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Intestinal Polyposis Syndromes

Background

Although intestinal polyposis syndromes are relatively rare, awareness of the existing health risks is important for patients and their families affected by these disorders. Intestinal polyposis syndromes can be divided, based on histology, into the broad categories of familial adenomatous polyposis (FAP), hamartomatous polyposis syndromes, and other rare polyposis syndromes, such as hereditary-mixed polyposis syndrome (HMPS) and serrated polyposis syndrome (SPS).

In 1859, Charelaigue described the first definitive accounts of adenomatous polyposis in a 16-year-old girl and a 21-year-old man.

Several genetic disorders may present with GI polyps. FAP is the most common inherited polyposis syndrome, encompassing multiple phenotypes. These phenotypes range from a mild phenotype in attenuated polyposis syndrome to specific clinical syndromes recognized many decades prior to the discovery of the adenomatous polyposis (APC) gene.

Several specified variants of FAP, namely Gardner syndrome, Turcot syndrome, and MYH-variant, have been identified. Individuals with Gardner syndrome (Online Mendelian Inheritance in Man [OMIM] 175100, 135290) develop adenomatous polyps throughout the GI tract, accompanied by extracolonic manifestations, including periampullary adenomas, papillary carcinoma of the thyroid, hepatoblastoma, osteomas of the mandible and skull, epidermal cysts, and desmoid tumors. Gardner syndrome, which has autosomal dominant inheritance, is a term used to refer to patients in whom these extraintestinal features are unusually prominent. It was first described in 1951, when Gardner described colonic polyposis in a Utah family whose 9 members died due to colon cancer within 3 generations

Turcot syndrome (OMIM 276300), another variant of FAP, is a rare autosomal recessive disorder that can present with brain tumors (glioblastoma multiforme, medulloblastoma) and colonic adenomas that frequently become malignant in those younger than 30 years. It was initially described in 1959 by Turcot,
and again in 1969 by Baughman et al.

First described in 2002, MYH-associated polyposis, or MutYH – associated polyposis (MAP), occurs in a small number of patients with FAP and results from a mutation in the human MutY homolog gene instead of the APC gene. Unlike FAP, MAP is autosomal recessive, with complete penetrance by age 60 years.

The broad category of hamartomatous polyposis syndromes encompasses several syndromes, mainly Peutz-Jeghers Syndrome (PJS), PTEN -associated hamartomatous syndromes (including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome [BRR]), familial juvenile polyposis, and Cronkhite-Canada syndrome.

PJS is named for the clinicians who initially described the disease and its characteristics in 1921 and 1941.
In PJS (OMIM 175200), an autosomal dominant disease, polyps can occur anywhere within the digestive tract (consistently within the jejunum) and are accompanied by characteristic melanin spots on the lips and digits. Scattered studies have reported malignant degeneration within GI polyps and development of extraintestinal malignancies, including pancreatic, testicular, and gynecologic malignancies. Development of gynecomastia commonly preceded the development of gynecologic or testicular malignancy.

In 1963, Lloyd and Dennis initially described the features associated with Cowden disease (OMIM 158350).
In 1972, Weary et al described the manifestations of Cowden disease and classified it as a multiple hamartomatous syndrome with autosomal dominant inheritance.
In 1991, Padberg et al suggested that the disorder known as cerebelloparenchymal disorder VI (Lhermitte-Duclos disease) is part of the multiple hamartoma syndrome.
Individuals with Cowden disease present at age 10-30 years with hyperplastic hamartomatous polyps throughout the GI tract (including the esophagus), glycogenic acanthosis of the esophagus, orocutaneous hamartomas of the face, pulmonary hamartomas, and neoplasia (breast, thyroid, adenocarcinoma of the colon [rare]).

BRR syndrome, also termed Bannayan-Zonana syndrome, was first described by Riley and Smith in 1961, was next described by Bannayan in 1971, and was further characterized by Zonana et al in 1975.
In BRR syndrome (OMIM 153480), hamartomatous polyps of the colon and tongue are present along with macrocephaly, lipomas, and hemangiomata.

Initially, BRR syndrome and Cowden syndrome were thought to be the same condition, but multiple studies had failed to demonstrate a consistent genotype-phenotype relationship. However, more recent studies have supported the argument that they are the same disease with variable expression and age-related penetrance.
The PTEN-associated hamartomatous syndromes can also include Proteus syndrome and Proteus-like syndrome.

FJP, also described in the literature as juvenile polyposis, is characterized by multiple inflammatory polyps throughout the colon that are associated with painless rectal bleeding (rare serious hemorrhage), rectal prolapse, and failure to thrive. This entity is different than solitary juvenile polyps, which are common in children and do not have the lifetime risk of malignancy.

First described in 1955, individuals with Cronkhite-Canada syndrome, which presents at an average age of 59 years, exhibit multiple intestinal polyps and ectoderm abnormalities, including hyperpigmentation of the skin, alopecia, and onychoheterotopia. Cronkhite-Canada syndrome is acquired rather than inherited and is associated with a high mortality rate.

HMPS is extremely rare. It is characterized by familial presentation of colorectal polyps that have mixed histologic elements with both adenomatous and hyperplastic features.
 In 1960, Gorlin and Goltz initially described Gorlin syndrome (GS), also termed nevoid basal cell carcinoma syndrome, in 1960.
Herzberg and Wiskemann further associated GS with medulloblastoma in 1963. GS (OMIM 109400) commonly presents with hamartomatous gastric polyps, palmar pits, short metacarpals, odontogenic keratocysts, intracranial calcifications, skeletal malformations, and neoplasia (basal cell carcinoma, ovarian carcinoma, medulloblastoma).

First defined in 2000, Burt and Jass described SPS, which is characterized by multiple, large serrated polyps within the colon leading to a high risk of colorectal cancer. Although its inheritance is unclear, hereditary and sporadic cases have been described in the literature.

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