Familial Adenomatous Polyposis 4

A number sign (#) is used with this entry because of evidence that familial adenomatous polyposis-4 (FAP4) is caused by compound heterozygous mutation in the MSH3 gene (600887) on chromosome 5q11.

Description

Familial adenomatous polyposis-4 is an autosomal recessive tumor predisposition syndrome characterized by the development of multiple colonic adenomas in adulthood, often with progression to colorectal cancer. Proliferative lesions in other tissues may also occur (summary by Adam et al., 2016).

For a discussion of genetic heterogeneity of familial adenomatous polyposis, see FAP1 (175100).

Clinical Features

Adam et al. (2016) reported 2 pairs of sibs from 2 unrelated families of central European origin with colorectal adenomatous polyposis. Three patients were diagnosed with polyps in their thirties; the fourth patient was diagnosed with colorectal adenocarcinoma at age 56. The 3 older patients, including both probands, had additional significant proliferative disorders affecting other organs, including thyroid adenoma, duodenal polyps, intraductal papillomas of the breast, uterine myoma, cutaneous fibrolipoma, astrocytoma, and gastric carcinoma.

Inheritance

The transmission pattern of FAP4 in the families reported by Adam et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 2 unrelated families with FAP4, Adam et al. (2016) identified 4 different mutations in the MSH3 gene in compound heterozygosity (600887.0001-600887.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Each patient carried a truncating mutation on 1 allele and a splice site mutation on the other allele, all with a loss-of-function effect. Normal and adenomatous colonic samples from 1 patient showed complete loss of nuclear MSH3 immunostaining. Tumor tissue from both probands showed high microsatellite instability of di- and tetranucleotides (EMAST). Adenomatous tissue from 1 patient also showed several different somatic mutations in the APC gene (611731).