An unusually severe phenotype for familial adenomatous polyposis

Abstract

Familial adenomatous polyposis (FAP) is a dominantly inherited predisposition to the development of many hundreds to thousands of adenomatous polyps of the colon. The mean age of onset is around 15 years, symptoms may arise in the third decade, and the median age for the development of colonic cancer is 35-40 years. Prophylactic colectomy reduces the risk of death from colorectal cancer to such an extent that late sequelae such as upper gastrointestinal tumours have become the main cause of mortality in appropriately managed patients. The age at which colonic surveillance begins reflects the natural history of the disease. Onset of polyp formation and cancer in childhood is very unusual, but has recently been associated with a specific mutation at codon 1309 in exon 15 where a more severe phenotype is sometimes observed. The case histories of two families are reported in which there is childhood onset of polyps in the youngest generation and in one case a carcinoma, in whom mutations have been identified in exon 11 of the APC gene. Several other aVected relatives were diagnosed at ages ranging from 5-48 years, some already with a cancer at the time of first screening. Since the aim of screening for colonic polyps is prevention of colonic cancer, family members at risk should be oVered genetic assessment and direct mutation testing where this is possible, usually in the early teens. In the absence of a genetic test (the situation in about one third of families) or in a known gene carrier, annual colonoscopy examination is advised from the same age. Clinicians should take note of the family history and be prepared to consider much earlier intervention if symptoms occur in a child with a family history of FAP. Where childhood onset of polyps has occurred, other children at risk in the family must be oVered earlier genetic testing and endoscopic surveillance.

Investigation of APC Mutations in a Turkish Familial Adenomatous Polyposis Family by Heterodublex Analysis

“…20 It was been reported that mutations located in the 5Ј one-half of exon 15 seem to lead to a more severe phenotype. 22,23 Some features such as appearance of adenomas at early ages (younger than aged 40 years), and aggressive metastatic carcinoma seen in our family were in agreement to those findings. Case 15 of this family was very interesting.…”

Colorectal cancer in two pre-teenage siblings with familial adenomatous polyposis

“…However, like our cases, there are also young children who present with a primary adenocarcinoma of the colon. Besides the early onset cases described here, Eccles and coworkers [3] reported a family where the index case was diagnosed with FAP at 7 years of age and with colon cancer at 9 years of age. Children with colorectal cancer usually have a far more advanced stage of disease at the time of recognition when compared to the general population.…”

The Impact of Presymptomatic Molecular Testing in Hereditary Cancers

“…In each family, DNA from an affected individual should always be tested in the first instance to identify the causative mutation [7]. If there is no living affected individual in a family from whom DNA can be obtained, it may still be feasible to carry out mutation detection if formalin-fixed paraffin blocks of tissue removed at the time of surgery are available from which DNA can be extracted [11].…”

“…For example, a particularly severe phenotype has been seen in two families with mutations in exon 11. In these families, affected individuals were diagnosed as young as 5 years of age and cancer was detected in 1 individual aged 9 [7]. The presence of extracolonic manifestations can be used, however, to indicate where to look initially for mutations [30].…”

“…Incorporation of a positive result in a child's medical record could for example also lead to problems in later life such as with employment and insurance issues. However, some conditions, such as familial adenomatous polyposis, develop during adolescence, and it may therefore be appropriate to carry out the testing in childhood [2,6,7]. In other conditions such as hereditary non-polyposis colon cancer, the majority of individuals do not develop the disease until they are in their 20s and 30s, so predictive testing can be delayed until individuals reach adult life.…”