Although juvenile polyps have a distinct morphology, small tumours and incomplete biopsies in particular may be a challenge. The presence of inflammatory infiltrates and intraepithelial neoplasia is a consistent feature of juvenile new polyps. In all of our 13 cases with identified pathogenic germline mutation in which initially only hyperplastic, adenomatous, or inflammatory polyps had been diagnosed, juvenile polyps were uncovered by an experienced pathologist, who had been asked for a second opinion (table 22).). This was particularly true for the gastric polyposis, even though appropriate diagnostic criteria have been defined. Our observation and that of others demonstrates the need for a critical interpretation of histopathological results in patients with gastrointestinal polyposis.

10,19 Owing to the striking histological overlap between JPS and HMPS, the existence of a clinically defined HMPS is questionable. As a fraction of our mutation�\positive patients with JPS would also have fulfilled the poorly defined criteria for HMPS, a substantial number of HMPS cases seem actually to be histopathological variants of JPS. Our data support the conclusion of Cao et al. that JPS and HMPS might be (at least in part) allelic entities,27 suggesting that particularly HMPS2 is neither clinically nor genetically a distinct condition. One patient was referred for mutation analysis with the diagnosis of CCS, a rare and poorly delineated entity with a significant phenotypic overlap to JPS.

It is usually described as late�\onset, sporadic, non�\inherited gastrointestinal polyposis of unknown aetiology accompanied by diffuse skin pigmentation, alopecia and onychodystrophy.28,29 As underlined by our patient, a proportion of polyposis cases might be misdiagnosed as sporadic CCS. In particular, young age at diagnosis and absence of typical ectodermal manifestations in patient JUV�\88 argues against CCS.30 PTEN mutations Mutation analysis of the PTEN gene in the 41 SMAD4 and BMPR1A mutation�\negative patients revealed a germline mutation in two (5%); one of the mutations was found by chance using MLPA. Both patients (JUV�\16, JUV�\18) had a variety of different polyp types; one case presented with extraintestinal tumours not typical for JPS. Our results are in accordance with those reported by Sweet et al, who identified two PTEN germline mutations in 23 patients (9%) with a mixture of hyperplastic and adenomatous polyps. In both cases the reviewed Carfilzomib clinical phenotype revealed features reminiscent of Cowden syndrome.10 Genetic heterogeneity and phenotype overlap in hamartoma syndromes is well known.