Lymphatic malformation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]

=Overview

Lymphatic Malformations (LM)

Common (cystic) LM
  • benign lesions consisting of dilated lymphatic channels or cysts lined by cells of endothelial origin with lymphatic differentiation.[1] If these lesions are associated with overgrowth then some of these lesions belong to the PIK3CA-related overgrowth spectrum. [2]
  • 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.[3] 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.[4][5] 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.[6]
  • Considered to b sporadic and non-hereditary, it may present in childhood or can be diagnosed later in life.[7][8] 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.[9] 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.[4][10][11][8]
  • 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.[4][12][13] Sometimes surgery is required that can be both diagnostic and therapeutic.[4]
  • 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.[4]
    1. Kaposiform lymphangiomatosis (KLA)
      • A rare subtype with worse pronosis.[14] Malformed vessels occur with cluster and sheets of spindle lymphatic endothelial cells.[15] Consumptive coagulopathy is also a feature.[16]
      • Intra-thoracic component is often the cause of mortality.[15] Currently there are no treatment guidelines.[14]
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.[17][18][19] 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[19] The osteolysis is progressive in GSD as compared to non-progressive osteolysis in GLA.[19]
  • 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.[20]
  • 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.[21][22][23] IL-6 has been found to be elevated in some patients.[24]
  • 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.[25][26] The involvement of thorax and development of chylothorax indicate poor prognosis.[26]
  • 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.[26][27] If disease affects neuro-vascular structures then surgery is indicated.[28][29]
“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.[30][31][32][33]
  • Excision is usually the treatment of choice but some other therapies such as Imiquimod 5% cream have been tried.[34][35]
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.[36]
  • 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.[36]
    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.[37][38][39][40]
      • 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).[39][40][38]
    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.[41][42]
      • 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.[42][41]
    3. Primary hereditary lymphedema
      • Edema typically first appears in legs and then progresses to involve the arms.[43]
      • 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.[43][44]
    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.[45][46][47][48][49][50]
      • Inherited in autosomal dominant pattern mutation in FOXC2 gene that encodes for transcription factors. Inheritance also shows variable expression.[51][52][49]
      • 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.[45][53]
    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.[54][55][56][57]
      • 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.[58][59][60][61][62][63][64]
      • There is no definitive treatment for this syndrome. Management is based on genetic counseling and symptomatic treatment.[65][66]
    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.[67][68][69][70]
      • 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.[67][68][69][71][72][70]
      • 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. [69][67][73][74]
    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.[75][76][77]
      • 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.[78][75][77][79]
      • 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.[80][75][77][80]
    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.[81][82][83][84][85]
      • 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.[81][86][87][88][89]
      • Diagnosis requires genetic testing in addition to clinical findings. Long term cardiac and ophthalmologic follow-ups are recommended.[84][89]
    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.[90]
      • 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.[90]

References

Template:Reflist2

  1. ↑ 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 (July 2015). "Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies". Pediatrics. 136 (1): e203–14. doi:10.1542/peds.2014-3673. PMID 26055853.
  2. ↑ http://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf
  3. ↑ Çalışkan E, Altunel CT, Özkan CK, Tunca M (August 2018). "A case of microcystic lymphatic malformation successfully treated with topical sirolimus". Dermatol Ther: e12673. doi:10.1111/dth.12673. PMID 30133999.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C (June 2018). "Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report". J Cardiothorac Surg. 13 (1): 59. doi:10.1186/s13019-018-0752-3. PMC 5989411. PMID 29871646.
  5. ↑ 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 (May 2018). "Somatic NRAS mutation in patient with generalized lymphatic anomaly". Angiogenesis. 21 (2): 287–298. doi:10.1007/s10456-018-9595-8. PMID 29397482.
  6. ↑ Levine C (March 1989). "Primary disorders of the lymphatic vessels--a unified concept". J. Pediatr. Surg. 24 (3): 233–40. PMID 2709285.
  7. ↑ Faul JL, Berry GJ, Colby TV, Ruoss SJ, Walter MB, Rosen GD, Raffin TA (March 2000). "Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome". Am. J. Respir. Crit. Care Med. 161 (3 Pt 1): 1037–46. doi:10.1164/ajrccm.161.3.9904056. PMID 10712360.
  8. ↑ 8.0 8.1 Kadakia KC, Patel SM, Yi ES, Limper AH (2013). "Diffuse pulmonary lymphangiomatosis". Can. Respir. J. 20 (1): 52–4. doi:10.1155/2013/971350. PMC 3628648. PMID 23457676.
  9. ↑ Ludwig KF, Slone T, Cederberg KB, Silva AT, Dellinger M (June 2016). "A New Case and Review of Chylothorax in Generalized Lymphatic Anomaly and Gorham-Stout Disease". Lymphology. 49 (2): 73–84. PMID 29906363.
  10. ↑ Aviv RI, McHugh K, Hunt J (March 2001). "Angiomatosis of bone and soft tissue: a spectrum of disease from diffuse lymphangiomatosis to vanishing bone disease in young patients". Clin Radiol. 56 (3): 184–90. doi:10.1053/crad.2000.0606. PMID 11247693.
  11. ↑ Satria MN, Pacheco-Rodriguez G, Moss J (2011). "Pulmonary lymphangiomatosis". Lymphat Res Biol. 9 (4): 191–3. doi:10.1089/lrb.2011.0023. PMC 3246407. PMID 22196284.
  12. ↑ Sevick-Muraca EM, Kwon S, Rasmussen JC (March 2014). "Emerging lymphatic imaging technologies for mouse and man". J. Clin. Invest. 124 (3): 905–14. doi:10.1172/JCI71612. PMC 3938259. PMID 24590275.
  13. ↑ Lohrmann C, Foeldi E, Langer M (November 2011). "Assessment of the lymphatic system in patients with diffuse lymphangiomatosis by magnetic resonance imaging". Eur J Radiol. 80 (2): 576–81. doi:10.1016/j.ejrad.2009.10.021. PMID 19913379.
  14. ↑ 14.0 14.1 Wang Z, Li K, Yao W, Dong K, Xiao X, Zheng S (July 2015). "Successful treatment of kaposiform lymphangiomatosis with sirolimus". Pediatr Blood Cancer. 62 (7): 1291–3. doi:10.1002/pbc.25422. PMID 25598153.
  15. ↑ 15.0 15.1 Croteau SE, Kozakewich HP, Perez-Atayde AR, Fishman SJ, Alomari AI, Chaudry G, Mulliken JB, Trenor CC (February 2014). "Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly". J. Pediatr. 164 (2): 383–8. doi:10.1016/j.jpeds.2013.10.013. PMC 3946828. PMID 24252784.
  16. ↑ Fernandes VM, Fargo JH, Saini S, Guerrera MF, Marcus L, Luchtman-Jones L, Adams D, Meier ER (May 2015). "Kaposiform lymphangiomatosis: unifying features of a heterogeneous disorder". Pediatr Blood Cancer. 62 (5): 901–4. doi:10.1002/pbc.25278. PMID 25307772.
  17. ↑ Klein M, Metelmann HR, Gross U (October 1996). "Massive osteolysis (Gorham-Stout syndrome) in the maxillofacial region: an unusual manifestation". Int J Oral Maxillofac Surg. 25 (5): 376–8. PMID 8961021.
  18. ↑ Radhakrishnan K, Rockson SG (2008). "The clinical spectrum of lymphatic disease". Ann. N. Y. Acad. Sci. 1131: 155–84. doi:10.1196/annals.1413.015. PMID 18519969.
  19. ↑ 19.0 19.1 19.2 Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G (July 2013). "Gorham-Stout disease and generalized lymphatic anomaly--clinical, radiologic, and histologic differentiation". Skeletal Radiol. 42 (7): 917–24. doi:10.1007/s00256-012-1565-4. PMID 23371338.
  20. ↑ Tanoue N, Moedano L, Witte M, Montague M, Lukefahr A, Bernas M (2018). "Primary versus trauma-induced Gorham-Stout disease". Lymphology. 51 (1): 18–27. PMID 30248728.
  21. ↑ Meijer-Jorna LB, van der Loos CM, de Boer OJ, van der Horst CM, van der Wal AC (July 2007). "Microvascular proliferation in congenital vascular malformations of skin and soft tissue". J. Clin. Pathol. 60 (7): 798–803. doi:10.1136/jcp.2006.038885. PMC 1995770. PMID 16816171.
  22. ↑ Radhakrishnan K, Rockson SG (2008). "Gorham's disease: an osseous disease of lymphangiogenesis?". Ann. N. Y. Acad. Sci. 1131: 203–5. doi:10.1196/annals.1413.022. PMID 18519972.
  23. ↑ 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 (December 2006). "Platelet-derived growth factor receptor-beta in Gorham's disease". Nat Clin Pract Oncol. 3 (12): 693–7. doi:10.1038/ncponc0660. PMC 2693369. PMID 17139320.
  24. ↑ Devlin RD, Bone HG, Roodman GD (May 1996). "Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease". J. Clin. Endocrinol. Metab. 81 (5): 1893–7. doi:10.1210/jcem.81.5.8626854. PMID 8626854.
  25. ↑ Garbers E, Reuther F, Delling G (2011). "Report of a rare case of gorham-stout disease of both shoulders: bisphosphonate treatment and shoulder replacement". Case Rep Rheumatol. 2011: 565142. doi:10.1155/2011/565142. PMC 3420766. PMID 22937447.
  26. ↑ 26.0 26.1 26.2 Duffy BM, Manon R, Patel RR, Welsh JS (May 2005). "A case of Gorham's disease with chylothorax treated curatively with radiation therapy". Clin Med Res. 3 (2): 83–6. PMC 1183437. PMID 16012125.
  27. ↑ Fontanesi J (October 2003). "Radiation therapy in the treatment of Gorham disease". J. Pediatr. Hematol. Oncol. 25 (10): 816–7. PMID 14528108.
  28. ↑ Mulvihill D, Kumar RS, Muzaffar J, Irving R (March 2018). "Gorham-Stout disease of the temporal bone involving the temporomandibular joint". J Laryngol Otol. 132 (3): 279–281. doi:10.1017/S0022215118000099. PMID 29363434.
  29. ↑ Noda M, Endo C, Hoshikawa Y, Ishibashi N, Suzuki T, Okada Y, Kondo T (June 2013). "Successful management of intractable chylothorax in Gorham-Stout disease by awake thoracoscopic surgery". Gen Thorac Cardiovasc Surg. 61 (6): 356–8. doi:10.1007/s11748-012-0130-3. PMID 22865280.
  30. ↑ Alkhalili E, Ayoubieh H, O'Brien W, Billings SD (September 2014). "Acquired progressive lymphangioma of the nipple". BMJ Case Rep. 2014. doi:10.1136/bcr-2014-205966. PMC 4173197. PMID 25246470.
  31. ↑ Messeguer F, Sanmartín O, Martorell-Calatayud A, Nagore E, Requena C, Guillén-Barona C (November 2010). "[Acquired progressive lymphangioma (benign lymphangioendothelioma)]". Actas Dermosifiliogr (in Spanish; Castilian). 101 (9): 792–7. PMID 21034710.
  32. ↑ Meunier L, Barneon G, Meynadier J (November 1994). "Acquired progressive lymphangioma". Br. J. Dermatol. 131 (5): 706–8. PMID 7999605.
  33. ↑ Paredes Esteban RM, Velasco Sánchez B, Martínez-Victoria Muñoz JM, Cuevas C, García Ruiz M (October 2000). "[Progressive acquired lymphangioma: report of a case and review of the literature]". Cir Pediatr (in Spanish; Castilian). 13 (4): 170–1. PMID 12601956.
  34. ↑ Larkin SC, Wentworth AB, Lehman JS, Tollefson MM (July 2018). "A case of extensive acquired progressive lymphangioma". Pediatr Dermatol. 35 (4): 486–489. doi:10.1111/pde.13486. PMID 29633311.
  35. ↑ Salman A, Sarac G, Can Kuru B, Cinel L, Yucelten AD, Ergun T (November 2017). "Acquired progressive lymphangioma: Case report with partial response to imiquimod 5% cream". Pediatr Dermatol. 34 (6): e302–e304. doi:10.1111/pde.13283. PMID 28940760.
  36. ↑ 36.0 36.1 Szuba A, Rockson SG (1998). "Lymphedema: classification, diagnosis and therapy". Vasc Med. 3 (2): 145–56. doi:10.1177/1358836X9800300209. PMID 9796078.
  37. ↑ Lev-Sagie A, Hamani Y, Raas-Rothschild A, Yagel S, Anteby EY (January 2003). "Prenatal ultrasonographic diagnosis of atypical Nonne-Milroy lymphedema". Ultrasound Obstet Gynecol. 21 (1): 72–4. doi:10.1002/uog.16. PMID 12528167.
  38. ↑ 38.0 38.1 Zbranca V, Aramă A, Mihăescu T, Covic M (1990). "[Hereditary lymphedema (Nonne-Milroy-Meige syndrome) associated with chylothorax. Comments on 2 cases]". Rev Med Chir Soc Med Nat Iasi (in Romanian). 94 (1): 189–92. PMID 2075326.
  39. ↑ 39.0 39.1 "Milroy disease - Genetics Home Reference - NIH".
  40. ↑ 40.0 40.1 Spiegel R, Ghalamkarpour A, Daniel-Spiegel E, Vikkula M, Shalev SA (2006). "Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3". J. Hum. Genet. 51 (10): 846–50. doi:10.1007/s10038-006-0031-3. PMID 16924388.
  41. ↑ 41.0 41.1 Nadarajah N, Schulte D, McConnell V, Martin-Almedina S, Karapouliou C, Mortimer PS, Jeffery S, Schulte-Merker S, Gordon K, Mansour S, Ostergaard P (August 2018). "A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon". Int J Mol Sci. 19 (8). doi:10.3390/ijms19082259. PMC 6121331. PMID 30071673.
  42. ↑ 42.0 42.1 "VEGFC gene - Genetics Home Reference - NIH".
  43. ↑ 43.0 43.1 "GJC2 gene - Genetics Home Reference - NIH".
  44. ↑ Brice G, Ostergaard P, Jeffery S, Gordon K, Mortimer PS, Mansour S (October 2013). "A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family". Clin. Genet. 84 (4): 378–81. doi:10.1111/cge.12158. PMID 23550541.
  45. ↑ 45.0 45.1 Marques NS, Miranda A, Barros S, Parreira S (January 2016). "Lymphoedema-distichiasis syndrome". BMJ Case Rep. 2016. doi:10.1136/bcr-2015-213651. PMC 4716369. PMID 26759405.
  46. ↑ Yabuki S, Kikuchi S, Ikegawa S (April 2007). "Spinal extradural arachnoid cysts associated with distichiasis and lymphedema". Am. J. Med. Genet. A. 143A (8): 884–7. doi:10.1002/ajmg.a.31669. PMID 17366583.
  47. ↑ Brice G, Mansour S, Bell R, Collin JR, Child AH, Brady AF, Sarfarazi M, Burnand KG, Jeffery S, Mortimer P, Murday VA (July 2002). "Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24". J. Med. Genet. 39 (7): 478–83. PMC 1735188. PMID 12114478.
  48. ↑ Sardesai VR, Mhatre MA, Patil RM (2012). "Lymphoedema - distichiasis syndrome with recurrent abortions". Indian J Med Sci. 66 (5–6): 141–3. doi:10.4103/0019-5359.114202. PMID 23806988.
  49. ↑ 49.0 49.1 Planinsek Rucigaj T, Rijavec M, Miljkovic J, Selb J, Korosec P (September 2017). "A Novel Mutation in the FOXC2 Gene: A Heterozygous Insertion of Adenosine (c.867insA) in a Family with Lymphoedema of Lower Limbs without Distichiasis". Radiol Oncol. 51 (3): 363–368. doi:10.1515/raon-2017-0026. PMC 5612002. PMID 28959174.
  50. ↑ De Niear MA, Breazzano MP, Mawn LA (2018). "Novel FOXC2 Mutation and Distichiasis in a Patient With Lymphedema-Distichiasis Syndrome". Ophthalmic Plast Reconstr Surg. 34 (3): e88–e90. doi:10.1097/IOP.0000000000001079. PMID 29406328.
  51. ↑ Zhu LL, Lv YN, Chen HD, Gao XH (August 2014). "A Chinese pedigree of lymphoedema-distichiasis syndrome with a novel mutation in the FOXC2 gene". Clin. Exp. Dermatol. 39 (6): 731–3. doi:10.1111/ced.12389. PMID 24984567.
  52. ↑ Zhang L, He J, Han B, Lu L, Fan J, Zhang H, Ge S, Zhou Y, Jia R, Fan X (2016). "Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation". Int. J. Biol. Sci. 12 (9): 1114–20. doi:10.7150/ijbs.13774. PMC 4997055. PMID 27570485.
  53. ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Mansour S, Brice GW, Jeffery S, Mortimer P. PMID 20301630. Vancouver style error: initials (help); Missing or empty |title= (help)
  54. ↑ "Hypotrichosis-lymphedema-telangiectasia syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program".
  55. ↑ Wünnemann F, Kokta V, Leclerc S, Thibeault M, McCuaig C, Hatami A, Stheneur C, Grenier JC, Awadalla P, Mitchell GA, Andelfinger G, Preuss C (January 2016). "Aortic Dilatation Associated With a De Novo Mutation in the SOX18 Gene: Expanding the Clinical Spectrum of Hypotrichosis-Lymphedema-Telangiectasia Syndrome". Can J Cardiol. 32 (1): 135.e1–7. doi:10.1016/j.cjca.2015.04.004. PMID 26148450.
  56. ↑ Moalem S, Brouillard P, Kuypers D, Legius E, Harvey E, Taylor G, Francois M, Vikkula M, Chitayat D (April 2015). "Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene". Clin. Genet. 87 (4): 378–82. doi:10.1111/cge.12388. PMID 24697860.
  57. ↑ Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M (June 2003). "Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia". Am. J. Hum. Genet. 72 (6): 1470–8. doi:10.1086/375614. PMC 1180307. PMID 12740761.
  58. ↑ Valenzuela I, Fernández-Alvarez P, Plaja A, Ariceta G, Sabaté-Rotés A, García-Arumí E, Vendrell T, Tizzano E (May 2018). "Further delineation of the SOX18-related Hypotrichosis, Lymphedema, Telangiectasia syndrome (HTLS)". Eur J Med Genet. 61 (5): 269–272. doi:10.1016/j.ejmg.2018.01.001. PMID 29307792.
  59. ↑ Bastaki F, Mohamed M, Nair P, Saif F, Tawfiq N, Al-Ali MT, Brandau O, Hamzeh AR (February 2016). "A novel SOX18 mutation uncovered in Jordanian patient with hypotrichosis-lymphedema-telangiectasia syndrome by Whole Exome Sequencing". Mol. Cell. Probes. 30 (1): 18–21. doi:10.1016/j.mcp.2015.11.005. PMID 26631803.
  60. ↑ Wünnemann F, Kokta V, Leclerc S, Thibeault M, McCuaig C, Hatami A, Stheneur C, Grenier JC, Awadalla P, Mitchell GA, Andelfinger G, Preuss C (January 2016). "Aortic Dilatation Associated With a De Novo Mutation in the SOX18 Gene: Expanding the Clinical Spectrum of Hypotrichosis-Lymphedema-Telangiectasia Syndrome". Can J Cardiol. 32 (1): 135.e1–7. doi:10.1016/j.cjca.2015.04.004. PMID 26148450.
  61. ↑ Moalem S, Brouillard P, Kuypers D, Legius E, Harvey E, Taylor G, Francois M, Vikkula M, Chitayat D (April 2015). "Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene". Clin. Genet. 87 (4): 378–82. doi:10.1111/cge.12388. PMID 24697860.Downes M, François M, Ferguson C, Parton RG, Koopman P (August 2009). "Vascular defects in a mouse model of hypotrichosis-lymphedema-telangiectasia syndrome indicate a role for SOX18 in blood vessel maturation". Hum. Mol. Genet. 18 (15): 2839–50. doi:10.1093/hmg/ddp219. PMID 19429912.
  62. ↑ 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 (December 2008). "Sox18 induces development of the lymphatic vasculature in mice". Nature. 456 (7222): 643–7. doi:10.1038/nature07391. PMID 18931657.
  63. ↑ Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M (June 2003). "Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia". Am. J. Hum. Genet. 72 (6): 1470–8. doi:10.1086/375614. PMC 1180307. PMID 12740761.
  64. ↑ "Hypotrichosis-lymphedema-telangiectasia syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program".
  65. ↑ "Hypotrichosis-lymphedema-telangiectasia syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program".
  66. ↑ Valenzuela I, Fernández-Alvarez P, Plaja A, Ariceta G, Sabaté-Rotés A, García-Arumí E, Vendrell T, Tizzano E (May 2018). "Further delineation of the SOX18-related Hypotrichosis, Lymphedema, Telangiectasia syndrome (HTLS)". Eur J Med Genet. 61 (5): 269–272. doi:10.1016/j.ejmg.2018.01.001. PMID 29307792.
  67. ↑ 67.0 67.1 67.2 Seo SK, Kim KY, Han SA, Yoon JS, Shin SY, Sohn SK, Moon JH (January 2016). "First Korean case of Emberger syndrome (primary lymphedema with myelodysplasia) with a novel GATA2 gene mutation". Korean J. Intern. Med. 31 (1): 188–90. doi:10.3904/kjim.2016.31.1.188. PMC 4712426. PMID 26767875.
  68. ↑ 68.0 68.1 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 (September 2011). "Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome)". Nat. Genet. 43 (10): 929–31. doi:10.1038/ng.923. PMID 21892158.
  69. ↑ 69.0 69.1 69.2 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 (September 2010). "Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases". Am. J. Med. Genet. A. 152A (9): 2287–96. doi:10.1002/ajmg.a.33445. PMID 20803646.
  70. ↑ 70.0 70.1 Zawawi F, Sokolov M, Mawby T, Gordon KA, Papsin BC, Cushing SL (May 2018). "Emberger syndrome: A rare association with hearing loss". Int. J. Pediatr. Otorhinolaryngol. 108: 82–84. doi:10.1016/j.ijporl.2018.02.014. PMID 29605372.
  71. ↑ Hsu AP, McReynolds LJ, Holland SM (February 2015). "GATA2 deficiency". Curr Opin Allergy Clin Immunol. 15 (1): 104–9. doi:10.1097/ACI.0000000000000126. PMC 4342850. PMID 25397911.
  72. ↑ 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 (February 2014). "The evolution of cellular deficiency in GATA2 mutation". Blood. 123 (6): 863–74. doi:10.1182/blood-2013-07-517151. PMC 3916878. PMID 24345756.
  73. ↑ Hirabayashi S, Wlodarski MW, Kozyra E, Niemeyer CM (August 2017). "Heterogeneity of GATA2-related myeloid neoplasms". Int. J. Hematol. 106 (2): 175–182. doi:10.1007/s12185-017-2285-2. PMID 28643018.
  74. ↑ Crispino JD, Horwitz MS (April 2017). "GATA factor mutations in hematologic disease". Blood. 129 (15): 2103–2110. doi:10.1182/blood-2016-09-687889. PMC 5391620. PMID 28179280.
  75. ↑ 75.0 75.1 75.2 Frosk P, Chodirker B, Simard L, El-Matary W, Hanlon-Dearman A, Schwartzentruber J, Majewski J, Rockman-Greenberg C (April 2015). "A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature". BMC Med. Genet. 16: 28. doi:10.1186/s12881-015-0175-0. PMC 4630843. PMID 25925991.
  76. ↑ 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 (November 2002). "Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review". Am. J. Med. Genet. 112 (4): 412–21. doi:10.1002/ajmg.10707. PMID 12376947.
  77. ↑ 77.0 77.1 77.2 Deng XL, Yin F, Zhang GY, Duan YD (January 2015). "[A complicated case study: Hennekam syndrome]". Zhongguo Dang Dai Er Ke Za Zhi (in Chinese). 17 (1): 77–80. PMID 25616299.
  78. ↑ Roukens MG, Peterson-Maduro J, Padberg Y, Jeltsch M, Leppänen VM, Bos FL, Alitalo K, Schulte-Merker S, Schulte D (May 2015). "Functional Dissection of the CCBE1 Protein: A Crucial Requirement for the Collagen Repeat Domain". Circ. Res. 116 (10): 1660–9. doi:10.1161/CIRCRESAHA.116.304949. PMID 25814692.
  79. ↑ Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen VM, Holopainen T, Kivelä R, Ortega S, Kärpanen T, Alitalo K (May 2014). "CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation". Circulation. 129 (19): 1962–71. doi:10.1161/CIRCULATIONAHA.113.002779. PMID 24552833.
  80. ↑ 80.0 80.1 Lee YG, Kim SC, Park SB, Kim MJ (February 2018). "Hennekam Syndrome: A Case Report". Ann Rehabil Med. 42 (1): 184–188. doi:10.5535/arm.2018.42.1.184. PMC 5852224. PMID 29560340.
  81. ↑ 81.0 81.1 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 (May 2015). "No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome". Orphanet J Rare Dis. 10: 52. doi:10.1186/s13023-015-0271-4. PMC 4464120. PMID 25934493.
  82. ↑ McKusick VA, Stauffer M, Knox DL, Clark DB (May 1966). "Chorioretinopathy with hereditary microcephaly". Arch. Ophthalmol. 75 (5): 597–600. PMID 5936364.
  83. ↑ Vasudevan PC, Garcia-Minaur S, Botella MP, Perez-Aytes A, Shannon NL, Quarrell OW (July 2005). "Microcephaly-lymphoedema-chorioretinal dysplasia: three cases to delineate the facial phenotype and review of the literature". Clin. Dysmorphol. 14 (3): 109–16. PMID 15930898.
  84. ↑ 84.0 84.1 Eventov-Friedman S, Singer A, Shinwell ES (April 2009). "Microcephaly, lymphedema, chorioretinopathy and atrial septal defect: a case report and review of the literature". Acta Paediatr. 98 (4): 758–9. doi:10.1111/j.1651-2227.2008.01161.x. PMID 19076985.
  85. ↑ 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 (November 2014). "Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature". Am. J. Med. Genet. A. 164A (11): 2879–86. doi:10.1002/ajmg.a.36707. PMC 4205200. PMID 25115524.
  86. ↑ Mears K, Bakall B, Harney LA, Penticoff JA, Stone EM (June 2015). "Autosomal Dominant Microcephaly Associated With Congenital Lymphedema and Chorioretinopathy Due to a Novel Mutation in KIF11". JAMA Ophthalmol. 133 (6): 720–1. doi:10.1001/jamaophthalmol.2015.199. PMID 25764055.
  87. ↑ Hu H, Xiao X, Li S, Jia X, Guo X, Zhang Q (February 2016). "KIF11 mutations are a common cause of autosomal dominant familial exudative vitreoretinopathy". Br J Ophthalmol. 100 (2): 278–83. doi:10.1136/bjophthalmol-2015-306878. PMID 26472404.
  88. ↑ Balikova I, Robson AG, Holder GE, Ostergaard P, Mansour S, Moore AT (February 2016). "Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11". Acta Ophthalmol. 94 (1): 92–8. doi:10.1111/aos.12759. PMID 25996076.
  89. ↑ 89.0 89.1 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 (July 2014). "Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations". Eur. J. Hum. Genet. 22 (7): 881–7. doi:10.1038/ejhg.2013.263. PMC 3938398. PMID 24281367.
  90. ↑ 90.0 90.1 Au AC, Hernandez PA, Lieber E, Nadroo AM, Shen YM, Kelley KA, Gelb BD, Diaz GA (September 2010). "Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans". Am. J. Hum. Genet. 87 (3): 436–44. doi:10.1016/j.ajhg.2010.08.008. PMC 2933336. PMID 20826270.
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