Intestinal Polyposis Syndromes

Although intestinal polyposis syndromes are relatively rare, awareness of the existing health risks is important for patients and their families affected by these disorders. Intestinal polyposis syndromes can be divided, based on histology, into the broad categories of familial adenomatous polyposis (FAP), hamartomatous polyposis syndromes, and other rare polyposis syndromes, such as hereditary-mixed polyposis syndrome (HMPS) and serrated polyposis syndrome (SPS).

In 1859, Charelaigue described the first definitive accounts of adenomatous polyposis in a 16-year-old girl and a 21-year-old man.[1]

Several genetic disorders may present with GI polyps. FAP is the most common inherited polyposis syndrome, encompassing multiple phenotypes. These phenotypes range from a mild phenotype in attenuated polyposis syndrome to specific clinical syndromes recognized many decades prior to the discovery of the adenomatous polyposis (APC) gene.

Several specified variants of FAP, namely Gardner syndrome, Turcot syndrome, and MYH-variant, have been identified. Individuals with Gardner syndrome (Online Mendelian Inheritance in Man [OMIM] 175100, 135290) develop adenomatous polyps throughout the GI tract, accompanied by extracolonic manifestations, including periampullary adenomas, papillary carcinoma of the thyroid, hepatoblastoma, osteomas of the mandible and skull, epidermal cysts, and desmoid tumors. Gardner syndrome, which has autosomal dominant inheritance, is a term used to refer to patients in whom these extraintestinal features are unusually prominent. It was first described in 1951, when Gardner described colonic polyposis in a Utah family whose 9 members died due to colon cancer within 3 generations

Turcot syndrome (OMIM 276300), another variant of FAP, is a rare autosomal recessive disorder that can present with brain tumors (glioblastoma multiforme, medulloblastoma) and colonic adenomas that frequently become malignant in those younger than 30 years. It was initially described in 1959 by Turcot,[2] and again in 1969 by Baughman et al.[3]

First described in 2002, MYH-associated polyposis, or MutYH - associated polyposis (MAP), occurs in a small number of patients with FAP and results from a mutation in the human MutY homolog gene instead of the APC gene. Unlike FAP, MAP is autosomal recessive, with complete penetrance by age 60 years.[4]

The broad category of hamartomatous polyposis syndromes encompasses several syndromes, mainly Peutz-Jeghers Syndrome (PJS), PTEN -associated hamartomatous syndromes (including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome [BRR]), familial juvenile polyposis, and Cronkhite-Canada syndrome.

PJS is named for the clinicians who initially described the disease and its characteristics in 1921 and 1941.[5, 6] In PJS (OMIM 175200), an autosomal dominant disease, polyps can occur anywhere within the digestive tract (consistently within the jejunum) and are accompanied by characteristic melanin spots on the lips and digits. Scattered studies have reported malignant degeneration within GI polyps and development of extraintestinal malignancies, including pancreatic, testicular, and gynecologic malignancies. Development of gynecomastia commonly preceded the development of gynecologic or testicular malignancy.

In 1963, Lloyd and Dennis initially described the features associated with Cowden disease (OMIM 158350).[7] In 1972, Weary et al described the manifestations of Cowden disease and classified it as a multiple hamartomatous syndrome with autosomal dominant inheritance.[8] In 1991, Padberg et al suggested that the disorder known as cerebelloparenchymal disorder VI (Lhermitte-Duclos disease) is part of the multiple hamartoma syndrome.[9] Individuals with Cowden disease present at age 10-30 years with hyperplastic hamartomatous polyps throughout the GI tract (including the esophagus), glycogenic acanthosis of the esophagus, orocutaneous hamartomas of the face, pulmonary hamartomas, and neoplasia (breast, thyroid, adenocarcinoma of the colon [rare]).

BRR syndrome, also termed Bannayan-Zonana syndrome, was first described by Riley and Smith in 1961, was next described by Bannayan in 1971, and was further characterized by Zonana et al in 1975.[10, 11] In BRR syndrome (OMIM 153480), hamartomatous polyps of the colon and tongue are present along with macrocephaly, lipomas, and hemangiomata.

Initially, BRR syndrome and Cowden syndrome were thought to be the same condition, but multiple studies had failed to demonstrate a consistent genotype-phenotype relationship. However, more recent studies have supported the argument that they are the same disease with variable expression and age-related penetrance.[12] The PTEN-associated hamartomatous syndromes can also include Proteus syndrome and Proteus-like syndrome.

FJP, also described in the literature as juvenile polyposis, is characterized by multiple inflammatory polyps throughout the colon that are associated with painless rectal bleeding (rare serious hemorrhage), rectal prolapse, and failure to thrive. This entity is different than solitary juvenile polyps, which are common in children and do not have the lifetime risk of malignancy.

First described in 1955, individuals with Cronkhite-Canada syndrome, which presents at an average age of 59 years, exhibit multiple intestinal polyps and ectoderm abnormalities, including hyperpigmentation of the skin, alopecia, and onychoheterotopia. Cronkhite-Canada syndrome is acquired rather than inherited and is associated with a high mortality rate.

HMPS is extremely rare. It is characterized by familial presentation of colorectal polyps that have mixed histologic elements with both adenomatous and hyperplastic features.[13]  In 1960, Gorlin and Goltz initially described Gorlin syndrome (GS), also termed nevoid basal cell carcinoma syndrome, in 1960.[14] Herzberg and Wiskemann further associated GS with medulloblastoma in 1963. GS (OMIM 109400) commonly presents with hamartomatous gastric polyps, palmar pits, short metacarpals, odontogenic keratocysts, intracranial calcifications, skeletal malformations, and neoplasia (basal cell carcinoma, ovarian carcinoma, medulloblastoma).

First defined in 2000, Burt and Jass described SPS, which is characterized by multiple, large serrated polyps within the colon leading to a high risk of colorectal cancer. Although its inheritance is unclear, hereditary and sporadic cases have been described in the literature.[15]

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

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

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

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

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

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

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

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

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

Frequency

United  States

The frequency depends on the specific syndrome and does not vary drastically between the United States and other countries. Estimates are gained from large scale registries and can widely vary. FAP is inherited in an autosomal dominant fashion and is the most common intestinal polyposis syndrome with an estimated frequency of 1:13,000 births.[24]

Some overlap between kindreds with Gardner syndrome and kindreds with Turcot syndrome may be observed, but these variants of FAP are much rarer than FAP itself. In 1997, Paraf et al described a series of 100 patients with manifestations of Turcot syndrome.[25] 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.[26] From this data, PJS has an estimated prevalence of between 1:120,000 and 1:200,000 births.

The estimated incidence of Cowden syndrome is 1:200,000 but is likely higher than that due to its penchant for being underdiagnosed.[27] BRR syndrome is extremely rare despite its autosomal dominant inheritance.

FJP is thought to have an incidence of 1:100,000, making it the most common hamartomatous polyposis syndrome.[28]

Cronkhite-Canada Syndrome is considered to be a rare, sporadic, and acquired syndrome.[13] To date, barely over 500 cases have been reported worldwide. Estimated incidence is 1:1,000,000. Disease presents later in age, with a mean age of diagnosis of 59 years.[29]

Farndon et al have conservatively estimated the prevalence of GS at 1:57,000 births.[30] In individuals who develop basal cell carcinoma before age 19 years, the incidence of GS rises markedly to 1:5.

Initial studies estimated the prevalence of SPS at 1:3,000 patients who were screened. However, the true prevalence is most likely closer to less than 0.09%. If screened after a positive fecal occult blood test result, the prevalence increases to 0.34% to 0.66%.[31]

International

Worldwide studies of Gardner syndrome kindreds have shown an increased incidence of APC gene mutation (I1307K mutation) in persons of Ashkenazi Jewish descent with a family history of colorectal cancer. Burn et al calculated the prevalence of APC mutations in northern England at 2.29 X 10-5.[32] Bisgaard et al estimated that the incidence of Gardner syndrome among Danish individuals is 1:13,528.

BRR syndrome is also a rare syndrome with probable autosomal dominant inheritance. Cowden syndrome is also relatively uncommon, estimated to affect 1:200,000 births.[33] Nelen et al have estimated that the prevalence of Cowden disease among Dutch persons is 1:200,000-250,000 population.[34] FJP can affect 1:100,000 births.[33]

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

Mortality/Morbidity

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

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

Morbidity and mortality in Turcot syndrome arises from complications of CNS tumors (eg, medulloblastoma, astrocytoma, gliomas, glioblastoma multiforme, gliomas), GI neoplasia (eg, colonic adenocarcinomas, gastric carcinomas), and basal cell carcinomas of the scalp. Van Meir reported mean survival rates of 5.6 years from diagnosis for patients with medulloblastoma and colonic adenomas and 27.5 months from diagnosis for patients with glioblastoma and adenomas.[35]

Morbidity and mortality in PJS arises from complications of polyps such as intussusception and bleeding and the development of malignancies of the stomach, pancreas, and lung. An increased risk for breast, ovarian, uterine and cervical cancer is noted in young women along with Sertoli cell tumors in young men; 93% of patients with PJS develop cancer by age 65 years, with a mean age of 42 years.[18]  GI cancer develops in 70% of patients with PJS.[28]

Individuals with PTEN- hamartomatous syndromes, such as Cowden syndrome and BRR syndrome, are at risk from non-GI malignancies such as breast, uterine, cerebellum, thyroid, kidney, and skin; complications from lipomas and arteriovenous malformations; and thyroid disease. Female breast cancer has an 85% lifetime risk.[36]

Similar to PJS, in FJP, polyps may bleed or cause obstruction. Sporadic reports detail gastric, small bowel, and pancreatic cancers, but a more substantial increased risk of colon cancer is seen in these individuals, with cumulative lifetime risk of 50%.[37]

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

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

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

Race

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

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

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).[39] Bell and Mazzaferri reported that 94% of patients with Gardner syndrome who had thyroid carcinoma were women.[40]

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

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

The PTEN- hamartomatous syndromes are considered to be autosomal dominant. In a 1993 series by Hanssen et al, an excess of affected female patients was reported in Cowden disease.[41] In that survey of 87 patients, 70% (61) of the patients were female. Female patients with Cowden syndrome are predisposed to the development of breast neoplasia and neoplasia of the urogenital system.

Cronkhite-Canada syndrome exhibits a slight male predominance at a ratio of 3:2.[29]

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

SPS has no documented sex predominance.

Age

Patients with FAP generally present in late adolescence with symptoms of polyposis (GI bleeding). Some patients have reported GI bleeding in early childhood, and case reports have noted colon cancer presenting in children aged 5 years old and younger.[42] Children with Gardner syndrome and Turcot syndrome can present with extraintestinal manifestations before symptoms of polyposis arise, including medulloblastoma, hepatoblastoma, osteomas, or retinal pigment epithelium hypertrophy. Patients in the Turcot syndrome subgroup develop glioblastomas; colonic adenomas develop somewhat later (mean age 18 y; range 4-70 y).[25]

Children with PJS have presented in the neonatal period with complications of GI polyposis.[43] The average age of diagnosis of PJS is 24.3 years.

Patients with PTEN- hamartomatous syndrome can often be diagnosed in childhood, with congenital findings of macrocephaly and mild or moderate developmental delay. During later childhood, trichilemmomas within the nasolabial folds, palmar pits, subcutaneous lipomas, and hemangiomas manifest.[44]

Patients with Cronkhite-Canada syndrome present in middle to late adulthood; mean age of presentation is 59 years. The rare reported pediatric cases have features similar to infantile juvenile polyposis.[29]

Patients with FJP present in childhood and adolescence, most commonly with isolated rectal bleeding.[45]

Neonates with GS present with lung cysts, rib and vertebral anomalies, palmar pits, hydrocephalus, and cleft palate. Symptoms of medulloblastoma in GS manifest in patients younger than 2 years. Basal cell carcinomas generally appear in patients with GS who are in their early twenties but may present in patients younger than 10 years.[38]

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) presents with multiple adenomatous polyps, anywhere from 100s to 1000s, 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.[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:

• GI bleeding

• Intussusception

• Rectal prolapse

• Nasal polyposis (chronic sinusitis)

• Pigmented macules on the lips and digits

• 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:

• Developmental delay

• Macrocephaly (38%)

• Cerebellar dysfunction

• Scoliosis

• Cutaneous hamartomas

• Thyroid disease (>50%) such as Hashimoto thyroiditis

• 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.[49] This association has been attributed to hypothesized function of the PTEN gene in the suppression of angiogenesis.

• 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:

• 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[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:

• Generalized GI polyposis (sparing the esophagus)
• Dermal pigmentation and atrophy of the nail beds, alopecia

• Other characteristics may include anosmia, cataracts, thrombosis, cardiac failure, peripheral neuropathy, psychiatric issues, and acute pancreatitis. 

• 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:

• At least 5 serrated polyps proximal to the sigmoid colon, 2 of which are greater than 10 mm in diameter
• Any number of serrated polyps occurring proximal to sigmoid colon in individual with first degree relative already diagnosed with SPS
• More than 20 serrated polyps of any size throughout the colon
• Patients with SPS can have conventional adenomas in addition to serrated polyps.

Familial adenomatous polyposis

Physical examination findings of FAP include the following:

• Ocular: Congenital hypertrophy of the retinal pigment epithelium (characteristic pigmented fundus lesions) occur in roughly 70-80% of patients with FAP.[4]

• 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.

Gardner syndrome

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)[52]

• Endocrine - Cushing syndrome (adrenal carcinoma), multiple endocrine neoplasia 2B

Turcot syndrome

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

Peutz-Jeghers Syndrome

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

Manifestations of Cowden disease include the following:

• 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)
• Cerebrospinal, head - Craniomegaly, adenoid facies, ataxia, increased intracranial pressure, cerebellar degeneration, mental retardation, tremors, tonsillar herniation, seizures
• Endocrine - Thyroid hamartomas and nonmedullary 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

Common findings associated with BRR syndrome 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

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 , 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:

• 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 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]

The following studies are indicated in patients with intestinal polyposis syndromes:

• CBC count with differential and platelets

• Stools for occult blood

• Prothrombin time/activated partial thromboplastin time (if significant bleeding is present)

• Serum albumin levels (if weight loss is present)

• Genetic testing, including band 5q21-22 for Gardner syndrome (ie, familial adenomatous polyposis [FAP]), band 7p22, 5q21-22, and 3p21.3 for Turcot syndrome, band 19q13.3-13.4 for Peutz-Jeghers syndrome (PJS), band 10q23.3 for Bannayan-Riley-Ruvalcaba syndrome (BRR) and Cowden disease, band 9q22.3-q31 for Gorlin syndrome (GS)

• Fecal alpha1-antitrypsin or fecal calprotectin (if albumin is low and weight loss is present; to evaluate for protein-losing enteropathy)

• Levothyroxine (T4), triiodothyronine (T3), thyroid-stimulating hormone (TSH), thyroid antimicrosomal or thyroid peroxidase antibody to exclude Hashimoto thyroiditis in individuals with symptomatic BRR syndrome

• Liver function tests and alpha-fetoprotein level to screen for hepatoblastoma in patients with suspected Gardner syndrome and an abdominal mass; electrolytes, plasma or urine cortisol, and adrenocorticotropic hormone (ACTH) in patients with suspected Gardner syndrome if Cushing syndrome is present

The role of imaging studies in favor of endoscopic examination has not been well established for individuals with intestinal polyposis syndromes.[60] Examples of endoscopic findings are shown in the images below.

For those individuals with small bowel polyposis, double balloon enteroscopy (DBE), both antegrade and retrograde, can be successful in reaching and resecting targeted polyps.[61]  

Upper GI with small bowel follow through (SBFT) can be used to evaluate for polyps but incurs radiation exposure.

Thus, video capsule endoscopy is an emerging modality used to evaluate for small bowel polyps that spares radiation for the patient (see the image below).[62, 63] It has been shown to be better than UGI with SBFT for polyp detection rate, comfort, and patient preference.[64]

Air-contrast barium enema (BE) can be used to evaluate for colonic polyps in patients who are not candidates for colonoscopic examination.

Magnetic resonance enterography can be used for small bowel surveillance of polyps as well and serves as a complementary study to video capsule endoscopy, especially because the capsule can overestimate polyps secondary to retrograde flow.[64]

Air-contrast barium enema (BE) can be used to evaluate for colonic polyps in patients who are not candidates for colonoscopic examination.

Contrast-enhanced ultrasonography is emerging as a noninvasive technique to characterize vascular patterns of polyps with the aim of recognizing neoangiogenic traits of colorectal adenomas and carcinomas. This imaging modality may help differentiate hamartomatous polyps from adenomatous polyps, which may have malignant potential, especially in PJS.[65]

Additional imaging studies in patients with Gardner syndrome may include the following:

• Radiographs of the skull, teeth, and mandible to screen for osteomas and plan management of dental anomalies

• CT scanning, ultrasonography, or MRI of the abdomen to evaluate abdominal masses (hepatoblastoma, adrenal carcinoma, mesenteric fibromas/desmoids)

In patients with Turcot syndrome, CNS imaging, GI imaging, and other imaging modalities are indicated if Gardner syndrome is suspected, as clinically warranted.

For patients with known PJS, perform routine screening, mammogram, and breast ultrasound for early detection of occult neoplasms. Perform ultrasonography or CT scanning of the pelvis or testicles to screen for possible malignancies in patients with conditions such as gynecomastia and precocious puberty.

For patients with known PTEN- hamartomatous syndrome imaging studies include the following:

• Routine breast imaging to screen for neoplasia (Seventy five percent of females develop breast neoplasia.)

• Imaging of the thyroid, if suggestive of malignancy

• Imaging of the ovaries, if suggestive of malignancy

• MRI of the head, if symptomatic

• Radiography of the spine to monitor for scoliosis

For patients with known GS, perform radiography of the mandible, ribs, and spine to diagnose and treat anomalies. Perform CNS imaging to exclude hydrocephalus and medulloblastoma if warranted by clinical evaluation. Perform imaging of the ovaries to exclude pathologic conditions of the ovaries in women with suggestive symptoms.

Patients with GS should not require SBFT or BE for detection of polyps (only gastric polyps have been reported). In a series of 105 patients with GS, Kimonis et al reported the following radiologic findings:[38]

• Calcification of the falx cerebri (65%)

• Bridged sella (68%)

• Flame-shaped lucencies in the phalanges, carpals, and metacarpals (30%)

• Bifid ribs (26%)

• Calcification of the tentorium cerebri (20%)

• Hemivertebrae (15%)

• Fused vertebral bodies (10%)

All patients with polyposis syndromes require serial endoscopy and colonoscopy to evaluate for the degree of polyposis and survey for malignant transformation.

In patients who have PJS and chronic sinusitis, endoscopic evaluation for possible nasal polyposis may be required. Squamous cell carcinoma has been reported in a patient with PJS and nasal polyps.

In patients with Cowden disease, biopsies of suspicious lesions seen on the mammogram are warranted to exclude neoplasia, and biopsies of other suspicious areas are indicated to exclude malignancy.

In patients with GS, skin biopsies may be required to exclude basal cell carcinomas.

Adenomatous polyps, found in patients with FAP and its variants, vary in size, ranging from single crypt adenomas to microadenomas of 2-5 crypts in size to sessile tubular adenomas visualized with endoscopy. Adenomas are composed of immature epithelial cells with increased proliferation rates above crypt requirements. Increased growth in size of adenomas enhances the formation of dysplasia. No smooth muscle bundles are present in adenomatous polyps.

Gruber et al characterized PJS hamartomas are exophytic with an elongated frondlike epithelium possessing cystic dilatation of glands that contain hypermucinous goblet cells atop a network of arborizing smooth muscle bundles.[66] PJS polyps show areas of florid epithelial misplacement and dysplasia.[18]

Patients with Cowden disease and BRR syndrome also present with hamartomatous intestinal polyps, which are small and dome-shaped. Polyps in Cowden syndrome are mainly colonic, sessile, and small, without surface erosion and show mildly inflamed fibrotic lamina propria with smooth muscle proliferation and lymphoid follicles. They have the least cystic glands and no thick mucin. Ganglion cells and nerve fibers are present within the lamina propria and mucosal fat.[28]

In contrast, other forms of juvenile polyposis consist of abundant lamina propria without the presence of smooth muscle bundles. Large, inflammatory polyps contain a well-differentiated mature epithelial layer with a smooth dome but lobulated appearance due to cyst formation with thick mucin but without smooth muscle bundles. They have a strikingly edematous, markedly fibrotic and inflamed lamina propria.[28]

Polyps in Cronkhite-Canada syndrome are broad-based, sessile with cryptic features ranging in size from a few mm to 1.5 cm. One can see polyps distributed over other polyps similar to a hydatidiform mole. Specific histology of these polyps exhibits a hamartomatous appearance, an expanded edematous lamina propria, inflammatory cell infiltration, and tortuous, dilated cystic glands or crypts.[29]

Endoscopically, polyps of serrated polyposis syndrome are hyperplastic, which are 2-5 mm in size. They appear pale, glisten, are covered with mucous, look similar to the surrounding mucosa, and have minimal vascularity. Serrated polyps are usually sessile or flat. They are defined as epithelial lesions with serrated appearance on histology secondary to infolding of crypt epithelium.[15]

Examples of histologic findings are shown in the images below.

In several of the polyposis syndromes, medical care encompasses screening and intervention for malignant transformation. Particularly in the case of familial adenomatous polyposis (FAP), in which an inevitable progression to colorectal cancer occurs by age 35-40 years,[24] screening of patients and family members has led to an improvement in cumulative survival and a 55% reduction in colorectal cancer at diagnosis of FAP.[67] Approximately 50% of patients with familial juvenile polyposis (FJP) develop GI cancer.[68]

Familial adenomatous polyposis

Unless a family history of early and aggressive disease is noted, children at risk for FAP should be screened twice yearly starting at age 10-12 years. Flexible sigmoidoscopy is sufficient because the adenomas are distributed throughout the colon. The American Gastroenterological Association recommends an annual sigmoidoscopy or colonoscopy for patients with a genetic diagnosis of FAP or for at-risk family members who have not undergone genetic testing.[69] Narrow-band imaging can identify higher numbers of duodenal adenomas, but it did not lead to a clinically relevant upgrade in stage when compared with high-resolution endoscopy.[70]

If the patient undergoes prophylactic colectomy, the ileal pouch is at risk for developing adenomatous carcinoma and should be screened with endoscopy on a yearly basis. Gastric and duodenal lesions occur in 45% of patients with the APC mutation, and upper endoscopy should begin when colonic adenomas are identified or at age 20-25 years. A study of pediatric patients with APC mutations suggests that upper endoscopy should begin even earlier.[71]

The risk of developing malignancy in these lesions is lower than the risk from colonic lesions but is still approximately 12%. Depending on the polyp burden, front and/or side-viewing endoscopies of the stomach, duodenum, and periampullary region should occur every 6 months to 4 years. The risk of periampullary tumors is increased in these patients. The tumors are best viewed with both side-viewing and end-viewing instruments.[72] Current options for management include endoscopy, chemoprevention, duodenectomy, the Whipple procedure, and ampullectomy, none of which have been especially successful. 

Patients with the APC gene mutation at codon 1309 are at risk for a more aggressive phenotype, and early screening and colectomy is advocated for in children with this mutation.[71]

Postcolectomy, mesenteric or abdominal wall desmoids can develop and may cause fatal complications from sepsis or hemorrhage. They are more common in females and can cause obstruction of the mesenteric blood supply, intestines, or urinary tract.[4]

Gardner syndrome

In addition to the above recommendations for FAP, patients with Gardner syndrome require medical care and management of cutaneous cysts, osteomas, fibromas, polyposis, and diligent surveillance for neoplasia.

Carcinoma may develop at any age, from late childhood through senior years.

Young children with gene mutations related to Gardner syndrome have an increased risk for development of hepatoblastoma. Hughes and Michels noted Gardner syndrome in 2 of 470 children who had parents with Gardner syndrome versus an incidence of 1 per 100,000 general population.[73]

Patients with Gardner syndrome are predisposed to the development of polyposis throughout the GI tract and to carcinomas of the stomach, periampullary region, biliary tract, and colon.

Women with Gardner syndrome have an increased risk of desmoid tumors and thyroid carcinoma.

Development of thyroid carcinoma is 100 times more likely among patients with Gardner syndrome.

Osteosarcomas and adrenal carcinomas (with Cushing syndrome) have been previously reported in patients with Gardner syndrome.

Turcot syndrome

As with Gardner syndrome, in addition to the above recommendations for FAP, patients with Turcot syndrome require management of basal cell carcinomas and treatment of CNS malignancies, including astrocytoma, glioblastoma, and medulloblastoma.

Patients with Turcot syndrome are predisposed to the development of hepatic focal nodular hyperplasia.

Peutz-Jeghers syndrome

Patients require medical management for problems attributed to polyposis and for detection of malignancy.

Patients with Peutz-Jeghers syndrome (PJS) may develop significant GI bleeding, intussusception, and rectal prolapse, requiring diagnosis and treatment, including endoscopy and surgical resection.

Nasal endoscopy may be necessary in the presence of chronic sinusitis to exclude the presence of significant nasal polyps.

Long-term surveillance strategies to monitor for GI malignancies, including bowel, pancreatic, and periampullary malignancies. Colonoscopy is recommended every 3 years starting when symptoms occur or in the early teenage years in asymptomatic patients. At age 10 years, twice yearly upper endoscopies and barium imaging of the upper GI tract are recommended.[72]

Long-term surveillance to monitor for extraintestinal malignancies (eg, breast, gynecologic, testicular) is indicated.

The use of the potassium titanyl phosphate (KTP) laser to treat mucocutaneous melanosis of the lips and hands in a patient with PJS has been reported in the United Kingdom.

PTEN-hamartomatous syndromes

If a patient remains asymptomatic, a first colonoscopy is recommended between the ages of 35-40 years, with follow-up determined by number and type of polyps found on screening.[74]

Patients require medical therapy for CNS abnormalities, complications of lipomas and arteriovenous malformations, treatment of Hashimoto thyroiditis, and surveillance for malignancy.

Children may exhibit hypotonia, developmental delay, and mild mental retardation that requires coordinated speech and occupational and physical therapies to maximize potential. Development of pediatric nonmedullary thyroid cancer should raise clinical suspicion for PHTS.[74]

Significant lipomatous or vascular lesions (hemangiomas, arteriovenous malformations) have resulted in CNS complications (eg, seizures), amputations, and premature death.

Patients appear to have an increased risk for CNS tumors.

Increased incidence of Hashimoto thyroiditis, along with abnormalities of the PTEN gene (tumor suppressor gene), enhance the likelihood for development of neoplasia, especially thyroid and breast.

Patients require careful monitoring for the development of malignancies within the cerebellum, breast, skin (Merkel cell), and kidneys (renal cell adenocarcinoma) with scheduled screening of mammograms, dermatological examinations, and appropriate imaging.

Familial juvenile polyposis

Esophagogastroduodenoscopy (EGD) and colonoscopy should be performed at age of onset of symptoms or at age 15 years in asymptomatic patients at risk. If no polyps are present, this should be repeated every 3 years. If polyps are seen, they should be removed and EGD and colonoscopy should be performed yearly until no polyps are seen.[75]

Cronkhite-Canada syndrome

Patients should be regularly screened for colorectal and gastric cancer because they are at higher risk of developing malignancy in these areas.

Gorlin syndrome

Patients may require medical attention for craniofacial, vertebral, dental, and ophthalmologic abnormalities, in addition to diagnosis and treatment of potential neoplasia.

Bale reported that 3% of patients with Gorlin syndrome (GS) presented with cleft lip and palate at birth.[59]

Scoliosis is commonly associated with GS.

Jaw cysts are noted in more than 50% of patients, accompanied by symptoms of optic nerve compression, abnormalities of taste, and facial paresthesias.

Fibrosarcomas of the jaw have been encountered in patients with GS.

Glaucoma and cataracts have been described in patients with GS.

Patients with GS are predisposed to the development of neoplasia of the CNS, skin, and reproductive organs.

In childhood, medulloblastomas have been reported in 5% of patients with GS.

Basal cell carcinomas may present in patients younger than 10 years, especially with prior history of exposure to ionizing radiation. Nearly all patients with GS develop basal cell carcinomas by the fourth decade of life.

Individuals with GS may present with abdominal symptoms that arise from abnormalities of the GI (lymphatic, mesenteric cysts) and gynecologic systems. Young girls with GS may develop ovarian fibromas (predisposed to torsion) and fibrosarcomas. Khalifa et al reported endometrial adenocarcinoma in a 37-year-old woman with GS.

Serrated polyposis syndrome

Patients with serrated polyposis syndrome (SPS) require regular screening colonoscopies to remove premalignant lesions that could lead to colorectal cancer. First-degree relatives of patients with SPS should begin screening 10 years prior to the index case. Screening should occur every 1-2 years with removal of all visualized polyps.[15]

Familial adenomatous polyposis

The inevitable course is the development of colorectal cancer. To prevent this, surgical intervention is required, in the form of total proctocolectomy with ileoanal anastomosis, subtotal colectomy with ileorectal anastomosis, or total proctocolectomy with permanent ileostomy.

In patients who have subtotal colectomy with ileorectal anastomosis, the remaining rectal stump must be monitored for polyp recurrence. Timing of prophylactic colectomy or proctocolectomy has not been standardized, with most authors recommending that once polyposis is confirmed, severely affected patients should have prophylactic surgery as soon as possible. Mildly affected patients are recommended to have surgery within the year.[76]

Patients with Gardner syndrome require surgical treatment of the following:

• Cutaneous cysts

• Symptomatic dental anomalies and osteomas

• Biopsy and resection for malignancies, including hepatoblastoma, thyroid carcinoma, osteocarcinoma, gastric carcinoma, periampullary carcinoma, and biliary tract carcinoma

• Liver transplantation may be required in patients with hepatoblastoma

Patients with Turcot syndrome require surgical intervention for diagnosis and management of CNS lesions, gastric lesions and hepatic lesions.

Peutz-Jeghers syndrome

Patients may require surgical intervention for symptomatic GI lesions and biopsy of suspicious areas to exclude the possibility of malignancy.

Some patients with PJS develop manifestations of short-bowel syndrome secondary to long-term resections for potential malignancies (ie, antrectomy, duodenectomy).

PTEN-hamartomatous syndromes

Patients may require surgical intervention for management of serious lipomatous, vascular lesions, and undescended testicles and biopsy of suggestive areas to exclude the possibility of occult malignancy.

Later in age, these patients may require surgical intervention for management of symptomatic polyposis, scoliosis, and increased intracranial pressure

Biopsy and resection of lesions within the cerebellum (dysplastic gangliocytomas), breast, and kidneys (renal cell adenocarcinoma) may be required.

Consideration of prophylactic mastectomy is recommended for women

Familial juvenile polyposis

With the cumulative risk of malignancy greater than 50%, no guidelines have been established; however, some authors are recommending subtotal colectomy with ileorectal anastomosis in children with anemia, hypoproteinemia, and failure to thrive.[77]

Prophylactic colectomy with ileorectal anastomosis is recommended for children who have severe or repeated bleeding and adults with FJP.[78]

Gorlin syndrome

Patients with GS may require surgical management for the following:

• Craniofacial lesions (cleft lip and palate, jaw cysts, other mandibular lesions)

• Abdominal masses (mesenteric cysts, lymphatic cysts, ovarian fibromas)

• Diagnostic and therapeutic interventions for potential neoplasia within the CNS (medulloblastoma), skin (basal cell carcinoma), jaw (fibrosarcoma), ovaries (fibrosarcoma), and endometrium (adenocarcinoma)

Serrated polyposis syndrome

Prophylactic colectomy with ileorectal anastomosis is recommended for those with detection of cancer, inability of colonoscopy to control polyps, or patient preference.[79]

Familial adenomatous polyposis

Patients with Gardner syndrome may require consultation with the following:

• Gastroenterologist - For monitoring and surveillance for malignancies

• Oncologist - For treatment of malignancies

• Surgeon - For biopsy or resection of suspicious areas

• Dentist or maxillofacial surgeon - For mandibular osteomas or dental anomalies

• Ophthalmologist - For evaluation for retinal anomalies

• Endocrinologist - For evaluation and management of thyroid carcinoma and adrenal carcinoma

Patients with Turcot syndrome may require medical consultation with the following:

• Gastroenterologist - For monitoring and surveillance for malignancies

• Oncologist - For monitoring and treatment of malignancies

• Dermatologist

• Surgeon - For management of CNS, cutaneous, and GI malignancies

Peutz-Jeghers syndrome

Patients with PJS may require consultation with the following:

• Gastroenterologist: Assistance from a gastroenterologist may localize sites of polyps or bleeding.

• Surgeon: Surgical intervention may include resection of symptomatic areas and biopsy for suspicious malignancy.

• Dermatologist: Some patients with PJS may initially present to the dermatologist for diagnosis of cutaneous lesions.

• Endocrinologist

• Gynecologist

• Urologist

• Otolaryngologist

• Oncologist: An oncologist directs appropriate therapy in the presence of intestinal or extraintestinal malignancy.

PTEN-hamartomatous syndromes

Patients with BRR may require consultation with the following:

• Dermatologist

• Developmental pediatrician: The developmental pediatrician manages seizures and develops strategies for neurodevelopmental stimulation.

• Endocrinologist: An endocrinologist treats Hashimoto thyroiditis and cryptorchidism.

• Gastroenterologist: A gastroenterologist evaluates for polyposis, manages symptoms of drooling, and establishes GI surveillance.

• Gynecologist: A gynecologist establishes surveillance strategies for breast neoplasia.

• Neurologist: The neurologist manages seizures and develops strategies for neurodevelopmental stimulation.

• Oncologist: An oncologist directs appropriate therapy if malignant transformation occurs.

• Surgeon: Consultation with a surgeon is indicated for treatment of increased intracranial pressure, cerebellar lesions, breast cancer, thyroid lesions, and renal carcinoma.

Gorlin syndrome

Patients with GS may require subspecialty support for treatment of craniofacial and ophthalmologic abnormalities, management of scoliosis, and surveillance and treatment of potential neoplasias (eg, medulloblastoma, basal cell carcinoma, ovarian fibromas and sarcomas, mesenteric cysts).

Serrated polyposis syndrome

Patients with SPS may require subspecialty consultation from oncology and general surgery if colorectal cancer occurs.

The benefits of low-fat/high-fiber diets and supplementation with either calcium or antioxidants, including ascorbic acid and alpha-tocopherol, is controversial in patients with FAP. Several controlled trials in adults have studied dietary interventions, including wheat bran, vitamin intake, and fiber on the rate of development of adenomatous polyps.[80]

Yang et al noted a decrease in colonic epithelial proliferation activity via increasing calcium intake to 1200 mg with low-fat dairy foods;[81] however, the Toronto polyp prevention trial found no difference in the incidence of polyp recurrence between a low-fat/high-fiber diet and a typical Western diet with placebo fiber.[82] Fuchs et al also noted no protective effect of dietary fiber against colorectal adenomas and carcinoma in women.[83]

No studies are currently available regarding dietary modification in patients with PJS. Development of short-bowel syndrome from repetitive intestinal resections requires special nutritional interventions, including vitamin and nutrient supplementation, continuous enteral feedings, or parenteral nutrition.

No studies are currently available regarding dietary modification in patients with PTEN -hamartomatous syndromes or GS. Nutritional support is the mainstay of treatment of Cronkhite-Canada syndrome, especially in light of protein-losing enteropathy.

No limitation of activity is mandated for patients with Gardner syndrome, Turcot syndrome, PJS, and BRR syndrome unless other medical issues necessitate restrictions.

No limitation of physical activity is mandated for patients with Cowden disease unless other physical conditions are present. Patients with Cowden disease have an increased risk for development of thyroid carcinoma and may wish to minimize exposure of the neck to ionizing radiation.

Patients with GS should minimize exposure to ultraviolet light and ionizing radiation to reduce the risk of developing basal cell carcinomas.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have been consistently associated with diminished risk of colorectal cancer. Sulindac has been reported to cause regression of adenomas in patients with Gardner syndrome. NSAIDs suppress cyclooxygenase-2 (COX-2), which affects epithelial proliferation and apoptosis.

Studies by Watanabe et al suggest an important role of antagonistic agents for the prostaglandin EP1 receptor for chemoprotection against the development of colon cancer.[47]

Many future therapies will target the actual signaling pathways disrupted by the affected genes in polyposis syndromes. For example, a trial studying rapamycin use in Cowden syndrome has been conducted.[27]

In additional to nutritional support, steroids have also been shown to be the mainstay of medical treatment that can lead to remission in Cronkhite-Canada syndrome. Azathioprine is also used as a steroid-sparing agent.[56]

Class Summary

Growing evidence suggests a protective role for NSAIDs against the development of colorectal cancer. In addition, a significant effect in reversing adenoma growth has been illustrated with the use of sulindac and celecoxib in patients with FAP. Aspirin may also be useful to reduce the recurrence of polyps or cancer, but because of the potential for these drugs to cause damage to the upper gastrointestinal tract, they are not routinely recommended for this purpose.

Studies have shown that APC inactivation and EGFR signaling increase COX2 expression, which may lead to intestinal neoplasia. The mechanism of NSAID-induced polyp regression is not completely known, but it thought that it is at least in part due to inhibition of cyclooxygenase 2 (COX2) and the resultant decrease in prostaglandin synthesis although a non-COX mechanism may also contribute.

The mechanism of NSAID-induced polyp regression is not known, but it thought that it is at least in part due to inhibition of cyclooxygenase 2 (COX2) and the resultant decrease in prostaglandin synthesis although non-COX mechanism may also contribute.

Sulindac (Clinoril)

Has been reported to cause regression of adenomas in patients with Gardner syndrome (ie, FAP).

A recent study randomized patents to Sulindac 150 mg twice daily along with Erlotinib 75 mg daily versus placebo for 6 months and measured polyp burden. The patients on medications had a lower duodenal polyp burden at 6 months but many patients developed adverse events such as an acne-like rash, and it is unknown whether the medications prevent new duodenal adenomas from forming.

Class Summary

These agents inhibit COX-2, thus suppress production of prostaglandin E2 at inflammation sites.

Celecoxib (Celebrex)

Recently was approved by the FDA for treatment of Gardner syndrome as an adjunct to endoscopy and surgery. The mean reduction in the number of polyps was 28% with 400 mg PO bid and 12% with 100 mg PO bid (5% placebo).

Outpatient treatment for the patient with Gardner syndrome includes treatment of cutaneous cysts; symptomatic osteomas (eg, mandibular); dental anomalies; and diligent surveillance for neoplasia within the GI tract, liver (hepatoblastoma), thyroid, bone, and adrenal glands.

Outpatient treatment for the patient with Turcot syndrome includes surveillance for malignancy and treatment of complications within the GI tract, skin, and CNS.

Outpatient treatment for the patient with Cowden disease includes management of thyroid disease, scoliosis, and CNS abnormalities. Patients with Cowden disease have a predisposition for development of cerebellar, breast, skin (Merkel cell), and renal malignancies.

Outpatient treatment for the patient with BRR syndrome includes therapies for neurologic and developmental issues, management of thyroid disease, and surveillance and treatment of underlying malignancies.

Outpatient treatment for the patient with GS includes evaluation and treatment of ophthalmologic abnormalities (eg, strabismus, glaucoma), cleft lip and palate, odontogenic cysts, scoliosis, and cardiac fibromas. Patients with Gorlin syndrome require lifetime surveillance for malignancies, including basal cell carcinoma (adolescence, adulthood), ovarian and uterine carcinoma, medulloblastoma and astrocytoma (early childhood), lymphatic and mesenteric cysts, and sarcomas.

Outpatient treatment for the patient with SPS includes frequent surveillance for the development of further polyps and colorectal cancer.

Patients with Gardner syndrome may require inpatient management for evaluation and treatment of suspicious lesions.

Patients with Turcot syndrome may require inpatient management for evaluation and treatment of potential malignancies within the CNS and GI tract.

Patients with Peutz-Jeghers syndrome (PJS) may require inpatient treatment of intussusception, significant GI bleeding, and evaluation for malignancy. Both invasive and noninvasive evaluations may be indicated, including endoscopy, biopsy, and resection for diagnosis, with treatment of associated medical issues (eg, anemia) as dictated by the clinical scenario.

Patients with Cowden disease may require inpatient treatment of CNS abnormalities and surgical treatment of malignancies.

Patients with Bannayan-Riley-Ruvalcaba syndrome (BRR) may require inpatient treatment of clinically significant lipomatous and vascular lesions resulting in compromised organ function or circulatory compromise. Patients with Bannayan-Riley-Ruvalcaba syndrome may also require treatment of seizures and evaluation for suspected malignancy.

Patients with Gorlin syndrome (GS) may need inpatient assessment of symptomatic cardiac fibromas, surgical correction of palatal abnormalities and scoliosis, and treatment of neoplasia.

Patients with SPS may require inpatient treatment for rectal bleeding and surgical treatment of colorectal cancer. 

Patients with polyposis may require transfer for diagnosis and treatment if appropriate support is not available.

Familial adenomatous polyposis

Well-established guidelines published by the American Gastroenterological Association for surveillance in individuals with FAP, and are discussed above in medical management.[69]

A study of patients who have had an early colectomy (younger than 14 y) showed that 43% reported daytime or nighttime incontinence, which was associated with lower levels of psychosocial functioning.[84]

Patients with Gardner syndrome require routine surveillance for GI malignancy via guaiac cards in the asymptomatic patient and serial upper and lower endoscopies and small bowel evaluation.

Patients with Turcot syndrome require surveillance for malignant transformation within gastric and colonic polyps, cutaneous surveillance for basal cell carcinomas, and possible CNS malignancies.

Peutz-Jeghers syndrome

In patients with PJS, establishment of surveillance programs for occult malignancies may permit early detection. Specifics of surveillance are detailed in medical management.

The development of gynecomastia of precocious puberty in a child with PJS merits further diagnostic investigation to exclude underlying testicular or gynecologic malignancy.

PTEN-hamartomatous syndromes

The Cleveland Clinic PTEN Risk Calculation tool calculates a patient’s risk for PTEN mutation risk, which can allow for earlier recognition of the syndrome, initiation of a cancer genetics consultation, and early screening practices for the syndrome’s sequelae.[74]

Patients have an increased risk for development of breast cancer. Early institution of screening programs and consideration of prophylactic mastectomy should be considered.

In addition, these patients are predisposed to the development of thyroid disease; complications from hamartomatous GI polyps; and cerebellar, skin, and renal malignancies.

Gorlin syndrome

Patients with GS should minimize exposure to ultraviolet light and ionizing radiation to deter the development of basal cell carcinomas.

Establishment of skin self-examination programs may facilitate early detection of basal cell carcinomas.

Patients with GS should have ophthalmologic screening for glaucoma and cataracts.

Patients should have routine dental follow-up care if cysts are present within the jaw.

Women should undergo routine gynecologic examinations.

Serrated polyposis syndrome

Patients with SPS should undergo regular screening colonoscopies for polyp removal and detection of colorectal cancer.

Gardner syndrome

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

Turcot syndrome

Patients with Turcot syndrome may experience complications from malignancies.

Peutz-Jeghers syndrome

Patients may develop medical and surgical complications from GI polyps and malignancies. Some reports suggest that approximately one fourth of patients require laparotomy for small bowel intussusception by age 10 years.[85]

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

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

Complications from GI polyps and malignancies may reduce life expectancy.

PTEN-hamartomatous syndromes

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

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

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

Patients with BRR syndrome have a higher incidence of CNS tumors and can develop metaplastic changes within hamartomatous GI polyps.

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

Gorlin syndrome

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

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

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

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

Serrated polyposis syndrome

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

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

Patients with Turcot syndrome have an increased incidence of gastric and colonic carcinomas, basal cell carcinomas, and CNS malignancies.

Patients with PJS have increased morbidity and mortality rates that arise from the complications of GI polyps and potential development of malignancies.

Patients with PTEN -hamartomatous syndromes have increased morbidity and mortality rates because of complications of cutaneous lesions (eg, lipomas, arteriovenous malformations), increased incidence of CNS abnormalities, as well as malignancies within the cerebellum, breast, skin, and kidneys.

Patients with GS have an increased incidence of malignancies, which include basal cell carcinoma, sarcomas, ovarian carcinomas, medulloblastoma, and astrocytoma.

Patients with SPS have increased risk of colorectal cancer. 

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

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

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

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

For excellent patient education resources, visit eMedicineHealth's Thyroid and Metabolism Center. Also, see eMedicineHealth's patient education article Thyroid Problems.