History
Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) presents with multiple adenomatous polyps, anywhere from 100s to 1000s, throughout the colon (see the image below).
Familial adenomatous polyposis, total colectomy specimen. The colonic mucosa is studded with innumerable sessile and small pedunculated polyps, which involve the entire length of the specimen.
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. [46] 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. [47]
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. [35] 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. [16] These patients also have manifested ocular fundus lesions, epidermal inclusion cysts, and osteosclerotic jaw lesions consistent with Gardner syndrome.
Peutz-Jeghers 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%). [48] They tend to present with the following symptoms:
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GI bleeding
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Intussusception
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Rectal prolapse
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Nasal polyposis (chronic sinusitis)
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Pigmented macules on the lips and digits
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Gynecomastia
The diagnosis of PJS should be made with 2 or more histologically confirmed polyps, polyps associated with characteristic pigmentation, or polyps in setting of family history.
The development of gynecomastia in a child with suspected PJS should prompt investigation for underlying testicular or gynecologic malignancy.
PTEN-hamartomatous syndromes
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:
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Developmental delay
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Macrocephaly (38%)
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Cerebellar dysfunction
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Scoliosis
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Cutaneous hamartomas
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Thyroid disease (>50%) such as Hashimoto thyroiditis
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Chronic diarrhea
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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
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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. [49] This association has been attributed to hypothesized function of the PTEN gene in the suppression of angiogenesis.
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Bannayan-Riley-Ruvalcaba (BRR) syndrome: Features commonly associated with the entity that is known as 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 freckling of the glans penis (85% of male patients), 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 one patient.
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:
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5 (some sources say 10) juvenile polyps in the colon
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Juvenile polyps throughout the GI tract
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Any number of juvenile polyps with a family history of juvenile polyposis [50]
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). [13] Congenital findings are more common in sporadic cases than the familial form of FJP.
Cronkhite-Canada syndrome
Cronkhite-Canada syndrome is a clinical syndrome with high mortality that presents with the following:
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Generalized GI polyposis (sparing the esophagus)
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Dermal pigmentation and atrophy of the nail beds, alopecia
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Other characteristics may include anosmia, cataracts, thrombosis, cardiac failure, peripheral neuropathy, psychiatric issues, and acute pancreatitis.
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Severe protein-losing enteropathy, leading to malabsorption with electrolyte disturbances [13]
Gorlin syndrome
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. [51] 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.
Serrated polyposis syndrome
Serrated polyposis syndrome (SPS) is characterized by progression from hyperplastic polyps to serrated carcinoma and require the following criteria for diagnosis as per WHO guidelines:
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At least 5 serrated polyps proximal to the sigmoid colon, 2 of which are greater than 10 mm in diameter
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Any number of serrated polyps occurring proximal to sigmoid colon in individual with first degree relative already diagnosed with SPS
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More than 20 serrated polyps of any size throughout the colon
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Patients with SPS can have conventional adenomas in addition to serrated polyps.
Physical
Familial adenomatous polyposis
Physical examination findings of FAP include the following:
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Ocular: Congenital hypertrophy of the retinal pigment epithelium (characteristic pigmented fundus lesions) occur in roughly 70-80% of patients with FAP. [4]
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GI: Multiple gastric polyps, multiple duodenal polyps, multiple colonic polyps, and mesenteric fibromas (desmoids) are noted.
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Oncologic: Malignant transformation of polyps, gastric carcinoma, periampullary carcinoma, hepatoblastoma, biliary ductal carcinoma, osteosarcoma, adrenal carcinoma (Cushing syndrome), and thyroid carcinoma are noted.
Gardner syndrome
Physical features commonly associated with Gardner syndrome, addition to those listed above for FAP, include the following:
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Skin - Epidermal cysts (commonly on the back), sebaceous cysts (commonly on the back)
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Craniofacial - Osteomas (including the mandible), skin fibromas, dental anomalies (supernumerary teeth, impacted teeth, missing teeth, root anomalies) [52]
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Endocrine - Cushing syndrome (adrenal carcinoma), multiple endocrine neoplasia 2B
Turcot syndrome
Attributes of Turcot syndrome include the following:
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Skin - Café au lait spots, multiple lipomas, basal cell carcinoma of the scalp
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GI - Colonic polyps (including adenomatous), hepatic focal nodular hyperplasia, adenocarcinoma of the colon, gastric carcinoma
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CNS - Glioma, glioblastoma multiforme, astrocytoma
Peutz-Jeghers Syndrome
The following findings are common in PJS:
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Skin - Melanin spots on the lips, digits, and oral mucosa
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GI - Multiple GI polyps (especially jejunal), intussusception, GI bleeding, rectal prolapse
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Genitourinary (GU) - Polyps within ureter, bladder, and renal pelvis
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Pulmonary - Nasal and bronchial polyps
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Thorax - Gynecomastia (testis, ovarian tumors)
PTEN hamartomatous syndromes
Manifestations of Cowden disease include the following:
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Skin - Multiple hamartomas of skin and mucus membranes, verrucous lesions, acral keratoses, papules of gingival and buccal mucosa, facial trichilemmomas (benign tumors of the lower outer root sheath epithelium of a hair follicle)
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Cerebrospinal, head - Craniomegaly, adenoid facies, ataxia, increased intracranial pressure, cerebellar degeneration, mental retardation, tremors, tonsillar herniation, seizures
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Endocrine - Thyroid hamartomas and nonmedullary carcinoma
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Chest - Breast hamartomas and carcinomas, pectus excavatum
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GI - Scrotal tongue, intestinal polyps (hamartomatous)
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Oncology - Dysplastic cerebellar gangliocytoma, breast carcinoma, ovarian carcinomas, Merkel cell skin carcinomas, renal cell adenocarcinomas, thyroid carcinomas
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Spine – Scoliosis
Common findings associated with BRR syndrome include the following:
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General - Increased weight and length at birth, macrocephaly, scaphocephaly, broad thumb, and hallux
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CNS - Hypotonia and myopathy, developmental delay, mild mental retardation
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Cardiovascular - Arteriovenous malformation, congenital heart disease (eg, ventricular septal defect)
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Pulmonary - Pectus excavatum
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GI - High palate, hamartomatous intestinal polyps (colon, tongue)
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GU - Enlarged penis, spotted pigment of glans penis, testicular enlargement
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Ocular - Pseudopapilledema, exotropia
Familial juvenile polyposis
Common findings with FJP include the following:
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GI - Numerous hamartomatous polyps throughout the GI tract that may cause bleeding or obstruction, malrotation, Meckel diverticulum
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Cardiac - Congenital heart disease (eg, tetralogy of Fallot, atrial septal defect, coarctation of the aorta, patent ductus arteriosus, subvalvular aortic stenosis)
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CNS - Macrocephaly, hydrocephalus, spina bifida
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GI - Undescended testes, bifid uterus and vagina, abnormal UPJ insertion, unilateral renal agenesis
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Skeletal - Osteoma , abnormal facies, cleft lip/palate
Cronkhite-Canada syndrome
This syndrome typically presents with complications from generalized polyposis associated with typical hyperpigmented skin findings. [53]
Gorlin syndrome
Physical characteristics associated with GS include the following:
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Skin - Basal cell nevi and carcinoma
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Craniofacial - Broad facies, including nasal root, bossing of frontal and parietal bones, cleft lip and palate, mandibular prognathism, dental anomalies (odontogenic keratocysts)
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Ocular - Strabismus, hypertelorism, colobomas, subconjunctival epithelial cysts, glaucoma
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Cardiac - Cardiac fibromas
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Pulmonary - Congenital lung cyst, rib anomalies
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GI - Hamartomatous gastric polyps, lymphomesenteric cysts
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GU - Ovarian fibromas and carcinomas
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CNS - Congenital hydrocephalus, mental retardation, medulloblastoma
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Skeletal - Scoliosis, kyphoscoliosis, cervical anomalies, rib anomalies, brachydactyly, short fourth metacarpal and thumb
Causes
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. [54]
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 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. Additional mutation events may also be necessary for the development of PJS.
PTEN-hamartomatous syndromes
Cowden disease and BRR syndrome have been localized to band 10q23.3, which is the location of the PTEN, a tumor suppressor gene. [34, 55]
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
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 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. [56]
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. [57, 58, 59]
Bale noted that phenotypic expression of GS varied more among families, suggesting the importance of neighboring genes in modulation of phenotypic expression. [59]
Serrated polyposis syndrome
Although the syndrome 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]
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Familial adenomatous polyposis, total colectomy specimen. The colonic mucosa is studded with innumerable sessile and small pedunculated polyps, which involve the entire length of the specimen.
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Pedunculated tubular adenoma. Note the contrast between the goblet cell-rich glands along the pedicle of the polyp and in the underlying normal colonic mucosa at the bottom and the dysplastic glands in the polyp proper. The dysplastic glands are more crowded and exhibit decreased mucin production. (Hematoxylin and eosin stain; 1X magnification).
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Sessile tubular adenoma. The glands on the superficial aspect of the specimen are dysplastic and exhibit increased nuclear size, hyperchromasia, crowding, and decreased mucin production. (Hematoxylin and eosin stain, 4X magnification).
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Hamartomatous (Peutz-Jeghers) polyp, small bowel. This pedunculated polyp has a cerebriform appearance due to the arborizing frond-like growth with delicate finger-like projections of the stroma. (Hematoxylin and eosin stain, 1X magnification).
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Hamartomatous (Peutz-Jeghers) polyp, small bowel. Closer view of the fingerlike projections of the stroma demonstrates prominent smooth muscle fascicles between the glandular elements. (Hematoxylin and eosin stain, 4X magnification).
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Hamartomatous polyp, as seen in the stomach. (Endoscopic image).
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Colon in familial adenomatous polyposis (FAP). (Endoscopic image).
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Small bowel polyp. (Video capsule image).
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Multiple large polyps in the colon. The polyp in the center of the image is situated on a stalk. (Endoscopic image).
