Introduction

Familial adenomatous polyposis (FAP) is an inherited, autosomal dominant syndrome caused by germ line mutations in the adenomatous polyposis coli (APC) gene [1, 2]. FAP is classified on the basis of the presence of over 100 colonic adenomas with variable age of onset (age10–40 years), which progresses to colorectal cancer (CRC) at an average age of 40 years if left untreated [3].

FAP may be manifested by various phenotypes [4–7]. Attenuated adenomatous polyposis coli (AAPC) is one of the phenotypically distinguished variants of FAP [6, 8]. AAPC is manifested by the occurrence of sparse polyps (>100) in the colon [9]. The occurrence of gastric fundic polyps and duodenal adenomas in AAPC is common [6, 9, 10]. In some cases, congenital hypertrophy of the retinal pigment epithelium (CHRPE) lesions and desmoid tumors have been described [6, 10]. The average age of the onset of the colorectal cancer is delayed in AAPC patients (average age 55 years) than in classical FAP. AAPC is caused by mutations of the APC gene occurring at the 5′ end [9, 11, 12, 17], but AAPC was also described in the cases of mutations localized at the 3′ end of the APC gene and at splice junctions [9, 13].

Mutations at 5′ end of the APC gene were described in exons 3 and 4. The mutations in the region encompassing codons 140 to 170 reveal phenotype FAP and AAPC. The possible explanation of this may be he occurrence of the AUG (start codon) at codon 184 and the sequence encompassing internal ribosome entry site (IRES) upstream this codon. The FAP phenotype may be attenuated by translations of nearly full-length protein lacking the first 184 amino acids [14].

Materials and methods

Clinical history

The family 9170 is the one of the nearly 200 Polish FAP families collected in our DNA bank established in the year 1997. The male proband has started to complain about gastric ailment at the age of 15. Approximately 30 polyps (histopathologically tubular adenoma), 1–4 mm in diameter, developed when he was 17 years old. The adenomatous polyps were located on the right side of the colon. Over a dozen of gastric fundic polyps and polyps of the body of the stomach and a few small duodenal adenomas were observed. We collected information about three generations of this family (Fig. 1). The proband’s father and grandfather (I-1, II-1) died due to colorectal cancer at 35 and 40 years of age respectively (Fig. 1). The father of the proband was diagnosed for polyp occurrence at the age of 23. Neither of these patients agreed for surgical intervention. In other branches of the family, two mutation carriers after colectomy do not reveal any colorectal cancer feature at 35 (II-3) and 70 (I-3) years of age.

Fig. 1
figure 1

Polyps and colorectal cancer in the proband’s family for three generations

Full size image

Molecular analysis

DNA was extracted from peripheral blood cells as described by Miller [15]. The APC gene was screened for mutations involving the analysis of the heteroduplex formation (HA) and detection of single-strand conformational polymorphisms (SSCP) [16]. DNA fragments forming heteroduplex in HA analysis or different patterns in SSCP analysis were further analyzed by direct PCR product sequencing using ALFExpress sequencer (Amersham-Pharmacia Biotech) according to the manufacturer’s specifications.

Results and discussions

The proband was classified as a typical case of AAPC according to features observed in the gastrointestinal tract. The APC gene novel mutation has not been described previously and involved CCTT deletion at codon 173, which causes premature APC gene termination of protein translation at the same codon. Based on current literature, the mutations should be associated with typical FAP phenotype. In contrast, the affected family members developed low number of polyps at an early age with extra colon features observed in AAPC. The onset of polyps and age of death covered by colorectal carcinoma in family members who refused prophylactic colectomy reflects clinical diagnosis of FAP rather than AAPC.

Localization of the APC gene mutations is associated with the phenotype of the FAP. In the presented case, the mutation occurred at codon 173. In the region proximal to codon 170, the AAPC phenotypes of the disease were observed [10, 15]. The explanation for the AAPC phenotype could be that the small protein product could not form dimers with functional APC protein and attenuates the disease phenotype. However, the FAP phenotype was also described in the region proximal to codon 170. The various phenotypes observed at this region seem to contradict this explanation.

The study of this region reveals that this fragment of APC gene includes an IRES region [14]. The occurrence of an IRES may cause translation reinitiating or initiation from codon 184 (AUG), and it may exclude the possibility of determining the borderline between mutations causing FAP or AAPC. We can expect that the mutation 517-520delAATT does not disrupt the IRES activity of this region and it causes the AAPC phenotype, but the early onset of polyps was not expected.

In the case of the presented family, an exceptionally early onset of CRC was observed in the in father and grandfather of the proband (Fig. 1). The age of the onset of colorectal cancer could not be established exactly for these two family members; however, we are certain of their age of death due to colorectal cancer. The development of polyps into CRC (which caused the patient’s death in a period of 12 years) proceeded very fast. This AAPC case revealed an atypical disease course, and our observations must be taken into consideration both in genetic counseling and in qualifying the patients with AAPC for the surgical treatment.