Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation

Hennekam, Raoul C. M.; Geerdink, R. A.; Hamel, B.C.J.; Hennekam, F. A. M.; Kraus, P. H.; Rammeloo, J. A.; Tillemans, A. A. W.

doi:10.1002/ajmg.1320340429

Cited by 172 publications

(158 citation statements)

References 31 publications

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“…The Hennekam syndrome, characterized by lymphangiectasia, lymphedema, and typical facial features and cognitive impairment, was described in 1989 (20). In 2009, CCBE1 recessive mutations were shown to cause this syndrome (HKLLS1; OMIM 235510) (15).…”

Section: Discussionmentioning

confidence: 99%

Loss of ADAMTS3 activity causes Hennekam lymphangiectasia–lymphedema syndrome 3

Brouillard

Dupont

Helaers

et al. 2017

Human Molecular Genetics

103

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Primary lymphedema is due to developmental and/or functional defects in the lymphatic system. It may affect any part of the body, with predominance for the lower extremities. Twenty-seven genes have already been linked to primary lymphedema, either isolated, or as part of a syndrome. The proteins that they encode are involved in VEGFR3 receptor signaling. They account for about one third of all primary lymphedema cases, underscoring the existence of additional genetic factors. We used whole-exome sequencing to investigate the underlying cause in a non-consanguineous family with two children affected by lymphedema, lymphangiectasia and distinct facial features. We discovered bi-allelic missense mutations in ADAMTS3. Both were predicted to be highly damaging. These amino acid substitutions affect well-conserved residues in the prodomain and in the peptidase domain of ADAMTS3. In vitro, the mutant proteins were abnormally processed and sequestered within cells, which abolished proteolytic activation of pro-VEGFC. VEGFC processing is also affected by CCBE1 mutations that cause the Hennekam lymphangiectasia-lymphedema syndrome syndrome type1. Our data identifies ADAMTS3 as a novel gene that can be mutated in individuals affected by the Hennekam syndrome. These patients have distinctive facial features similar to those with mutations in CCBE1. Our results corroborate the recent in vitro and murine data that suggest a close functional interaction between ADAMTS3 and CCBE1 in triggering VEGFR3 signaling, a cornerstone for the differentiation and function of lymphatic endothelial cells.

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Section: Discussionmentioning

confidence: 99%

Loss of ADAMTS3 activity causes Hennekam lymphangiectasia–lymphedema syndrome 3

Brouillard

Dupont

Helaers

et al. 2017

Human Molecular Genetics

103

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“…This is an autosomal recessive syndrome characterized by lymphangiectasia, severe peripheral lymphedema, facial anomalies, seizures, mild growth retardation, and variable mental retardation [Hennekam et al, 1989]. Six children from five different families from the UAE with this syndrome were evaluated and all had flat midface with hypertelorism, but only two of them had dysplastic ear with atretic ear canal [Al-Gazali et al, 2003b] (unpublished data).…”

Section: Hennekam Syndromementioning

confidence: 99%

Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE)

Al‐Gazali

Ali

2010

Hum. Mutat.

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“…It can present in utero with ascites, pleural/pericardial effusions and hydrops fetalis. In 1989, Hennekam et al described an autosomal recessive condition in which members of a consanguineous family were reported with congenital severe peripheral lymphoedema, intestinal lymphangiectasia, facial anomalies, seizures, mild growth retardation and mental retardation (Hennekam et al 1989). The phenotype of Hennekam syndrome has since been expanded and the degree of mental retardation is reported to be very variable, even within families, ranging from near normal development to severe delay (Forzano et al 2002;Van Balkom et al 2002;Yasunaga et al 1993).…”

Section: Introductionmentioning

confidence: 99%

Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia

et al. 2009

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Generalised lymphatic dysplasia (GLD) is chararacterised by extensive peripheral lymphoedema with visceral involvement. In some cases it presents in utero with hydrops fetalis. Autosomal dominant and recessive inheritance has been reported. A large, non-consanguineous family with three affected siblings with generalised lymphatic dysplasia is presented. One child died aged 5 months, one spontaneously miscarried at 17 weeks gestation, and the third has survived with extensive lymphoedema. All three presented with hydrops fetalis. There are seven other siblings who are clinically unaffected.Linkage analysis produced two loci on chromosome 18, covering 22Mb and containing 150 genes, one of which is CCBE1. A homozygous cysteine to serine change in CCBE1 has been identified in the proband, in exon 3, in a residue that is conserved across species. High density SNP analysis revealed homozygosity (a region of 900kb) around the locus for CCBE1 in all three affected cases. This indicates a likely ancestral mutation that is common to both parents; an example of a homozygous mutation representing Identity by Descent (IBD) in this pedigree. Recent studies in zebrafish have shown this gene to be required for lymphangiogenesis and venous sprouting and are therefore supportive of our findings. In view of the conserved nature of the cysteine, the nature of the amino acid change, the occurrence of a homozygous region around the locus, the segregation within the family, and the evidence from zebrafish, we propose that this mutation is causative for the generalised lymphatic dysplasia in this family, and may be of relevance in cases of non-immune hydrops fetalis.Introduction.

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Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation

Cited by 172 publications

References 31 publications

Loss of ADAMTS3 activity causes Hennekam lymphangiectasia–lymphedema syndrome 3

Loss of ADAMTS3 activity causes Hennekam lymphangiectasia–lymphedema syndrome 3

Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE)

Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia

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