Patient PresentationA 21-year-old Hispanic male presented with multiple nodules on the forehead, neck, chest and back for more than 10 years. He reported that his mother and brother had similar lesions. The patient’s general medical history was unremarkable. On physical examination, there were multiple, nontender, round, mobile, flesh-colored nodules with central pores. An ophthalmic examination revealed congenital hypertrophy of the retinal pigment epithelium. The patient failed to present for a scheduled gastrointestinal examination and was lost to follow-up.What’s Your Diagnosis? Diagnosis: Gardner’s SyndromeGardner’s syndrome is a rare autosomal dominant disorder first described in 1953.1 It is considered a phenotypic variant of familial adenomatous polyposis (FAP), a condition in which gastrointestinal polyps are associated with osteomas and skin and soft tissue tumors. In Gardner’s syndrome, the extracolonic manifestations are predominant. Pathogenesis The genetic basis of Gardner’s syndrome and FAP lies in the germline mutation of the adenomatous polyposis coli (APC) tumor suppressor gene located on chromosome 5q21-q22.2,3 This mutation leads to an accumulation of cytoplasmic ß-catenin and alters the proliferation, differentiation, migration, and apoptosis of cells. Extracolonic manifestations in Gardner’s syndrome correlate with a specific mutation on the APC gene. More than 1,000 APC mutations leading to different phenotypes have been reported.4 Epidemiology The overall prevalence of Gardner’s syndrome is estimated at 1 in 7,300 to 1 in 16,000.5,7 There is no racial, gender or geographical predilection. Approximately 25% to 45% of newly diagnosed cases represent de novo mutations.6,7 Clinical Presentation 1. Polyposis. Colon/Rectum. The hallmark of FAP and Gardner’s syndrome is polyposis of the colon and/or rectum. It usually arises during the second decade of life but may occur in early childhood. Unless surgical resection is performed, there is a 100% lifetime risk of developing colon cancer. Progression to malignancy is usually in the third or fourth decade of life. Metastatic colorectal carcinoma is the major cause of death.8 The most important parameters of disease severity are the size and number of adenomas in the colon and the age of the patient at initial presentation.9Duodenum/Stomach. Duodenal polyps are present in 45% to 90% of patients. Periampullary carcinoma is the third leading cause of death. Individuals with Gardner’s syndrome have a 61% to 84% incidence of fundic gland polyps compared to the 0.8% to 1.9% experienced by the general population.10,11,12 No increased cancer risk is reported.2. Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE). CHRPE is a benign, asymptomatic ophthalmologic manifestation usually present at birth and can be used as an early, noninvasive diagnostic measure. The incidence in patients with Gardner’s syndrome is between 70% to 80%.13,14,15 CHRPE is otherwise uncommon in the general population. Diagnostic criteria for CHRPE include detection of either four small pigmented lesions or two lesions if one is greater than 25% of the disc area.13,14,16 CHRPE correlates with the APC gene mutation situated between codons 543 and 1309.173. Desmoid Tumors. Desmoid tumors are rare in the general population, but appear in 4% to 20% of patients with Gardner’s syndrome.18,19 The peak incidence is between 28 and 31 years, with a 2:1 female predominance.20 These nonmetastatic tumors are locally invasive, can be solitary or numerous and may arise on the abdominal wall (48%), the mesentery (50%), or less often, on the trunk and limbs.18 They may cause complications by local expansion and obstruction of adjacent structures. Approximately 50% of desmoid tumors remain stable over time, while 30% undergo cycles of progression and resolution. They are the second leading cause of death in patients with Gardner’s syndrome (11%).8 4. Other Cutaneous Findings. Epidermoid cysts make up 50% to 60% of cutaneous findings in Gardner’s syndrome. They usually appear in groups, develop at an early age, and often appear in atypical locations. Their presence prior to puberty should alert the physician to evaluate the colon and rectum for polyps.21 Other cutaneous findings may include fibromas, lipomas, pigmented skin lesions, neurofibromas, leiomyomas, and nasal angiomas. 5. Osteomas. Osteomas appearing around puberty are seen in 46% to 93% of patients with Gardner’s syndrome. Osteomas tend to localize in the mandible, maxilla, skull, and long bones and usually remain stable after puberty. While osteomas are asymptomatic benign tumors, they may restrict mandibular movement and/or present a cosmetic concern. Patients presenting with greater than three osteomas should be urged to undergo medical examination for polyposis.22 6. Dental Abnormalities. Odontomas are well-defined and encapsulated hard tissue growths that appear as opaque, irregular structures on radiographs. Odontomas, as well as supernumerary and impacted teeth, are dental abnormalities that are more common in patients with Gardner’s syndrome.7. Adrenal Adenomas. Adrenal adenomas have been reported in 7% to 13% of patients with Gardner’s syndrome. 8. Cancers. Thyroid carcinoma. The most common thyroid cancer found in patients with Gardner’s syndrome is a papillary tumor with multicentric and unilateral growth. The risk is increased eight-fold compared with the general population, with an absolute lifetime risk of around 2%.23 These tumors have low metastatic potential. The average age of diagnosis is 25 to 33 years, with a female-to-male ratio of 17:1. Hepatoblastoma. Hepatoblastoma is a rapidly progressing embryonal liver tumor affecting children. Patients with Gardner’s syndrome have an 800-fold increased risk of developing hepatoblastoma.24 Other tumors that occur more commonly in Gardner’s syndrome include osteosarcoma, pancreatic adenocarcinoma, neoplasms of the gallbladder and bile ducts, chondrosarcoma, liposarcoma, and central nervous system(CNS) tumors.Histology The histological features of epidermoid cysts occurring in individuals with Gardner’s syndrome are similar to common epidermoid cysts but may be more likely to show pilomatricoma-like changes. Prognosis The prevalence of cancer in symptomatic patients is 47% to 67%, and is 2% in asymptomatic patients. One study estimated the risk of developing extracolonic cancer by the age of 50 as 11%, and 52% by the age of 75.25 The incidence of selected malignancies is shown in Table 1. A list of differential diagnoses is shown in Table 2. Family ScreeningGenetic counseling should always be given prior to genetic testing. Genetic testing is usually offered at about the age of 10 to 12 years. Detectable APC gene mutations are absent in 20% to 30% of classic FAP patients.26 If no mutation is found in the affected family member, genetic testing is uninformative, and other at-risk family members should not be genotyped. If a mutation is found, at-risk family members should be tested to determine if they are indeed carriers of the mutation. Gene carriers, at-risk family members who have not had genetic testing, or those from families in whom genetic testing is uninformative should be offered a flexible sigmoidoscopy or colonoscopy every 12 months. This may be started around the age of 10 to 12 years and should continue until age 35 to 40 if all tests are negative. An ophthalmic examination to detect CHRPE in at-risk patients is a highly reliable risk assessment.27 CHRPE-positive at-risk persons have nearly a 100% probability of inheriting the disease. CHRPE-negative members of CHRPE-positive families should undergo further investigation with colonoscopy or genetic testing. The presence of osteomas can confirm an early diagnosis of Gardner’s syndrome. Osteomas are easily detected by cranial radiographs or panoramic orthopantomographs. If radio-opaque bony lesions are seen, further evaluation with a biopsy is recommended. Treatment Colon/Rectal Polyposis Surgical resection is recommended if >30 polyps are detected on colonoscopy, or if biopsy results reveal dysplasia or malignant degeneration. This should preferably be performed before the age of 25.28 Proctocolectomy or colectomy should be followed by sigmoidoscopic surveillance and rectal polypectomy. Several authors have reported that sulindac (Clinoril) induces polyp regression. However, one placebo-controlled study of 22 patients suggested that while sulindac reduces the number and size of colorectal adenomas, its effect is incomplete.29 COX-2 inhibitors (celecoxib) were reported to significantly reduce duodenal polyps in one placebo-controlled trial.30 Desmoid Tumors Desmoid tumors may be treated by wide surgical resection. The treatment is only indicated if desmoid tumors cause symptoms, obstruct adjacent structures, or present cosmetic concerns. The recurrence rate is high, and tumors tend to be more frequent and aggressive with each surgical intervention. The surgical treatment of intra-abdominal desmoids is correlated with high morbidity.Radiation therapy is an alternative for non-resectable desmoid tumors or can be used as an adjuvant therapy. There are studies using hormonal therapy (anti-estrogens, progesterone, testolactone, goserelin), interferons, methotrexate, vinblastine (or vinorelbine), and other chemotherapy agents, with a complete response ratio of 20%, 26%, 20%, 11% and 20%, respectively. The duration of response varies greatly, ranging from several months up to 15 years.31Osteomas No treatment is necessary except for symptomatic relief or to treat cosmetic concerns. Extirpation is the treatment of choice but recurrence is common.Epidermoid Cyst No treatment is necessary except for symptomatic or cosmetic concerns. Follow-Up Annual flexible sigmoidoscopy or colonoscopy is recommended from the age of 10 until 35 or 40 years if results continue to be negative. In the case of a positive result, colectomy should be recommended. Patients who have undergone colectomy still remain at risk for the development of adenomas and adenocarcinoma in the ileum.32 Upper gastrointestinal endoscopy should be performed at the time of colectomy or early in the third decade of life. If no polyps are observed, the patient should be re-examined at 5-year intervals. If adenomas are discovered, biopsy and periodic endoscopy is recommended. The frequency of exams and need for prophylactic surgery should be determined by the duodenal polyp stage. Careful palpation of the thyroid is recommended annually. Periodic ultrasonography can be considered. Children at risk for FAP should undergo testing for serum alpha-fetoprotein and have abdominal palpation every 6 months until the age of 6 years.33 Biliary examination is only indicated in patients with symptoms or abnormal liver function tests. An abdominal CT is recommended every 3 years from age 20, with special attention on the pancreas, small bowel, and adrenal glands. The patient should be asked regularly about possible neurological symptoms. Periodic magnetic resonance imaging is recommended for patients with a family history of CNS malignancy. Further investigations for malignancy are based on symptoms and family history.