=September 2011 |pmid=21892158 |doi=10.1038/ng.923 |url=}}</ref><ref name="pmid20803646">{{cite journal |vauthors=Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S, Lunt P, Jeffery S, Dokal I, Vulliamy T, Gibson B, Hodgson S, Cottrell S, Kiely L, Tinworth L, Kalidas K, Mufti G, Cornish J, Keenan R, Mortimer P, Murday V |title=Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases |journal=Am. J. Med. Genet. A |volume=152A |issue=9 |pages=2287–96 |date=September 2010 |pmid=20803646 |doi=10.1002/ajmg.a.33445 |url=}}</ref><ref name="pmid29605372">{{cite journal |vauthors=Zawawi F, Sokolov M, Mawby T, Gordon KA, Papsin BC, Cushing SL |title=Emberger syndrome: A rare association with hearing loss |journal=Int. J. Pediatr. Otorhinolaryngol. |volume=108 |issue= |pages=82–84 |date=May 2018 |pmid=29605372 |doi=10.1016/j.ijporl.2018.02.014 |url=}}</ref>
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| *#* Deficiency of transcription factor GATA2 due to mutations in GATA2 gene is thought to play the critical role. Inheritance tends to follow autosomal-dominant pattern.<ref name="pmid26767875">{{cite journal |vauthors=Seo SK, Kim KY, Han SA, Yoon JS, Shin SY, Sohn SK, Moon JH |title=First Korean case of Emberger syndrome (primary lymphedema with myelodysplasia) with a novel GATA2 gene mutation |journal=Korean J. Intern. Med. |volume=31 |issue=1 |pages=188–90 |date=January 2016 |pmid=26767875 |pmc=4712426 |doi=10.3904/kjim.2016.31.1.188 |url=}}</ref><ref name="pmid21892158">{{cite journal |vauthors=Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, Dafou D, Kilo T, Smithson S, Lunt P, Murday VA, Hodgson S, Keenan R, Pilz DT, Martinez-Corral I, Makinen T, Mortimer PS, Jeffery S, Trembath RC, Mansour S |title=Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome) |journal=Nat. Genet. |volume=43 |issue=10 |pages=929–31 |date=September 2011 |pmid=21892158 |doi=10.1038/ng.923 |url=}}</ref><ref name="pmid20803646">{{cite journal |vauthors=Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S, Lunt P, Jeffery S, Dokal I, Vulliamy T, Gibson B, Hodgson S, Cottrell S, Kiely L, Tinworth L, Kalidas K, Mufti G, Cornish J, Keenan R, Mortimer P, Murday V |title=Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases |journal=Am. J. Med. Genet. A |volume=152A |issue=9 |pages=2287–96 |date=September 2010 |pmid=20803646 |doi=10.1002/ajmg.a.33445 |url=}}</ref><ref name="pmid25397911">{{cite journal |vauthors=Hsu AP, McReynolds LJ, Holland SM |title=GATA2 deficiency |journal=Curr Opin Allergy Clin Immunol |volume=15 |issue=1 |pages=104–9 |date=February 2015 |pmid=25397911 |pmc=4342850 |doi=10.1097/ACI.0000000000000126 |url=}}</ref><ref name="pmid24345756">{{cite journal |vauthors=Dickinson RE, Milne P, Jardine L, Zandi S, Swierczek SI, McGovern N, Cookson S, Ferozepurwalla Z, Langridge A, Pagan S, Gennery A, Heiskanen-Kosma T, Hämäläinen S, Seppänen M, Helbert M, Tholouli E, Gambineri E, Reykdal S, Gottfreðsson M, Thaventhiran JE, Morris E, Hirschfield G, Richter AG, Jolles S, Bacon CM, Hambleton S, Haniffa M, Bryceson Y, Allen C, Prchal JT, Dick JE, Bigley V, Collin M |title=The evolution of cellular deficiency in GATA2 mutation |journal=Blood |volume=123 |issue=6 |pages=863–74 |date=February 2014 |pmid=24345756 |pmc=3916878 |doi=10.1182/blood-2013-07-517151 |url=}}</ref><ref name="pmid29605372">{{cite journal |vauthors=Zawawi F, Sokolov M, Mawby T, Gordon KA, Papsin BC, Cushing SL |title=Emberger syndrome: A rare association with hearing loss |journal=Int. J. Pediatr. Otorhinolaryngol. |volume=108 |issue= |pages=82–84 |date=May 2018 |pmid=29605372 |doi=10.1016/j.ijporl.2018.02.014 |url=}}</ref>
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| *#* Screening for GATA2 muations is indicated in patients who present with lymphedema and hematological abnormalities. Children should be screened for hematological disorders if they present with lower limb lymphedema. Besides symptomatic treatment for lymphedema and standard treatment for deafness, primary stem cell transplant is indicated for hematological malignancies. <ref name="pmid20803646">{{cite journal |vauthors=Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S, Lunt P, Jeffery S, Dokal I, Vulliamy T, Gibson B, Hodgson S, Cottrell S, Kiely L, Tinworth L, Kalidas K, Mufti G, Cornish J, Keenan R, Mortimer P, Murday V |title=Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases |journal=Am. J. Med. Genet. A |volume=152A |issue=9 |pages=2287–96 |date=September 2010 |pmid=20803646 |doi=10.1002/ajmg.a.33445 |url=}}</ref><ref name="pmid26767875">{{cite journal |vauthors=Seo SK, Kim KY, Han SA, Yoon JS, Shin SY, Sohn SK, Moon JH |title=First Korean case of Emberger syndrome (primary lymphedema with myelodysplasia) with a novel GATA2 gene mutation |journal=Korean J. Intern. Med. |volume=31 |issue=1 |pages=188–90 |date=January 2016 |pmid=26767875 |pmc=4712426 |doi=10.3904/kjim.2016.31.1.188 |url=}}</ref><ref name="pmid28643018">{{cite journal |vauthors=Hirabayashi S, Wlodarski MW, Kozyra E, Niemeyer CM |title=Heterogeneity of GATA2-related myeloid neoplasms |journal=Int. J. Hematol. |volume=106 |issue=2 |pages=175–182 |date=August 2017 |pmid=28643018 |doi=10.1007/s12185-017-2285-2 |url=}}</ref><ref name="pmid28179280">{{cite journal |vauthors=Crispino JD, Horwitz MS |title=GATA factor mutations in hematologic disease |journal=Blood |volume=129 |issue=15 |pages=2103–2110 |date=April 2017 |pmid=28179280 |pmc=5391620 |doi=10.1182/blood-2016-09-687889 |url=}}</ref>
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| *# '''Primary generalized lymphatic anomaly'''
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| *#* Also called Hennekam lymphangiectasia-lymphedema syndrome, this disorder is characterized by generalized lymphatic anomalies such as lymphangiectasia and lymphedema, typical dysmorphic features such as flat nasal bridge, hypertelorism, small mouth and variable intellectual disability that may present as developmental delay. Lymphangiectasias are typically found in intestines and can cause generalized body swelling due to loss of proteins but can also be found in other organs such as kidney, thyroid gland and pleura.<ref name="pmid25925991">{{cite journal |vauthors=Frosk P, Chodirker B, Simard L, El-Matary W, Hanlon-Dearman A, Schwartzentruber J, Majewski J, Rockman-Greenberg C |title=A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature |journal=BMC Med. Genet. |volume=16 |issue= |pages=28 |date=April 2015 |pmid=25925991 |pmc=4630843 |doi=10.1186/s12881-015-0175-0 |url=}}</ref><ref name="pmid12376947">{{cite journal |vauthors=Van Balkom ID, Alders M, Allanson J, Bellini C, Frank U, De Jong G, Kolbe I, Lacombe D, Rockson S, Rowe P, Wijburg F, Hennekam RC |title=Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review |journal=Am. J. Med. Genet. |volume=112 |issue=4 |pages=412–21 |date=November 2002 |pmid=12376947 |doi=10.1002/ajmg.10707 |url=}}</ref><ref name="pmid25616299">{{cite journal |vauthors=Deng XL, Yin F, Zhang GY, Duan YD |title=[A complicated case study: Hennekam syndrome] |language=Chinese |journal=Zhongguo Dang Dai Er Ke Za Zhi |volume=17 |issue=1 |pages=77–80 |date=January 2015 |pmid=25616299 |doi= |url=}}</ref>
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| *#* Mutations in CCBE1 gene are thought to be the main culprit although mutations in FAT4 gene has also be linked by some studies. CCBE1 encodes for Collagen- and calcium-binding EGF domain-containing protein 1 (CCBE1) that plays a crucial role in activation of vascular endothelial growth factor-C (VEGFC) through its collagen domain. Inheritance tends to follow autosomal-recessive pattern.<ref name="pmid25814692">{{cite journal |vauthors=Roukens MG, Peterson-Maduro J, Padberg Y, Jeltsch M, Leppänen VM, Bos FL, Alitalo K, Schulte-Merker S, Schulte D |title=Functional Dissection of the CCBE1 Protein: A Crucial Requirement for the Collagen Repeat Domain |journal=Circ. Res. |volume=116 |issue=10 |pages=1660–9 |date=May 2015 |pmid=25814692 |doi=10.1161/CIRCRESAHA.116.304949 |url=}}</ref><ref name="pmid25925991">{{cite journal |vauthors=Frosk P, Chodirker B, Simard L, El-Matary W, Hanlon-Dearman A, Schwartzentruber J, Majewski J, Rockman-Greenberg C |title=A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature |journal=BMC Med. Genet. |volume=16 |issue= |pages=28 |date=April 2015 |pmid=25925991 |pmc=4630843 |doi=10.1186/s12881-015-0175-0 |url=}}</ref><ref name="pmid25616299">{{cite journal |vauthors=Deng XL, Yin F, Zhang GY, Duan YD |title=[A complicated case study: Hennekam syndrome] |language=Chinese |journal=Zhongguo Dang Dai Er Ke Za Zhi |volume=17 |issue=1 |pages=77–80 |date=January 2015 |pmid=25616299 |doi= |url=}}</ref><ref name="pmid24552833">{{cite journal |vauthors=Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen VM, Holopainen T, Kivelä R, Ortega S, Kärpanen T, Alitalo K |title=CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation |journal=Circulation |volume=129 |issue=19 |pages=1962–71 |date=May 2014 |pmid=24552833 |doi=10.1161/CIRCULATIONAHA.113.002779 |url=}}</ref>
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| *#* Diagnosis depends on history and examination, lab findings, and genetic testing for associated mutations. Analysis for CCBE1 mutation should be considered in patients presenting with unexplained lymphatic anomalies, and/or unexplained intellectual disability. No definitive management is available at this point. Conservative measures for lymphedema and protein deficiency, and rehabilitation for intellectual disability is the mainstay of management.<ref name="pmid29560340">{{cite journal |vauthors=Lee YG, Kim SC, Park SB, Kim MJ |title=Hennekam Syndrome: A Case Report |journal=Ann Rehabil Med |volume=42 |issue=1 |pages=184–188 |date=February 2018 |pmid=29560340 |pmc=5852224 |doi=10.5535/arm.2018.42.1.184 |url=}}</ref><ref name="pmid25925991">{{cite journal |vauthors=Frosk P, Chodirker B, Simard L, El-Matary W, Hanlon-Dearman A, Schwartzentruber J, Majewski J, Rockman-Greenberg C |title=A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature |journal=BMC Med. Genet. |volume=16 |issue= |pages=28 |date=April 2015 |pmid=25925991 |pmc=4630843 |doi=10.1186/s12881-015-0175-0 |url=}}</ref><ref name="pmid25616299">{{cite journal |vauthors=Deng XL, Yin F, Zhang GY, Duan YD |title=[A complicated case study: Hennekam syndrome] |language=Chinese |journal=Zhongguo Dang Dai Er Ke Za Zhi |volume=17 |issue=1 |pages=77–80 |date=January 2015 |pmid=25616299 |doi= |url=}}</ref><ref name="pmid29560340">{{cite journal |vauthors=Lee YG, Kim SC, Park SB, Kim MJ |title=Hennekam Syndrome: A Case Report |journal=Ann Rehabil Med |volume=42 |issue=1 |pages=184–188 |date=February 2018 |pmid=29560340 |pmc=5852224 |doi=10.5535/arm.2018.42.1.184 |url=}}</ref>
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| *# '''Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome'''
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| *#* As name indicates, this syndrome is characterized by microcephaly that is often accompanied by intellectual disability, congenital lymphedema and ocular findings. Ocular defects, often because of chorioretinal dysplasia, may include peripheral retinal pigmentation, retinal folds, chorioretinopathy, widespread chorioretinal atrophy, hyperopia, small corneas, nystagmus and small optic nerves. Microcephaly can be variable and imaging often shows small size brain. Intellectual disability can also vary from normal developmental to severe mental retardation. Lymphedema most often involves lower limbs and may or may not resolve spontaneously. Facial features are distinct with broad nose, anteverted nares, upslanting palpebral fissures, a rounded nasal tip, a long philtrum, a pointed chin, a thin upper lip, prominent ears, and patient may also have atrial septal defects.<ref name="pmid25934493">{{cite journal |vauthors=Schlögel MJ, Mendola A, Fastré E, Vasudevan P, Devriendt K, de Ravel TJ, Van Esch H, Casteels I, Arroyo Carrera I, Cristofoli F, Fieggen K, Jones K, Lipson M, Balikova I, Singer A, Soller M, Mercedes Villanueva M, Revencu N, Boon LM, Brouillard P, Vikkula M |title=No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome |journal=Orphanet J Rare Dis |volume=10 |issue= |pages=52 |date=May 2015 |pmid=25934493 |pmc=4464120 |doi=10.1186/s13023-015-0271-4 |url=}}</ref><ref name="pmid5936364">{{cite journal |vauthors=McKusick VA, Stauffer M, Knox DL, Clark DB |title=Chorioretinopathy with hereditary microcephaly |journal=Arch. Ophthalmol. |volume=75 |issue=5 |pages=597–600 |date=May 1966 |pmid=5936364 |doi= |url=}}</ref><ref name="pmid15930898">{{cite journal |vauthors=Vasudevan PC, Garcia-Minaur S, Botella MP, Perez-Aytes A, Shannon NL, Quarrell OW |title=Microcephaly-lymphoedema-chorioretinal dysplasia: three cases to delineate the facial phenotype and review of the literature |journal=Clin. Dysmorphol. |volume=14 |issue=3 |pages=109–16 |date=July 2005 |pmid=15930898 |doi= |url=}}</ref><ref name="pmid19076985">{{cite journal |vauthors=Eventov-Friedman S, Singer A, Shinwell ES |title=Microcephaly, lymphedema, chorioretinopathy and atrial septal defect: a case report and review of the literature |journal=Acta Paediatr. |volume=98 |issue=4 |pages=758–9 |date=April 2009 |pmid=19076985 |doi=10.1111/j.1651-2227.2008.01161.x |url=}}</ref><ref name="pmid25115524">{{cite journal |vauthors=Mirzaa GM, Enyedi L, Parsons G, Collins S, Medne L, Adams C, Ward T, Davitt B, Bicknese A, Zackai E, Toriello H, Dobyns WB, Christian S |title=Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature |journal=Am. J. Med. Genet. A |volume=164A |issue=11 |pages=2879–86 |date=November 2014 |pmid=25115524 |pmc=4205200 |doi=10.1002/ajmg.a.36707 |url=}}</ref>
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| *#* Mutations in KIF11 gene that encodes for spindle motor protein of kinesin family, a protein that plays a role in mitosis, are thought to cause this syndrome. These mutations can be sporadic or hereditary, and when hereditary they follow autosomal-dominant pattern with variable expression and reduced penetrance.<ref name="pmid25934493">{{cite journal |vauthors=Schlögel MJ, Mendola A, Fastré E, Vasudevan P, Devriendt K, de Ravel TJ, Van Esch H, Casteels I, Arroyo Carrera I, Cristofoli F, Fieggen K, Jones K, Lipson M, Balikova I, Singer A, Soller M, Mercedes Villanueva M, Revencu N, Boon LM, Brouillard P, Vikkula M |title=No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome |journal=Orphanet J Rare Dis |volume=10 |issue= |pages=52 |date=May 2015 |pmid=25934493 |pmc=4464120 |doi=10.1186/s13023-015-0271-4 |url=}}</ref><ref name="pmid25764055">{{cite journal |vauthors=Mears K, Bakall B, Harney LA, Penticoff JA, Stone EM |title=Autosomal Dominant Microcephaly Associated With Congenital Lymphedema and Chorioretinopathy Due to a Novel Mutation in KIF11 |journal=JAMA Ophthalmol |volume=133 |issue=6 |pages=720–1 |date=June 2015 |pmid=25764055 |doi=10.1001/jamaophthalmol.2015.199 |url=}}</ref><ref name="pmid26472404">{{cite journal |vauthors=Hu H, Xiao X, Li S, Jia X, Guo X, Zhang Q |title=KIF11 mutations are a common cause of autosomal dominant familial exudative vitreoretinopathy |journal=Br J Ophthalmol |volume=100 |issue=2 |pages=278–83 |date=February 2016 |pmid=26472404 |doi=10.1136/bjophthalmol-2015-306878 |url=}}</ref><ref name="pmid25996076">{{cite journal |vauthors=Balikova I, Robson AG, Holder GE, Ostergaard P, Mansour S, Moore AT |title=Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11 |journal=Acta Ophthalmol |volume=94 |issue=1 |pages=92–8 |date=February 2016 |pmid=25996076 |doi=10.1111/aos.12759 |url=}}</ref><ref name="pmid24281367">{{cite journal |vauthors=Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, Quarrell O, Brady AF, Spier I, Hazan F, Moldovan O, Wieczorek D, Mikat B, Petit F, Coubes C, Saul RA, Brice G, Gordon K, Jeffery S, Mortimer PS, Vasudevan PC, Mansour S |title=Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations |journal=Eur. J. Hum. Genet. |volume=22 |issue=7 |pages=881–7 |date=July 2014 |pmid=24281367 |pmc=3938398 |doi=10.1038/ejhg.2013.263 |url=}}</ref>
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| *#* Diagnosis requires genetic testing in addition to clinical findings. Long term cardiac and ophthalmologic follow-ups are recommended.<ref name="pmid19076985">{{cite journal |vauthors=Eventov-Friedman S, Singer A, Shinwell ES |title=Microcephaly, lymphedema, chorioretinopathy and atrial septal defect: a case report and review of the literature |journal=Acta Paediatr. |volume=98 |issue=4 |pages=758–9 |date=April 2009 |pmid=19076985 |doi=10.1111/j.1651-2227.2008.01161.x |url=}}</ref><ref name="pmid24281367">{{cite journal |vauthors=Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, Quarrell O, Brady AF, Spier I, Hazan F, Moldovan O, Wieczorek D, Mikat B, Petit F, Coubes C, Saul RA, Brice G, Gordon K, Jeffery S, Mortimer PS, Vasudevan PC, Mansour S |title=Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations |journal=Eur. J. Hum. Genet. |volume=22 |issue=7 |pages=881–7 |date=July 2014 |pmid=24281367 |pmc=3938398 |doi=10.1038/ejhg.2013.263 |url=}}</ref>
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| *# '''Lymphedema-choanal atresia'''
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| *#* A very rare syndrome described in 1982 in a Middle Eastern family when individuals in the family presented with bilateral posterior choanal atresia with other developmental abnormalities such as high arched palate, hypoplastic nipples, pericardial effusion, and pectus excavatum. Follow up detected lymphedema in five individuals with choanal atresia in the family later in 1991.<ref name="pmid20826270">{{cite journal |vauthors=Au AC, Hernandez PA, Lieber E, Nadroo AM, Shen YM, Kelley KA, Gelb BD, Diaz GA |title=Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans |journal=Am. J. Hum. Genet. |volume=87 |issue=3 |pages=436–44 |date=September 2010 |pmid=20826270 |pmc=2933336 |doi=10.1016/j.ajhg.2010.08.008 |url=}}</ref>
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| *#* Deletion in PTPN14 gene that appeared to follow autosomal-recessive pattern are thought to be the cause. This gene encodes for a protein that is thought to be involved in cell-signaling pathways and regulation of cellular functions.<ref name="pmid20826270">{{cite journal |vauthors=Au AC, Hernandez PA, Lieber E, Nadroo AM, Shen YM, Kelley KA, Gelb BD, Diaz GA |title=Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans |journal=Am. J. Hum. Genet. |volume=87 |issue=3 |pages=436–44 |date=September 2010 |pmid=20826270 |pmc=2933336 |doi=10.1016/j.ajhg.2010.08.008 |url=}}</ref>
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| ====Venous malformations (VM)====
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| =====Common VM=====
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| * Localized defects characterized by dilated venous channels. Microscopically they consist of thin endothelial cells lined by fewer, disorganized smooth muscle cells and extracellular matrix. Patient may present with deforming lesions, bleeding, thrombosis, significant acute or chronic pain, and pressure symptoms. Located on skin and mucosa for majority of the times, lesions often are present at birth.<ref name="pmid26319232">{{cite journal |vauthors=Nätynki M, Kangas J, Miinalainen I, Sormunen R, Pietilä R, Soblet J, Boon LM, Vikkula M, Limaye N, Eklund L |title=Common and specific effects of TIE2 mutations causing venous malformations |journal=Hum. Mol. Genet. |volume=24 |issue=22 |pages=6374–89 |date=November 2015 |pmid=26319232 |pmc=4614705 |doi=10.1093/hmg/ddv349 |url=}}</ref><ref name="pmid27030595">{{cite journal |vauthors=Castillo SD, Tzouanacou E, Zaw-Thin M, Berenjeno IM, Parker VE, Chivite I, Milà-Guasch M, Pearce W, Solomon I, Angulo-Urarte A, Figueiredo AM, Dewhurst RE, Knox RG, Clark GR, Scudamore CL, Badar A, Kalber TL, Foster J, Stuckey DJ, David AL, Phillips WA, Lythgoe MF, Wilson V, Semple RK, Sebire NJ, Kinsler VA, Graupera M, Vanhaesebroeck B |title=Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans |journal=Sci Transl Med |volume=8 |issue=332 |pages=332ra43 |date=March 2016 |pmid=27030595 |pmc=5973268 |doi=10.1126/scitranslmed.aad9982 |url=}}</ref><ref name="pmid26637981">{{cite journal |vauthors=Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, Vikkula M |title=Somatic Activating PIK3CA Mutations Cause Venous Malformation |journal=Am. J. Hum. Genet. |volume=97 |issue=6 |pages=914–21 |date=December 2015 |pmid=26637981 |pmc=4678782 |doi=10.1016/j.ajhg.2015.11.011 |url=}}</ref>
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| * Sporadic mutations in the TEK gene, that encodes the tyrosine kinase receptor TIE2 that functions to regulate cellular growth and proliferation are found in half of the patients with sporadic venous malformations.<ref name="pmid26319232">{{cite journal |vauthors=Nätynki M, Kangas J, Miinalainen I, Sormunen R, Pietilä R, Soblet J, Boon LM, Vikkula M, Limaye N, Eklund L |title=Common and specific effects of TIE2 mutations causing venous malformations |journal=Hum. Mol. Genet. |volume=24 |issue=22 |pages=6374–89 |date=November 2015 |pmid=26319232 |pmc=4614705 |doi=10.1093/hmg/ddv349 |url=}}</ref><ref name="pmid27030595">{{cite journal |vauthors=Castillo SD, Tzouanacou E, Zaw-Thin M, Berenjeno IM, Parker VE, Chivite I, Milà-Guasch M, Pearce W, Solomon I, Angulo-Urarte A, Figueiredo AM, Dewhurst RE, Knox RG, Clark GR, Scudamore CL, Badar A, Kalber TL, Foster J, Stuckey DJ, David AL, Phillips WA, Lythgoe MF, Wilson V, Semple RK, Sebire NJ, Kinsler VA, Graupera M, Vanhaesebroeck B |title=Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans |journal=Sci Transl Med |volume=8 |issue=332 |pages=332ra43 |date=March 2016 |pmid=27030595 |pmc=5973268 |doi=10.1126/scitranslmed.aad9982 |url=}}</ref><ref name="pmid26637981">{{cite journal |vauthors=Limaye N, Kangas J, Mendola A, Godfraind C, Schlögel MJ, Helaers R, Eklund L, Boon LM, Vikkula M |title=Somatic Activating PIK3CA Mutations Cause Venous Malformation |journal=Am. J. Hum. Genet. |volume=97 |issue=6 |pages=914–21 |date=December 2015 |pmid=26637981 |pmc=4678782 |doi=10.1016/j.ajhg.2015.11.011 |url=}}</ref>
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| * Diagnosis is clinical. Current treatment options include sclerotherapy and surgery, alone or in combination but inaccessible lesions and high recurrence rate remains a problem. mTOR inhibitor rapamycin has been used in some studies with success.<ref name="pmid27030595">{{cite journal| author=Castillo SD, Tzouanacou E, Zaw-Thin M, Berenjeno IM, Parker VE, Chivite I et al.| title=Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans. | journal=Sci Transl Med | year= 2016 | volume= 8 | issue= 332 | pages= 332ra43 | pmid=27030595 | doi=10.1126/scitranslmed.aad9982 | pmc=5973268 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27030595 }}</ref>
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| =====Familial VM cutaneo-mucosal (VMCM)=====
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| * Venous malformations that appear both on skin and mucous membranes. Present at birth, they may not be apparent early in life and can appear after trauma and during pregnancy and puberty because of rapid growth. Patient may present with sequela of these malformations such as cosmetic deformation, pain, bleeding.<ref name="pmid28316284">{{cite journal |vauthors=Brahami N, Subramaniam S, Al-Ddafari MS, Elkaim C, Harmand PO, Sari BE, Lefranc G, Aribi M |title=Facial cutaneo-mucosal venous malformations can develop independently of mutation of TEK gene but may be associated with excessive expression of Src and p-Src |journal=J Negat Results Biomed |volume=16 |issue=1 |pages=9 |date=March 2017 |pmid=28316284 |pmc=5357811 |doi=10.1186/s12952-017-0072-5 |url=}}</ref>
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| * Associated with mutation in TEK/TIE2 receptor tyrosine kinase that plays critical role in development of vessels and cardiovascular system.<ref name="pmid28316284">{{cite journal |vauthors=Brahami N, Subramaniam S, Al-Ddafari MS, Elkaim C, Harmand PO, Sari BE, Lefranc G, Aribi M |title=Facial cutaneo-mucosal venous malformations can develop independently of mutation of TEK gene but may be associated with excessive expression of Src and p-Src |journal=J Negat Results Biomed |volume=16 |issue=1 |pages=9 |date=March 2017 |pmid=28316284 |pmc=5357811 |doi=10.1186/s12952-017-0072-5 |url=}}</ref><ref name="pmid19888299">{{cite journal |vauthors=Wouters V, Limaye N, Uebelhoer M, Irrthum A, Boon LM, Mulliken JB, Enjolras O, Baselga E, Berg J, Dompmartin A, Ivarsson SA, Kangesu L, Lacassie Y, Murphy J, Teebi AS, Penington A, Rieu P, Vikkula M |title=Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects |journal=Eur. J. Hum. Genet. |volume=18 |issue=4 |pages=414–20 |date=April 2010 |pmid=19888299 |pmc=2841708 |doi=10.1038/ejhg.2009.193 |url=}}</ref>
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| =====Blue rubber bleb nevus (Bean) syndrome VM=====
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| * Also called Bean's syndrome and diffuse angiomatosis, venous malformations in this disorder involve the skin, oral cavity and internal organs, most typically the gastrointestinal tract. Cutaneous malformations are bluish in color, generally smaller than 1-2 cm, often hyperkeratotic, compressible and often found at palms and soles. Anomalies on the skin are usually asymptomatic but GI malformations can cause hemorrhage that can lead to anemia, most frequent presentation in patient population. Other manifestation can include GI infarction, telescoping or twisting of GI tract leading to intussusception and volvulus.<ref name="pmid29515720">{{cite journal |vauthors=El Bakkaly A, Ettayebi F, Oubeja H, Erraji M, Zerhouni H |title=[Bean's syndrome in children: about two cases] |language=French |journal=Pan Afr Med J |volume=28 |issue= |pages=102 |date=2017 |pmid=29515720 |pmc=5837144 |doi=10.11604/pamj.2017.28.102.11109 |url=}}</ref><ref name="pmid27519652">{{cite journal |vauthors=Soblet J, Kangas J, Nätynki M, Mendola A, Helaers R, Uebelhoer M, Kaakinen M, Cordisco M, Dompmartin A, Enjolras O, Holden S, Irvine AD, Kangesu L, Léauté-Labrèze C, Lanoel A, Lokmic Z, Maas S, McAleer MA, Penington A, Rieu P, Syed S, van der Vleuten C, Watson R, Fishman SJ, Mulliken JB, Eklund L, Limaye N, Boon LM, Vikkula M |title=Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations |journal=J. Invest. Dermatol. |volume=137 |issue=1 |pages=207–216 |date=January 2017 |pmid=27519652 |doi=10.1016/j.jid.2016.07.034 |url=}}</ref><ref name="pmid23272612">{{cite journal |vauthors=Akutko K, Krzesiek E, Iwańczak B |title=[Blue rubber bleb naevus syndrome] |language=Polish |journal=Pol. Merkur. Lekarski |volume=33 |issue=196 |pages=226–8 |date=October 2012 |pmid=23272612 |doi= |url=}}</ref>
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| * Thought to be caused by somatic double (cis) muatations in TEK gene although autosomal-dominant inheritance has also been described in some cases. The gene that encodes TIE2, receptor tyrosine kinase involved in cell-signaling.<ref name="pmid24003209">{{cite journal |vauthors=Jeltsch M, Leppänen VM, Saharinen P, Alitalo K |title=Receptor tyrosine kinase-mediated angiogenesis |journal=Cold Spring Harb Perspect Biol |volume=5 |issue=9 |pages= |date=September 2013 |pmid=24003209 |pmc=3753715 |doi=10.1101/cshperspect.a009183 |url=}}</ref><ref name="pmid23272612">{{cite journal |vauthors=Akutko K, Krzesiek E, Iwańczak B |title=[Blue rubber bleb naevus syndrome] |language=Polish |journal=Pol. Merkur. Lekarski |volume=33 |issue=196 |pages=226–8 |date=October 2012 |pmid=23272612 |doi= |url=}}</ref><ref name="pmid29537205">{{cite journal |vauthors=Gawlikowska-Sroka A, Glura B, Mokrzycka M, Ociepa T |title=[Bean Syndrome (blue rubber bleb nevus syndrome)] |language=Polish |journal=Pomeranian J Life Sci |volume=62 |issue=2 |pages=5–7 |date=2016 |pmid=29537205 |doi= |url=}}</ref><ref name="pmid27519652">{{cite journal |vauthors=Soblet J, Kangas J, Nätynki M, Mendola A, Helaers R, Uebelhoer M, Kaakinen M, Cordisco M, Dompmartin A, Enjolras O, Holden S, Irvine AD, Kangesu L, Léauté-Labrèze C, Lanoel A, Lokmic Z, Maas S, McAleer MA, Penington A, Rieu P, Syed S, van der Vleuten C, Watson R, Fishman SJ, Mulliken JB, Eklund L, Limaye N, Boon LM, Vikkula M |title=Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations |journal=J. Invest. Dermatol. |volume=137 |issue=1 |pages=207–216 |date=January 2017 |pmid=27519652 |doi=10.1016/j.jid.2016.07.034 |url=}}</ref>
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| * The documentation of gastrointestinal lesions by endoscopy, colonoscopy, CT scan or MRI is considered pathognomonic. Sclerotherapy and surgery such as enterotomy remain the mainstay of treatment along with symptomatic management such as long term iron supplementation and/or blood transfusions.<ref name="pmid27519652">{{cite journal |vauthors=Soblet J, Kangas J, Nätynki M, Mendola A, Helaers R, Uebelhoer M, Kaakinen M, Cordisco M, Dompmartin A, Enjolras O, Holden S, Irvine AD, Kangesu L, Léauté-Labrèze C, Lanoel A, Lokmic Z, Maas S, McAleer MA, Penington A, Rieu P, Syed S, van der Vleuten C, Watson R, Fishman SJ, Mulliken JB, Eklund L, Limaye N, Boon LM, Vikkula M |title=Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations |journal=J. Invest. Dermatol. |volume=137 |issue=1 |pages=207–216 |date=January 2017 |pmid=27519652 |doi=10.1016/j.jid.2016.07.034 |url=}}</ref><ref name="pmid29515720">{{cite journal |vauthors=El Bakkaly A, Ettayebi F, Oubeja H, Erraji M, Zerhouni H |title=[Bean's syndrome in children: about two cases] |language=French |journal=Pan Afr Med J |volume=28 |issue= |pages=102 |date=2017 |pmid=29515720 |pmc=5837144 |doi=10.11604/pamj.2017.28.102.11109 |url=}}</ref><ref name="pmid24133559">{{cite journal |vauthors=Lindsey SF, Reiders B, Mechaber HF |title=Life-threatening pharyngeal edema after sclerotherapy of oral venous malformations in a patient with blue rubber bleb nevus syndrome |journal=J Dermatol Case Rep |volume=7 |issue=3 |pages=74–6 |date=2013 |pmid=24133559 |pmc=3797012 |doi=10.3315/jdcr.2013.1145 |url=}}</ref>
| |
| =====Glomuvenous malformation (GVM)=====
| |
| * Defined by presence of glomus cells in in smooth muscle layer of the vessels, these mesynchymal vascular anomaly arises from glomus bodies, arteriovenous anastomosis that help regulate temperature via shunting of blood through its unique neuromyoarterial structure. Classically found in digits, they can occur anywhere but widespread lesions are not common. Clinical presentation varies from asymptomatic bluish to reddish plaques and nodules that are often partially compressible and are tender to painful disfiguring lesions.<ref name="pmid28683898">{{cite journal |vauthors=Wortsman X, Millard F, Aranibar L |title=Color Doppler Ultrasound Study of Glomuvenous Malformations with its Clinical and Histologic Correlations |journal=Actas Dermosifiliogr |volume=109 |issue=3 |pages=e17–e21 |date=April 2018 |pmid=28683898 |doi=10.1016/j.ad.2017.04.013 |url=}}</ref><ref name="pmid28163461">{{cite journal |vauthors=Jha A, Khunger N, Malarvizhi K, Ramesh V, Singh A |title=Familial Disseminated Cutaneous Glomuvenous Malformation: Treatment with Polidocanol Sclerotherapy |journal=J Cutan Aesthet Surg |volume=9 |issue=4 |pages=266–269 |date=2016 |pmid=28163461 |pmc=5227083 |doi=10.4103/0974-2077.197083 |url=}}</ref><ref name="pmid27065433">{{cite journal |vauthors=Whipple KM, Godfrey KJ, Solomon JP, Lin JH, Korn BS, Kikkawa DO |title=Glomuvenous Malformation: A Rare Periorbital Lesion of the Thermoregulatory Apparatus |journal=Ophthalmic Plast Reconstr Surg |volume=33 |issue=2 |pages=e36–e37 |date=2017 |pmid=27065433 |pmc=5118188 |doi=10.1097/IOP.0000000000000695 |url=}}</ref><ref name="pmid25382523">{{cite journal |vauthors=Jha A, Ramesh V, Singh A |title=Disseminated cutaneous glomuvenous malformation |journal=Indian J Dermatol Venereol Leprol |volume=80 |issue=6 |pages=556–8 |date=2014 |pmid=25382523 |doi=10.4103/0378-6323.144200 |url=}}</ref>
| |
| * Mutations in glomulin (GLMN) gene that leads to defective GLMN protein is thought to be the cause. GMLN protein binds Rbx1 and inhibits its E3 ubiquitin ligase activity. If GMLN is defective then it leads to increased activity of Rbx1 causing decreased levels of Fbw7 and thus increased levels of Cyclin E and c-Myc because Fbw7 facilitates the ubiquitination and degradation Cyclin E and c-Myc.Mutations are inherited in autosomal-dominant pattern with incomplete pattern and variable expression although sporadic cases have been reported.<ref name="pmid24345188">{{cite journal |vauthors=Borroni RG, Grassi S, Concardi M, Puccio I, Giordano C, Agozzino M, Caspani C, Grasso M, Diegoli M, Arbustini E |title=Glomuvenous malformations with smooth muscle and eccrine glands: unusual histopathologic features in a familial setting |journal=J. Cutan. Pathol. |volume=41 |issue=3 |pages=308–15 |date=March 2014 |pmid=24345188 |doi=10.1111/cup.12283 |url=}}</ref><ref name="pmid23801931">{{cite journal |vauthors=Brouillard P, Boon LM, Revencu N, Berg J, Dompmartin A, Dubois J, Garzon M, Holden S, Kangesu L, Labrèze C, Lynch SA, McKeown C, Meskauskas R, Quere I, Syed S, Vabres P, Wassef M, Mulliken JB, Vikkula M |title=Genotypes and phenotypes of 162 families with a glomulin mutation |journal=Mol Syndromol |volume=4 |issue=4 |pages=157–64 |date=April 2013 |pmid=23801931 |pmc=3666456 |doi=10.1159/000348675 |url=}}</ref><ref name="pmid22405651">{{cite journal |vauthors=Tron AE, Arai T, Duda DM, Kuwabara H, Olszewski JL, Fujiwara Y, Bahamon BN, Signoretti S, Schulman BA, DeCaprio JA |title=The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7 |journal=Mol. Cell |volume=46 |issue=1 |pages=67–78 |date=April 2012 |pmid=22405651 |pmc=3336104 |doi=10.1016/j.molcel.2012.02.005 |url=}}</ref><ref name="pmid15689436">{{cite journal |vauthors=Brouillard P, Ghassibé M, Penington A, Boon LM, Dompmartin A, Temple IK, Cordisco M, Adams D, Piette F, Harper JI, Syed S, Boralevi F, Taïeb A, Danda S, Baselga E, Enjolras O, Mulliken JB, Vikkula M |title=Four common glomulin mutations cause two thirds of glomuvenous malformations ("familial glomangiomas"): evidence for a founder effect |journal=J. Med. Genet. |volume=42 |issue=2 |pages=e13 |date=February 2005 |pmid=15689436 |pmc=1735996 |doi=10.1136/jmg.2004.024174 |url=}}</ref>
| |
| * Imaging such as MRI and CT scan and ultrasound can localize and define the extent of disease but definitive diagnosis requires biopsy following by histopathological studies demonstrating proliferation of glomus cells and venous malformations. Current treatment modalities include surgical excision and sclerotherapy although recurrence is common. Recently electron beam radiation and Nd:YAG laser have been used with success.<ref name="pmid28683898">{{cite journal |vauthors=Wortsman X, Millard F, Aranibar L |title=Color Doppler Ultrasound Study of Glomuvenous Malformations with its Clinical and Histologic Correlations |journal=Actas Dermosifiliogr |volume=109 |issue=3 |pages=e17–e21 |date=April 2018 |pmid=28683898 |doi=10.1016/j.ad.2017.04.013 |url=}}</ref><ref name="pmid28163461">{{cite journal |vauthors=Jha A, Khunger N, Malarvizhi K, Ramesh V, Singh A |title=Familial Disseminated Cutaneous Glomuvenous Malformation: Treatment with Polidocanol Sclerotherapy |journal=J Cutan Aesthet Surg |volume=9 |issue=4 |pages=266–269 |date=2016 |pmid=28163461 |pmc=5227083 |doi=10.4103/0974-2077.197083 |url=}}</ref><ref name="pmid27065433">{{cite journal |vauthors=Whipple KM, Godfrey KJ, Solomon JP, Lin JH, Korn BS, Kikkawa DO |title=Glomuvenous Malformation: A Rare Periorbital Lesion of the Thermoregulatory Apparatus |journal=Ophthalmic Plast Reconstr Surg |volume=33 |issue=2 |pages=e36–e37 |date=2017 |pmid=27065433 |pmc=5118188 |doi=10.1097/IOP.0000000000000695 |url=}}</ref><ref name="pmid26177926">{{cite journal |vauthors=Rivers JK, Rivers CA, Li MK, Martinka M |title=Laser Therapy for an Acquired Glomuvenous Malformation (Glomus Tumour): A Nonsurgical Approach |journal=J Cutan Med Surg |volume=20 |issue=1 |pages=80–3 |date=January 2016 |pmid=26177926 |doi=10.1177/1203475415596121 |url=}}</ref><ref name="pmid25933083">{{cite journal |vauthors=Phillips CB, Guerrero C, Theos A |title=Nd:YAG laser offers promising treatment option for familial glomuvenous malformation |journal=Dermatol. Online J. |volume=21 |issue=4 |pages= |date=April 2015 |pmid=25933083 |doi= |url=}}</ref><ref name="pmid24996811">{{cite journal |vauthors=Flors L, Norton PT, Hagspiel KD |title=Glomuvenous malformation: magnetic resonance imaging findings |journal=Pediatr Radiol |volume=45 |issue=2 |pages=286–90 |date=February 2015 |pmid=24996811 |doi=10.1007/s00247-014-3086-x |url=}}</ref><ref name="pmid17511950">{{cite journal |vauthors=Henning JS, Kovich OI, Schaffer JV |title=Glomuvenous malformations |journal=Dermatol. Online J. |volume=13 |issue=1 |pages=17 |date=January 2007 |pmid=17511950 |doi= |url=}}</ref>
| |
| =====Cerebral cavernous malformation (CCM)=====
| |
| * Characterized by clusters of malformed endothelial channels forming densely arranged sinusoids that possess little to no intervening brain tissues. Because they lack smooth muscles and connective tissue and are malformed, they are prone to leakage causing micro-hemorrhages and thrombosis leading to hemosiderin deposits and gliosis around them. They can remain asymptomatic throughout life making them incidental finding but can cause symptoms associated with hemorrhage and pressure effects such as headaches, seizures, stroke, and focal neurologic deficits.<ref name="pmid24481819">{{cite journal |vauthors=Draheim KM, Fisher OS, Boggon TJ, Calderwood DA |title=Cerebral cavernous malformation proteins at a glance |journal=J. Cell. Sci. |volume=127 |issue=Pt 4 |pages=701–7 |date=February 2014 |pmid=24481819 |pmc=3924200 |doi=10.1242/jcs.138388 |url=}}</ref><ref name="pmid30252265">{{cite journal |vauthors=Zyck S, Gould GC |title= |journal= |volume= |issue= |pages= |date= |pmid=30252265 |doi= |url=}}</ref><ref name="pmid25896717">{{cite journal |vauthors=Trapani E, Retta SF |title=Cerebral cavernous malformation (CCM) disease: from monogenic forms to genetic susceptibility factors |journal=J Neurosurg Sci |volume=59 |issue=3 |pages=201–9 |date=September 2015 |pmid=25896717 |doi= |url=}}</ref>
| |
| * Mutations in CCM1 Krev interaction trapped protein 1 (KRIT1), CCM2 Malcavernin, and CCM3 Programmed cell death protein 10 (PDCD10) are thought to be the cause of familial cases that tend to be inherited in autosomal-dominant pattern with incomplete penetrance, and variable expression. These proteins interact with cytoskeleton and endothelial tight junctions during vascular development in neural tissues to help maintain endothelial barrier function. they can occur due to sporadic mutations, usually presenting as single cavernous malformation while familial cases typically present as multiple cavernous malformations.<ref name="pmid24481819">{{cite journal |vauthors=Draheim KM, Fisher OS, Boggon TJ, Calderwood DA |title=Cerebral cavernous malformation proteins at a glance |journal=J. Cell. Sci. |volume=127 |issue=Pt 4 |pages=701–7 |date=February 2014 |pmid=24481819 |pmc=3924200 |doi=10.1242/jcs.138388 |url=}}</ref><ref name="pmid30252265">{{cite journal |vauthors=Zyck S, Gould GC |title= |journal= |volume= |issue= |pages= |date= |pmid=30252265 |doi= |url=}}</ref><ref name="pmid30252535">{{cite journal |vauthors=Wang Y, Li Y, Zou J, Polster SP, Lightle R, Moore T, Dimaano M, He TC, Weber CR, Awad IA, Shen L |title=The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation |journal=FASEB J. |volume= |issue= |pages=fj201800343R |date=September 2018 |pmid=30252535 |doi=10.1096/fj.201800343R |url=}}</ref><ref name="pmid30161288">{{cite journal |vauthors=Nardella G, Visci G, Guarnieri V, Castellana S, Biagini T, Bisceglia L, Palumbo O, Trivisano M, Vaira C, Scerrati M, Debrasi D, D'Angelo V, Carella M, Merla G, Mazza T, Castori M, D'Agruma L, Fusco C |title=A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion |journal=Hum. Mutat. |volume= |issue= |pages= |date=August 2018 |pmid=30161288 |doi=10.1002/humu.23629 |url=}}</ref>
| |
| * Magnetic resonance (MR) imaging techniques are diagnostic modality of choice. Current treatment options depend on clinical history and location of the malformations. Surgery is usually preferred for symptomatic lesions in easily accessible locations and by some, for refractory epilepsy. If asymptomatic, observation is recommended but in case of single accessible asymptomatic malformation, surgical resection can be done. Surgery is also not recommended for malformations located in brain-stem due to significant mortality and morbidity associated with surgery while some recommend surgery after a second symptomatic bleed. Guidelines for symptomatic lesions located deep vary. Radiosurgery can be an alternative modality for single, symptomatic lesion if risks associated with surgery are unacceptable.<ref name="pmid30252265">{{cite journal |vauthors=Zyck S, Gould GC |title= |journal= |volume= |issue= |pages= |date= |pmid=30252265 |doi= |url=}}</ref><ref name="pmid25629087">{{cite journal |vauthors=Mouchtouris N, Chalouhi N, Chitale A, Starke RM, Tjoumakaris SI, Rosenwasser RH, Jabbour PM |title=Management of cerebral cavernous malformations: from diagnosis to treatment |journal=ScientificWorldJournal |volume=2015 |issue= |pages=808314 |date=2015 |pmid=25629087 |pmc=4300037 |doi=10.1155/2015/808314 |url=}}</ref><ref name="pmid26923303">{{cite journal |vauthors=Kim J |title=Introduction to cerebral cavernous malformation: a brief review |journal=BMB Rep |volume=49 |issue=5 |pages=255–62 |date=May 2016 |pmid=26923303 |pmc=5070704 |doi= |url=}}</ref><ref name="pmid15987569">{{cite journal |vauthors=Wurm G, Schnizer M, Fellner FA |title=Cerebral cavernous malformations associated with venous anomalies: surgical considerations |journal=Neurosurgery |volume=57 |issue=1 Suppl |pages=42–58; discussion 42–58 |date=July 2005 |pmid=15987569 |doi= |url=}}</ref><ref name="pmid20809765">{{cite journal |vauthors=Washington CW, McCoy KE, Zipfel GJ |title=Update on the natural history of cavernous malformations and factors predicting aggressive clinical presentation |journal=Neurosurg Focus |volume=29 |issue=3 |pages=E7 |date=September 2010 |pmid=20809765 |doi=10.3171/2010.5.FOCUS10149 |url=}}</ref>
| |
| =====Familial intraosseous vascular malformation (VMOS)=====
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| * Described as enlargement and expansion of malformed blood vessels that is severe and progressive, typically in skull, face, and vertebral column. Another typical finding is mid-line abnormalities such as diastasis recti, supraumbilical raphe, and hiatus hernia. Clinical presentation can vary but increasing intracranial pressure and hemorrhage after any surgical procedure such as extraction of tooth are of major concern. Other common findings include pain, enlarging tissues such as expanding jaw, bluish mass/swelling, loose tooth, spontaneous bleeding, and ulceration.<ref name="pmid27476657">{{cite journal |vauthors=Cetinkaya A, Xiong JR, Vargel İ, Kösemehmetoğlu K, Canter Hİ, Gerdan ÖF, Longo N, Alzahrani A, Camps MP, Taskiran EZ, Laupheimer S, Botto LD, Paramalingam E, Gormez Z, Uz E, Yuksel B, Ruacan Ş, Sağıroğlu MŞ, Takahashi T, Reversade B, Akarsu NA |title=Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling |journal=Am. J. Hum. Genet. |volume=99 |issue=2 |pages=299–317 |date=August 2016 |pmid=27476657 |pmc=4974086 |doi=10.1016/j.ajhg.2016.06.008 |url=}}</ref><ref name="pmid11932989">{{cite journal |vauthors=Vargel I, Cil BE, Er N, Ruacan S, Akarsu AN, Erk Y |title=Hereditary intraosseous vascular malformation of the craniofacial region: an apparently novel disorder |journal=Am. J. Med. Genet. |volume=109 |issue=1 |pages=22–35 |date=April 2002 |pmid=11932989 |doi= |url=}}</ref><ref name="pmid24701461">{{cite journal |vauthors=Handa H, Naidu GS, Dara BG, Deshpande A, Raghavendra R |title=Diverse imaging characteristics of a mandibular intraosseous vascular lesion |journal=Imaging Sci Dent |volume=44 |issue=1 |pages=67–73 |date=March 2014 |pmid=24701461 |pmc=3972408 |doi=10.5624/isd.2014.44.1.67 |url=}}</ref>
| |
| * Mutations in ELMO2 gene encoding engulfment and cell motility protein 2 (ELMO2) are thought to be the cause of these malformations. This protein s involved cell-signaling cascade through its attachment to cell membrane. Majority of the cases are sporadic but recently some familial cases with autosomal-recessive inheritance have been described.<ref name="pmid27476657">{{cite journal |vauthors=Cetinkaya A, Xiong JR, Vargel İ, Kösemehmetoğlu K, Canter Hİ, Gerdan ÖF, Longo N, Alzahrani A, Camps MP, Taskiran EZ, Laupheimer S, Botto LD, Paramalingam E, Gormez Z, Uz E, Yuksel B, Ruacan Ş, Sağıroğlu MŞ, Takahashi T, Reversade B, Akarsu NA |title=Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling |journal=Am. J. Hum. Genet. |volume=99 |issue=2 |pages=299–317 |date=August 2016 |pmid=27476657 |pmc=4974086 |doi=10.1016/j.ajhg.2016.06.008 |url=}}</ref><ref name="pmid27539661">{{cite journal |vauthors=Peotter JL, Phillips J, Tong T, Dimeo K, Gonzalez JM, Peters DM |title=Involvement of Tiam1, RhoG and ELMO2/ILK in Rac1-mediated phagocytosis in human trabecular meshwork cells |journal=Exp. Cell Res. |volume=347 |issue=2 |pages=301–11 |date=October 2016 |pmid=27539661 |pmc=5333770 |doi=10.1016/j.yexcr.2016.08.009 |url=}}</ref>
| |
| * CT angiography and magnetic resonance techniques are the preferred diagnostic modalities and may show widening of neurovascular canal on CTA, hyperintense signal on MRI. Honeycomb and sunburst radiographic appearances have been described as well. Management options include embolization, sclerotherapy, and surgical extirpation.<ref name="pmid27476657">{{cite journal |vauthors=Cetinkaya A, Xiong JR, Vargel İ, Kösemehmetoğlu K, Canter Hİ, Gerdan ÖF, Longo N, Alzahrani A, Camps MP, Taskiran EZ, Laupheimer S, Botto LD, Paramalingam E, Gormez Z, Uz E, Yuksel B, Ruacan Ş, Sağıroğlu MŞ, Takahashi T, Reversade B, Akarsu NA |title=Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling |journal=Am. J. Hum. Genet. |volume=99 |issue=2 |pages=299–317 |date=August 2016 |pmid=27476657 |pmc=4974086 |doi=10.1016/j.ajhg.2016.06.008 |url=}}</ref><ref name="pmid24701461">{{cite journal |vauthors=Handa H, Naidu GS, Dara BG, Deshpande A, Raghavendra R |title=Diverse imaging characteristics of a mandibular intraosseous vascular lesion |journal=Imaging Sci Dent |volume=44 |issue=1 |pages=67–73 |date=March 2014 |pmid=24701461 |pmc=3972408 |doi=10.5624/isd.2014.44.1.67 |url=}}</ref><ref name="pmid29670739">{{cite journal |vauthors=Cariati P, Marín-Fernández AB, Julia-Martínez MÁ, Pérez-de Perceval-Tara M, Sánchez-López D, Martínez-Lara I |title=Endovascular treatment of an intraosseous arteriovenous malformation of the mandible in a child. A case Report |journal=J Clin Exp Dent |volume=10 |issue=2 |pages=e189–e191 |date=February 2018 |pmid=29670739 |pmc=5899801 |doi=10.4317/jced.54550 |url=}}</ref>
| |
| =====Verrucous venous malformation=====
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| * Formerly verrucous hemangioma, this rare congenital malformation is characterized by dilated blood vessels reaching out from papillary layer of dermis into subcutaneous tissue. Earlier presentation is bluish lesion that develops warty surface later on. Painful enlarging mass is the typical complain in symptomatic patients.<ref name="pmid28761841">{{cite journal |vauthors=Singh J, Sharma P, Tandon S, Sinha S |title=Multiple Verrucous Hemangiomas: A Case Report with New Therapeutic Insight |journal=Indian Dermatol Online J |volume=8 |issue=4 |pages=254–256 |date=2017 |pmid=28761841 |pmc=5518576 |doi=10.4103/idoj.IDOJ_313_16 |url=}}</ref><ref name="pmid30156622">{{cite journal |vauthors=Oppermann K, Boff AL, Bonamigo RR |title=Verrucous hemangioma and histopathological differential diagnosis with angiokeratoma circumscriptum neviforme |journal=An Bras Dermatol |volume=93 |issue=5 |pages=712–715 |date=2018 |pmid=30156622 |pmc=6106676 |doi=10.1590/abd1806-4841.20187259 |url=}}</ref>
| |
| * Somatic mutation in MAP3K3 mitogen-activated protein kinase kinase kinase 3 are thought to be the cause.<ref name="pmid25728774">{{cite journal |vauthors=Couto JA, Vivero MP, Kozakewich HP, Taghinia AH, Mulliken JB, Warman ML, Greene AK |title=A somatic MAP3K3 mutation is associated with verrucous venous malformation |journal=Am. J. Hum. Genet. |volume=96 |issue=3 |pages=480–6 |date=March 2015 |pmid=25728774 |pmc=4375628 |doi=10.1016/j.ajhg.2015.01.007 |url=}}</ref>
| |
| * MRI is the diagnostic modality of choice but histopathological confirmation is gold standard for accurate diagnosis because of its close resemblance with angiokeratoma. Superficial ablation, surgical excision are treatment choices. Recently sirolimus has been used in some studies.<ref name="pmid28761841">{{cite journal |vauthors=Singh J, Sharma P, Tandon S, Sinha S |title=Multiple Verrucous Hemangiomas: A Case Report with New Therapeutic Insight |journal=Indian Dermatol Online J |volume=8 |issue=4 |pages=254–256 |date=2017 |pmid=28761841 |pmc=5518576 |doi=10.4103/idoj.IDOJ_313_16 |url=}}</ref><ref name="pmid30156622">{{cite journal |vauthors=Oppermann K, Boff AL, Bonamigo RR |title=Verrucous hemangioma and histopathological differential diagnosis with angiokeratoma circumscriptum neviforme |journal=An Bras Dermatol |volume=93 |issue=5 |pages=712–715 |date=2018 |pmid=30156622 |pmc=6106676 |doi=10.1590/abd1806-4841.20187259 |url=}}</ref><ref name="pmid30048660">{{cite journal |vauthors=Zhang G, Chen H, Zhen Z, Chen J, Zhang S, Qin Q, Liu X |title=Sirolimus for treatment of verrucous venous malformation: A retrospective cohort study |journal=J. Am. Acad. Dermatol. |volume= |issue= |pages= |date=July 2018 |pmid=30048660 |doi=10.1016/j.jaad.2018.07.014 |url=}}</ref>
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| ==Medical Therapy==
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| ==Naural History==
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| ==Historical Perspective==
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| ==References==
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