Intestinal Polyposis Syndromes

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. ^[1]

Several genetic disorders may present with gastrointestinal (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, ^[2] and again in 1969 by Baughman et al. ^[3]

First described in 2002, 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. ^[4]

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. ^{[5, 6]} 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). ^[7] In 1972, Weary et al described the manifestations of Cowden disease and classified it as a multiple hamartomatous syndrome with autosomal dominant inheritance. ^[8] In 1991, Padberg et al suggested that the disorder known as cerebelloparenchymal disorder VI (Lhermitte-Duclos disease) is part of the multiple hamartoma syndrome. ^[9] 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. ^{[10, 11]} 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. ^[12] 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. ^[13] In 1960, Gorlin and Goltz initially described Gorlin syndrome (GS), also termed nevoid basal cell carcinoma syndrome, in 1960. ^[14] 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. ^[15]

With the exception of Cronkhite-Canada Syndrome, all of the intestinal polyposis syndromes have been associated with genetic mutations. Mutations within the loci of tumor suppressor genes result in the myriad of clinical manifestations of disease.

FAP arises from germline mutations in the adenomatous polyposis coli (APC) gene on band 5q21-22. The APC gene encodes a 2843 amino acid protein involved in cell adhesion and signal transduction. The presentation and severity of disease is related to the site of the APC gene mutation. Proximal APC mutations (proximal to codon 1249) produce a milder attenuated phenotype with sparse polyposis. APC mutations between codons 1250 and 1330 present with tremendous degrees of polyposis. Local factors may enhance the potential for development of manifestations of FAP.

Turcot syndrome is associated with mutations in the following genes: bands 7p22, 5q21-22, and 3p21.3. ^[16] Several patients with manifestations of Turcot syndrome have documented APC mutations in addition to ocular fundus lesions and jaw lesions consistent with Gardner syndrome; however, patients with Turcot syndrome have a lower degree of colonic polyposis (20-100 total), with malignant transformation by the third decade. Tops et al proposed that band 5q21-22 is the nonallelic site to the APC locus. ^[17] Studies performed by Paraf and colleagues revealed germline mutations in DNA repair genes (MLH1, MSH2) in Turcot syndrome.

MYH-associated results from a mutation in the MutY gene, which is a DNA glycosylase involved in oxidative DNA damage repair on band 1p34.3. ^[18]

PJS has been localized via gene linkage and logarithm of odds (LOD) score to mutations in band 19p13.3-13.4, which is now known to encode a serine-threonine kinase (STK11/LKB1) within this region. ^{[19, 20]} The types of tumors that present in PJS are consistent with the notion that STK11/LKB1 is a tumor suppressor gene. Approximately 80% of patients with PJS have this gene mutation. ^[21]

Bannayan-Riley-Ruvalcaba syndrome (BRR) syndrome and Cowden disease have both been mapped to chromosome 10q23.3, which encodes the phosphatase and tensin homolog (PTEN) gene, a phosphatase that functions within the phosphatidylinositol 3-kinase pathway. PTEN deficiency in the mouse predisposes to tumors in the thymus, endometrium, liver, prostate, and gastrointestinal lymph tissue. ^[22]

FJP has been associated with germline mutations in bone morphogenic protein receptor 1A (BMPR1A), mothers against decapentaplegic homolog 4 (SMAD4), or endoglin (ENG), suggesting that the tumor growth factor (TGF)-beta pathway is critical in its pathogenesis.

GS is caused by an autosomal dominant mutation localized to band 9q22.3-31, which encodes a human analogue to the Drosophila PTCH gene, a tumor suppressor gene. Advanced paternal age may produce spontaneous GS mutations. ^[23]

SPS is caused by an activating mutation of the BRAF oncogene, which controls the serrated pathway of colorectal carcinogenesis. This alternative pathway is not associated with the APC gene and leads to a CpG island methylator phenotype carcinoma. ^[15]

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) arises from mutations within the APC gene. The APC protein contains several functional regions that serve as binding and turnover loci for beta-catenin. Beta-catenin structures tissue architecture and activates E-cadherin, which regulates adherens junctions between epithelial cells. Based on experimental data within a Drosophila model, Peifer hypothesized that the APC complex governs the signaling of contact inhibition within the cell. ^[24]

Most mutations within the APC gene occur within the central area (mutation cluster region) and generate truncated APC proteins. Mutations situated within either the first or last third of the APC gene result in a late-onset attenuated polyposis phenotype; however, central region APC mutations exhibit a severe phenotype, with vast numbers of polyps occurring early in life and extracolonic manifestations.

Peutz-Jeghers syndrome

The cause for Peutz-Jeghers syndrome (PJS) appears to be multifactorial, although 80% of cases are associated with a gene mutation. Abnormalities in the STK11/LKB-1 gene, a serine-threonine kinase and tumor suppressor gene involved in the development of hamartomas, on band 19p13.3 may facilitate the development of carcinomas. ^[25] Additional mutation events may also be necessary for the development of PJS.

PTEN-hamartomatous syndromes

Cowden disease and Bannayan-Riley-Ruvalcaba syndrome (BRR) syndrome have been localized to band 10q23.3, which is the location of the PTEN, a tumor suppressor gene. ^{[26, 27]}

The phosphatase encoded by the PTEN gene functions within the phosphatidylinositol-3-kinase pathway, modulating the phosphoinositide-3-kinase signaling pathway via phosphorylation of phosphoinositides to regulate cell growth and survival.

Loss of gene function predisposes to future development of neoplasia.

Familial juvenile polyposis

Familial juvenile polyposis (FJP) has been associated with gene mutations in SMAD4 and BMPR1A, which are proteins that function as mediators in the transforming growth factor b (TGF-b) pathway. This pathway has a role in regulating cell proliferation, differentiation, survival, and apoptosis. An estimated 25% of cases are caused by an inherited defect in the gene; the other 75% arise from de novo mutations or environmental factor causes.

Cronkite-Canada syndrome

The etiology of Cronkite-Canada syndrome (CCS) in unknown. As of now, no mutations causing the syndrome have been discovered, and familial predisposition is not evident. Studies favor a possible autoimmune process based on dysregulation, which is suggested by the syndrome’s association with ANA, hypothyroidism, rheumatological diseases, and elevated IgG4. ^[28]

Gorlin syndrome

Gorlin syndrome (GS) has been mapped to band 9q22.3-q31. Studies by Hahn et al, Johnson et al, and Bale have explored similarities in GS to the Drosophila PTCH gene that is expressed in the sclerotome, branchial arch, limb, skin, and spinal cord. ^{[29, 30, 31]}

Bale noted that phenotypic expression of GS varied more among families, suggesting the importance of neighboring genes in modulation of phenotypic expression. ^[31]

Serrated polyposis syndrome

Although serrated polyposis syndrome (SPS) is considered a mainly genetic disease, autosomal dominant and autosomal recessive inheritance has been proposed. One study linked SPS to 2q32.2-q33.3 in half of the SPS families studied. In addition, environmental factors such as smoking, weight, and some drugs have been described as potential risk factors for developing SPS. ^[15]

United States data

The frequency depends on the specific syndrome and does not vary drastically between the United States and other countries. Estimates are gained from large scale registries and can widely vary. Familial adenomatous polyposis (FAP) is inherited in an autosomal dominant fashion and is the most common intestinal polyposis syndrome with an estimated frequency of 1:13,000 births. ^[32]

Some overlap between kindreds with Gardner syndrome and kindreds with Turcot syndrome may be observed, but these variants of FAP are much rarer than FAP itself. In 1997, Paraf et al described a series of 100 patients with manifestations of Turcot syndrome. ^[33] The Johns Hopkins Hospital Colonic Polyposis Registry, which encompasses 6 states and the District of Columbia, registered 98 Gardner syndrome kindreds and 19 Peutz-Jeghers syndrome (PJS) kindreds from 1973-1988. ^[34] From this data, PJS has an estimated prevalence of between 1:120,000 and 1:200,000 births.

The estimated incidence of Cowden syndrome is 1:200,000 but is likely higher than that due to its penchant for being underdiagnosed. ^[35] Bannayan-Riley-Ruvalcaba syndrome (BRR) syndrome is extremely rare despite its autosomal dominant inheritance.

Familial juvenile polyposis (FJP) is thought to have an incidence of 1:100,000, making it the most common hamartomatous polyposis syndrome. ^[36]

Cronkhite-Canada syndrome (CSS) is considered to be a rare, sporadic, and acquired syndrome. ^[13] To date, barely over 500 cases have been reported worldwide. Estimated incidence is 1:1,000,000. Disease presents later in age, with a mean age of diagnosis of 59 years. ^[37]

Farndon et al have conservatively estimated the prevalence of Gorlin syndrome (GS) at 1:57,000 births. ^[38] In individuals who develop basal cell carcinoma before age 19 years, the incidence of GS rises markedly to 1:5.

Initial studies estimated the prevalence of serrated polyposis syndrome (SPS) at 1:3,000 patients who were screened. However, the true prevalence is most likely closer to less than 0.09%. If screened after a positive fecal occult blood test result, the prevalence increases to 0.34% to 0.66%. ^[39]

International data

Worldwide studies of Gardner syndrome kindreds have shown an increased incidence of APC gene mutation (I1307K mutation) in persons of Ashkenazi Jewish descent with a family history of colorectal cancer. Burn et al calculated the prevalence of APC mutations in northern England at 2.29 X 10-5. ^[40] Bisgaard et al estimated that the incidence of Gardner syndrome among Danish individuals is 1:13,528.

BRR syndrome is also a rare syndrome with probable autosomal dominant inheritance. Cowden syndrome is also relatively uncommon, estimated to affect 1:200,000 births. ^[41] Nelen et al have estimated that the prevalence of Cowden disease among Dutch persons is 1:200,000-250,000 population. ^[26] FJP can affect 1:100,000 births. ^[41]

The distribution of GS is similar to that in the United States.

Race-, sex-, and age-related demographics

Race

FAP, PJS, the PTEN- hamartomatous syndromes, FJP, and Cronkhite-Canada syndrome have no reported race predilection.

Patients who have Gorlin syndrome and are of Mediterranean or African descent have diminished risk for developing basal cell carcinomas secondary to skin pigmentation. Kimonis noted that basal cell carcinomas develop in 80% of white patients compared with 38% of black patients. ^[42]

Sex

The inheritance for Gardner syndrome is autosomal dominant, with nearly 100% penetrance of the APC mutation by age 40 years. Women with Gardner syndrome have an increased risk for the development of thyroid cancer and desmoid tumors. Klemmer et al found an increased incidence of desmoid tumors among females (8% of male vs 13% of females). ^[43] Bell and Mazzaferri reported that 94% of patients with Gardner syndrome who had thyroid carcinoma were women. ^[44]

The inheritance of Turcot syndrome is autosomal recessive. No differences in symptom manifestations between the sexes has been reported.

The inheritance for PJS is autosomal dominant. The life expectancy for women with PJS may be decreased by development of gynecologic malignancies. Males with PJS are at increased risk for development of testicular cancer.

The PTEN- hamartomatous syndromes are considered to be autosomal dominant. In a 1993 series by Hanssen et al, an excess of affected female patients was reported in Cowden disease. ^[45] In that survey of 87 patients, 70% (61) of the patients were female. Female patients with Cowden syndrome are predisposed to the development of breast neoplasia and neoplasia of the urogenital system.

Cronkhite-Canada syndrome exhibits a slight male predominance at a ratio of 3:2. ^[37]

GS is inherited in an autosomal dominant pattern, without reported differences in disease manifestation by gender. FJP is also autosomal dominant.

SPS has no documented sex predominance.

Age

Patients with FAP generally present in late adolescence with symptoms of polyposis (GI bleeding). Some patients have reported GI bleeding in early childhood, and case reports have noted colon cancer presenting in children aged 5 years old and younger. ^[46] Children with Gardner syndrome and Turcot syndrome can present with extraintestinal manifestations before symptoms of polyposis arise, including medulloblastoma, hepatoblastoma, osteomas, or retinal pigment epithelium hypertrophy. Patients in the Turcot syndrome subgroup develop glioblastomas; colonic adenomas develop somewhat later (mean age 18 y; range 4-70 y). ^[33]

Children with PJS have presented in the neonatal period with complications of GI polyposis. ^[47] The average age of diagnosis of PJS is 24.3 years.

Patients with PTEN- hamartomatous syndrome can often be diagnosed in childhood, with congenital findings of macrocephaly and mild or moderate developmental delay. During later childhood, trichilemmomas within the nasolabial folds, palmar pits, subcutaneous lipomas, and hemangiomas manifest. ^[48]

Patients with Cronkhite-Canada syndrome present in middle to late adulthood; mean age of presentation is 59 years. The rare reported pediatric cases have features similar to infantile juvenile polyposis. ^[37]

Patients with FJP present in childhood and adolescence, most commonly with isolated rectal bleeding. ^[49]

Neonates with GS present with lung cysts, rib and vertebral anomalies, palmar pits, hydrocephalus, and cleft palate. Symptoms of medulloblastoma in GS manifest in patients younger than 2 years. Basal cell carcinomas generally appear in patients with GS who are in their early twenties but may present in patients younger than 10 years. ^[42]

Morbidity and mortality in intestinal polyposis syndromes are largely due to complications from polyps or development of associated malignancies. Complications from the polyps include bleeding and intussusception.

Patients with familial adenomatous polyposis (FAP) and its variants have an increased incidence of malignancies, including gastric carcinoma, colonic carcinoma, periampullary carcinoma, biliary tract carcinoma, thyroid carcinoma, osteosarcomas, and adrenal carcinoma.

The development of associated malignancies differs based on the specific intestinal polyposis syndrome. Individuals with FAP have a 100% lifetime risk of colorectal cancer if they do not undergo colectomy. Cancer usually develops at age 20-40 years. ^[18]  In addition, a 5-10% lifetime risk of duodenal adenocarcinoma and/or periampullary adenocarcinoma is also noted. The lifetime risk of thyroid cancer and gastric adenocarcinoma is less than 1%. Other malignancies, including desmoid tumors (especially after surgery), hepatoblastoma, adrenal cortical carcinoma, thyroid carcinoma, sarcoma, glioblastoma, and medulloblastoma have been associated with Gardner syndrome.

Morbidity and mortality in Turcot syndrome arises from complications of central nervous system (CNS) tumors (eg, medulloblastoma, astrocytoma, gliomas, glioblastoma multiforme, gliomas), gastrointestinal (GI) neoplasia (eg, colonic adenocarcinomas, gastric carcinomas), and basal cell carcinomas of the scalp. Van Meir reported mean survival rates of 5.6 years from diagnosis for patients with medulloblastoma and colonic adenomas and 27.5 months from diagnosis for patients with glioblastoma and adenomas. ^[50]

Morbidity and mortality in Peutz-Jeghers syndrome (PJS) arises from complications of gastrointestinal polyps such as intussusception and bleeding and the development of malignancies of the stomach, pancreas, and lung. An increased risk for breast, ovarian, uterine and cervical cancer is noted in young women along with Sertoli cell tumors in young men; 93% of patients with PJS develop cancer by age 65 years, with a mean age of 42 years. ^{[25, 18, 36]}

Individuals with PTEN hamartomatous syndromes, such as Cowden syndrome and BRR syndrome, are at risk from non-GI malignancies such as breast, uterine, cerebellum, thyroid, kidney, and skin; complications from lipomas and arteriovenous malformations; and thyroid disease. Female breast cancer has an 85% lifetime risk. ^[51]

Similar to PJS, in familial juvenile polyposis (FJP), polyps may bleed or cause obstruction. Sporadic reports detail gastric, small bowel, and pancreatic cancers, but a more substantial increased risk of colon cancer is seen in these individuals, with cumulative lifetime risk of 50%. ^[52]

Cronkhite-Canada syndrome has an extremely unfavorable prognosis, with a 5-year mortality rate of 55%, secondary to life-threatening GI bleeding, intussusception, infection, malnutrition, heart failure, and protein-losing enteropathy leading to electrolyte disturbances. ^[13]

White individuals who have Gorlin syndrome (GS) develop basal cell carcinomas when younger than 20 years. Patients with GS are at increased risk for ovarian carcinoma and medulloblastoma. Children who are younger than 5 years and have medulloblastoma should be tested for GS before initiation of radiation therapy to diminish the risk for early development of basal cell carcinoma.

Patients diagnosed with serrated polyposis syndrome (SPS) have between a 25-75% risk of colorectal cancer, which increases as the number of polyps and serrated adenomas increase. ^[15]

Gardner syndrome

Patients with Gardner syndrome may experience complications from malignancies and from benign lesions, such as mandibular osteomas or dental anomalies.

Turcot syndrome

Patients with Turcot syndrome may experience complications from malignancies.

Peutz-Jeghers syndrome

Patients may develop medical and surgical complications from gastrointestinal (GI) polyps and malignancies. Some reports suggest that approximately one fourth of patients require laparotomy for small bowel intussusception by age 10 years. ^[53]

Repeated intestinal resections may result in short-bowel syndrome with total parenteral nutrition (TPN) dependence.

Patients with PJS have an increased risk for the development of malignancies within the GI tract, pancreas, breast, uterus, and testicles.

Complications from GI polyps and malignancies may reduce life expectancy.

PTEN-hamartomatous syndromes

Patients may develop medical and surgical complications from lipomas, vascular lesions, and malignancies.

Lipomas regress with advancing age; however, 2 children have died in early childhood with severe visceral lipomatosis.

Vascular lesions within the CNS have resulted in bleeding with impairment and chronic seizures. Vascular anomalies in other areas can compromise pulmonary function and result in high-output cardiac failure.

Patients with Bannayan-Riley-Ruvalcaba syndrome (BRR) syndrome have a higher incidence of CNS tumors and can develop metaplastic changes within hamartomatous GI polyps.

Mutations within PTEN, a tumor suppressor gene found in patients with BRR syndrome, may predispose to malignant transformation, especially thyroid and breast.

Gorlin syndrome

Patients may experience complications from malignancies, cardiac fibromas, ophthalmologic abnormalities, and skeletal anomalies.

In patients with malignancies, ionizing radiation should be avoided, if possible, to deter the development of basal cell carcinomas.

Approximately 3% of patients with GS develop cardiac fibromas, requiring excision if symptomatic.

Routine ophthalmologic screening minimizes visual losses from strabismus, glaucoma, and cataracts.

Serrated polyposis syndrome

Complications from GI polyps and development of colorectal cancer will affect life expectancy.

Patients with FAP and its variants should undergo routine medical examinations and endoscopic and radiologic evaluations for surveillance of potential malignancies. In particular, patients with Turcot syndrome should be routinely screened for basal cell carcinomas, gastrointestinal cancer and breast cancer.

Routine screening of stools for occult blood and early institution screening for the detection of breast cancer (self-examination, mammography) may improve life expectancy in patients with PJS. The presence of gynecomastia or precious puberty in the patient with suspected PJS should prompt careful evaluation to exclude testicular or gynecologic malignancy.

Early institution of screening for the detection of breast cancer (self-examination, mammography) and awareness of the increased risk for development of malignancy may improve the life expectancy of patients with PTEN-hamartomatous syndromes.

Minimizing exposure to ultraviolet light and ionizing radiation in patients with GS may diminish the potential for development of basal cell carcinomas. Establishment of skin self-detection programs may permit early detection of basal cell carcinomas. Patients should undergo routine ophthalmologic, dental, gynecologic, and medical examinations.