Pediatric Gardner Syndrome

Gardner syndrome is a familial polyposis syndrome, better classified as a variant of familial adenomatous polyposis (FAP). In Gardner syndrome, the symptoms of classic FAP syndrome are present; this consists of the development of approximately 500-2500 colonic adenomas that blanket the surface of the colonic mucosa. Multiple adenomas are also often present throughout the GI tract, especially in the periampullary region and the stomach.[1]

In addition to the classic findings of FAP, other findings include multiple osteomas (commonly of the skull, mandible, and long bones), dental abnormalities (including supernumerary teeth and odontomas), epidermal cysts, thyroid carcinoma, pancreatic adenocarcinoma, congenital hypertrophy of the retinal pigmented epithelium (CHRPE), and fibromatosis or desmoid tumors (commonly in the abdominal wall and retroperitoneum).[2, 3, 4] Less commonly, lipomas, leiomyomas, neurofibromas, hepatoblastomas, and pigmented skin lesions are also seen.

The pathogenesis of both FAP and Gardner syndrome is caused by mutations on the adenomatous polyposis coli (APC) gene on chromosome 5q21.[5, 6] The loss or mutation of this gene is thought to lead to the formation of colonic adenomas and fulfills the first hit of the double hit concept of colorectal cancer development.[7] The loss of APC function prevents apoptosis and allows beta-catenin to build up within cells, which subsequently stimulates cell growth resulting in development of adenomas.[8]

What is exceptional in patients with FAP and Gardner syndrome is the development of hundreds to thousands of these adenomas. This puts them at increased risk, simply by numbers alone, of ultimately having one or more adenomas undergo malignant transformation into adenocarcinoma or colorectal cancer.

Gardner syndrome is a variant of FAP, which is caused by a germline mutation of the APC tumor suppressor gene on chromosome 5q21.

United States Statistics

The estimated frequency of FAP in the general population in the United States ranges from 1 in 8,000 to 1 in 14,000.[9] No specific estimate is available for Gardner syndrome.

International Statistics

The estimated frequency of FAP in the general population in the world is the same as the United States, ranging from 1 in 8,000 to 1 in 14,000.[9]

Racial Differences in Incidence

Gardner syndrome has no racial predilection.

Sexual Differences in Incidence

The male-to-female ratio in patients with Gardner syndrome is 1:1.[9]

Age-related Differences in Incidence

Patients with a positive family history of FAP, who carry the FAP mutation, should have their screening colonoscopy performed at 12 years of age. If multiple adenomas are identified on colonoscopy, patients should be considered for colectomy.

Complications

Complications of Gardner syndrome have been mentioned previously and include colorectal adenocarcinoma, invasive fibromatosis, thyroid carcinoma, and duodenal and periampullary adenocarcinoma. In patients who have a retained rectal pouch after surgery, rectal adenocarcinoma may be a complication.

Mortality/morbidity

The main cause of morbidity and mortality in patients with Gardner syndrome stems from the high frequency of colorectal adenocarcinoma in these patients, which is essentially 100% unless the patients are treated.

In patients who have had a prophylactic colectomy, a common cause of morbidity and mortality is periampullary adenoma and adenocarcinoma.[10]

Desmoid tumors may be a significant cause of morbidity, affecting 10-25% percent of patients.[11] Although these tumors are considered to be benign because they do not metastasize, they can show an infiltrative pattern of local growth. This growth can extend along fascial planes and may cause compression of blood vessels and nerves as well as other abdominal organs including the small bowel, colon, bladder, and ureter.[12]

Pancreatic adenocarcinoma carries a significant morbidity and mortality risk as well. In patients treated by surgical resection, the 1-year survival rate is approximately 25%, and the overall 5-year survival rate is 6%.[13]

Lifelong compliance with screening for tumors is essential in patients with FAP and Gardner syndrome. Patients must be well educated by physicians in the importance of screening.[14] Family members of affected individuals must also be well informed that they are at risk for Gardner syndrome.

Adequate screening is a necessity to avoid legal action. Patients must be screened properly to prevent development of cancer once the diagnosis of Gardner syndrome is made.

Osteomas of the skull and the mandible are often present as painless bony overgrowths. These can often be detected before the colonic manifestations. Multiple osteomas may be a clue to the physician that Gardner syndrome is present.

Dental abnormalities include supernumerary teeth and odontomas and are typically diagnosed by physical examination of the mouth and teeth. However, they may only be detected on plain radiography.

Multiple epidermal cysts are often present and are another easily visible clue to the physician that colorectal disease may be present as well. They are commonly found on the face, scalp, and arms, but can occur anywhere on the skin surface. These cysts are benign but may pose a cosmetic concern for the patient.

Fibromatosis may present as an abdominal mass that is easily detected by palpation of the abdomen.

Congenital hypertrophy of the retinal pigmented epithelium is easily detectable by slit-lamp examination. It is a flat pigmented lesion on the retina. Oftentimes, they may be present bilaterally. These lesions do not cause clinical problems.

Thyroid carcinoma may present as a painful or painless mass in the thyroid, sometimes palpable on physical examination.

A complete blood count (CBC) may show anemia, which may be a sign of colorectal disease, due to GI bleeding.

Colonoscopy and flexible sigmoidoscopy are the most common methods used to detect the presence of colorectal polyps. The presence of greater than 100 polyps is diagnostic of FAP. Barium enemas may also be used.

See the images below.

Esophagogastroduodenoscopy (EGD) is used to screen patients for gastric, duodenal, and periampullary polyps. This is essential in patients with previously diagnosed Gardner syndrome because these polyps, if present, may undergo malignant transformation.

Plain radiography may be used to diagnose both osteomas and dental abnormalities. See the image below.

Ultrasound may be used to diagnose both thyroid and abdominal masses and may be used as a screening tool for both. CT scanning or MRI may also be used.

Colonic adenomas occur in varying shapes and sizes but consistently share several histological characteristics, including hyperchromatic nuclei, increased nuclear-to-cytoplasmic ratio, pseudostratification of the nuclei, mucin dropout, and increased mitotic activity. Three main types of adenomas are noted: tubular, villous, and tubulovillous. Tubular adenomas are the most common, whereas villous adenomas have a higher propensity to become adenocarcinoma. Villous adenomas differ from tubular adenomas in that they show large papillary villous projections, often with a larger base and no stalk. Tubulovillous adenomas show characteristics of both and must have at least 25% of both tubular and villous components.

See the images below.

Odontomas are the most common odontogenic tumor and are considered to be hamartomas. Typically, they are found in the maxilla or the mandible. Histologically, they arise from the epithelium and show extensive deposits of enamel and dentin, which typically form small, irregular supernumerary teeth.

Epidermal cysts are the most common type of keratinous cysts. They are benign cysts lined by cornified epithelium. Lamellated keratin is found within the cystic wall. Often, these cysts are associated with trauma or irritation; thus, inflammatory cells may also be found associated with them. See the image below.

Fibromatosis (or desmoid tumor) is defined by the proliferation of well-differentiated fibroblasts, typically with abundant collagen in between. It is not defined as a malignant lesion because it does not distantly metastasize and shows benign cytologic features with little to no mitotic activity. However, these lesions often show aggressive growth locally, with a tendency to infiltrate neighboring tissue (see the image below).

Pancreatic adenocarcinoma has multiple histological subtypes. By far the most common is ductal adenocarcinoma. This tumor typically shows ductlike structures that show enlarged hyperchromatic nuclei, at least 4 times the size of normal duct nuclei, as well as increased mitotic activity, enlarged nucleoli, and incomplete gland structures. A desmoplastic response can often be found surrounding the tumor cells.

Most medical care for patients diagnosed with Gardner syndrome involves screening on a regular basis for the occurrence of the previously mentioned tumors. These screening tools, previously discussed above, include the use of colonoscopy and flexible sigmoidoscopy to detect the presence of polyps, EGD to detect polyps in the upper GI tract, plain radiography to screen for osteomas and dental abnormalities, and ultrasonography to screen for thyroid and abdominal masses.

Typically, patients diagnosed with Gardner syndrome should undergo yearly colonoscopy starting between ages 10-12 years to screen for polyps. Once detected, endoscopic resection is recommended to remove large polyps in patients prior to resection of the colon. This is especially important because surgical resection of the colon, which is the treatment of choice, is often delayed in younger patients until they are old enough to understand the physical and psychological ramifications of the disease process.

Screening for upper GI polyps using EGD is typically recommended every 1-3 years after the diagnosis is made. Pigmented lesions of the gastric fundus are common findings on endoscopy in infants and are often the first sign of disease. Performing specific surveillance of the peri-ampullary region after adolescence is important.

Capsule endoscopy (CE) may have limited use in screening for rare jejunal-ileal polyps in these patients. However, screening for duodenal polyps is not useful because polyps identified endoscopically are often missed or underestimated by CE. Identifying the ampulla of Vater by CE is also difficult; thus, periampullary carcinomas may also be missed.[15]

Nonsteroidal anti-inflammatory drugs (NSAIDs) also play a role in the treatment of FAP and Gardner syndrome. This topic is discussed more thoroughly below.

Remember that Gardner syndrome is an inherited condition; thus, the family members of an affected individual should be screened for the disease as well.

Surgical care is the treatment of choice in patients with Gardner syndrome. As the development of colorectal cancer in these patients is essentially 100% without treatment, total colectomy is the proven treatment of choice for prevention of cancer.

Currently, colectomy with mucosal proctectomy and ileoanal pouch pull-through is the mainstay of treatment. This procedure is useful because it allows retention of rectal function. However, annual screening for the presence of polyps using flexible sigmoidoscopy is important if this procedure is performed.

In patients who develop duodenal polyp disease, endoscopic resection or local surgical resection often results in recurrence and is not an effective treatment.[16] Johnson et al concluded that definitive resection in the form of pancreaticoduodenectomy, pancreas-sparing duodenectomy, or segmental duodenectomy offers the best chance for polyp eradication and prevention of carcinoma, regardless of polyp etiology.

Fibromatosis can present a challenge in terms of management. For extra-abdominal fibromatosis, surgery is the first-line treatment. For intra-abdominal fibromatosis, often the best treatment is complete surgical resection in combination with radiation to the affected area. However, complete resection of the tumor is challenging due to location (ie, retroperitoneum, abdominal wall).[17] Thus, medical management with sulindac or chemotherapeutic agents may be used in cases in which surgical management is unlikely to be effective.[18] Local recurrence is very common with these tumors.

Consultations with both gastroenterologists and geneticists are important in the management of Gardner syndrome. Gastroenterologists must be consulted to ensure proper screening through colonoscopic and EGD surveillance. Geneticists should screen family members who may be affected with the disease.

Dental consultation may be necessary in those patients affected with dental abnormalities.

Dermatologic consultation may prove useful to ensure proper removal of epidermal cysts for cosmetic purposes.

NSAIDs have been found to decrease the size of colon polyps in patients with FAP and Gardner syndrome. The first is celecoxib, a COX-2 inhibitor, which was previously approved by the US Food and Drug Administration (FDA) for treatment of colonic polyps in patients with FAP.[19] The indication was rescinded because of incomplete data required by the FDA for the accelerated approval; hence, it is no longer approved for FAP in the United States but is used off-label.

Celecoxib is not curative and has not been shown to reduce the risk of developing adenocarcinoma. A recent trial has also shown celecoxib to show similar efficacy in the pediatric population.[20]

Other NSAIDs used in the past include sulindac and aspirin. Although these medications are effective at reducing the size of colonic polyps, they typically also cause significant GI side effects such as GI bleeding and are not typically used at this time. Sulindac has also been used as an initial conservative treatment for intra-abdominal and abdominal wall desmoids.[21]

Class Summary

These agents inhibit growth of adenomatous polyps and cause regression of existing polyps in patients with familial adenomatous polyposis (FAP).

Celecoxib (Celebrex)

This agent inhibits primarily COX-2. COX-2 has been found to be up-regulated in a variety of premalignant disorders and malignancies. It appears to play role in tumor growth, promotion, and metastasis. NSAIDs have been shown to inhibit angiogenesis in cell culture and rodent models of angiogenesis. Since angiogenesis is a feature of both benign and malignant disease and COX-2 is up-regulated in the neovasculature of malignant tumors and their surrounding stroma, selective COX-2 inhibitors may be able to modify the progression of these disorders through control of angiogenesis.

Growing evidence suggests a protective role for NSAIDs against the development of colorectal cancer. A significant effect in reversing adenoma growth has also been illustrated with the use of celecoxib in patients with FAP. Because of this, the drug is used off-label for FAP. Data are limited for use in children.

Sulindac (Clinoril)

Sulindac is a sulfoxide, which is metabolized to the anti-inflammatory sulfide metabolite and a sulfone metabolite. Both metabolites are known to have apoptotic activity on colonic epithelial cells, but whether this is required for the chemoregressive activity of these drugs is not known. Multiple systemic effects, including analgesia, antipyretic, and anti-inflammatory, are mostly mediated by inhibition of prostaglandin synthesis. This agent may be considered for off-label use in adults with FAP.