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Familial adenomatous polyposis: two different APC gene mutations in two unrelated Arab families with differing response to genetic counselling

Marafie, Makia J.a; Al-Elwani, Farah L.b; Al Suliman, Ibrahim S.a

Middle East Journal of Medical Genetics: January 2014 - Volume 3 - Issue 1 - p 31–36
doi: 10.1097/01.MXE.0000441099.60123.9c
Original articles

Introduction Familial adenomatous polyposis (FAP) is an autosomal dominant condition caused by a mutation in the APC tumour-suppressor gene, located on chromosome 5q21–q22. The clinical presentation includes multiple adenomatous large bowel and rectal polyps, in childhood and adolescence. The risk of colorectal carcinoma development reaches 100% in the mutation carriers. Gardner syndrome is a phenotypic variant of FAP with extracolonic manifestations such as dental anomalies, osteomas, congenital hypertrophy of retinal pigment epithelium, desmoids tumour and varieties of extracolonic cancers. Attenuated FAP is another variant, where the condition is mild with less than 100 polyps, for which mutation in either APC or in MUTYH gene is responsible.

Patients and methods Here we present two FAP-associated families; harbouring two different germline APC gene mutations, discuss the clinical expression and therapeutic decisions for each of their members, based on the phenotypic–genotypic findings. We also describe the attitude of high-risk counselees towards genetic counselling.

Conclusion Early informed medical intervention will help in better decision making and cancer prevention in the family.

aKuwait Medical Genetics Centre, Maternity Hospital, Safat

bMubarak Al-Kabeer polyclinic, Mubarak Al-Kabeer Area, Kuwait

Correspondence to Makia J. Marafie, MBBCH, PhD, FRCP (Edn), Kuwait Medical Genetics Centre, Maternity Hospital, Sabah Medical Area, PO Box 5833, Safat 13059, Kuwait Tel: +965 2481 0563; fax: +965 2484 2073; e-mail:

Received April 27, 2013

Accepted July 13, 2013

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Familial adenomatous polyposis (FAP) (MIM# 175100) is an autosomal dominant inherited disorder with a high degree of penetrance. The prevalence of the disease has been estimated at 3–10/100 000 individuals in the European Union (Half et al., 2009). It is characterized by the development of hundreds to several thousand colorectal adenomas of different sizes in the rectum and colon during the second decade of life. Without proper surgical intervention at an early stage, the risk for colorectal cancer (CRC) development reaches 100% in the mutation carriers (Gardner and Richards, 1953; Gardner, 1962). Mutations in the adenomatous polyposis coli (APC) gene, a tumour-suppressor gene located on the long arm of chromosome 5q21–q22 (Groden et al., 1991; Kinzler et al., 1991; Half et al., 2009), are responsible for the condition. About 20–25% of all FAP patients harbour de-novo gene mutations. Extraintestinal manifestations are variably present in FAP patients, including polyps in the gastric fundus, duodenum and to a lesser extent in the small intestine, osteomas, dental anomalies (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts and adontomas) and congenital hypertrophy of the retinal pigment epithelium, which is a predictive marker of the disease in 70% of FAP families. Furthermore, variable extracolonic cancers have been reported including thyroid, liver, bile duct, central nervous system, soft tissue and desmoid tumours (Giardiello et al., 1994; Tiret and Parc, 1999; Half et al., 2009; Leal et al., 2010). A genotype–phenotype correlation has been found depending on the location of the pathogenic mutation in the gene. This correlation would help in decisions concerning screening and surgical management of high-risk affected families (Dobbie et al., 1996; Friedl et al., 2001; Sheng et al., 2006; Nieuwenhuis and Vasen, 2007; Aretz, 2010; Cooper et al., 2010; Qiu et al., 2010). Gardner syndrome is the term used to describe the coexistence of FAP, epidermoid cyst, desmoids and osteomas. Attenuated FAP is a less aggressive variant with fewer polyps between 10 and 100, later age of appearance and lower cancer risk than the classical type. This is associated with mutations in the extreme 5′ part of the APC gene and the 3′ part of exon 15 proximal to codon 1517 or distal to codon 1900 (Half et al., 2009). MUTYH-associated polyposis is a second type of attenuated FAP (10–100 polyps) that follows an autosomal recessive inheritance pattern and is caused by biallelic mutations in the MUTYH gene, leading to an increased risk for CRC development. The juvenile polyposis syndrome is characterized by multiple juvenile polyps either confined to the colon or also in the stomach and duodenum and is caused by mutations in the SMAD4 or BMPRIA genes in the majority of families. Furthermore, in Turcot syndrome variant, colonic adenomatous polyposis is in association with central nervous system tumours, usually of the medulloblastoma type, and a mutation in the APC gene is responsible, or rarely glioblastoma due to a mutation in one of the mismatch repair genes (PMS2 or MLH1) is responsible (Half et al., 2009; Aretz, 2010). We have investigated the possibility of APC gene mutation in two unrelated Arab patients with classical adenomatous polyposis of colon; one occurred because of a de-novo event, whereas the second was inherited in the family. Two pathogenic alterations were identified, one being novel and the other recurrent, as reported by the International Society for Gastrointestinal Hereditary Tumours ( Genetic testing helped in providing proper management to the patients and some members of their families.

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Patients and methods

Family 1

A 19-year-old Arab female (proband 1) with more than 1000 polyps in the colon was referred to the Kuwait Medical Genetics Centre (KMGC) by the gastroenterologist for genetic counselling and investigation of her genomic mutational status. Colonoscopy revealed large number of polyps of variable shapes and sizes, ranging from subcentimetric to 2 cm and carpeting the whole rectum, sigmoid up to transverse colon and distal hepatic flexure. The number of polyps was lower in the ascending colon and caecum. First, histopathology report showed multiple tubular adenomatous polyps with no evidence of malignancy in many examined levels. Endoscopy showed gastroduodenitis but no polyps. However, a second colonoscopy and biopsy was performed 6 months later; six fragments of the colon mucosa were examined, five showed tubular adenomatous changes with low-grade dysplasia. Endoscopy showed one tubular adenomatous polyp in the body of the stomach with mild chronic gastritis as well as a single adenomatous duodenal polyp. The patient had a history of generalized abdominal pain for 1.5 year with no other complaints. Her parents were first cousins. The mother had a history of intrauterine foetal death at ∼30 weeks of gestation, the reason for which was not clarified. Pedigree analysis revealed colon cancer in one male first cousin of her mother, who died at the age of 35 years (Fig. 1). The colonoscopic and endoscopic surveillance of her 36-year-old mother revealed colonic diverticulosis; however, no polyps were found anywhere in the examined parts of the gastrointestinal tract (GIT). Furthermore, she had a history of unrelated lipomas in the scalp and right arm, which were removed surgically at the age of 34 years. She claimed the presence of a few colonic polyps in a distant deceased male relative on her maternal side, but no medical report was available for clarification. The proband and two of her younger sisters had a history of teeth crowding, which was corrected; however, no radiogram was available for confirmation. Her eldest sister died at the age of 23 years because of an accident. Her elder brother aged 23 years had a history of chondromyxoid fibroma of the left proximal femur (possibly after an old accident) and had undergone proximal femoral resection with reconstruction using Mutars prosthesis. Endoscopic or colonoscopic screening of both parents and their other children showed no polyps in any examined parts of the GIT.

Figure 1

Figure 1

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Family 2

At the age of 40, this female (proband 2) was referred to KMGC for genetic counselling, with a clinical, histological and family history suspecting the diagnosis of FAP. She had a history of persistent lower abdominal pain. Colonoscopy showed hundreds of colonic sessile polyps from the rectum to caecum, more in both the proximal and distal sigmoid colon. Histopathology examination of biopsies taken from the sigmoid colon, which were 3–4 mm in size, revealed tubular adenomata with low-grade dysplasia. She also had a histologically verified sebaceous cyst in the scalp, which was removed surgically 2 years before. Furthermore, she gave a distant history of an abnormally positioned upper right canine tooth followed by crown placement on her four upper anterior teeth. This abnormality was also segregating in two of her sisters and in a female first cousin on her maternal side (Fig. 2). Her father, the only child to his unrelated parents, died of colon cancer at the age of 42 years; medical records were no longer available. Her mother died at the age of 55 years because of the complications of hypertension. None of her relatives were available for testing as they lived abroad. One sister developed colon cancer at the age of 39 years and died 4 years later. Her 55-year-old living sister had undergone colonoscopy at the age of 35 years, which had revealed numerous colonic polyps, and consequently underwent total colectomy with ileorectal anastomosis. Furthermore, the proband had three asymptomatic brothers aged 43, 42 and 41 years and another 30-year-old sister receiving treatment for hyperthyroidism. Because of the proband’s medical history and her family history, mutation screening of the APC gene was performed to confirm the diagnosis.

Figure 2

Figure 2

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Methods and results

The genomic DNA was extracted from the peripheral blood taken from the proband in each family and their available relatives, after obtaining informed consent for DNA testing. Sequence analysis of the entire coding region of the APC gene showed that proband 1 was a heterozygous carrier for the c.1660C>T, p.Arg554X mutation in exon 13 (Fig. 3). This is a previously reported pathogenic protein-truncating mutation. However, this mutation was not detected in both parents and the siblings. The patient then underwent laparoscopic total proctocolectomy, ileostomy and ileoanal J-pouch. She was prescribed NSAIDs, Celebrex 200 mg capsule (Searle Ltd., Caguas, Puerto Rico), once a day for a short period to reduce the future formation of GIT polyps. For proband 2, the DNA analysis proved that she is a heterozygous carrier for a novel pathogenic truncating APC gene mutation in exon 15, c3336-3340del, p.Asn1113fs (Fig. 4). Therefore, the predictive genetic testing was provided to her sibship. The sister who had a history of colectomy for multiple polyposis as well as two brothers were found to be heterozygous carriers for the same mutation. Both brothers had never undergone a colonoscopic screening and refused to attend the clinic for further investigation and management. Mutation was ruled out in the youngest brother and sister. The proband was subjected to prophylactic proctocolectomy with ileal pouch-anal anastomosis. In addition, she was given Celebrex 200 mg capsule once a day for a short period.

Figure 3

Figure 3

Figure 4

Figure 4

The mutations found in both probands were protein-truncating pathogenic mutation, with an increased risk of developing colon cancer and extracolonic tumours. Both patients were subjected to surgical resection of the colon to reduce the risk for CRC, with a periodic clinical follow-up and surveillance of the GIT and other sites. In both families, relatives with no mutation were excluded from the periodic intensive surveillance program.

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The Kuwait Cancer Genetics Clinic started providing its services in September 2000. Since then, many patients with hereditary cancers and their families have been referred for genetic counselling and testing. However, only two unrelated patients with FAP have been seen during this period. FAP is relatively uncommon in Arabs from the Gulf region (Isbister, 2000), and so far there are no published data in the literature involving the prevalence of this disease in the Arab population. However, a molecular epidemiology study on MUTYH-associated polyposis in the highly consanguineous Moroccan population, involving three recurrent MUTYH gene mutations, estimated the carrier frequency for one of the mutations to be 1.4%, whereas the homozygous or compound heterozygous frequency for all three recurrent mutations was estimated to be 1/10 000 (Laarabi et al., 2011).

We investigated the two unrelated patients presented with typical adenomatous polyposis of the colon. Both were found to harbour two different germline mutations in the APC tumour-suppressor gene, being recurrent in proband 1/family 1 and novel in proband 2/family 2. One had occurred de novo (proband 1), whereas the other was inherited in the family (proband 2). Although neither parent in family 1 carried the mutation, we investigated all children for fear of gonadal mosaicism in one of the parents. In family 2, it is most likely that the mutation had been arisen de novo in their affected father, who died a long time ago, or one of his ancestors. This could not be proven, as he was the only born child to his parents with a small family size and we had no absolute information about other relatives on his side, who lived in Iraq. In addition, in family 2, four members carried heterozygous mutations, being two sisters and two brothers. The two sisters underwent prophylactic colon dissection, whereas the two high-risk brothers discontinued the genetic counselling sessions before knowing the result of their DNA test for unclear reasons. For each family, group education sessions and knowledge about the reasons and implications of the genetic testing results were provided before and during the DNA testing process. Family 1 was very cooperative and continued the follow-up sessions to date, discussing the reproduction options available for proband 1 in the near future and favoured preimplantation genetic diagnosis, a procedure generally accepted by the religion of Islam. In family 2, however, after mutation identification, apart from proband 2, other members of the family showed no interest in attending the genetic clinic any more despite several phone calls and appointments arranged by the proband, on an individual basis or as groups. Therefore, we were unable to offer further genetic counselling, discussion of the results, education and cascade genetic screening to the whole family, nor were we able to provide appropriate periodic surveillance tailored to each individual’s clinical manifestation, such as abdominal ultrasound and/or computed tomography, annual endoscopies and colonoscopies for other mutation carriers. Parental attitude towards reproduction decisions and genetic screening of their children varied between the two families here, similar to other families reported in different studies (Fernández-Suárez et al., 2005; Douma et al., 2010).

Family 2 showed the Gardner syndrome phenotypic variant of FAP, as some members had abnormal dental manifestation of the APC gene mutation. This is consistent with the position of the mutation in the gene sequence.

The two probands were prescribed NSAIDs, Celebrex 200 mg, once a day for a short period after the surgery, which was performed at the end of 2010; both were informed about the associated side effects. It has been shown to cause regression of adenomas in FAP and to decrease the number of polyps requiring ablation in the remaining rectum of individuals who had undergone a colectomy with ileorectal anastomosis. It was reported that chemoprevention of colon cancer by NSAIDs depends on the elimination of stem cells that are inappropriately activated by the oncogenic events through induction of apoptosis (Qiu et al., 2010). However, the cardiovascular and gastrointestinal complications associated with long-term use of NSAID limit their use to selected cases and under close observation (Manzano and Pérez-Segura, 2012). The dose we used (200 mg/day) was less than that (400 mg/day) associated with the high incidence celecoxib trials in sporadic adenoma prevention (Bertagnolli et al., 2006).

Kuwait is one of the countries with the highest consanguinity rate, similar to some other Middle Eastern countries (Al-Awadi et al., 1985; Teebi, 1994). In a study on Qatari population, the prevalence of some diseases was reported to be higher in individuals from consanguineous mating compared with those from nonconsanguineous mating, including cancer, mental disorders, heart diseases, gastrointestinal disorders, hypertension, hearing deficit and diabetes mellitus. Indeed, adult cancer was one of the highest reported diseases among this population (Bener et al., 2007). Furthermore, carriers for biallelic mutations in the autosomal dominant mismatch repair genes, causing familial cancers, have been reported worldwide, including Kuwait (Marafie et al., 2009; Wimmer and Kratz, 2010). Therefore, premarital genetic counselling and molecular screening should be offered to the members of highly consanguineous families with hereditary cancers.

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Appropriate genetic counselling and predictive gene testing for FAP-associated families help in identifying presymptomatic members at risk and also support the exclusion of noncarriers from lifetime tedious and potentially dangerous endoscopy/colonoscopy surveillance.

Furthermore, in APC-related individuals, localizing the pathogenic alteration site in the gene can be useful in predicting the position of GIT polyps, their severity and the risk for extracolonic manifestation in affected individuals. This in turn enable them to be benefited from the available intensive surveillance measures, which could reduce their overall cancer risk. Hence, an early informed medical intervention will help in better decision making and cancer prevention in the family.

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Conflicts of interest

There are no conflicts of interest.

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APC gene; Arab; colorectal cancer; familial adenomatous polyposis; genetic counselling; genetic screening; Kuwait

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