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Gastroenterology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
This is a rare pathological dilatation of lymhatic vessels of the small intestine. Children may also have extraintestinal manifestation such as limb or lung involvement. Hennekam syndrome is a rare autosomal recessive form of intestinal lympangiectasia with lymphoedema, characteristic facial appearance and developmental delay affecting < 1 in 1000,000 (Fig. 9.32).
Fetal hydrops – a review and a clinical approach to identifying the cause
Published in Expert Opinion on Orphan Drugs, 2020
Esther Dempsey, Tessa Homfray, John M Simpson, Steve Jeffery, Sahar Mansour, Pia Ostergaard
Hennekam syndrome was first described in 1989 in a series of related individuals with severe limb, genital and facial lymphedema as well as poor growth, seizures and intellectual impairment [118]. One type of Hennekam syndrome is caused by pathogenic mutations in CCBE1 [119]. CCBE1 is crucial to lymphangiogenesis due to its role in lymphangioblast budding [120], and mutations have been shown to cause recurrent fetal hydrops [121,122]. Mutations in FAT4, ADAMTS3 and FBXL7 have also been implicated in Hennekam Syndrome [123–125].
Whole genome sequencing and inheritance-based variant filtering as a tool for unraveling missing heritability in pediatric cancer
Published in Pediatric Hematology and Oncology, 2023
Charlotte Derpoorter, Ruben Van Paemel, Katrien Vandemeulebroecke, Jolien Vanhooren, Bram De Wilde, Geneviève Laureys, Tim Lammens
This study aims to combine the advantages of NGS for the identification of rare variants with familial pedigree information in an inheritance-based filtering approach. This strategy reduces substantially the number of candidate variants, without predefined assumptions on gene function and/or mutation type. In a family with two pediatric BL patients, only 18 protein-coding variants remained after filtering, enabling further genetic and functional exploration for all these genes and variants. Additional refinement is possible using functional prediction software, but caution is needed as those tools are only able to model part of the true biological complexity. Therefore, multiple prediction scores were combined and variants were prioritized accordingly, highlighting two missense variants in FAT4 and DCHS2 with a CADD score > 10, multiple deleterious prediction scores and located in a conserved region. Although knowledge about the exact biological function of FAT4 or DCHS2 remains limited, tissue specific roles in embryonic development and epithelial-to-mesenchymal transition have been described.33,35,42–44 This is especially relevant as several lines of evidence indicate a developmental origin of childhood cancer.45 For example, a fetal origin of tumors for hepatoblastoma and childhood lymphoblastic leukemia has been shown.45 By contrast, most adult cancers arise in aging cells as a consequence of accumulated DNA damage. Interestingly, both genes are involved in planar cell polarity and Hippo signaling, which could indicate a combined signaling effect as possible mechanism of cancer predisposition. FAT4 has been shown to interact with DCHS1, a paralog of DCHS2.43 Mice deficient for FAT4 or DCHS1 show developmental abnormalities and die shortly after birth.43 DCHS2 null mice are viable and fertile, probably related to functional redundancy between DCHS2 and DCHS1.46 Biallelic mutations in FAT4 have been identified in Hennekam syndrome, a disorder characterized by lymphedema, lymphangiectasia and cognitive impairment and uncovered an important role for FAT4 in the lymphatic vasculature.47,48FAT4 is recurrently mutated in several cancer types and gene suppression by mutagenesis or silencing induces tumorigenesis in breast and gastric cancers.49,50 Interestingly, TEAD transcription factors act downstream of the Hippo signaling pathway and were shown to form a regulatory feedback mechanism with MYC to coordinate gene expression required for cell proliferation.51 In addition, FAT4 downregulation has been associated with increased MYC expression in gastric cancer, ovarian cancer and oral squamous cells carcinoma.35,52,53