Attenuated Familial Adenomatous Polyposis: A Phenotypic Diagnosis but Obsolete Term?

BACKGROUND: Attenuated familial adenomatous polyposis is characterised by low number (≤100) and delayed development of colorectal adenomas. Various definitions have been used, and genotype-phenotype correlations have been suggested. OBJECTIVE: We aimed to evaluate phenotypic and genotypic correlation in patients with presumed attenuated familial adenomatous polyposis and assess familial variability. DESIGN: This is a retrospective study. SETTINGS: This study was conducted at a tertiary polyposis registry. PATIENTS: Individuals with attenuated familial adenomatous polyposis were identified. Phenotypic group was defined as 100 or fewer adenomas at age 25 years and genotypic group was defined as a variant in the adenomatous polyposis coli region associated with attenuated familial adenomatous polyposis. Pathology polyp count was used for patients who had undergone surgery and endoscopic polyp count for those with intact colon. MAIN OUTCOME MEASURES: We evaluated phenotypic and genotypic correlation in patients with presumed attenuated familial adenomatous polyposis and familial variability. RESULTS: A total of 69 patients were identified in the phenotypic group, of whom 54 (78%) had a pathogenic variant in the attenuated regions of the adenomatous polyposis coli gene. Forty-eight (70%) had intact colon (median age at last colonoscopy 43 [25-73] years; median endoscopic polyp count 20 [0-100]) and 21 (30%) had undergone colectomy (median age at surgery 45 [25-54] years; median pathology polyp count 43 [3-100]). Eighty-three patients were identified in the genotypic group of which 54 (65%) had attenuated phenotype. Inter- and intrafamilial variability were observed. LIMITATIONS: This study was limited by its retrospective nature and single-center experience. CONCLUSION: Phenotype in familial adenomatous polyposis lies on a spectrum and is determined in part by genotype and age at adenoma count. Diagnosis of attenuated familial adenomatous polyposis should be based on phenotype; genotype is not a reliable indicator. Management should be personalized according to the phenotype of each individual. See Video Abstract at http://links.lww.com/DCR/B775. POLIPOSIS ADENOMATOSA FAMILIAR ATENUADA UN DIAGNSTICO FENOTPICO PERO TRMINO OBSOLETO: ANTECEDENTES:La poliposis adenomatosa familiar atenuada se caracteriza por un número bajo (≤100) y desarrollo retardado de adenomas colorrectales. Se han utilizado varias definiciones y se han sugerido correlaciones genotipo-fenotipo.OBJETIVO:Nuestro objetivo es evaluar la correlación fenotípica y genotípica en pacientes con presunta poliposis adenomatosa familiar atenuada y evaluar la variabilidad familiar.DISEÑO:Este es un estudio retrospectivo.AJUSTE:Este estudio se realizó en un registro terciario de poliposis.PACIENTES:Se identificaron individuos con poliposis adenomatosa familiar atenuada. El grupo fenotípico se definió como ≤100 adenomas a la edad de 25 años y el grupo genotípico se definió como una variante en la región de poliposis coli adenomatosa asociada con poliposis adenomatosa familiar atenuada. Se utilizó el recuento de pólipos en patología para los pacientes que se habían sometido a cirugía y el recuento de pólipos endoscópico para los que tenían el colon intacto.PRINCIPALES MEDIDAS DE RESULTADO:Evaluamos la correlación fenotípica y genotípica en pacientes con presunta poliposis adenomatosa familiar atenuada y variabilidad familiar.RESULTADOS:Un total de 69 pacientes se identificaron en el grupo fenotípico de los cuales 54 (78%) tenían una variante patogénica en las regiones atenuadas del gen de la poliposis coli adenomatosa. Cuarenta y ocho (70%) tenían colon intacto (edad media en la última colonoscopia 43 [25-73] años; mediana del recuento de pólipos endoscópicos 20 [0-100]) y 21 (30%) se habían sometido a colectomía (edad edia en el momento de la cirugía 45 [25-54] años; mediana del recuento de pólipos patológicos 43 [3-100]). Se identificaron 83 pacientes en el grupo genotípico de los cuales 54 (65%) tenían fenotipo atenuado. Se observó variabilidad inter e intrafamiliar.LIMITACIONES:Este estudio estuvo limitado por su naturaleza retrospectiva y la experiencia de un solo centro.CONCLUSIÓNES:El fenotipo en la poliposis adenomatosa familiar se encuentra en un espectro, determinado en parte por el genotipo y la edad en el momento del recuento de adenomas. El diagnóstico de poliposis adenomatosa familiar atenuada debe basarse en el fenotipo; el genotipo no es un indicador confiable. El manejo debe personalizarse según el fenotipo de cada individuo. Consulte Video Resumen en http://links.lww.com/DCR/B775.

Disease expression in juvenile polyposis syndrome: a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers.

PURPOSE: Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. METHODS: We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature. RESULTS: We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%). CONCLUSION: This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.

Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome.

BACKGROUND: Juvenile polyposis syndrome is phentoypically and genotypically heterogeneous. It is associated with an increased risk of GI cancers, and surveillance is recommended. Few data exist that detail the outcomes of surveillance in juvenile polyposis syndrome. OBJECTIVE: The aim of this study was to review clinical features, genetic mutations, and long-term outcome data in patients with juvenile polyposis syndrome. DESIGN: This study is a retrospective review. SETTING: The Polyposis Registry, St Mark's Hospital, was used in the performance of this study. PATIENTS: Patients with juvenile polyposis syndrome who were followed up at our institution were included. RESULTS: Forty-four patients (27 male) from 30 kindreds were included. Fifteen were diagnosed by screening, and 29 presented symptomatically. Nineteen patients had SMAD4 mutation and 9 had BMPR1A mutation. Five patients (11%) had valvular heart disease. Telangiectasia/vascular abnormalities were observed in 4 (9%) patients, and macrocephaly was observed in 5 (11%). Six patients (14%) developed cancer; 4 had cancer at the time of diagnosis of juvenile polyposis syndrome, 3 developed cancer while on surveillance (1 patient had a second primary). All patients with advanced upper GI disease had SMAD4 mutations. Where germline mutation was known, all patients with telangiectasia had SMAD4 mutation. Seven patients required GI surgery at our institution: colectomy and ileorectal anastomosis (1), restorative proctocolecotomy (1), anteroposterior excision for rectal cancer (1), gastrectomy (2), and laparotomy and intraoperative enteroscopy (1). There were no complications of endoscopic surveillance. Colonic polyps predominated; 535 of 767 (69.8%) of colonic polyps were right sided. One patient had a solitary significant small-bowel polyp. Sixty-five juvenile polyps contained dysplasia (mild to moderate). Two patients had severe dysplasia or cancer found in carpeting polyps. LIMITATIONS: This is a retrospective review. The cohort size, although modest, is good for such a rare condition. CONCLUSION: Extraintestinal features are common. Gastrointestinal surveillance is safe. Most colonic polyps are right sided, and detecting dysplasia is uncommon. Carpeting polyps are of particular concern.

Features of duodenal cancer in patients with familial adenomatous polyposis.

BACKGROUND & AIMS: Most patients with familial adenomatous polyposis (FAP) develop duodenal adenomas; duodenal cancer is a major cause of mortality in this patient group. We reviewed cases of duodenal cancer in patients with FAP to identify factors that determine long-term cancer risk. METHODS: Twenty FAP patients (12 male) were identified from a registry database search. Data from registry and medical notes and endoscopic and histopathologic reports were evaluated. RESULTS: Of the cancers that developed in these patients, 11 were ampullary and 9 were duodenal. The median age at cancer diagnosis was 53 years. Seventeen patients died (median age at death, 57 y; median survival from diagnosis, 11 mo); the cause of death was metastatic or duodenal/ampullary cancer in 14 patients. Fifteen patients presented symptomatically (including 3 interval cancers while on surveillance). Two were diagnosed at surveillance and 3 were diagnosed during surgery performed for endoscopic features of advanced benign disease. Duodenal cancers were associated with a significantly lower mean colonic polyp count than ampullary cancers (496 +/- 282 vs 1322 +/- 735; P = .025); there appeared to be familial clustering of this cancer. When endoscopic data were available (n = 11 of 20), all ampullary cancers arose from ampullas greater than 1 cm. The Spigelman stage did not predict risk of ampullary cancer but did predict duodenal cancer (median stage 2 vs stage 4 for duodenal cancer). CONCLUSIONS: Once cancer arises in patients with FAP, prognosis is poor, so cancer prevention should be the main goal. Surveillance intervals should reflect both Spigelman staging and ampullary disease.