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| ==Vascular malformations== | | ==Vascular malformations== |
| ===Simple vascular malformations=== | | ===Simple vascular malformations=== |
| ====Lymphatic malformations (LM)====
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| =====Common (cystic) LM=====
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| * benign lesions consisting of dilated lymphatic channels or cysts lined by cells of endothelial origin with lymphatic differentiation.<ref name="pmid26055853">{{cite journal |vauthors=Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, Burrows P, Frieden IJ, Garzon MC, Lopez-Gutierrez JC, Lord DJ, Mitchel S, Powell J, Prendiville J, Vikkula M |title=Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies |journal=Pediatrics |volume=136 |issue=1 |pages=e203–14 |date=July 2015 |pmid=26055853 |doi=10.1542/peds.2014-3673 |url=}}</ref> If these lesions are associated with overgrowth then some of these lesions belong to the PIK3CA-related overgrowth spectrum. <ref>http://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf</ref>
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| * These are classified as follows:
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| ** Macrocystic LM
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| ** Microcystic LM
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| ** Mixed cystic LM
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| *# '''Macrocystic LM'''
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| *#* Also called cystic hygroma, and cystic lymphangioma. A cystic growth consisting of large, interconnected lymphatic cysts lined by a thin endothelium. Usually found in neck, axilla and groin. Presents as a large, poorly delineated, translucent, soft cystic mass covered by normal skin.
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| *#* May be associated with chromosomal abnormalities such as Down syndrome, Turner syndrome. To learn more click here.
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| *# '''Microcystic LM'''
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| *#* Also known as 'lymphangioma circumscriptum', these lymphatic anomalies may be present at birth or may develop in first few years of life. Usual presentation is as a cluster of clear, translucent or hemorrhagic vesicles that may cause pressure symptoms as they grow in size.
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| *#* Usually affect deep seated structures and frequent locations are proximal extremities, trunk, axilla, and the oral cavity.
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| *#* Diagnosis is clinical and treatment options include surgery, sclerotherapy, radiotherapy, and laser therapy. Recently topical sirolimus has also been used.<ref name="pmid30133999">{{cite journal |vauthors=Çalışkan E, Altunel CT, Özkan CK, Tunca M |title=A case of microcystic lymphatic malformation successfully treated with topical sirolimus |journal=Dermatol Ther |volume= |issue= |pages=e12673 |date=August 2018 |pmid=30133999 |doi=10.1111/dth.12673 |url=}}</ref> To learn more click here.
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|
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| =====Generalized lymphatic anomaly (GLA)=====
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| * Diffuse or multicentric proliferation of dilated lymphatic vessels that may involve skin, bones, and internal organs. The proliferating vessels resemble common lymphatic malformations but the disease involvement is multi-system.<ref name="pmid29871646">{{cite journal |vauthors=Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C |title=Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report |journal=J Cardiothorac Surg |volume=13 |issue=1 |pages=59 |date=June 2018 |pmid=29871646 |pmc=5989411 |doi=10.1186/s13019-018-0752-3 |url=}}</ref><ref name="pmid29397482">{{cite journal |vauthors=Manevitz-Mendelson E, Leichner GS, Barel O, Davidi-Avrahami I, Ziv-Strasser L, Eyal E, Pessach I, Rimon U, Barzilai A, Hirshberg A, Chechekes K, Amariglio N, Rechavi G, Yaniv K, Greenberger S |title=Somatic NRAS mutation in patient with generalized lymphatic anomaly |journal=Angiogenesis |volume=21 |issue=2 |pages=287–298 |date=May 2018 |pmid=29397482 |doi=10.1007/s10456-018-9595-8 |url=}}</ref> Lungs, bones and mediastinum are most commonly affected but skin, liver and spleen are commonly affected as well. Liver, spleen, and thoracic duct involvement typically indicates worse prognosis.<ref name="pmid2709285">{{cite journal |vauthors=Levine C |title=Primary disorders of the lymphatic vessels--a unified concept |journal=J. Pediatr. Surg. |volume=24 |issue=3 |pages=233–40 |date=March 1989 |pmid=2709285 |doi= |url=}}</ref>
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| * Considered to b sporadic and non-hereditary, it may present in childhood or can be diagnosed later in life.<ref name="pmid10712360">{{cite journal |vauthors=Faul JL, Berry GJ, Colby TV, Ruoss SJ, Walter MB, Rosen GD, Raffin TA |title=Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome |journal=Am. J. Respir. Crit. Care Med. |volume=161 |issue=3 Pt 1 |pages=1037–46 |date=March 2000 |pmid=10712360 |doi=10.1164/ajrccm.161.3.9904056 |url=}}</ref><ref name="pmid23457676">{{cite journal |vauthors=Kadakia KC, Patel SM, Yi ES, Limper AH |title=Diffuse pulmonary lymphangiomatosis |journal=Can. Respir. J. |volume=20 |issue=1 |pages=52–4 |date=2013 |pmid=23457676 |pmc=3628648 |doi=10.1155/2013/971350 |url=}}</ref> Etiology is unknown but high levels of VEGFR-3 have been reported in patient population.
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| * Chylothorax due to leakage of lymphtic fluid is commonly encountered and is difficult to treat.<ref name="pmid29906363">{{cite journal |vauthors=Ludwig KF, Slone T, Cederberg KB, Silva AT, Dellinger M |title=A New Case and Review of Chylothorax in Generalized Lymphatic Anomaly and Gorham-Stout Disease |journal=Lymphology |volume=49 |issue=2 |pages=73–84 |date=June 2016 |pmid=29906363 |doi= |url=}}</ref> Patient may present with respiratory symptoms such as chest pain, wheezing, SOB, cough, repeated infections or symptoms due to involvement of other organs such as bone pain, pathological fractures, pelvic or abdominal pain, swelling, fever, internal bleeding, skin lesions.<ref name="pmid29871646">{{cite journal |vauthors=Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C |title=Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report |journal=J Cardiothorac Surg |volume=13 |issue=1 |pages=59 |date=June 2018 |pmid=29871646 |pmc=5989411 |doi=10.1186/s13019-018-0752-3 |url=}}</ref><ref name="pmid11247693">{{cite journal |vauthors=Aviv RI, McHugh K, Hunt J |title=Angiomatosis of bone and soft tissue: a spectrum of disease from diffuse lymphangiomatosis to vanishing bone disease in young patients |journal=Clin Radiol |volume=56 |issue=3 |pages=184–90 |date=March 2001 |pmid=11247693 |doi=10.1053/crad.2000.0606 |url=}}</ref><ref name="pmid22196284">{{cite journal |vauthors=Satria MN, Pacheco-Rodriguez G, Moss J |title=Pulmonary lymphangiomatosis |journal=Lymphat Res Biol |volume=9 |issue=4 |pages=191–3 |date=2011 |pmid=22196284 |pmc=3246407 |doi=10.1089/lrb.2011.0023 |url=}}</ref><ref name="pmid23457676">{{cite journal |vauthors=Kadakia KC, Patel SM, Yi ES, Limper AH |title=Diffuse pulmonary lymphangiomatosis |journal=Can. Respir. J. |volume=20 |issue=1 |pages=52–4 |date=2013 |pmid=23457676 |pmc=3628648 |doi=10.1155/2013/971350 |url=}}</ref>
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| * Diagnosis of GLA is very challenging and requires multidisciplinary input. It depends on history, examination, imaging studies such as MRI, contrast ultrasound, magnetic resonance lymphangiogram, CXR,near-infrared fluorescence lymphatic imaging, nanotechnology-based MRI agents and biopsy.<ref name="pmid29871646">{{cite journal |vauthors=Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C |title=Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report |journal=J Cardiothorac Surg |volume=13 |issue=1 |pages=59 |date=June 2018 |pmid=29871646 |pmc=5989411 |doi=10.1186/s13019-018-0752-3 |url=}}</ref><ref name="pmid24590275">{{cite journal |vauthors=Sevick-Muraca EM, Kwon S, Rasmussen JC |title=Emerging lymphatic imaging technologies for mouse and man |journal=J. Clin. Invest. |volume=124 |issue=3 |pages=905–14 |date=March 2014 |pmid=24590275 |pmc=3938259 |doi=10.1172/JCI71612 |url=}}</ref><ref name="pmid19913379">{{cite journal |vauthors=Lohrmann C, Foeldi E, Langer M |title=Assessment of the lymphatic system in patients with diffuse lymphangiomatosis by magnetic resonance imaging |journal=Eur J Radiol |volume=80 |issue=2 |pages=576–81 |date=November 2011 |pmid=19913379 |doi=10.1016/j.ejrad.2009.10.021 |url=}}</ref> Sometimes surgery is required that can be both diagnostic and therapeutic.<ref name="pmid29871646">{{cite journal |vauthors=Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C |title=Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report |journal=J Cardiothorac Surg |volume=13 |issue=1 |pages=59 |date=June 2018 |pmid=29871646 |pmc=5989411 |doi=10.1186/s13019-018-0752-3 |url=}}</ref>
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| * Management is usually focused on symptomatic improvement. Options include chest drainage, open thorax surgery, sclerotherapy, surgical removal (debulking), lymphatic anastomosis and medical therapies such as sirolimus and interferon.<ref name="pmid29871646">{{cite journal |vauthors=Du H, Xiong M, Liao H, Luo Y, Shi H, Xie C |title=Chylothorax and constrictive pericarditis in a woman due to generalized lymphatic anomaly: a case report |journal=J Cardiothorac Surg |volume=13 |issue=1 |pages=59 |date=June 2018 |pmid=29871646 |pmc=5989411 |doi=10.1186/s13019-018-0752-3 |url=}}</ref>
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| *# '''Kaposiform lymphangiomatosis (KLA)'''
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| *#* A rare subtype with worse pronosis.<ref name="pmid25598153">{{cite journal |vauthors=Wang Z, Li K, Yao W, Dong K, Xiao X, Zheng S |title=Successful treatment of kaposiform lymphangiomatosis with sirolimus |journal=Pediatr Blood Cancer |volume=62 |issue=7 |pages=1291–3 |date=July 2015 |pmid=25598153 |doi=10.1002/pbc.25422 |url=}}</ref> Malformed vessels occur with cluster and sheets of spindle lymphatic endothelial cells.<ref name="pmid24252784">{{cite journal |vauthors=Croteau SE, Kozakewich HP, Perez-Atayde AR, Fishman SJ, Alomari AI, Chaudry G, Mulliken JB, Trenor CC |title=Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly |journal=J. Pediatr. |volume=164 |issue=2 |pages=383–8 |date=February 2014 |pmid=24252784 |pmc=3946828 |doi=10.1016/j.jpeds.2013.10.013 |url=}}</ref> Consumptive coagulopathy is also a feature.<ref name="pmid25307772">{{cite journal |vauthors=Fernandes VM, Fargo JH, Saini S, Guerrera MF, Marcus L, Luchtman-Jones L, Adams D, Meier ER |title=Kaposiform lymphangiomatosis: unifying features of a heterogeneous disorder |journal=Pediatr Blood Cancer |volume=62 |issue=5 |pages=901–4 |date=May 2015 |pmid=25307772 |doi=10.1002/pbc.25278 |url=}}</ref>
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| *#* Intra-thoracic component is often the cause of mortality.<ref name="pmid24252784">{{cite journal |vauthors=Croteau SE, Kozakewich HP, Perez-Atayde AR, Fishman SJ, Alomari AI, Chaudry G, Mulliken JB, Trenor CC |title=Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly |journal=J. Pediatr. |volume=164 |issue=2 |pages=383–8 |date=February 2014 |pmid=24252784 |pmc=3946828 |doi=10.1016/j.jpeds.2013.10.013 |url=}}</ref> Currently there are no treatment guidelines.<ref name="pmid25598153">{{cite journal |vauthors=Wang Z, Li K, Yao W, Dong K, Xiao X, Zheng S |title=Successful treatment of kaposiform lymphangiomatosis with sirolimus |journal=Pediatr Blood Cancer |volume=62 |issue=7 |pages=1291–3 |date=July 2015 |pmid=25598153 |doi=10.1002/pbc.25422 |url=}}</ref>
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|
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| =====LM in Gorham-Stout disease=====
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| * Lymphatic malformation in Gorham-Stout disease affect a single or multiple bones and adjacent soft tissues, leading to progressive osteolysis and invasion of the bone cortex.<ref name="pmid8961021">{{cite journal |vauthors=Klein M, Metelmann HR, Gross U |title=Massive osteolysis (Gorham-Stout syndrome) in the maxillofacial region: an unusual manifestation |journal=Int J Oral Maxillofac Surg |volume=25 |issue=5 |pages=376–8 |date=October 1996 |pmid=8961021 |doi= |url=}}</ref><ref name="pmid18519969">{{cite journal |vauthors=Radhakrishnan K, Rockson SG |title=The clinical spectrum of lymphatic disease |journal=Ann. N. Y. Acad. Sci. |volume=1131 |issue= |pages=155–84 |date=2008 |pmid=18519969 |doi=10.1196/annals.1413.015 |url=}}</ref><ref name="pmid23371338">{{cite journal |vauthors=Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G |title=Gorham-Stout disease and generalized lymphatic anomaly--clinical, radiologic, and histologic differentiation |journal=Skeletal Radiol. |volume=42 |issue=7 |pages=917–24 |date=July 2013 |pmid=23371338 |doi=10.1007/s00256-012-1565-4 |url=}}</ref> Was originally described as disappearing or vanishing bone disease. GSD progression often leads to visceral, abdominal and thoracic involvement that may cause effusion and ascites<ref name="pmid23371338">{{cite journal |vauthors=Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G |title=Gorham-Stout disease and generalized lymphatic anomaly--clinical, radiologic, and histologic differentiation |journal=Skeletal Radiol. |volume=42 |issue=7 |pages=917–24 |date=July 2013 |pmid=23371338 |doi=10.1007/s00256-012-1565-4 |url=}}</ref> The osteolysis is progressive in GSD as compared to non-progressive osteolysis in GLA.<ref name="pmid23371338">{{cite journal |vauthors=Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G |title=Gorham-Stout disease and generalized lymphatic anomaly--clinical, radiologic, and histologic differentiation |journal=Skeletal Radiol. |volume=42 |issue=7 |pages=917–24 |date=July 2013 |pmid=23371338 |doi=10.1007/s00256-012-1565-4 |url=}}</ref>
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| * There are two distinct forms of GSD. Primary form involves multiple bones and tissues with multi-focal lesions as described above versus trauma induced GSD that typically involves one or closely adjacent one and is usually self limited.<ref name="pmid30248728">{{cite journal |vauthors=Tanoue N, Moedano L, Witte M, Montague M, Lukefahr A, Bernas M |title=Primary versus trauma-induced Gorham-Stout disease |journal=Lymphology |volume=51 |issue=1 |pages=18–27 |date=2018 |pmid=30248728 |doi= |url=}}</ref>
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| * The etiology has not been established and gender, genetic inheritance, or race seem to play no role but inflammation, trauma and puberty have been thought to pay a role. Activation of platelet derived growth factor pathway and up regulation of lymphangiogenesis stimulating pathways may play a role in pathogenesis.<ref name="pmid16816171">{{cite journal |vauthors=Meijer-Jorna LB, van der Loos CM, de Boer OJ, van der Horst CM, van der Wal AC |title=Microvascular proliferation in congenital vascular malformations of skin and soft tissue |journal=J. Clin. Pathol. |volume=60 |issue=7 |pages=798–803 |date=July 2007 |pmid=16816171 |pmc=1995770 |doi=10.1136/jcp.2006.038885 |url=}}</ref><ref name="pmid18519972">{{cite journal |vauthors=Radhakrishnan K, Rockson SG |title=Gorham's disease: an osseous disease of lymphangiogenesis? |journal=Ann. N. Y. Acad. Sci. |volume=1131 |issue= |pages=203–5 |date=2008 |pmid=18519972 |doi=10.1196/annals.1413.022 |url=}}</ref><ref name="pmid17139320">{{cite journal |vauthors=Hagendoorn J, Padera TP, Yock TI, Nielsen GP, di Tomaso E, Duda DG, Delaney TF, Gaissert HA, Pearce J, Rosenberg AE, Jain RK, Ebb DH |title=Platelet-derived growth factor receptor-beta in Gorham's disease |journal=Nat Clin Pract Oncol |volume=3 |issue=12 |pages=693–7 |date=December 2006 |pmid=17139320 |pmc=2693369 |doi=10.1038/ncponc0660 |url=}}</ref> IL-6 has been found to be elevated in some patients.<ref name="pmid8626854">{{cite journal |vauthors=Devlin RD, Bone HG, Roodman GD |title=Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease |journal=J. Clin. Endocrinol. Metab. |volume=81 |issue=5 |pages=1893–7 |date=May 1996 |pmid=8626854 |doi=10.1210/jcem.81.5.8626854 |url=}}</ref>
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| * Symptoms depend on the bone involved and extent of involvement. Patient can experience chest pain, dyspnea, tachypnea, wheezing, SOB, dull ache, back pain, paralysis, loose teeth and facial deformation.<ref name="pmid22937447">{{cite journal |vauthors=Garbers E, Reuther F, Delling G |title=Report of a rare case of gorham-stout disease of both shoulders: bisphosphonate treatment and shoulder replacement |journal=Case Rep Rheumatol |volume=2011 |issue= |pages=565142 |date=2011 |pmid=22937447 |pmc=3420766 |doi=10.1155/2011/565142 |url=}}</ref><ref name="pmid16012125">{{cite journal |vauthors=Duffy BM, Manon R, Patel RR, Welsh JS |title=A case of Gorham's disease with chylothorax treated curatively with radiation therapy |journal=Clin Med Res |volume=3 |issue=2 |pages=83–6 |date=May 2005 |pmid=16012125 |pmc=1183437 |doi= |url=}}</ref> The involvement of thorax and development of chylothorax indicate poor prognosis.<ref name="pmid16012125">{{cite journal |vauthors=Duffy BM, Manon R, Patel RR, Welsh JS |title=A case of Gorham's disease with chylothorax treated curatively with radiation therapy |journal=Clin Med Res |volume=3 |issue=2 |pages=83–6 |date=May 2005 |pmid=16012125 |pmc=1183437 |doi= |url=}}</ref>
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| * 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>
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| =====“Acquired” progressive lymphatic anomaly=====
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| * 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>
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| * 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>
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| =====Primary lymphedema=====
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| * 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>
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| * 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>
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| *# '''Nonne-Milroy syndrome'''
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| *#* A hereditary disorder that usually presents as bilateral edema of lower limbs that may involve the whole extremity or may be limited to legs, feet or toes. This may or may not be accompanied by toenail changes such as upslanting toenails and deep creases in the toes, papillomatosis, hydrocele, hydrothorax, lung hypoplasia and prominent leg veins. A case of unilateral phenotype have also been reported. Swellings may be complicated by recurrent episodes of cellulitis.<ref name="pmid12528167">{{cite journal |vauthors=Lev-Sagie A, Hamani Y, Raas-Rothschild A, Yagel S, Anteby EY |title=Prenatal ultrasonographic diagnosis of atypical Nonne-Milroy lymphedema |journal=Ultrasound Obstet Gynecol |volume=21 |issue=1 |pages=72–4 |date=January 2003 |pmid=12528167 |doi=10.1002/uog.16 |url=}}</ref><ref name="pmid2075326">{{cite journal |vauthors=Zbranca V, Aramă A, Mihăescu T, Covic M |title=[Hereditary lymphedema (Nonne-Milroy-Meige syndrome) associated with chylothorax. Comments on 2 cases] |language=Romanian |journal=Rev Med Chir Soc Med Nat Iasi |volume=94 |issue=1 |pages=189–92 |date=1990 |pmid=2075326 |doi= |url=}}</ref><ref name="urlMilroy disease - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/condition/milroy-disease#inheritance |title=Milroy disease - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref><ref name="pmid16924388">{{cite journal |vauthors=Spiegel R, Ghalamkarpour A, Daniel-Spiegel E, Vikkula M, Shalev SA |title=Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3 |journal=J. Hum. Genet. |volume=51 |issue=10 |pages=846–50 |date=2006 |pmid=16924388 |doi=10.1007/s10038-006-0031-3 |url=}}</ref>
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| *#* The disease typically follows autosomal-dominant pattern though cases of autosomal-recessive inheritance and variable expression has also been reported. The defect thought to be responsible has been located on VEGFR3 (FLT4) gene that codes for vascular endothelial growth factor receptor 3 (VEGFR3).<ref name="urlMilroy disease - Genetics Home Reference - NIH">{{cite web |url=+https://ghr.nlm.nih.gov/condition/milroy-disease#inheritance |title=Milroy disease - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref><ref name="pmid16924388">{{cite journal |vauthors=Spiegel R, Ghalamkarpour A, Daniel-Spiegel E, Vikkula M, Shalev SA |title=Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3 |journal=J. Hum. Genet. |volume=51 |issue=10 |pages=846–50 |date=2006 |pmid=16924388 |doi=10.1007/s10038-006-0031-3 |url=}}</ref><ref name="pmid2075326">{{cite journal |vauthors=Zbranca V, Aramă A, Mihăescu T, Covic M |title=[Hereditary lymphedema (Nonne-Milroy-Meige syndrome) associated with chylothorax. Comments on 2 cases] |language=Romanian |journal=Rev Med Chir Soc Med Nat Iasi |volume=94 |issue=1 |pages=189–92 |date=1990 |pmid=2075326 |doi= |url=}}</ref>
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| *# '''Primary hereditary lymphedema'''
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| *#* Chronic edema that can appear in any body part due to blockage or malfunctioning of lymphatic channels that may lead to recurrent infections and impairment.<ref name="pmid30071673">{{cite journal |vauthors=Nadarajah N, Schulte D, McConnell V, Martin-Almedina S, Karapouliou C, Mortimer PS, Jeffery S, Schulte-Merker S, Gordon K, Mansour S, Ostergaard P |title=A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon |journal=Int J Mol Sci |volume=19 |issue=8 |pages= |date=August 2018 |pmid=30071673 |pmc=6121331 |doi=10.3390/ijms19082259 |url=}}</ref><ref name="urlVEGFC gene - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/gene/VEGFC#conditions |title=VEGFC gene - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref>
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| *#* Results from mutations in VEGFC gene that encodes the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4). This gene plays an important role in lymphangiogenesis.<ref name="urlVEGFC gene - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/gene/VEGFC#conditions |title=VEGFC gene - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref><ref name="pmid30071673">{{cite journal |vauthors=Nadarajah N, Schulte D, McConnell V, Martin-Almedina S, Karapouliou C, Mortimer PS, Jeffery S, Schulte-Merker S, Gordon K, Mansour S, Ostergaard P |title=A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon |journal=Int J Mol Sci |volume=19 |issue=8 |pages= |date=August 2018 |pmid=30071673 |pmc=6121331 |doi=10.3390/ijms19082259 |url=}}</ref>
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| *# '''Primary hereditary lymphedema'''
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| *#* Edema typically first appears in legs and then progresses to involve the arms.<ref name="urlGJC2 gene - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/gene/GJC2#conditions |title=GJC2 gene - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref>
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| *#* Thought to be associated with muatation in GJC2 gene that encodes for connexin-47, a member of the gap junction connecxin family. Mutation in this gene has also been linked to Pelizaeus-Merzbacher-like disease type 1 and spastic paraplegia type 44.<ref name="urlGJC2 gene - Genetics Home Reference - NIH">{{cite web |url=https://ghr.nlm.nih.gov/gene/GJC2#conditions |title=GJC2 gene - Genetics Home Reference - NIH |format= |work= |accessdate=}}</ref><ref name="pmid23550541">{{cite journal |vauthors=Brice G, Ostergaard P, Jeffery S, Gordon K, Mortimer PS, Mansour S |title=A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family |journal=Clin. Genet. |volume=84 |issue=4 |pages=378–81 |date=October 2013 |pmid=23550541 |doi=10.1111/cge.12158 |url=}}</ref>
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| *# '''Lymphedema-distichiasis'''
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| *#* A syndrome that is characterized by edema that typically manifests in lower limb and distichiasis that is an anomaly of eyelashes. Distichiasis appears earlier in life than lymphedema and manifests as extra eyelashes that typically arise from meibomian glands. This syndrome has been associated with congenital heart disease, varicose veins, cleft palate, ptosis, strabismus, renal abnormalities, spinal extradural cysts, and neck webbing.<ref name="pmid26759405">{{cite journal |vauthors=Marques NS, Miranda A, Barros S, Parreira S |title=Lymphoedema-distichiasis syndrome |journal=BMJ Case Rep |volume=2016 |issue= |pages= |date=January 2016 |pmid=26759405 |pmc=4716369 |doi=10.1136/bcr-2015-213651 |url=}}</ref><ref name="pmid17366583">{{cite journal |vauthors=Yabuki S, Kikuchi S, Ikegawa S |title=Spinal extradural arachnoid cysts associated with distichiasis and lymphedema |journal=Am. J. Med. Genet. A |volume=143A |issue=8 |pages=884–7 |date=April 2007 |pmid=17366583 |doi=10.1002/ajmg.a.31669 |url=}}</ref><ref name="pmid12114478">{{cite journal |vauthors=Brice G, Mansour S, Bell R, Collin JR, Child AH, Brady AF, Sarfarazi M, Burnand KG, Jeffery S, Mortimer P, Murday VA |title=Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24 |journal=J. Med. Genet. |volume=39 |issue=7 |pages=478–83 |date=July 2002 |pmid=12114478 |pmc=1735188 |doi= |url=}}</ref><ref name="pmid23806988">{{cite journal |vauthors=Sardesai VR, Mhatre MA, Patil RM |title=Lymphoedema - distichiasis syndrome with recurrent abortions |journal=Indian J Med Sci |volume=66 |issue=5-6 |pages=141–3 |date=2012 |pmid=23806988 |doi=10.4103/0019-5359.114202 |url=}}</ref><ref name="pmid28959174">{{cite journal |vauthors=Planinsek Rucigaj T, Rijavec M, Miljkovic J, Selb J, Korosec P |title=A Novel Mutation in the FOXC2 Gene: A Heterozygous Insertion of Adenosine (c.867insA) in a Family with Lymphoedema of Lower Limbs without Distichiasis |journal=Radiol Oncol |volume=51 |issue=3 |pages=363–368 |date=September 2017 |pmid=28959174 |pmc=5612002 |doi=10.1515/raon-2017-0026 |url=}}</ref><ref name="pmid29406328">{{cite journal |vauthors=De Niear MA, Breazzano MP, Mawn LA |title=Novel FOXC2 Mutation and Distichiasis in a Patient With Lymphedema-Distichiasis Syndrome |journal=Ophthalmic Plast Reconstr Surg |volume=34 |issue=3 |pages=e88–e90 |date=2018 |pmid=29406328 |doi=10.1097/IOP.0000000000001079 |url=}}</ref>
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| *#* Inherited in autosomal dominant pattern mutation in FOXC2 gene that encodes for transcription factors. Inheritance also shows variable expression.<ref name="pmid24984567">{{cite journal |vauthors=Zhu LL, Lv YN, Chen HD, Gao XH |title=A Chinese pedigree of lymphoedema-distichiasis syndrome with a novel mutation in the FOXC2 gene |journal=Clin. Exp. Dermatol. |volume=39 |issue=6 |pages=731–3 |date=August 2014 |pmid=24984567 |doi=10.1111/ced.12389 |url=}}</ref><ref name="pmid27570485">{{cite journal |vauthors=Zhang L, He J, Han B, Lu L, Fan J, Zhang H, Ge S, Zhou Y, Jia R, Fan X |title=Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation |journal=Int. J. Biol. Sci. |volume=12 |issue=9 |pages=1114–20 |date=2016 |pmid=27570485 |pmc=4997055 |doi=10.7150/ijbs.13774 |url=}}</ref><ref name="pmid28959174">{{cite journal |vauthors=Planinsek Rucigaj T, Rijavec M, Miljkovic J, Selb J, Korosec P |title=A Novel Mutation in the FOXC2 Gene: A Heterozygous Insertion of Adenosine (c.867insA) in a Family with Lymphoedema of Lower Limbs without Distichiasis |journal=Radiol Oncol |volume=51 |issue=3 |pages=363–368 |date=September 2017 |pmid=28959174 |pmc=5612002 |doi=10.1515/raon-2017-0026 |url=}}</ref>
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| *#* Diagnosis is clinical. Treatment for lymphedema is mainly conservative with management of complications such as cellulitis. Treatment for distichiasis consists of symptomatic management such as lubrication or definitive management such as surgery, cryotherapy, or electrolysis.<ref name="pmid26759405">{{cite journal |vauthors=Marques NS, Miranda A, Barros S, Parreira S |title=Lymphoedema-distichiasis syndrome |journal=BMJ Case Rep |volume=2016 |issue= |pages= |date=January 2016 |pmid=26759405 |pmc=4716369 |doi=10.1136/bcr-2015-213651 |url=}}</ref><ref name="pmid20301630">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Mansour S, Brice GW, Jeffery S, Mortimer P |title= |journal= |volume= |issue= |pages= |date= |pmid=20301630 |doi= |url=}}</ref>
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| *# '''Hypotrichosis-lymphedema-telangiectasia'''
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| *#* Characterized by less than normal body hair (hypotrichosis), chronic swelling of the body (lymphedema), and dilated blood vessels (telangiectasia). These usually appear at birth or early in life and then progressively worsen over time. Hypotrichosis may present as absent eyebrows, eyelashes and alopecia or may manifest as sparse body hair. Lymphedema typically has predilection for lower limbs and telangiectasia are more commonly seen on palms although plantar telangiectasia are also seen. This syndrome has also been associated with cutis marmorata, hydrocele, palpebral edema, ascites, dermal atrophy, small cutaneous papular vascular lesions, skin degeneration, hydrops fetalis, pleural effusion, renal defects, aortic dilation and abnormal nails.<ref>{{cite web |url=https://rarediseases.info.nih.gov/diseases/12827/hypotrichosis-lymphedema-telangiectasia-syndrome |title=Hypotrichosis-lymphedema-telangiectasia syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |format= |work= |accessdate=}}</ref><ref>{{cite journal |vauthors=Wünnemann F, Kokta V, Leclerc S, Thibeault M, McCuaig C, Hatami A, Stheneur C, Grenier JC, Awadalla P, Mitchell GA, Andelfinger G, Preuss C |title=Aortic Dilatation Associated With a De Novo Mutation in the SOX18 Gene: Expanding the Clinical Spectrum of Hypotrichosis-Lymphedema-Telangiectasia Syndrome |journal=Can J Cardiol |volume=32 |issue=1 |pages=135.e1–7 |date=January 2016 |pmid=26148450 |doi=10.1016/j.cjca.2015.04.004 |url=}}</ref><ref>{{cite journal |vauthors=Moalem S, Brouillard P, Kuypers D, Legius E, Harvey E, Taylor G, Francois M, Vikkula M, Chitayat D |title=Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene |journal=Clin. Genet. |volume=87 |issue=4 |pages=378–82 |date=April 2015 |pmid=24697860 |doi=10.1111/cge.12388 |url=}}</ref><ref>{{cite journal |vauthors=Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M |title=Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia |journal=Am. J. Hum. Genet. |volume=72 |issue=6 |pages=1470–8 |date=June 2003 |pmid=12740761 |pmc=1180307 |doi=10.1086/375614 |url=}}</ref>
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| *#* Mutation in SOX18 gene that encodes for transcription factor SOX18 is thought to be the cause of this syndrome. This transcription factor is expressed widely in body tissues and that may explain the wide ranging manifestations of this syndrome. Inheritance can both be autosomal-dominant and autosomal-recessive.<ref>{{cite journal |vauthors=Valenzuela I, Fernández-Alvarez P, Plaja A, Ariceta G, Sabaté-Rotés A, García-Arumí E, Vendrell T, Tizzano E |title=Further delineation of the SOX18-related Hypotrichosis, Lymphedema, Telangiectasia syndrome (HTLS) |journal=Eur J Med Genet |volume=61 |issue=5 |pages=269–272 |date=May 2018 |pmid=29307792 |doi=10.1016/j.ejmg.2018.01.001 |url=}}</ref><ref>{{cite journal |vauthors=Bastaki F, Mohamed M, Nair P, Saif F, Tawfiq N, Al-Ali MT, Brandau O, Hamzeh AR |title=A novel SOX18 mutation uncovered in Jordanian patient with hypotrichosis-lymphedema-telangiectasia syndrome by Whole Exome Sequencing |journal=Mol. Cell. Probes |volume=30 |issue=1 |pages=18–21 |date=February 2016 |pmid=26631803 |doi=10.1016/j.mcp.2015.11.005 |url=}}</ref><ref>{{cite journal |vauthors=Wünnemann F, Kokta V, Leclerc S, Thibeault M, McCuaig C, Hatami A, Stheneur C, Grenier JC, Awadalla P, Mitchell GA, Andelfinger G, Preuss C |title=Aortic Dilatation Associated With a De Novo Mutation in the SOX18 Gene: Expanding the Clinical Spectrum of Hypotrichosis-Lymphedema-Telangiectasia Syndrome |journal=Can J Cardiol |volume=32 |issue=1 |pages=135.e1–7 |date=January 2016 |pmid=26148450 |doi=10.1016/j.cjca.2015.04.004 |url=}}</ref><ref>{{cite journal |vauthors=Moalem S, Brouillard P, Kuypers D, Legius E, Harvey E, Taylor G, Francois M, Vikkula M, Chitayat D |title=Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene |journal=Clin. Genet. |volume=87 |issue=4 |pages=378–82 |date=April 2015 |pmid=24697860 |doi=10.1111/cge.12388 |url=}}{{cite journal |vauthors=Downes M, François M, Ferguson C, Parton RG, Koopman P |title=Vascular defects in a mouse model of hypotrichosis-lymphedema-telangiectasia syndrome indicate a role for SOX18 in blood vessel maturation |journal=Hum. Mol. Genet. |volume=18 |issue=15 |pages=2839–50 |date=August 2009 |pmid=19429912 |doi=10.1093/hmg/ddp219 |url=}}</ref><ref>{{cite journal |vauthors=François M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C, Paavonen K, Karnezis T, Shayan R, Downes M, Davidson T, Tutt D, Cheah KS, Stacker SA, Muscat GE, Achen MG, Dejana E, Koopman P |title=Sox18 induces development of the lymphatic vasculature in mice |journal=Nature |volume=456 |issue=7222 |pages=643–7 |date=December 2008 |pmid=18931657 |doi=10.1038/nature07391 |url=}}</ref><ref>{{cite journal |vauthors=Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M |title=Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia |journal=Am. J. Hum. Genet. |volume=72 |issue=6 |pages=1470–8 |date=June 2003 |pmid=12740761 |pmc=1180307 |doi=10.1086/375614 |url=}}</ref><ref>{{cite web |url=https://rarediseases.info.nih.gov/diseases/12827/hypotrichosis-lymphedema-telangiectasia-syndrome |title=Hypotrichosis-lymphedema-telangiectasia syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |format= |work= |accessdate=}}</ref>
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| *#* There is no definitive treatment for this syndrome. Management is based on genetic counseling and symptomatic treatment.<ref>{{cite web |url=https://rarediseases.info.nih.gov/diseases/12827/hypotrichosis-lymphedema-telangiectasia-syndrome |title=Hypotrichosis-lymphedema-telangiectasia syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |format= |work= |accessdate=}}</ref><ref>{{cite journal |vauthors=Valenzuela I, Fernández-Alvarez P, Plaja A, Ariceta G, Sabaté-Rotés A, García-Arumí E, Vendrell T, Tizzano E |title=Further delineation of the SOX18-related Hypotrichosis, Lymphedema, Telangiectasia syndrome (HTLS) |journal=Eur J Med Genet |volume=61 |issue=5 |pages=269–272 |date=May 2018 |pmid=29307792 |doi=10.1016/j.ejmg.2018.01.001 |url=}}</ref>
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| *# '''Primary lymphedema with myelodysplasia'''
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| *#* Also called Emberger syndrome, this anomaly presents with wide variety of phenotypes including congenital sensorineural deafness, lymphedema, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), hypotelorism, epicanthic folds, long tapering fingers and/or neck webbing, and generalized warts.. Lymphedema has predisposition for lower limbs. Patient may present with complication of these phenotypes such as infections, bleeding and recurrent cellulitis.<ref name="pmid26767875">{{cite journal |vauthors=Seo SK, Kim KY, Han SA, Yoon JS, Shin SY, Sohn SK, Moon JH |title=First Korean case of Emberger syndrome (primary lymphedema with myelodysplasia) with a novel GATA2 gene mutation |journal=Korean J. Intern. Med. |volume=31 |issue=1 |pages=188–90 |date=January 2016 |pmid=26767875 |pmc=4712426 |doi=10.3904/kjim.2016.31.1.188 |url=}}</ref><ref name="pmid21892158">{{cite journal |vauthors=Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, Dafou D, Kilo T, Smithson S, Lunt P, Murday VA, Hodgson S, Keenan R, Pilz DT, Martinez-Corral I, Makinen T, Mortimer PS, Jeffery S, Trembath RC, Mansour S |title=Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome) |journal=Nat. Genet. |volume=43 |issue=10 |pages=929–31 |date=September 2011 |pmid=21892158 |doi=10.1038/ng.923 |url=}}</ref><ref name="pmid20803646">{{cite journal |vauthors=Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S, Lunt P, Jeffery S, Dokal I, Vulliamy T, Gibson B, Hodgson S, Cottrell S, Kiely L, Tinworth L, Kalidas K, Mufti G, Cornish J, Keenan R, Mortimer P, Murday V |title=Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases |journal=Am. J. Med. Genet. A |volume=152A |issue=9 |pages=2287–96 |date=September 2010 |pmid=20803646 |doi=10.1002/ajmg.a.33445 |url=}}</ref><ref name="pmid29605372">{{cite journal |vauthors=Zawawi F, Sokolov M, Mawby T, Gordon KA, Papsin BC, Cushing SL |title=Emberger syndrome: A rare association with hearing loss |journal=Int. J. Pediatr. Otorhinolaryngol. |volume=108 |issue= |pages=82–84 |date=May 2018 |pmid=29605372 |doi=10.1016/j.ijporl.2018.02.014 |url=}}</ref>
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| *#* Deficiency of transcription factor GATA2 due to mutations in GATA2 gene is thought to play the critical role. Inheritance tends to follow autosomal-dominant pattern.<ref name="pmid26767875">{{cite journal |vauthors=Seo SK, Kim KY, Han SA, Yoon JS, Shin SY, Sohn SK, Moon JH |title=First Korean case of Emberger syndrome (primary lymphedema with myelodysplasia) with a novel GATA2 gene mutation |journal=Korean J. Intern. Med. |volume=31 |issue=1 |pages=188–90 |date=January 2016 |pmid=26767875 |pmc=4712426 |doi=10.3904/kjim.2016.31.1.188 |url=}}</ref><ref name="pmid21892158">{{cite journal |vauthors=Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, Dafou D, Kilo T, Smithson S, Lunt P, Murday VA, Hodgson S, Keenan R, Pilz DT, Martinez-Corral I, Makinen T, Mortimer PS, Jeffery S, Trembath RC, Mansour S |title=Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome) |journal=Nat. Genet. |volume=43 |issue=10 |pages=929–31 |date=September 2011 |pmid=21892158 |doi=10.1038/ng.923 |url=}}</ref><ref name="pmid20803646">{{cite journal |vauthors=Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S, Lunt P, Jeffery S, Dokal I, Vulliamy T, Gibson B, Hodgson S, Cottrell S, Kiely L, Tinworth L, Kalidas K, Mufti G, Cornish J, Keenan R, Mortimer P, Murday V |title=Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases |journal=Am. J. Med. Genet. A |volume=152A |issue=9 |pages=2287–96 |date=September 2010 |pmid=20803646 |doi=10.1002/ajmg.a.33445 |url=}}</ref><ref name="pmid25397911">{{cite journal |vauthors=Hsu AP, McReynolds LJ, Holland SM |title=GATA2 deficiency |journal=Curr Opin Allergy Clin Immunol |volume=15 |issue=1 |pages=104–9 |date=February 2015 |pmid=25397911 |pmc=4342850 |doi=10.1097/ACI.0000000000000126 |url=}}</ref><ref name="pmid24345756">{{cite journal |vauthors=Dickinson RE, Milne P, Jardine L, Zandi S, Swierczek SI, McGovern N, Cookson S, Ferozepurwalla Z, Langridge A, Pagan S, Gennery A, Heiskanen-Kosma T, Hämäläinen S, Seppänen M, Helbert M, Tholouli E, Gambineri E, Reykdal S, Gottfreðsson M, Thaventhiran JE, Morris E, Hirschfield G, Richter AG, Jolles S, Bacon CM, Hambleton S, Haniffa M, Bryceson Y, Allen C, Prchal JT, Dick JE, Bigley V, Collin M |title=The evolution of cellular deficiency in GATA2 mutation |journal=Blood |volume=123 |issue=6 |pages=863–74 |date=February 2014 |pmid=24345756 |pmc=3916878 |doi=10.1182/blood-2013-07-517151 |url=}}</ref><ref name="pmid29605372">{{cite journal |vauthors=Zawawi F, Sokolov M, Mawby T, Gordon KA, Papsin BC, Cushing SL |title=Emberger syndrome: A rare association with hearing loss |journal=Int. J. Pediatr. Otorhinolaryngol. |volume=108 |issue= |pages=82–84 |date=May 2018 |pmid=29605372 |doi=10.1016/j.ijporl.2018.02.014 |url=}}</ref>
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| *#* Screening for GATA2 muations is indicated in patients who present with lymphedema and hematological abnormalities. Children should be screened for hematological disorders if they present with lower limb lymphedema. Besides symptomatic treatment for lymphedema and standard treatment for deafness, primary stem cell transplant is indicated for hematological malignancies. <ref name="pmid20803646">{{cite journal |vauthors=Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S, Lunt P, Jeffery S, Dokal I, Vulliamy T, Gibson B, Hodgson S, Cottrell S, Kiely L, Tinworth L, Kalidas K, Mufti G, Cornish J, Keenan R, Mortimer P, Murday V |title=Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases |journal=Am. J. Med. Genet. A |volume=152A |issue=9 |pages=2287–96 |date=September 2010 |pmid=20803646 |doi=10.1002/ajmg.a.33445 |url=}}</ref><ref name="pmid26767875">{{cite journal |vauthors=Seo SK, Kim KY, Han SA, Yoon JS, Shin SY, Sohn SK, Moon JH |title=First Korean case of Emberger syndrome (primary lymphedema with myelodysplasia) with a novel GATA2 gene mutation |journal=Korean J. Intern. Med. |volume=31 |issue=1 |pages=188–90 |date=January 2016 |pmid=26767875 |pmc=4712426 |doi=10.3904/kjim.2016.31.1.188 |url=}}</ref><ref name="pmid28643018">{{cite journal |vauthors=Hirabayashi S, Wlodarski MW, Kozyra E, Niemeyer CM |title=Heterogeneity of GATA2-related myeloid neoplasms |journal=Int. J. Hematol. |volume=106 |issue=2 |pages=175–182 |date=August 2017 |pmid=28643018 |doi=10.1007/s12185-017-2285-2 |url=}}</ref><ref name="pmid28179280">{{cite journal |vauthors=Crispino JD, Horwitz MS |title=GATA factor mutations in hematologic disease |journal=Blood |volume=129 |issue=15 |pages=2103–2110 |date=April 2017 |pmid=28179280 |pmc=5391620 |doi=10.1182/blood-2016-09-687889 |url=}}</ref>
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| *# '''Primary generalized lymphatic anomaly'''
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| *#* Also called Hennekam lymphangiectasia-lymphedema syndrome, this disorder is characterized by generalized lymphatic anomalies such as lymphangiectasia and lymphedema, typical dysmorphic features such as flat nasal bridge, hypertelorism, small mouth and variable intellectual disability that may present as developmental delay. Lymphangiectasias are typically found in intestines and can cause generalized body swelling due to loss of proteins but can also be found in other organs such as kidney, thyroid gland and pleura.<ref name="pmid25925991">{{cite journal |vauthors=Frosk P, Chodirker B, Simard L, El-Matary W, Hanlon-Dearman A, Schwartzentruber J, Majewski J, Rockman-Greenberg C |title=A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature |journal=BMC Med. Genet. |volume=16 |issue= |pages=28 |date=April 2015 |pmid=25925991 |pmc=4630843 |doi=10.1186/s12881-015-0175-0 |url=}}</ref><ref name="pmid12376947">{{cite journal |vauthors=Van Balkom ID, Alders M, Allanson J, Bellini C, Frank U, De Jong G, Kolbe I, Lacombe D, Rockson S, Rowe P, Wijburg F, Hennekam RC |title=Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review |journal=Am. J. Med. Genet. |volume=112 |issue=4 |pages=412–21 |date=November 2002 |pmid=12376947 |doi=10.1002/ajmg.10707 |url=}}</ref><ref name="pmid25616299">{{cite journal |vauthors=Deng XL, Yin F, Zhang GY, Duan YD |title=[A complicated case study: Hennekam syndrome] |language=Chinese |journal=Zhongguo Dang Dai Er Ke Za Zhi |volume=17 |issue=1 |pages=77–80 |date=January 2015 |pmid=25616299 |doi= |url=}}</ref>
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| *#* Mutations in CCBE1 gene are thought to be the main culprit although mutations in FAT4 gene has also be linked by some studies. CCBE1 encodes for Collagen- and calcium-binding EGF domain-containing protein 1 (CCBE1) that plays a crucial role in activation of vascular endothelial growth factor-C (VEGFC) through its collagen domain. Inheritance tends to follow autosomal-recessive pattern.<ref name="pmid25814692">{{cite journal |vauthors=Roukens MG, Peterson-Maduro J, Padberg Y, Jeltsch M, Leppänen VM, Bos FL, Alitalo K, Schulte-Merker S, Schulte D |title=Functional Dissection of the CCBE1 Protein: A Crucial Requirement for the Collagen Repeat Domain |journal=Circ. Res. |volume=116 |issue=10 |pages=1660–9 |date=May 2015 |pmid=25814692 |doi=10.1161/CIRCRESAHA.116.304949 |url=}}</ref><ref name="pmid25925991">{{cite journal |vauthors=Frosk P, Chodirker B, Simard L, El-Matary W, Hanlon-Dearman A, Schwartzentruber J, Majewski J, Rockman-Greenberg C |title=A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature |journal=BMC Med. Genet. |volume=16 |issue= |pages=28 |date=April 2015 |pmid=25925991 |pmc=4630843 |doi=10.1186/s12881-015-0175-0 |url=}}</ref><ref name="pmid25616299">{{cite journal |vauthors=Deng XL, Yin F, Zhang GY, Duan YD |title=[A complicated case study: Hennekam syndrome] |language=Chinese |journal=Zhongguo Dang Dai Er Ke Za Zhi |volume=17 |issue=1 |pages=77–80 |date=January 2015 |pmid=25616299 |doi= |url=}}</ref><ref name="pmid24552833">{{cite journal |vauthors=Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen VM, Holopainen T, Kivelä R, Ortega S, Kärpanen T, Alitalo K |title=CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation |journal=Circulation |volume=129 |issue=19 |pages=1962–71 |date=May 2014 |pmid=24552833 |doi=10.1161/CIRCULATIONAHA.113.002779 |url=}}</ref>
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| *#* Diagnosis depends on history and examination, lab findings, and genetic testing for associated mutations. Analysis for CCBE1 mutation should be considered in patients presenting with unexplained lymphatic anomalies, and/or unexplained intellectual disability. No definitive management is available at this point. Conservative measures for lymphedema and protein deficiency, and rehabilitation for intellectual disability is the mainstay of management.<ref name="pmid29560340">{{cite journal |vauthors=Lee YG, Kim SC, Park SB, Kim MJ |title=Hennekam Syndrome: A Case Report |journal=Ann Rehabil Med |volume=42 |issue=1 |pages=184–188 |date=February 2018 |pmid=29560340 |pmc=5852224 |doi=10.5535/arm.2018.42.1.184 |url=}}</ref><ref name="pmid25925991">{{cite journal |vauthors=Frosk P, Chodirker B, Simard L, El-Matary W, Hanlon-Dearman A, Schwartzentruber J, Majewski J, Rockman-Greenberg C |title=A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature |journal=BMC Med. Genet. |volume=16 |issue= |pages=28 |date=April 2015 |pmid=25925991 |pmc=4630843 |doi=10.1186/s12881-015-0175-0 |url=}}</ref><ref name="pmid25616299">{{cite journal |vauthors=Deng XL, Yin F, Zhang GY, Duan YD |title=[A complicated case study: Hennekam syndrome] |language=Chinese |journal=Zhongguo Dang Dai Er Ke Za Zhi |volume=17 |issue=1 |pages=77–80 |date=January 2015 |pmid=25616299 |doi= |url=}}</ref><ref name="pmid29560340">{{cite journal |vauthors=Lee YG, Kim SC, Park SB, Kim MJ |title=Hennekam Syndrome: A Case Report |journal=Ann Rehabil Med |volume=42 |issue=1 |pages=184–188 |date=February 2018 |pmid=29560340 |pmc=5852224 |doi=10.5535/arm.2018.42.1.184 |url=}}</ref>
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| *# '''Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome'''
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| *#* As name indicates, this syndrome is characterized by microcephaly that is often accompanied by intellectual disability, congenital lymphedema and ocular findings. Ocular defects, often because of chorioretinal dysplasia, may include peripheral retinal pigmentation, retinal folds, chorioretinopathy, widespread chorioretinal atrophy, hyperopia, small corneas, nystagmus and small optic nerves. Microcephaly can be variable and imaging often shows small size brain. Intellectual disability can also vary from normal developmental to severe mental retardation. Lymphedema most often involves lower limbs and may or may not resolve spontaneously. Facial features are distinct with broad nose, anteverted nares, upslanting palpebral fissures, a rounded nasal tip, a long philtrum, a pointed chin, a thin upper lip, prominent ears, and patient may also have atrial septal defects.<ref name="pmid25934493">{{cite journal |vauthors=Schlögel MJ, Mendola A, Fastré E, Vasudevan P, Devriendt K, de Ravel TJ, Van Esch H, Casteels I, Arroyo Carrera I, Cristofoli F, Fieggen K, Jones K, Lipson M, Balikova I, Singer A, Soller M, Mercedes Villanueva M, Revencu N, Boon LM, Brouillard P, Vikkula M |title=No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome |journal=Orphanet J Rare Dis |volume=10 |issue= |pages=52 |date=May 2015 |pmid=25934493 |pmc=4464120 |doi=10.1186/s13023-015-0271-4 |url=}}</ref><ref name="pmid5936364">{{cite journal |vauthors=McKusick VA, Stauffer M, Knox DL, Clark DB |title=Chorioretinopathy with hereditary microcephaly |journal=Arch. Ophthalmol. |volume=75 |issue=5 |pages=597–600 |date=May 1966 |pmid=5936364 |doi= |url=}}</ref><ref name="pmid15930898">{{cite journal |vauthors=Vasudevan PC, Garcia-Minaur S, Botella MP, Perez-Aytes A, Shannon NL, Quarrell OW |title=Microcephaly-lymphoedema-chorioretinal dysplasia: three cases to delineate the facial phenotype and review of the literature |journal=Clin. Dysmorphol. |volume=14 |issue=3 |pages=109–16 |date=July 2005 |pmid=15930898 |doi= |url=}}</ref><ref name="pmid19076985">{{cite journal |vauthors=Eventov-Friedman S, Singer A, Shinwell ES |title=Microcephaly, lymphedema, chorioretinopathy and atrial septal defect: a case report and review of the literature |journal=Acta Paediatr. |volume=98 |issue=4 |pages=758–9 |date=April 2009 |pmid=19076985 |doi=10.1111/j.1651-2227.2008.01161.x |url=}}</ref><ref name="pmid25115524">{{cite journal |vauthors=Mirzaa GM, Enyedi L, Parsons G, Collins S, Medne L, Adams C, Ward T, Davitt B, Bicknese A, Zackai E, Toriello H, Dobyns WB, Christian S |title=Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature |journal=Am. J. Med. Genet. A |volume=164A |issue=11 |pages=2879–86 |date=November 2014 |pmid=25115524 |pmc=4205200 |doi=10.1002/ajmg.a.36707 |url=}}</ref>
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| *#* Mutations in KIF11 gene that encodes for spindle motor protein of kinesin family, a protein that plays a role in mitosis, are thought to cause this syndrome. These mutations can be sporadic or hereditary, and when hereditary they follow autosomal-dominant pattern with variable expression and reduced penetrance.<ref name="pmid25934493">{{cite journal |vauthors=Schlögel MJ, Mendola A, Fastré E, Vasudevan P, Devriendt K, de Ravel TJ, Van Esch H, Casteels I, Arroyo Carrera I, Cristofoli F, Fieggen K, Jones K, Lipson M, Balikova I, Singer A, Soller M, Mercedes Villanueva M, Revencu N, Boon LM, Brouillard P, Vikkula M |title=No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome |journal=Orphanet J Rare Dis |volume=10 |issue= |pages=52 |date=May 2015 |pmid=25934493 |pmc=4464120 |doi=10.1186/s13023-015-0271-4 |url=}}</ref><ref name="pmid25764055">{{cite journal |vauthors=Mears K, Bakall B, Harney LA, Penticoff JA, Stone EM |title=Autosomal Dominant Microcephaly Associated With Congenital Lymphedema and Chorioretinopathy Due to a Novel Mutation in KIF11 |journal=JAMA Ophthalmol |volume=133 |issue=6 |pages=720–1 |date=June 2015 |pmid=25764055 |doi=10.1001/jamaophthalmol.2015.199 |url=}}</ref><ref name="pmid26472404">{{cite journal |vauthors=Hu H, Xiao X, Li S, Jia X, Guo X, Zhang Q |title=KIF11 mutations are a common cause of autosomal dominant familial exudative vitreoretinopathy |journal=Br J Ophthalmol |volume=100 |issue=2 |pages=278–83 |date=February 2016 |pmid=26472404 |doi=10.1136/bjophthalmol-2015-306878 |url=}}</ref><ref name="pmid25996076">{{cite journal |vauthors=Balikova I, Robson AG, Holder GE, Ostergaard P, Mansour S, Moore AT |title=Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11 |journal=Acta Ophthalmol |volume=94 |issue=1 |pages=92–8 |date=February 2016 |pmid=25996076 |doi=10.1111/aos.12759 |url=}}</ref><ref name="pmid24281367">{{cite journal |vauthors=Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, Quarrell O, Brady AF, Spier I, Hazan F, Moldovan O, Wieczorek D, Mikat B, Petit F, Coubes C, Saul RA, Brice G, Gordon K, Jeffery S, Mortimer PS, Vasudevan PC, Mansour S |title=Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations |journal=Eur. J. Hum. Genet. |volume=22 |issue=7 |pages=881–7 |date=July 2014 |pmid=24281367 |pmc=3938398 |doi=10.1038/ejhg.2013.263 |url=}}</ref>
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| *#* Diagnosis requires genetic testing in addition to clinical findings. Long term cardiac and ophthalmologic follow-ups are recommended.<ref name="pmid19076985">{{cite journal |vauthors=Eventov-Friedman S, Singer A, Shinwell ES |title=Microcephaly, lymphedema, chorioretinopathy and atrial septal defect: a case report and review of the literature |journal=Acta Paediatr. |volume=98 |issue=4 |pages=758–9 |date=April 2009 |pmid=19076985 |doi=10.1111/j.1651-2227.2008.01161.x |url=}}</ref><ref name="pmid24281367">{{cite journal |vauthors=Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, Quarrell O, Brady AF, Spier I, Hazan F, Moldovan O, Wieczorek D, Mikat B, Petit F, Coubes C, Saul RA, Brice G, Gordon K, Jeffery S, Mortimer PS, Vasudevan PC, Mansour S |title=Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations |journal=Eur. J. Hum. Genet. |volume=22 |issue=7 |pages=881–7 |date=July 2014 |pmid=24281367 |pmc=3938398 |doi=10.1038/ejhg.2013.263 |url=}}</ref>
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| *# '''Lymphedema-choanal atresia'''
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| *#* A very rare syndrome described in 1982 in a Middle Eastern family when individuals in the family presented with bilateral posterior choanal atresia with other developmental abnormalities such as high arched palate, hypoplastic nipples, pericardial effusion, and pectus excavatum. Follow up detected lymphedema in five individuals with choanal atresia in the family later in 1991.<ref name="pmid20826270">{{cite journal |vauthors=Au AC, Hernandez PA, Lieber E, Nadroo AM, Shen YM, Kelley KA, Gelb BD, Diaz GA |title=Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans |journal=Am. J. Hum. Genet. |volume=87 |issue=3 |pages=436–44 |date=September 2010 |pmid=20826270 |pmc=2933336 |doi=10.1016/j.ajhg.2010.08.008 |url=}}</ref>
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| *#* Deletion in PTPN14 gene that appeared to follow autosomal-recessive pattern are thought to be the cause. This gene encodes for a protein that is thought to be involved in cell-signaling pathways and regulation of cellular functions.<ref name="pmid20826270">{{cite journal |vauthors=Au AC, Hernandez PA, Lieber E, Nadroo AM, Shen YM, Kelley KA, Gelb BD, Diaz GA |title=Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans |journal=Am. J. Hum. Genet. |volume=87 |issue=3 |pages=436–44 |date=September 2010 |pmid=20826270 |pmc=2933336 |doi=10.1016/j.ajhg.2010.08.008 |url=}}</ref>
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| ====Venous malformations (VM)==== | | ====Venous malformations (VM)==== |
| =====Common VM===== | | =====Common VM===== |