Intestinal Polyposis Syndromes Clinical Presentation
- Author: Evelyn K Hsu, MD; Chief Editor: Carmen Cuffari, MD more...
Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) presents with multiple adenomatous polyps throughout the colon (see the image below).
Eighty percent of these polyps present in the left colon. Patients with FAP are at risk for upper GI tract malignancies as well as for hepatoblastoma, which has an increased incidence in children with a family history of FAP. A single center 11-year study in Israel discovered that out of 50 patients identified with a polyposis syndrome, 32 were symptomatic, most with rectal bleeding. Only 1 of these children, a 12-year-old, was diagnosed with adenocarcinoma.
In variants of FAP, manifestations can affect the entire body. Talbot classifies the manifestations of Gardner syndrome via tissue distribution.
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 [CHRPE]), 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. 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. These patients also have manifested ocular fundus lesions, epidermal inclusion cysts, and osteosclerotic jaw lesions consistent with Gardner syndrome.
Patients with Peutz-Jeghers syndrome (PJS) generally have with multiple pedunculated GI hamartomatous polyps, with lesions distributed through the small intestine (78%), colon (42%), stomach (38%), and rectum (28%). They tend to present with the following symptoms:
Nasal polyposis (chronic sinusitis)
Pigmented macules on the lips and digits
The development of gynecomastia in a child with suspected PJS should prompt investigation for underlying testicular or gynecologic malignancy.
Features commonly associated with the entity that was known as Bannayan-Riley-Ruvalcaba (BRR) syndrome include increased 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, excessive drooling and hypotonia.
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.
Cowden disease, which is thought to be the same entity as BRR syndrome, manifests with variable penetrance at a later age and is typically associated with the following features:
Thyroid disease (>50%)
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.
Patients with Gorlin syndrome (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. 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.
Familial juvenile polyposis
Usually, polyps vary in number, with variation in size and location. They can present with rectal bleeding, abdominal pain, and diarrhea.
Patients with familial juvenile polyposis (FJP) are diagnosed when the following criteria are met:
5 (some sources say 10) juvenile polyps in the colon
Juvenile polyps throughout the GI tract
Any number of juvenile polyps with a family history of juvenile polyposis 
Associated congenital extracolonic anomalies are described in as many as 20% of these patients, ranging from neurologic (macrocephaly), thoracic (congenital heart disease), and urogenital, to GI(malrotation). Congenital findings are more common in sporadic cases than the familial form of FJP.
Cronkhite-Canada syndrome is a clinical syndrome with high mortality that presents with the following:
Generalized GI polyposis (sparing the esophagus)
Dermal pigmentation and atrophy of the nail beds
Severe protein-losing enteropathy with electrolyte disturbances 
Familial adenomatous polyposis
See the list below:
Ocular: Congenital hypertrophy of the retinal pigment epithelium (characteristic pigmented fundus lesions) occur in roughly 70-80% of patients with FAP. 
GI: Multiple gastric polyps, multiple duodenal polyps, multiple colonic polyps, and mesenteric fibromas (desmoids) are noted.
Oncologic: Malignant transformation of polyps, gastric carcinoma, periampullary carcinoma, hepatoblastoma, biliary ductal carcinoma, osteosarcoma, adrenal carcinoma (Cushing syndrome), and thyroid carcinoma are noted.
Physical features commonly associated with Gardner syndrome, addition to those listed above for FAP, 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) 
Endocrine - Cushing syndrome (adrenal carcinoma), multiple endocrine neoplasia 2B
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)
PTEN hamartomatous syndromes
Common findings associated with BRR include the following:
General - Increased 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
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 (benign tumors of the lower outer root sheath epithelium of a hair follicle)
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
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
Familial juvenile polyposis
Common findings with FJP include the following:
GI - Numerous hamartomatous polyps throughout the GI tract that may cause bleeding or obstruction, malrotation, Meckel diverticulum
Cardiac - Congenital heart disease (eg, tetralogy of Fallot, atrial septal defect, coarctation of the aorta, patent ductus arteriosus, subvalvular aortic stenosis)
CNS - Macrocephaly, hydrocephalus, spina bifida
GI - Undescended testes, bifid uterus and vagina, abnormal UPJ insertion, unilateral renal agenesis
Skeletal - Osteoma
This syndrome typically presents with complications from generalized polyposis associated with typical hyperpigmented skin findings.
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.
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, 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, may facilitate the development of carcinomas. Additional mutation events may also be necessary for the development of PJS.
BRR syndrome and Cowden disease have been localized to band 10q23.3, which is the location of the PTEN, a tumor suppressor gene.[28, 47]
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.
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.[48, 49, 50]
Bale noted that phenotypic expression of GS varied more among families, suggesting the importance of neighboring genes in modulation of phenotypic expression.
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.
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