:Hennekam syndrome

{{Infobox medical condition (new)

| name = Hennekam syndrome

| synonyms = ennekam lymphangiectasia–lymphedema syndrome, intestinal lymphagiectasia–lymphedema–mental retardation syndrome

| image = Autosomal recessive - en.svg

| caption = Hennekam syndrome is inherited in an autosomal recessive manner

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Hennekam syndrome, also known as intestinal lymphagiectasia–lymphedema–mental retardation syndrome,{{cite book |url=http://www.cags.org.ae/pdf/235510.pdf |date=2005 |author=Tadmouri GO |chapter=Hennekam lymphangiectasia–lymphedema syndrome |publisher=Centre for Arab Genomic Studies |title=Catalogue for Transmission Genetics in Arabs |access-date=2010-02-23 |archive-date=2017-02-02 |archive-url=https://web.archive.org/web/20170202002125/http://www.cags.org.ae/pdf/235510.pdf |url-status=dead }} is an autosomal recessive disorder consisting of intestinal lymphangiectasia, facial anomalies, peripheral lymphedema, and mild to moderate levels of growth and intellectual disability.{{cite journal |author=Erkan T, Kutlu T, Çullu F |display-authors=etal |title=Syndrome de hennekamHennekam syndrome |trans-title=Hennekam syndrome |language=French |journal=Arch Pediatr |volume=5 |issue=12 |pages=1344–6 |year=1998 |pmid=9885742 |doi=10.1016/S0929-693X(99)80054-2 }}

It is also known as "lymphedema-lymphangiectasia-mental retardation syndrome".{{cite journal |vauthors=Van Balkom ID, Alders M, Allanson J|display-authors=etal |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 }}

Hennekam syndrome is subdivided according to the causative genetic lesion, most (or all) of which are affecting the VEGF-C/VEGFR-3 signaling pathway:

• Type 1 (mutations in CCBE1) {{cite journal |vauthors=Alders M, Hogan BM, Gjini E|display-authors=etal |title=Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans |journal=Nat. Genet. |volume=41 |issue=12 |pages=1272–4 |date=December 2009 |pmid=19935664 |doi=10.1038/ng.484 |s2cid=205356254 }}
• Type 2 (mutations in FAT4){{cite journal |vauthors=Alders M, Al-Gazali L, Cordeiro I|display-authors=etal |title=Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome |journal=Hum. Genet. |volume=133 |issue=9 |pages=1161–7 |date=June 2014 |pmid=24913602 |doi=10.1007/s00439-014-1456-y |s2cid=14414158 }}
• Type 3 (mutations in ADAMTS3){{Cite journal| doi = 10.1093/hmg/ddx297| pmid = 28985353 | volume = 26| issue = 21| pages = 4095–4104| last1 = Brouillard| first1 = Pascal| last2 = Dupont| first2 = Laura| last3 = Helaers| first3 = Raphael| last4 = Coulie| first4 = Richard| last5 = Tiller| first5 = George E.| last6 = Peeden| first6 = Joseph| last7 = Colige| first7 = Alain| last8 = Vikkula| first8 = Miikka| title = Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3| journal = Hum. Mol. Genet. | date = 2017| doi-access = free}}

The first recognition of a genetic association was with CCBE1, published by its namesake, Raoul Hennekam.{{Cite journal| doi = 10.1002/ajmg.1320340429| pmid = 2624276 | volume = 34| issue = 4| pages = 593–600| last1 = Hennekam| first1 = R. C. M.| last2 = Geerdink| first2 = R. A.| last3 = Hamel| first3 = B. C. J.| last4 = Hennekam| first4 = F. a. M.| last5 = Kraus| first5 = P.| last6 = Rammeloo| first6 = J. A.| last7 = Tillemans| first7 = A. a. W.| title = Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation| journal = American Journal of Medical Genetics| date = 1989}} The molecular mechanism of the lymphedema phenotype in CCBE1-associated cases was identified as a diminished ability of the mutated CCBE1 to accelerate and focus the activation of the primary lymphangiogenic growth factor VEGF-C.{{cite journal |vauthors=Jeltsch M, Jha SK, Tvorogov D|display-authors=etal|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=February 2014 |pmid=24552833 |doi=10.1161/CIRCULATIONAHA.113.002779 |doi-access=free }} Mutations in the FAT4 gene had previously been only associated with van Maldergem syndrome, but the pathogenetic molecular mechanism and the function of FAT4 within lymphangiogenesis are still unknown.