Pedunculated spherical smooth polyps contain numerous large cystic spaces filled with a grayish or yellowish mucus surrounded by copious reddish stroma
Juvenile polyposis syndrome is an autosomal dominant condition that predisposes gene carriers to various types of tumors. The diagnosis is based on the occurrence of hamartomatous gastrointestinal polyps that turn into malignant lesions in approximately 20% of cases ... Juvenile polyposis syndrome is an autosomal dominant condition that predisposes gene carriers to various types of tumors. The diagnosis is based on the occurrence of hamartomatous gastrointestinal polyps that turn into malignant lesions in approximately 20% of cases (Handra-Luca et al., 2005). It had been suggested that juvenile polyposis can be caused by mutations in the PTEN gene (601728), the same gene that is mutant in Cowden disease (158350) and in Bannayan-Zonana syndrome (153480). In a comprehensive review of PTEN, Waite and Eng (2002) concluded that juvenile intestinal polyposis is not a so-called PTEN hamartoma-tumor syndrome (PHTS). They suggested that the discovery of the germline PTEN mutation in an individual considered to have JPS should raise a suspicion that the clinical diagnosis is incorrect and that such an individual should be managed medically in the same manner as all patients with PHTS.
Veale et al. (1966) investigated the families of 11 patients with juvenile polyposis syndrome. Juvenile polyps were isolated or multiple. The histology and natural history of these polyps suggested that they were hamartomas. In 4 families, multiple polyposis ... Veale et al. (1966) investigated the families of 11 patients with juvenile polyposis syndrome. Juvenile polyps were isolated or multiple. The histology and natural history of these polyps suggested that they were hamartomas. In 4 families, multiple polyposis and/or colonic carcinoma occurred in relatives. For example, the father of an affected brother and sister had colonic cancer. In 2 instances, a parent of a case of juvenile polyposis had colonic cancer and multiple polyposis. Smilow et al. (1966) described a 7-year-old boy with juvenile polyposis, his mother who at 10 years of age had noted a prolapsed polyp during defecation, and his maternal grandfather who at age 60 had surgery for adenocarcinoma of the colon. In the grandfather, various polyps were present, some resembling adenomatous polyps and others resembling the juvenile polyps found in the proband and his mother. In the proband's mother, the lesions were so numerous that total colectomy and ileostomy were performed. Although some cases of familial polyposis of the entire gastrointestinal tract represent juvenile polyposis, some seem to be adenomatous polyposis. Yonemoto et al. (1969) described a family with multiple cases consistent with dominant inheritance. Early development of symptoms was typical. One patient had a desmoid tumor of the abdominal wall. The case described by Ravitch (1948) proved to be juvenile polyposis (Ravitch, 1974). Haggitt and Pitcock (1970) described a girl who had onset of intermittent bright red rectal bleeding at age 3 years. Her father, an aunt and an uncle had 'well-differentiated adenocarcinoma with invasion of the submucosa.' The grandfather died at age 42 of colonic cancer. Gathright and Cofer (1974) described the disorder in a mother and 5 sons. Three brothers and a sister in another family were affected. Rozen and Baratz (1982) found multiple juvenile polyps of the colon in mother and son. The mother later developed a metastatic adenocarcinoma of the colon. In both patients, histology of the polyps showed no adenomas, but some of the juvenile polyps contained adenoma-like elements. Because of the mother's history and the adenomatous features of some of the son's polyps, he underwent subtotal colectomy. Grosfeld and West (1986) presented 5 isolated cases of juvenile polyposis coli. Clinical findings included abdominal pain, weakness, rectal bleeding, diarrhea, rectal prolapse, intussusception, digital clubbing, and failure to thrive. Laboratory findings included anemia, hypoalbuminemia, hypokalemia, and skin test anergy. The authors insisted that 'hamartomatous' was an inappropriate adjective to describe the polyps, since the histology in juvenile polyposis coli was quite different from that seen in Peutz-Jeghers (175200) syndrome. Soper (1986), in discussing the paper of Grosfeld and West (1986), stated that 'internists at the University of Iowa have studied a family through 4 generations, in which 15 members had juvenile polyposis...' GI malignancy was present in 11 of the 15, but no cancer arose in polyps. Walpole and Cullity (1989) described a patient with first presentation of polyposis in the second year of life. The patient had a large head, bilateral inguinal hernias and cryptorchidism, an umbilical hernia, and finger clubbing. Death occurred due to adenocarcinoma of the pancreas at age 19. Familial juvenile polyposis of the stomach (Watanabe et al., 1979) is presumably the same disorder. Gastric cancer was reported in association with juvenile polyposis of the stomach by Watanabe et al. (1979) and Sassatelli et al. (1993). In a discussion of juvenile polyps in relation to Bannayan-Riley-Ruvalcaba syndrome (153480), Gorlin et al. (1992) defined juvenile polyps as retention polyps usually presenting before 10 years of age, although at least 15% are found in adults. Rectal bleeding is the most common presentation. Grossly and histologically, juvenile polyps are distinctive. They are usually pedunculated and spherical with a smooth surface. A cut section demonstrates numerous large cystic spaces of variable size, filled with a grayish or yellowish mucus surrounded by copious reddish stroma; hence the term 'retention polyp.' In contrast to the hamartomatous polyps of Peutz-Jeghers syndrome, muscle fibers are not present in the stroma. Subramony et al. (1994) described an extensively affected kindred showing preponderance of right-sided polyps. Subtotal colectomy with ileorectal anastomosis resulted in prompt recurrence of polyps. It was followed by prompt recurrence of polyps in the retained rectum. Further investigations of the family were reported by Scott-Conner et al. (1995). Of 34 living members of the kindred, 15 were investigated, and histologically typical juvenile polyps were found in 11. In each instance, polyps were most numerous in the right colon, with few polyps in the descending colon and none in the rectum. Eight patients had had subtotal colectomies with ileorectal anastamoses; the other 3 patients were managed by polypectomy (with 1 recurrence after 10 years). In addition to juvenile polyps, polyps with adenomatous or villous elements were identified in 3 patients. Invasive adenocarcinoma in a large mixed polyp of the cecum was found in 1 of these patients. Coexisting carcinoma of the stomach was found in 2 patients with polyps. Polyps had recurred in the rectal remnants of 3 patients at a mean of 36 months after subtotal colectomy. Two patients had undergone conversion to total proctocolectomy with ileoanal anastomosis and J pouch; 1 patient was found to have juvenile polyps in the pouch 40 months after surgery. Scott-Conner et al. (1995) concluded that despite the preponderance of right-sided polyps at initial diagnosis, the rapid recurrence of polyps after subtotal colectomy argues in favor of performing proctocolectomy with preservation of anal sphincter function (restorative proctocolectomy) at the time of initial surgery. Patients with a small number of polyps may choose instead to undergo periodic colonoscopy with colonoscopic polypectomy. Histologically, juvenile polyps were comprised primarily of stromal elements, often overlaid with a thin layer of normal-appearing epithelium that was easily traumatized. The proliferative changes seen in adenomas were notably absent. The gross appearance of the surface was smooth, and cystic spaces containing retained mucus were often seen when the polyp was sectioned. The stock was thin and many of these polyps slough spontaneously. Sharma et al. (1995) described the clinical and pathologic features of affected members in a large family with juvenile polyposis. Five living affected members had typical juvenile colonic polyps as well as atypical lobulated polyps with adenomatous change in the rectosigmoid area. Four members of the family had died of colonic malignancy between ages 30 and 55. The presence of both juvenile polyposis and hereditary hemorrhagic telangiectasia (HHT) in an affected individual defines the syndrome of juvenile polyposis and HHT (JPHT; 175050). Gallione et al. (2004) described patients from 7 unrelated families meeting the diagnostic criteria for juvenile polyposis and HHT and carrying mutations in the MADH4 gene (SMAD4; 600993). The severity (pulmonary and hepatic arteriovenous malformations, cerebral involvement) and often early onset of HHT symptoms in these patients argue in favor of systemic screening for visceral manifestations in juvenile polyposis patients with MADH4 mutations (Gallione et al., 2004).
Friedl et al. (2002) examined 29 patients with the clinical diagnosis of JPS for germline mutations in the MADH4 or BMPR1A genes and identified MADH4 mutations in 7 patients (24%) and BMPR1A mutations in 5 (17%). A remarkable ... Friedl et al. (2002) examined 29 patients with the clinical diagnosis of JPS for germline mutations in the MADH4 or BMPR1A genes and identified MADH4 mutations in 7 patients (24%) and BMPR1A mutations in 5 (17%). A remarkable prevalence of massive gastric polyposis was observed in patients with MADH4 mutations when compared with patients with BMPR1A mutations or without identified mutations. This, they claimed, was the first genotype-phenotype correlation observed in JPS. Handra-Luca et al. (2005) identified mutations in 14 (33%) of 42 patients with juvenile polyposis syndrome: 5 in the BMPR1A gene and 9 in the SMAD4 gene. Five of 9 patients with SMAD4 mutations had high-grade adenomatous lesions, whereas no patients with BMPR1A mutation had high-grade adenomatous lesions, and only 1 patient with a BMPR1A mutation had low-grade adenomas. There were malformative vessels within the stromal components of all SMAD4-related polyps when the mutation involved codons prior to position 423; no BMPR1A-related polyps had malformative vessels. Polyps in SMAD4-mutation carriers were seen in the upper and lower digestive tracts; polyps in BMPR1A mutation carriers were exclusively located in the colorectum. Handra-Luca et al. (2005) concluded that SMAD4 germline mutations are responsible for a more aggressive phenotype in patients with JPS. Aretz et al. (2007) analyzed the SMAD4 and BMPR1A genes in 80 unrelated patients, 65 with typical JPS and 15 suspected of having JPS, and identified point mutations in 30 (46% of patients with typical JPS) and large deletions in 9 (14% of typical JPS). Among the 27 mutation carriers not previously reported by Friedl et al. (2002), 11 (69%) of 16 patients with SMAD4 mutations had gastric polyposis versus none of 11 patients with BMPR1A mutations (p less than 0.01); all 7 cases of gastric cancer occurred in 3 families with SMAD4 mutations. Including previously reported patients, 5 (22%) of 23 patients with SMAD mutations had hereditary hemorrhagic telangiectasia (see 175050); HHT was not seen in patients with BMPR1A mutations.
In patients with juvenile intestinal polyposis, Howe et al. (1998) demonstrated different heterozygous mutations in the SMAD4 gene (600993.0005-600993.0007).
Houlston et al. (1998) analyzed 8 families in which members had juvenile polyposis syndrome, looking for linkage ... In patients with juvenile intestinal polyposis, Howe et al. (1998) demonstrated different heterozygous mutations in the SMAD4 gene (600993.0005-600993.0007). Houlston et al. (1998) analyzed 8 families in which members had juvenile polyposis syndrome, looking for linkage to DPC4 (SMAD4). Overall, there was no evidence for linkage to DPC4; linkage could be excluded in 2 of the 8 pedigrees and was unlikely in 2 others. They then tested these 8 families and 13 familial and sporadic JPS cases for germline mutations in DPC4. Only 1 germline DPC4 mutation was found in a familial JPS patient with a pedigree unsuitable for linkage analysis. Houlston et al. (1998) concluded that the DPC4 gene is the site of the causative mutation in a minority of cases. Howe et al. (2001) demonstrated mutations in the BMPR1A gene (601299.0001-601299.0004) in juvenile polyposis kindreds in which a genomewide screen had demonstrated mapping to 10q22-q23. In 77 different familial and sporadic cases of JPS, Howe et al. (2004) identified germline MADH4 mutations in 14 cases (18.2%) and BMPR1A mutations in 16 cases (20.8%). No mutations were found in BMPR1B (603248), BMPR2 (600799), or ACVR1 (102576) in the 32 MADH4 and BMPR1A mutation-negative cases. The authors noted that because mutations were not found in more than half of the patients with JPS, either additional predisposing genes remain to be discovered or alternative means of inactivation of the 2 known genes account for these cases. Shikata et al. (2005) identified a heterozygous mutation in the SMAD4 gene (600993.0007) in a Japanese woman with juvenile polyposis restricted to the stomach. No polyps were identified in the intestine. She also had a pulmonary arteriovenous malformation. The same mutation had previously been identified in a patient with multiple colonic polyps at the age of 6 years. The findings confirmed that juvenile gastric polyposis is a phenotype of the juvenile polyposis syndrome. Sweet et al. (2005) sequenced the ENG gene (131195) in 14 patients with JPS who were negative for mutation in the SMAD4 and BMPR1A genes and identified germline missense mutations in the ENG gene in 2 patients, respectively. The mutations were not found in 105 North American controls. Neither patient had abnormalities in skin pigmentation or features consistent with a diagnosis of HHT; however, both patients had JPS of unusually early onset (age 3 and 5 years, respectively). In 3 of 31 patients with JPS who were negative for mutations in the SMAD4 and BMPR1A genes, Howe et al. (2007) identified 2 different nonsynonymous substitutions that had been previously identified as polymorphisms in patients with HTT. The 3 patients did not have clinical manifestations or a family history of HHT or upper gastrointestinal tract polyps, and had a mean age of 7.4 years versus 14.4 years for those without ENG mutations. Howe et al. (2007) stated that their findings did not confirm the suggestion that the ENG gene predisposes for JPS. - Exclusion of the PTEN Gene Olschwang et al. (1998) reported 3 patients with 'juvenile polyposis coli' and mutations in the PTEN gene (see 601728.0009-601728.0011). However, Eng and Peacocke (1998) questioned the role of PTEN mutations in the juvenile polyposis syndrome. They pointed out that 3 groups (Marsh et al., 1997; Riggins et al., 1997; Howe et al., 1998) had found no evidence of germline PTEN mutations in 21 JPS families and 16 sporadic cases, and power calculations indicated that if 10% of JPS cases were due to germline PTEN mutations, there should have been a 0.99 likelihood of detecting at least 1 mutation among these 37 cases. Eng and Peacocke (1998) and Eng and Ji (1998) suggested further that the 3 patients found by Olschwang et al. (1998) to have germline PTEN mutations had either Cowden disease or Bannayan-Zonana syndrome; a 74-year-old man had manifestations they interpreted as suggestive of Cowden disease, and the 2 children may not have yet demonstrated features of Cowden disease, which has a penetrance well below 10% under 15 years of age (Nelen et al., 1996). In a long review of the PTEN gene, Waite and Eng (2002) reviewed the evidence that juvenile polyposis syndrome is not one of the so-called PTEN hamartoma-tumor syndromes (PHTS). Lynch et al. (1997) referred to germline mutations in individuals with JPS, but it was obvious to Waite and Eng (2002), from the text, that all of the individuals had Cowden syndrome. Kurose et al. (1999) provided a single hospital-based series that looked for germline PTEN mutations in JPS. They identified 1 individual with a germline PTEN mutation, but on reexamination, classic cutaneous features of Cowden syndrome were found. PTEN was formally excluded as a JPS-susceptibility gene by Marsh et al. (1997) and it is known that germline mutations in MADH4 (600993) on 18q and BMPR1A (601299) on 10q account for 40 to 60% of JPS. Waite and Eng (2002) concluded that discovery of a germline PTEN mutation in an individual considered to have JPS should raise a suspicion that the clinical diagnosis is incorrect.