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A dramatic case of early‐onset familial adenomatous polyposis

To the Editor: Familial adenomatous polyposis (FAP) is an inherited predisposition to the development of hundreds to thousands of adenomatous polyps in the colon. Symptoms usually arise in the third decade of life, and the median age for the diagnosis of colon cancer is 35–40years (1). FAP is caused by an autosomal dominant mutation in the adenomatosis polyposis coli (APC) gene, located on the long arm of chromosome 5 (5q21). More than 730 germline mutations have been identified; most of these are nonsense or frameshift mutations that result in a premature stop codon, thus producing a truncated, inactive APC protein (2). The preferred genetic test for FAP is the protein truncation test (PTT), a test that can detect more than 80% of all germline mutations. Symptomatic young patients have been described previously, but always in the context of a positive family history (3, 4). We report a severe case of FAP with onset in the toddler years, which represents a de novo mutation. A 10-year-old female was evaluated for anemia and an 8-year-long history of recurrent hematochezia. Family history was negative for FAP, other polyposis syndromes, or colon cancer. The result of physical examination was normal. Laboratory evaluation revealed a hemoglobin level of 10.9 g/l, MCV of 68, and ferritin of 8mg/dl. Total colonoscopy revealed hundreds of sessile polyps measuring up to 1.0 cm, with pancolonic involvement.Histology confirmed classic adenomatous polyps, with an evidence ofmoderate dysplasia in some biopsies. Esophagogastroduodenoscopy (EGD) revealed polyps in the gastric fundus and duodenum, and histological examination showed adenomatous polyps without extension beyond the muscularis mucosae. Because of dysplasia in some of the colonic biopsies, the patient was referred for total proctocolectomy and ileoanal anastomosis with mucosectomy. She has remained well since then, with the ongoing EGD surveillance of the upper gastrointestinal mucosa. Mutation analysis was performed in the proband and both parents, with the APC PTT, single-strand conformational polymorphism (SSCP) and direct sequencing of amplified fragments of the gene, according to previously reported methods (4–6) (Fig. 1). With this method, we identified the causative mutation in the proband, i.e. a 5-bp deletion at nucleotides 3927–3931 (AAAGA) called ‘3927–3931delAAAGA’ and previously described by Miyoshi et al. (7), which resulted in a premature stop after codon 1309. As shown in the Fig. 2, PTT of the APC gene (exon 15, fragment 15ET7-15J, including nucleotides from 3085 to 5103) showed an expected normal polypeptide of about 74kDa, as well as a truncated polypeptide of about 31kDa. SSCP analysis showed a variant conformer of exon 15 (fragment G), and direct sequencing of this fragment confirmed the AAAGA deletion at nucleotides 3927–3931 (Fig. 3). Molecular diagnosis of both parents showed that they were not carriers of the mutation. Therefore, the APC mutation in the proband is a de novo mutation. In fact, microsatellite analysis of 15 markers (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, THO1, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D1BS51, D5S818, and FGA) and the amelogenina locus, performed onDNA from the parents and proband, excludes the possibility of a non-paternity case. We have described a patient with severe FAP, caused by a deletion of bases AAAGA from sites 3927 to 3931 on the APC gene. Twenty percent of all FAP pedigrees are associated with this mutation, which typically results in severe and early-onset disease, often associated with congenital hypertrophy of the retinal pigment