eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Intestinal Polyposis Syndromes

Author: Ann Scheimann, MD, MBA, Assistant Professor, Department of Pediatrics, Section of Nutrition and Gastroenterology, Baylor College of Medicine and Johns Hopkins Medical Institution
Contributor Information and Disclosures

Updated: Nov 27, 2007

Introduction

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.

Clinical

History

  • Manifestations of adenomatous polyposis can affect the entire body. Talbot classifies the manifestations of Gardner syndrome via tissue distribution.25
    • In most individuals, symptoms of polyposis manifest as sessile tubular adenomas in late adolescence; however, some individuals have developed polyps in early childhood.
    • Fundic gland polyps rarely develop into gastric cancer.
    • Mesodermal sites associated with Gardner syndrome include fibrous tissue (desmoid tumors), bone (osteomas, dental anomalies), and liver (hepatoblastoma).
    • Ectodermal tissues include the eyes (congenital hypertrophy of the retinal pigment), skin (cysts), CNS (medulloblastoma), and endocrine system (thyroid carcinoma, multiple endocrine neoplasia 2B).
  • Van Meir classified the presentation of patients with Turcot syndrome into 2 categories, stratified by the presence or absence of colorectal phenotype.20 Patients with medulloblastoma who expressed the colorectal phenotype were older than 17 years at disease onset, whereas patients with medulloblastoma in the absence of the colorectal phenotype were younger than 10 years at disease onset. Hamilton et al reported that several patients with Turcot syndrome have mutations in the APC gene.26 These patients also have manifested ocular fundus lesions, epidermal inclusion cysts, and osteosclerotic jaw lesions consistent with Gardner syndrome. 
  • Patients with PJS generally present with the following symptoms:
    • GI bleeding 
    • Intussusception 
    • Rectal prolapse
    • Nasal polyposis (chronic sinusitis)
    • Pigmented macules
    • Gynecomastia (The development of gynecomastia in a child with suspected PJS should prompt investigation for underlying testicular or gynecologic malignancy.)
  • Features commonly associated with BRR (ie, Bannayan-Zonana syndrome) include high weight and length at birth. Growth velocity generally tapers by the time the patient is aged 7 years.
    • Children often present with developmental delay, mild mental retardation, and hypotonia. Parents commonly report excessive drooling.
    • Cutaneous features frequently include lipomas (70% of patients), myopathy (60% of patients), hamartomatous GI polyps (45% of patients), hemangiomata (10% of patients), and telangiectasias. Typical dermatologic findings include vascular malformations, lipomatosis, speckled lentiginosis of the penis or vulva, facial verrucae–like or acanthosis nigricans–like lesions, and multiple acrochordons of the neck, axilla, and groin.
    • Other reported features include testicular enlargement, cryptorchidism, Hashimoto thyroiditis, and congenital heart disease (ventricular septal defect).
    • Gut malrotation has been documented in a patient.
  • Patients with GS may present in infancy with congenital hydrocephalus, cleft lip and palate, lung cysts, rib and vertebral anomalies, and palmar pits. A case report by Genevieve et al described a child with GS who presented prenatally with a chylothorax.27 Enamel hypoplasia has also been described in the dental literature and attributed to lyonization.
    • Children at risk for inheritance of the gene should undergo a detailed examination at birth to look for palmar pits and other physical features, as well as radiologic evaluation of the rib, skull, and spine. 
    • Children with GS may present with symptoms of medulloblastoma when younger than 5 years.
    • Dental anomalies and basal cell carcinoma can appear in adolescents.
  • Cowden disease is less common in children than in adults, but patients may present with the following features:
    • Developmental delay
    • Macrocephaly (38%)
    • Cerebellar dysfunction
    • Scoliosis
    • Cutaneous hamartomas
    • Thyroid disease (>50%)
    • Chronic diarrhea
    • Malignancies
      • Neoplasia of the breast develops in 75% of females with Cowden disease.
      • Other malignancies that have been reported in patients with Cowden disease include dysplastic gangliocytomas of the cerebellum, ovarian tumors, thyroid tumors, renal cell adenocarcinoma, and Merkel cell carcinomas
    • Visceral arteriovenous malformations
      • These malformations have been reported in a family diagnosed with Cowden syndrome and, based on genetic testing findings, were found to have a frameshift mutation in the PTEN gene.
      • This association has been attributed to hypothesized function of the PTEN gene in the suppression of angiogenesis.

Physical

  • Physical features commonly associated with Gardner syndrome include the following:
    • Skin - Epidermal cysts (commonly on the back), sebaceous cysts (commonly on the back)
    • Craniofacial - Osteomas (including the mandible), skin fibromas, dental anomalies (supernumerary teeth, impacted teeth, missing teeth, root anomalies)
    • Ocular - Congenital hypertrophy of the retinal pigment epithelium
    • GI - Multiple gastric polyps, multiple duodenal polyps, multiple colonic polyps, mesenteric fibromas (desmoids)
    • Endocrine - Cushing syndrome (adrenal carcinoma), multiple endocrine neoplasia 2B
    • Oncology - Malignant transformation of polyps, gastric carcinoma, periampullary carcinoma, hepatoblastoma, biliary ductal carcinoma, osteosarcoma, adrenal carcinoma (Cushing syndrome), thyroid carcinoma
  • Attributes of Turcot syndrome include the following:
    • Skin - Café au lait spots, multiple lipomas, basal cell carcinoma of the scalp
    • GI - Colonic polyps (including adenomatous), hepatic focal nodular
      hyperplasia, adenocarcinoma of the colon, gastric carcinoma
    • CNS - Glioma, glioblastoma multiforme, astrocytoma
  • The following findings are common in PJS:
    • Skin - Melanin spots on the lips, digits, and oral mucosa
    • GI - Multiple GI polyps (especially jejunal), intussusception, GI bleeding, rectal prolapse
    • Genitourinary (GU) - Polyps within ureter, bladder, and renal pelvis
    • Pulmonary - Nasal and bronchial polyps
    • Thorax - Gynecomastia (testis, ovarian tumors)
  • Common findings associated with BRR (ie, Bannayan-Zonana syndrome) include the following:
    • General - High weight and length at birth, macrocephaly, scaphocephaly, broad thumb and hallux
    • CNS - Hypotonia and myopathy, developmental delay, mild mental retardation
    • Cardiovascular - Arteriovenous malformation, congenital heart disease (eg, ventricular septal defect)
    • Pulmonary - Pectus excavatum
    • GI - High palate, hamartomatous intestinal polyps (colon, tongue)
    • GU - Enlarged penis, spotted pigment of glans penis, testicular enlargement
    • Ocular - Pseudopapilledema, exotropia
  • Physical characteristics associated with GS include the following:
     
    • Skin - Basal cell nevi and carcinoma
    • Craniofacial - Broad facies, including nasal root, bossing of frontal and parietal bones, cleft lip and palate, mandibular prognathism, dental anomalies (odontogenic keratocysts)
    • Ocular - Strabismus, hypertelorism, colobomas, subconjunctival epithelial cysts, glaucoma
    • Cardiac - Cardiac fibromas
    • Pulmonary - Congenital lung cyst, rib anomalies
    • GI - Hamartomatous gastric polyps, lymphomesenteric cysts
    • GU - Ovarian fibromas and carcinomas
    • CNS - Congenital hydrocephalus, mental retardation, medulloblastoma 
    • Skeletal - Scoliosis, kyphoscoliosis, cervical anomalies, rib anomalies, brachydactyly, short fourth metacarpal and thumb
  • Manifestations of Cowden disease include the following:
    • Skin - Multiple hamartomas of skin and mucus membranes, verrucous lesions, papules of gingival and buccal mucosa, facial trichilemmomas 
    • Cerebrospinal, head - Craniomegaly, adenoid facies, ataxia, increased intracranial pressure, cerebellar degeneration, mental retardation, tremors, tonsillar herniation, seizures
    • Endocrine - Thyroid hamartomas and carcinoma 
    • Chest - Breast hamartomas and carcinomas, pectus excavatum 
    • GI - Scrotal tongue, intestinal polyps (hamartomatous)
    • Oncology - Dysplastic cerebellar gangliocytoma, breast carcinoma, ovarian carcinomas, Merkel cell skin carcinomas, renal cell adenocarcinomas, thyroid carcinomas
    • Spine - Scoliosis

Causes

  • Gardner syndrome 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.28
    • 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.
  • The cause for PJS appears to be multifactorial.
    • Abnormalities in the STK11 gene, a serine-threonine kinase and tumor suppressor gene involved in the development of hamartomas, may facilitate the development of carcinomas. 
    • Additional mutation events may also be necessary for the development of PJS.
  • BRR (ie, Bannayan-Zonana) syndrome has been localized to band 10q23.3, the same region in which Cowden disease is located.
    • Further studies have localized the PTEN gene, a tumor suppressor, to this area.
    • The phosphatase encoded by the PTEN gene functions within the phosphatidylinositol-3-kinase pathway.
    • Loss of gene function predisposes to future development of neoplasia.
  • 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
  • Nelen et al confirmed that the PTEN gene is the locus for Cowden disease.19
    • The PTEN gene has been localized to band 10q22-23 and modulates the phosphoinositide-3-kinase signaling pathway via phosphorylation of phosphoinositides to regulate cell growth and survival. 
    • Arch et al noted overlap in features of BRR and Cowden syndrome, both of which are associated with PTEN mutations.32

More on Intestinal Polyposis Syndromes

Overview: Intestinal Polyposis Syndromes
Differential Diagnoses & Workup: Intestinal Polyposis Syndromes
Treatment & Medication: Intestinal Polyposis Syndromes
Follow-up: Intestinal Polyposis Syndromes
References
[ CLOSE WINDOW ]

References

  1. Chargelaigue A. Des Polypes du Rectum. Thesis Paris. 1859.

  2. Turcot J, Despres JP, St Pierre F. Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum. Sep-Oct 1959;2:465-8. [Medline].

  3. Baughman FA, List CF, Williams JR, et al. The glioma-polyposis syndrome. New England Journal of Medicine. 1969;281:1345-46. [Medline].

  4. Peutz JLA. Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane. Nederl Maandschr Geneesk. 1921;10:134-46.

  5. Jeghers H, McKusick VA, Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits; a syndrome of diagnostic significance. N Engl J Med. Dec 22 1949;241(25):993, illust; passim. [Medline].

  6. Riley HD, Smith WR. Macrocephaly, pseudopapilledema and multiple hemangiomata: a previously undescribed heredofamilial syndrome. Pediatrics. 1960;26:293-300.

  7. Bannayan GA. Lipomatosis, angiomatosis, and macrencephalia. A previously undescribed congenital syndrome. Arch Pathol. Jul 1971;92(1):1-5. [Medline].

  8. Lloyd KM 2nd, Dennis M. Cowden's disease. A possible new symptom complex with multiple system involvement. Ann Intern Med. Jan 1963;58:136-42. [Medline].

  9. Weary PE, Gorlin RJ, Gentry WC Jr, Comer JE, Greer KE. Multiple hamartoma syndrome (Cowden's disease). Arch Dermatol. Nov 1972;106(5):682-90. [Medline].

  10. Padberg GW, Schot JD, Vielvoye GJ, et al. Lhermitte-Duclos disease and Cowden disease: a single phakomatosis. Ann Neurol. May 1991;29(5):517-23. [Medline].

  11. Mahmoud NN, Dannenberg AJ, Bilinski RT, et al. Administration of an unconjugated bile acid increases duodenal tumors in a murine model of familial adenomatous polyposis. Carcinogenesis. Feb 1999;20(2):299-303. [Medline].

  12. Tops CM, Vasen HF, van Berge Henegouwen G, et al. Genetic evidence that Turcot syndrome is not allelic to familial adenomatous polyposis. Am J Med Genet. Jul 15 1992;43(5):888-93. [Medline].

  13. Paraf F, Jothy S, Van Meir EG, et al. Brain tumor-polyposis syndrome: two genetic diseases?. J Clin Oncol. Jul 1997;15(7):2744-58. [Medline].

  14. Hemminki A, Markie D, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. Jan 8 1998;391(6663):184-7. [Medline].

  15. Jenne DE, Reimann H, Nezu J, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. Jan 1998;18(1):38-43. [Medline].

  16. Krush AJ, Giardello FM. Development of a genetics registry: Hereditary intestinal polyposis and hereditary colon cancer registry at the Johns Hopkins Hospital, 1973–1988. In: Herrera L. Familial Adenomatous Polyposis. New York, NY: Alan R Liss Inc; 1990:43-60.

  17. Farndon PA, Del Mastro RG, Evans DG, Kilpatrick MW. Location of gene for Gorlin syndrome. Lancet. Mar 7 1992;339(8793):581-2. [Medline].

  18. Burn J, Chapman P, Delhanty J, et al. The UK Northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations. J Med Genet. May 1991;28(5):289-96. [Medline].

  19. Nelen MR, Kremer H, Konings IB, et al. Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet. Apr 1999;7(3):267-73. [Medline].

  20. Van Meir EG. Turcot's Syndrome: Phenotype of brain tumors, survival and mode of inheritance. International Journal of Cancer. 1998;75:162-64. [Medline].

  21. Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. Mar 31 1997;69(3):299-308. [Medline].

  22. Klemmer S, Pascoe L, DeCosse J. Occurrence of desmoids in patients with familial adenomatous polyposis of the colon. Am J Med Genet. Oct 1987;28(2):385-92. [Medline].

  23. Bell B, Mazzaferri EL. Familial adenomatous polyposis (Gardner's syndrome) and thyroid carcinoma. A case report and review of the literature. Dig Dis Sci. Jan 1993;38(1):185-90. [Medline].

  24. Hanssen AM, Fryns JP. Cowden syndrome. J Med Genet. Feb 1995;32(2):117-9. [Medline].

  25. Talbot IC. Pathology. In: Phillips RKS, Spigelman AD, Thompson JPS, eds. Familial Adenomatous Polyposis and Other Polyposis Syndromes. Oxford UP;. 1994:15-35.

  26. Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot's syndrome. N Engl J Med. Mar 30 1995;332(13):839-47. [Medline].

  27. Genevieve D, Walter E, Gorry P, et al. Gorlin syndrome presenting as prenatal chylothorax in a girl. Prenatal Diagnosis. 2005;25:997-9. [Medline].

  28. Peifer M. Cancer, catenins, and cuticle pattern: a complex connection. Science. Dec 10 1993;262(5140):1667-8. [Medline].

  29. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. Jun 14 1996;85(6):841-51. [Medline].

  30. Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. Jun 14 1996;272(5268):1668-71. [Medline].

  31. Bale AE. Variable expressivity of patched mutations in flies and humans. Am J Hum Genet. Jan 1997;60(1):10-2. [Medline].

  32. Arch EM, Goodman BK, Van Wesep RA, et al. Deletion of PTEN in a patient with Bannayan-Riley-Ruvalcaba syndrome suggests allelism with Cowden disease. Am J Med Genet. Sep 5 1997;71(4):489-93. [Medline].

  33. Gruber SB, Entius MM, Petersen GM, et al. Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res. Dec 1 1998;58(23):5267-70. [Medline].

  34. Hughes LJ, Michels VV. Risk of hepatoblastoma in familial adenomatous polyposis. Am J Med Genet. Aug 1 1992;43(6):1023-5. [Medline].

  35. Fuchs CS, Giovannucci EL, Colditz GA, et al. Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med. Jan 21 1999;340(3):169-76. [Medline].

  36. Watanabe K, Kawamori T, Nakatsugi S, et al. Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. Cancer Res. Oct 15 1999;59(20):5093-6. [Medline].

  37. Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. May 6 1993;328(18):1313-6. [Medline].

  38. Barnes CJ, Cameron IL, Hardman WE, Lee M. Non-steroidal anti-inflammatory drug effect on crypt cell proliferation and apoptosis during initiation of rat colon carcinogenesis. Br J Cancer. Feb 1998;77(4):573-80. [Medline].

  39. Bisgaard ML, Fenger K, Bulow S, et al. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat. 1994;3(2):121-5. [Medline].

  40. Boardman LA, Thibodeau SN, Schaid DJ, et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med. Jun 1 1998;128(11):896-9. [Medline].

  41. Bodmer WF, Bailey CJ, Bodmer J, et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. Aug 13-19 1987;328(6131):614-6. [Medline].

  42. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A. Apr 13 1999;96(8):4240-5. [Medline].

  43. DeCosse JJ, Miller HH, Lesser ML. Effect of wheat fiber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis. J Natl Cancer Inst. Sep 6 1989;81(17):1290-7. [Medline].

  44. Desai DC, Murday V, Phillips RK, et al. A survey of phenotypic features in juvenile polyposis. J Med Genet. Jun 1998;35(6):476-81. [Medline].

  45. Erkek E, Hizel S, Sanly C, et al. Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome. J Am Acad Dermatol. Oct 2005;53(4):639-43. [Medline].

  46. Fernandez Seara MJ, Martinez Soto MI, Fernandez Lorenzo JR. Peutz-Jeghers syndrome in a neonate. J Pediatr. Jun 1995;126(6):965-7. [Medline].

  47. Friedl W, Meuschel S, Caspari R, et al. Attenuated familial adenomatous polyposis due to a mutation in the 3' part of the APC gene. A clue for understanding the function of the APC protein. Hum Genet. May 1996;97(5):579-84. [Medline].

  48. Gardner EJ. A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet. Jun 1951;3(2):167-76. [Medline].

  49. Giardiello FM, Trimbath JD. Peutz-Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol. Apr 2006;4(4):408-15. [Medline].

  50. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore). Mar 1987;66(2):98-113. [Medline].

  51. Hanssen AM, Werquin H, Suys E, Fryns JP. Cowden syndrome: report of a large family with macrocephaly and increased severity of signs in subsequent generations. Clin Genet. Dec 1993;44(6):281-6. [Medline].

  52. Henney JE. From the Food and Drug Administration. JAMA. Mar 1 2000;283(9):1131. [Medline].

  53. Holt PR, Atillasoy EO, Gilman J, et al. Modulation of abnormal colonic epithelial cell proliferation and differentiation by low-fat dairy foods: a randomized controlled trial. JAMA. Sep 23-30 1998;280(12):1074-9. [Medline].

  54. Itoh H, Ohsato K, Yao T, Iida M, Watanabe H. Turcot's syndrome and its mode of inheritance. Gut. May 1979;20(5):414-9. [Medline].

  55. Jiang CY, Esufali S, Berk T, et al. STK11/LKB1 germline mutations are not identified in most Peutz-Jeghers syndrome patients. Clin Genet. Aug 1999;56(2):136-41. [Medline].

  56. Jones KL, Smith DW, Harvey MA, et al. Older paternal age and fresh gene mutation: data on additional disorders. J Pediatr. Jan 1975;86(1):84-8. [Medline].

  57. Kalgutkar AS, Crews BC, Rowlinson SW, et al. Aspirin-like molecules that covalently inactivate cyclooxygenase-2. Science. May 22 1998;280(5367):1268-70. [Medline].

  58. Lo Muzio L, Nocini PF, Savoia A, et al. Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals. Clin Genet. Jan 1999;55(1):34-40. [Medline].

  59. Lynch HT, Smyrk TC. Hereditary colorectal cancer. Semin Oncol. Oct 1999;26(5):478-84. [Medline].

  60. Macrae F. Wheat bran fiber and development of adenomatous polyps: evidence from randomized, controlled clinical trials. Am J Med. Jan 25 1999;106(1A):38S-42S. [Medline].

  61. Marsh DJ, Kum JB, Lunetta KL, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan- Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet. Aug 1999;8(8):1461-72. [Medline].

  62. Marshall WH, Martin FI, Mackay IR. Gardner's syndrome with adrenal carcinoma. Australas Ann Med. Aug 1967;16(3):242-4. [Medline].

  63. Mastronardi L, Ferrante L, Lunardi P, Cervoni L, Fortuna A. Association between neuroepithelial tumor and multiple intestinal polyposis (Turcot's syndrome): report of a case and critical analysis of the literature. Neurosurgery. Mar 1991;28(3):449-52. [Medline].

  64. Matsumine A, Ogai A, Senda T, et al. Binding of APC to the human homolog of the Drosophila discs large tumor suppressor protein. Science. May 17 1996;272(5264):1020-3. [Medline].

  65. Mehenni H, Blouin JL, Radhakrishna U, et al. Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19q13.4. Am J Hum Genet. Dec 1997;61(6):1327-34. [Medline].

  66. Mehenni H, Gehrig C, Nezu J, et al. Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet. Dec 1998;63(6):1641-50. [Medline].

  67. Nelen MR, van Staveren WC, Peeters EA, et al. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet. Aug 1997;6(8):1383-7. [Medline].

  68. Phillips RKS, Spigelman AD, Thompson JPS. Familial Adenomatous Polyposis and Other Polyposis Syndromes. Oxford University Press; 1994.

  69. Ruschak PJ, Kauh YC, Luscombe HA. Cowden's disease associated with immunodeficiency. Arch Dermatol. Sep 1981;117(9):573-5. [Medline].

  70. Ruvalcaba RH, Myhre S, Smith DW. Sotos syndrome with intestinal polyposis and pigmentary changes of the genitalia. Clin Genet. Dec 1980;18(6):413-6. [Medline].

  71. Solh HM, Azoury RS, Najjar SS. Peutz-Jeghers syndrome associated with precocious puberty. J Pediatr. Oct 1983;103(4):593-5. [Medline].

  72. Spirio L, Olschwang S, Groden J, et al. Alleles of the APC gene: an attenuated form of familial polyposis. Cell. Dec 3 1993;75(5):951-7. [Medline].

  73. Su LK, Vogelstein B, Kinzler KW. Association of the APC tumor suppressor protein with catenins. Science. Dec 10 1993;262(5140):1734-7. [Medline].

  74. Tejani Z, Batra P, Mason C, Atherton D. Focal dermal hypoplasia: oral and dental findings. Journal of Clinical Pediatric Dentistry. 2005;30:67-72. [Medline].

  75. Turnbull MM, Humeniuk V, Stein B, Suthers GK. Arteriovenous malformations in Cowden syndrome. Journal of Medical Genetics. 2005;42:e50. [Medline].

  76. van der Luijt RB, Tops CM, Khan PM, van der Klift HM. Molecular, cytogenetic, and phenotypic studies of a constitutional reciprocal translocation t(5;10)(q22;q25) responsible for familial adenomatous polyposis in a Dutch pedigree. Genes Chromosomes Cancer. Jul 1995;13(3):192-202. [Medline].

  77. Westerman AM, Entius MM, de Baar E, et al. Peutz-Jeghers syndrome: 78-year follow-up of the original family. Lancet. Apr 10 1999;353(9160):1211-5. [Medline].

  78. Wilson DM, Pitts WC, Hintz RL, Rosenfeld RG. Testicular tumors with Peutz-Jeghers syndrome. Cancer. Jun 1 1986;57(11):2238-40. [Medline].

  79. Winter HS. Intestinal Polyps. Pediatric Gastointestinal Disease. 1996;891-907.

  80. Zaheri S, Chong SK, Harland CC. Treatment of mucocutaneous pigmentation in Peutz-Jeghers with potassium titanyl phosphate (KTP) laser. Clinical and Experimental Dermatology. 2005;30:710-2. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

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

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Ann Scheimann, MD, MBA, Assistant Professor, Department of Pediatrics, Section of Nutrition and Gastroenterology, Baylor College of Medicine and Johns Hopkins Medical Institution
Ann Scheimann, MD, MBA is a member of the following medical societies: North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Medical Editor

Jayant Deodhar, MD, Associate Professor in Pediatrics, BJ Medical College, India; Honorary Associate Consultant, Departments of Pediatrics and Neonatology, King Edward Memorial Hospital, India
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Nothing to disclose.

Managing Editor

Stefano Guandalini, MD, Director, University of Chicago Celiac Disease Program, Section Chief of Gastroenterology, Hepatology and Nutrition; Professor, Department of Pediatrics, University of Chicago Comer Children's Hospital
Stefano Guandalini, MD is a member of the following medical societies: American Gastroenterological Association and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, State University of New York, Downstate Medical Center College of Medicine; Professor of Clinical Pediatrics, St George's University School of Medicine; Distinguished Lecturer, New York Medical College, School of Public Health; Chair and Consulting Staff, Department of Pediatrics, Long Island College Hospital
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.