Excerpt from Gardner Syndrome and Other Intestinal Polyposis Syndromes

Synonyms, Key Words, and Related Terms: Gardner syndrome, familial adenomatous polyposis, FAP, Turcot syndrome, Peutz-Jeghers syndrome, polyps-and-spots syndrome, Cronkhite-Canada syndrome, polyposis, skin pigmentation, alopecia, fingernail changes, juvenile polyposis coli, inflammatory polyps, Cowden disease, multiple hamartoma syndrome, Bannayan-Riley-Ruvalcaba syndrome, BRR, macrocephaly, multiple lipomas, hemangiomata, Bannayan-Zonana syndrome, Riley-Smith syndrome, Ruvalcaba-Myrhe-Smith syndrome, Gorlin syndrome, GS, basal cell nevus syndrome, Gorlin-Goltz syndrome, colonic polyposis, periampullary adenomas, papillary carcinoma of the thyroid, hepatoblastoma, osteoma, epidermal cyst, desmoid tumor, glioblastoma multiforme, medulloblastoma, gynecomastia, hamartomatous polyps, macrocephaly, limpomas, hemangiomata, nevoid basal cell carcinoma, palmar pits, cerebelloparenchymal disorder, Lhermitte-Duclos disease, glycogenic acanthosis, orocutaneous hamartomas, pulmonary hamartomas

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Background

In 1859, Charelaigue described the first definitive accounts of adenomatous polyposis in a 16-year-old girl and 21-year-old man.¹ In 1951, Gardner first published an article on familial polyposis, in which he described colonic polyposis in a Utah family whose members had 9 deaths due to colon cancer within 3 generations (average age 34 y). Several genetic disorders may present with GI polyps. Individuals with Gardner syndrome (ie, familial adenomatous polyposis [FAP]) (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.

Individuals with Turcot syndrome ([OMIM] 276300), a rare autosomal recessive disorder, present with brain tumors (glioblastoma multiforme, medulloblastoma) and colonic adenomas that frequently become malignant in those younger than 30 years. In 1959, Turcot initially described an affected brother and sister whose parents were third cousins.² In 1969, Baughman et al described a family with glioma and polyposis.³

Peutz initially described Peutz-Jeghers syndrome (PJS) in 1921, followed by Jeghers in 1941.^{4, 5} 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 PJS (OMIM 175200), polyps can occur anywhere within the digestive tract (consistently within the jejunum), accompanied by melanin spots on the lips and digits.

Bannayan-Riley-Ruvalcaba syndrome (BRR), also termed Bannayan-Zonana syndrome, was first described by Riley and Smith in 1961, next described by Bannayan in 1971, and further characterized by Zonana et al in 1975.^{6, 7} In BRR (OMIM 153480), hamartomatous polyps of the colon and tongue are present along with macrocephaly, lipomas, and hemangiomata.

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).

Individuals with Cronkhite-Canada syndrome (average age 62 y) exhibit multiple intestinal polyps and ectoderm abnormalities, including hyperpigmentation of the skin, alopecia, and onychoheterotopia. See Cronkhite-Canada Syndrome.

In 1963, Lloyd and Dennis initially described the features associated with Cowden disease in the family of Rachel Cowden.⁸ In 1972, Weary et al described the manifestations of Cowden disease and classified it as a multiple hamartomatous syndrome with autosomal dominant inheritance.⁹ In 1991, Padberg et al suggested that the disorder known as cerebelloparenchymal disorder VI (Lhermitte-Duclos disease) is part of the multiple hamartoma syndrome.¹⁰ 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]).

Inflammatory polyps are encountered in 1% of young children. Multiple inflammatory polyps throughout the colon that are associated with painless rectal bleeding (rare serious hemorrhage), rectal prolapse, and failure to thrive characterize juvenile polyposis coli. The malignant potential is far less than in Gardner syndrome, with rare scattered reports of adenocarcinoma development.

Pathophysiology

Mutations within the loci of tumor suppressor genes result in the myriad of clinical manifestations of disease. Gardner syndrome (ie, 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 of Gardner syndrome is related to the site of the APC gene mutation. Proximal APC mutations (proximal to codon 1249) produce a milder Gardner syndrome phenotype with sparse polyposis (<1000 adenomas). APC mutations between codons 1250 and 1330 present with tremendous degrees of polyposis (>5000 adenomas). Local factors may enhance the potential for development of manifestations of Gardner syndrome. Mahmoud et al suggest a role for unconjugated bile acids in the development of periampullary tumors.¹¹

Turcot syndrome is associated with bands 7p22, 5q21-22, and 3p21.3. 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 propose that band 5q21-22 is the nonallelic site to the APC locus.¹² Paraf and colleagues have divided the syndrome into 2 types: brain tumor polyposis type 1 (individuals without Gardner syndrome) and brain tumor polyposis type 2 (individuals with Gardner syndrome).¹³ Studies performed by Paraf and colleagues revealed germline mutations in DNA repair genes (MLH1, MSH2) in patients with brain tumor polyposis type 1.

PJS has been localized via gene linkage and logarithm of odds (LOD) score to band 19p13.3-13.4. Hemminki et al and Jenne et al have reported an abnormal serine-threonine kinase (STK11/LKB1) within this region.^{14, 15}

BRR and Cowden disease have both been mapped to chromosome 10q23.3, which encodes the PTEN gene, a phosphatase functioning within the phosphatidylinositol 3-kinase pathway.

GS is 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.

Current data suggest that Cronkhite-Canada syndrome develops from nongenetic etiologies. See Cronkhite-Canada Syndrome.

Frequency

United States

The Johns Hopkins Hospital Colonic Polyposis Registry, which encompasses 6 states and the District of Columbia, registered 98 Gardner syndrome kindreds and 19 PJS kindreds from 1973-1988.¹⁶ A prevalence of approximately 1:120,000 births is estimated for PJS.

Turcot syndrome is uncommon. In 1997, Paraf et al described a series of 100 patients with manifestations of Turcot syndrome.¹³ Some overlap between kindreds with Gardner syndrome and kindreds with Turcot syndrome may be observed.

BRR is extremely rare and has autosomal dominant inheritance.

Farndon et al have conservatively estimated the prevalence of GS at 1:57,000 population.¹⁷ In individuals who develop basal cell carcinoma when younger than 19 years, the incidence of GS rises markedly to 1:5.

Cowden disease is relatively uncommon. No current estimates of disease prevalence in the United States are available.

International

Gardner syndrome kindreds have been reported worldwide. An increased incidence of APC gene mutation (I1307K mutation) that results in a base transversion in the hypermutable region of the APC gene has been noted in persons of Ashkenazi Jewish descent who have a familial predisposition to colorectal cancer. Burn et al calculated the prevalence of APC mutations in northern England at 2.29 X 10^-5.¹⁸ Bisgaard et al estimated that the incidence of Gardner syndrome among Danish individuals is 1:13,528.

Turcot syndrome (brain tumor, polyposis) is relatively uncommon.

PJS is a rare syndrome with autosomal dominant inheritance in cases described throughout the world.

BRR is also a rare syndrome with probable autosomal dominant inheritance.

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

Nelen et al have estimated that the prevalence of Cowden disease among Dutch persons is 1:200,000-250,000 population.¹⁹

Mortality/Morbidity

Morbidity and mortality are due to complications from polyps or development of associated malignancies. If untreated, individuals with Gardner syndrome develop adenomatous polyps throughout the colon and rectum, with malignant transformation by age 40 years. Adenomatous polyps can occur in other portions of the GI tract. Periampullary cancer, gastric cancer (especially among Japanese persons), and, rarely, jejunal and ileal carcinomas have been observed. 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 CNS tumors (medulloblastoma, astrocytoma, gliomas, glioblastoma multiforme, gliomas), GI neoplasia (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 in the subgroup of glioblastoma and adenomas.²⁰

Morbidity and mortality in PJS arises from complications of polyps (eg, intussusception, bleeding, rare malignancy) and development of other malignancies (eg, gynecologic, testicular).

In individuals with BRR, complications from lipomas and arteriovenous malformations, thyroid disease, and an increased incidence of malignancies (eg, thyroid, breast) contribute to morbidity.

White individuals who have 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.

Morbidity and mortality in Cowden syndrome have arisen from complications of hamartomatous polyps and development of malignancies. Patients with Cowden syndrome have presented with chronic diarrhea and carcinomas of the breast, cerebellum (dysplastic gangliocytoma), thyroid, colon, kidney (renal cell adenocarcinoma), and skin (neuroendocrine [Merkel cell]) carcinoma.

Race

Gardner syndrome, Turcot syndrome, PJS, BRR, and Cowden disease have no race predilection.

Patients who have GS 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 versus 38% of African American patients.²¹

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).²² Bell and Mazzaferri reported that 94% of patients with Gardner syndrome who had thyroid carcinoma were women.²³

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.

In BRR, 80% of the reported cases have appeared in males.

GS is considered to be autosomal dominant. Approximately 40% of cases are new mutations.

Cowden disease is considered to be autosomal dominant. In a 1993 series by Hanssen et al, an excess of affected female patients was reported.²⁴ In Hanssen et al's 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.

Age

Patients with Gardner syndrome generally present in late adolescence with symptoms of polyposis (GI bleeding). Some patients with Gardner syndrome have reported GI bleeding in early childhood. Children with Gardner syndrome can present with extraintestinal manifestations before symptoms of polyposis arise, including medulloblastoma, hepatoblastoma, osteomas, or retinal pigment epithelium hypertrophy.

School-aged children have presented with Turcot syndrome and gene mutations related to Gardner syndrome (mean age 15.3 y, range 5-38 y) with medulloblastoma and colonic adenomas. Patients in the non–Gardner syndrome subgroup develop glioblastomas, and colonic adenomas develop somewhat later (mean age 18 y; range 4-70 y).

Children with PJS have presented in the neonatal period with complications of GI polyposis.

Children with BRR often exhibit high birthweight and length, hypotonia and diminished coordination, and mild mental retardation.

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 aged in their early twenties but may present in patients younger than 10 years.

Patients with Cowden syndrome may present during early childhood with craniomegaly, mild or moderate developmental delay, and scrotal tongue. During later childhood, trichilemmomas within the nasolabial folds, palmar pits, subcutaneous lipomas, and hemangiomas manifest. Symptoms from polyposis have resulted in colectomy during adolescence and have been reported in patients aged 18 months. Adults with Cowden disease have an increased incidence of breast cancer (30%), nonmedullary thyroid cancer, adrenal carcinoma, skin carcinoma, and dysplastic gangliocytomas.