Vascular malformation: Difference between revisions

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Revision as of 15:24, 4 October 2018

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Vascular malformation is a blood vessel abnormality. There are many types, but the most common is arteriovenous malformation.^[1] It may cause aesthetic problems as it has a growth cycle and can continue to grow throughout life. This is also known as Vascular giantism or lymphangiomas.

Vascular malformations

Simple vascular malformations

Capillary malformations (CM)

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.^[2]
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.^[3] 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.^[2]

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.^[4] 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.^[5] 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.^[5]
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.^[6]
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.^[7]
To learn more about PWS click here.

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.^[8]
These are found in Capillary malformation-arteriovenous malformation syndrome, an autosomal dominant syndrome associated with mutations in RASA1.^[9]

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. ^[10] ^[11]
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. ^[12]
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.^[13] Most cases tend be sporadic but autosomal recessive pattern has been observed in familial cases.^[14]
Diagnosis is clinical and depends on history and examination. Management depends on the systemic involvement. Skin lesions tend to improve spontaneously.^[15]^[16]

Telangiectasia

"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."^[17] To learn about Hereditary hemorrhagic telangiectasia (HHT) click here.

Lymphatic malformations (LM)

Common (cystic) LM

benign lesions consisting of dilated lymphatic channels or cysts lined by cells of endothelial origin with lymphatic differentiation.^[18] If these lesions are associated with overgrowth then some of these lesions belong to the PIK3CA-related overgrowth spectrum. ^[19]
These are classified as follows:
- Macrocystic LM
- Microcystic LM
- Mixed cystic LM
1. Macrocystic LM
  - 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.
  - May be associated with chromosomal abnormalities such as Down syndrome, Turner syndrome. To learn more click here.
2. Microcystic LM
  - 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.
  - Diagnosis is clinical and treatment options include surgery, sclerotherapy, radiotherapy, and laser therapy. Recently topical sirolimus has also been used.^[20] To learn more click here.

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.^[21]^[22] 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.^[23]
Considered to b sporadic and non-hereditary, it may present in childhood or can be diagnosed later in life.^[24]^[25] Etiology is unknown but high levels of VEGFR-3 have been reported in patient population.
Chylothorax due to leakage of lymphtic fluid is commonly encountered and is difficult to treat.^[26] 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.^[21]^[27]^[28]^[25]
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.^[21]^[29]^[30] Sometimes surgery is required that can be both diagnostic and therapeutic.^[21]
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.^[21]
1. Kaposiform lymphangiomatosis (KLA)
  - A rare subtype with worse pronosis.^[31] Malformed vessels occur with cluster and sheets of spindle lymphatic endothelial cells.^[32] Consumptive coagulopathy is also a feature.^[33]
  - Intra-thoracic component is often the cause of mortality.^[32] Currently there are no treatment guidelines.^[31]

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.^[34]^[35]^[36] 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^[36] The osteolysis is progressive in GSD as compared to non-progressive osteolysis in GLA.^[36]
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.^[37]
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.^[38]^[39]^[40] IL-6 has been found to be elevated in some patients.^[41]
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.^[42]^[43] The involvement of thorax and development of chylothorax indicate poor prognosis.^[43]
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.^[43]^[44] If disease affects neuro-vascular structures then surgery is indicated.^[45]^[46]

“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.^[47]^[48]^[49]^[50]
Excision is usually the treatment of choice but some other therapies such as Imiquimod 5% cream have been tried.^[51]^[52]

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.^[53]
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.^[53]
1. Nonne-Milroy syndrome
  - 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.^[54]^[55]^[56]^[57]
  - 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).^[56]^[57]^[55]
2. Primary hereditary lymphedema
  - 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.^[58]^[59]
  - 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.^[59]^[58]
3. Primary hereditary lymphedema
  - Edema typically first appears in legs and then progresses to involve the arms.^[60]
  - 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.^[60]^[61]
4. Lymphedema-distichiasis
  - 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.^[62]^[63]^[64]^[65]^[66]^[67]
  - Inherited in autosomal dominant pattern mutation in FOXC2 gene that encodes for transcription factors. Inheritance also shows variable expression.^[68]^[69]^[66]
  - 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.^[62]^[70]
5. Hypotrichosis-lymphedema-telangiectasia
  - 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.^[71]^[72]^[73]^[74]
  - 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.^[75]^[76]^[77]^[78]^[79]^[80]^[81]
  - There is no definitive treatment for this syndrome. Management is based on genetic counseling and symptomatic treatment.^[82]^[83]
6. Primary lymphedema with myelodysplasia
  - 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.^[84]^[85]^[86]^[87]
  - 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.^[84]^[85]^[86]^[88]^[89]^[87]
  - 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. ^[86]^[84]^[90]^[91]
7. Primary generalized lymphatic anomaly
  - 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.^[92]^[93]^[94]
  - 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.^[95]^[92]^[94]^[96]
  - 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.^[97]^[92]^[94]^[97]
8. Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome
  - 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.^[98]^[99]^[100]^[101]^[102]
  - 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.^[98]^[103]^[104]^[105]^[106]
  - Diagnosis requires genetic testing in addition to clinical findings. Long term cardiac and ophthalmologic follow-ups are recommended.^[101]^[106]
9. Lymphedema-choanal atresia
  - 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.^[107]
  - 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.^[107]

Venous malformations (VM)

Common VM

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.^[108]^[109]^[110]
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.^[108]^[109]^[110]
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.^[109]

Familial VM cutaneo-mucosal (VMCM)

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.^[111]
Associated with mutation in TEK/TIE2 receptor tyrosine kinase that plays critical role in development of vessels and cardiovascular system.^[111]^[112]

Blue rubber bleb nevus (Bean) syndrome VM

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.^[113]^[114]^[115]
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.^[116]^[115]^[117]^[114]
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.^[114]^[113]^[118]

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.^[119]^[120]^[121]^[122]
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.^[123]^[124]^[125]^[126]
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.^[119]^[120]^[121]^[127]^[128]^[129]^[130]

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.^[131]^[132]^[133]
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.^[131]^[132]^[134]^[135]
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.^[132]^[136]^[137]^[138]^[139]

Familial intraosseous vascular malformation (VMOS)

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.^[140]^[141]^[142]
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.^[140]^[143]
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.^[140]^[142]^[144]

Verrucous venous malformation

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.^[145]^[146]
Somatic mutation in MAP3K3 mitogen-activated protein kinase kinase kinase 3 are thought to be the cause.^[147]
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.^[145]^[146]^[148]

References

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↑ Lee JW, Chung HY (FebInvestigationsruary 2018). "Capillary Malformations (Portwine Stains) of the Head and Neck: Natural History, , Laser, and Surgical Management". Otolaryngol. Clin. North Am. 51 (1): 197–211. doi:10.1016/j.otc.2017.09.004. PMID 29217063. Check date values in: |date= (help)
↑ 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 (July 2008). "Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations". Hum. Mutat. 29 (7): 959–65. doi:10.1002/humu.20746. PMID 18446851.
↑ Thiex R, Mulliken JB, Revencu N, Boon LM, Burrows PE, Cordisco M, Dwight Y, Smith ER, Vikkula M, Orbach DB (April 2010). "A novel association between RASA1 mutations and spinal arteriovenous anomalies". AJNR Am J Neuroradiol. 31 (4): 775–9. doi:10.3174/ajnr.A1907. PMID 20007727.
↑ Amitai DB, Fichman S, Merlob P, Morad Y, Lapidoth M, Metzker A (2000). "Cutis marmorata telangiectatica congenita: clinical findings in 85 patients". Pediatr Dermatol. 17 (2): 100–4. PMID 10792796.
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↑ 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
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↑ 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 (April 2013). "Genotypes and phenotypes of 162 families with a glomulin mutation". Mol Syndromol. 4 (4): 157–64. doi:10.1159/000348675. PMC 3666456. PMID 23801931.
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↑ ^132.0 ^132.1 ^132.2 Zyck S, Gould GC. PMID 30252265. Missing or empty |title= (help)
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↑ Wang Y, Li Y, Zou J, Polster SP, Lightle R, Moore T, Dimaano M, He TC, Weber CR, Awad IA, Shen L (September 2018). "The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation". FASEB J.: fj201800343R. doi:10.1096/fj.201800343R. PMID 30252535.
↑ 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 (August 2018). "A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion". Hum. Mutat. doi:10.1002/humu.23629. PMID 30161288.
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↑ Vargel I, Cil BE, Er N, Ruacan S, Akarsu AN, Erk Y (April 2002). "Hereditary intraosseous vascular malformation of the craniofacial region: an apparently novel disorder". Am. J. Med. Genet. 109 (1): 22–35. PMID 11932989.
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↑ Couto JA, Vivero MP, Kozakewich HP, Taghinia AH, Mulliken JB, Warman ML, Greene AK (March 2015). "A somatic MAP3K3 mutation is associated with verrucous venous malformation". Am. J. Hum. Genet. 96 (3): 480–6. doi:10.1016/j.ajhg.2015.01.007. PMC 4375628. PMID 25728774.
↑ Zhang G, Chen H, Zhen Z, Chen J, Zhang S, Qin Q, Liu X (July 2018). "Sirolimus for treatment of verrucous venous malformation: A retrospective cohort study". J. Am. Acad. Dermatol. doi:10.1016/j.jaad.2018.07.014. PMID 30048660.

Template:Vascular diseases

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[urlVascular_Malformations_of_the_CNS-1] "Vascular Malformations of the CNS".

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@@ Line 20: / Line 20: @@
 '''Vascular malformation''' is a [[blood vessel]] [[vascular anomalies|abnormality]]. There are many types, but the most common is [[arteriovenous malformation]].<ref name="urlVascular Malformations of the CNS">{{cite web |url=http://rad.usuhs.mil/rad/home/vascmalf/malf0.html |title=Vascular Malformations of the CNS |work= |accessdate=}}</ref>
 It may cause aesthetic problems as it has a growth cycle and can continue to grow throughout life. This is also known as Vascular giantism or lymphangiomas.
+==Vascular malformations==
+===Simple vascular malformations===
+====Capillary malformations (CM)====
+=====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>
+=====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>
+* To learn more about PWS click here.
+=====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>
+=====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>
+* 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>
+* 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>
+=====Telangiectasia=====
+* "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.
+====Lymphatic malformations (LM)====
+=====Common (cystic) LM=====
+* 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>
+* These are classified as follows:
+** Macrocystic  LM
+** Microcystic  LM
+** Mixed cystic LM
+*# '''Macrocystic  LM'''
+*#* 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.
+*#* May be associated with chromosomal abnormalities such as Down syndrome, Turner syndrome. To learn more click here.
+*# '''Microcystic  LM'''
+*#* 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.
+*#* 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.
+=====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>
+* 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.
+* 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>
+* 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>
+* 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)'''
+*#* 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>
+*#* 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>
+=====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>
+* 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>
+* 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>
+* 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'''
+*#* 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>
+*#* 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>
+*# '''Primary hereditary lymphedema'''
+*#* 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>
+*#* 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>
+*# '''Primary hereditary lymphedema'''
+*#* 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>
+*#* 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>
+*# '''Lymphedema-distichiasis'''
+*#* 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>
+*#* 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>
+*#* 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>
+*# '''Hypotrichosis-lymphedema-telangiectasia'''
+*#* 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 &#124; 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>
+*#* 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 &#124; Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |format= |work= |accessdate=}}</ref>
+*#* 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 &#124; 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>
+*# '''Primary lymphedema with myelodysplasia'''
+*#* 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>
+*#* 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>
+*#* 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>
+*# '''Primary generalized lymphatic anomaly'''
+*#* 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>
+*#* 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>
+*#* 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>
+*# '''Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome'''
+*#* 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>
+*#* 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>
+*#* 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>
+*# '''Lymphedema-choanal atresia'''
+*#* 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>
+*#* 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>
+====Venous malformations (VM)====
+=====Common VM=====
+* 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>
+* 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>
+* 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>
+=====Familial VM cutaneo-mucosal (VMCM)=====
+* 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>
+* 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>
+=====Blue rubber bleb nevus (Bean) syndrome VM=====
+* 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>
+* 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>
+* 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)=====
+* 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=====
+* 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>
 ==See also==

v t e Congenital Vascular malformations / Vascular Defects (Q25-Q28, 747)
Great arteries/ other arteries	Template:Navbox subgroup
Great veins	Template:Navbox subgroup
Arteriovenous malformation	Cerebral arteriovenous malformation
See also non-congenital, neoplasia

Vascular malformation
Classification and external resources
MeSH	D054079