Cleft lip, cleft palate, hereditary diffuse gastric cancer and germline mutations in CDH1

In their recent article on Dutch families with hereditary diffuse gastric cancer syndrome (HDGC), Kluijt et al. reported cleft lip (CL) or cleft palate (CP) in four CDH1 mutation carriers from two distinct families.1 A French team had previously reported similar observations in five carriers from two families.2 We describe herein the case of a young patient with a history of CL, CP, and HDGC who turned out to carry a germline mutation in CDH1. A 17-year-old teenage girl of Southeast Asian origin was investigated for refractory iron-deficiency anemia. She had a history of CL with CP, with multiple operations throughout childhood and adolescence. Upper gastrointestinal endoscopy and colonoscopy were macroscopically normal, but epithelial signet ring cells, with spread beyond the basement membrane, were seen on gastric biopsies. Given the strong presumption of diffuse gastric carcinoma, the medical team in charge opted for gastrectomy. The presumption was confirmed as the pathologist, on careful and systematic examination of the surgical specimen, observed multiple foci of intramucosal adenocarcinoma of the diffuse type within the fundus and the body of the stomach. The patient was referred to the cancer genetics clinic. Family history was unknown as she had been adopted as a baby, but her personal history of diffuse gastric cancer at a young age was enough to warrant genetic testing.3 The laboratory sequenced the coding regions of CDH1 (including adjacent intronic base pairs) on DNA extracted from white blood cells, and found a deleterious c.832+1G > T mutation one base-pair downstream exon 6. The mutation affects intron 6 splicing, and as a result leads to exon 6 skipping during the transformation of primary RNA into mRNA. Including our patient, 10 cases of CDH1 mutation carriers with CL/CP have been reported to date. This association is unlikely to be the result of chance for the following reasons. First, there is a clear excess of CL/CP cases in CDH1 families. Indeed, CL/CP is rare in the general population with a reported frequency of 1–2/1000, whereas 4/58 (7%) mutations carriers in the Dutch study had CL/CP.1, 4 In France, where there are about 100 registered mutation carriers (French Cancer Genetics Network), six carriers (6%) including this one have CL/CP.2 Second, we expect CL/CP to be very much underreported in CDH1 families, as current guidelines do not require cancer geneticists to enquire about CL/CP among index cases and their relatives. Third, the CL/CP—CDH1 mutation association has strong biological plausibility, as CDH1 encodes for E-cadherin, a cell-cell adhesion protein that is overexpressed during the critical stages of lip and palate development.2, 5 We believe that from now on, a personal or family history of CL/CP should be rigorously and systematically looked for in any individual with a suspicion of HDGC, as it would, if positive, increase the probability of finding a mutation in CDH1. We would also encourage the HDGC expert panel to incorporate a personal or family history of CL/CP into a future, updated version of the HDGC-defining criteria.