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Gardner syndrome is an autosomal dominant phenotypic variant of familial adenomatous polyposis. Gardner's initial description in 1951 highlighted the presence of adenomatous polyps in the colon, along with extracolonic tumors, emphasizing their high malignancy potential. Extracolonic manifestations may include intestinal polyposis, desmoids, osteomas, and epidermoid cysts. Various noncutaneous manifestations also exist with this syndrome. A characteristic finding is bilateral, multiple, pigmented, ocular fundus lesions, known as congenital hypertrophy of the retinal epithelium. The development of intestinal polyposis and colorectal adenocarcinoma are critical features of Gardner syndrome. This activity describes the pathophysiology of Gardner syndrome and highlights the role of the interprofessional team in the management of patients with this condition. Objectives: Assess the clinical features and genetic markers associated with Gardner syndrome. Implement evidence-based management strategies encompassing pharmacological interventions and surgical options tailored to the patient's needs and disease progression. Select appropriate interventions, medications, and surgical procedures based on the specific manifestations and progression of Gardner syndrome. Collaborate with a multidisciplinary team, including genetic counselors, gastroenterologists, surgeons, and other specialists, to provide comprehensive, holistic care for patients with Gardner syndrome. Access free multiple choice questions on this topic.

Gardner syndrome is an autosomal dominant phenotypic variant of familial adenomatous polyposis, distinguished by extracolonic manifestations in addition to the colonic polyps observed in familial adenomatous polyposis.[1] The condition is characterized by numerous adenomatous polyps lining the intestinal mucosal surface, each carrying a high potential for malignancy. Gardner syndrome often includes the presence of multiple polyps in the colon and tumors outside the colon, referred to as extracolonic manifestations.[2][3] These manifestations encompass intestinal polyposis, desmoid tumors, osteomas, and epidermoid cysts.[4][5][6][7] Patients with Gardner syndrome may exhibit osteomas of the mandible and skull, epidermal cysts, or fibromatosis,[8][9] which are often asymptomatic but may lead to pruritus, inflammation, and rupture.[10][11] Moreover, noncutaneous manifestations are common with this syndrome. A characteristic feature is the presence of bilateral, multiple, pigmented, ocular fundus lesions, known as congenital hypertrophy of the retinal epithelium.[12][13] The development of intestinal polyposis and colorectal adenocarcinoma marks Gardner syndrome. Other neoplasms have also been reported, such as duodenal carcinoma around the ampulla of Vater, hepatoblastoma, adrenal adenoma, and papillary or follicular thyroid cancer.[14][15][16]

Research has revealed a genetic link to the development of Gardner syndrome within band 5q21, which is associated with the adenomatous polyposis coli (APC) gene located on chromosome 5. This gene is a tumor suppressor, producing the APC protein that regulates cell growth by ensuring appropriate timing in the cell cycle.[17][18][19] Patients with Gardner syndrome exhibit an aberration in this gene, resulting in uncontrolled cell growth. Studies analyzing the APC gene have identified that most of its mutations are nonsense mutations leading to the formation of a shortened protein, with most mutations at the 3' end rather than the 5' end.[17] Specific regions, such as the codons 1403 to 1578, are more closely associated with the development of mandibular lesions. However, those beyond codon 1444 are linked with a 2-fold increase in osteoma formation.[17] In addition to these genetic mutations, Gardner syndrome has been associated with a loss of DNA methylation, a mutation in the RAS gene on chromosome 12, a deletion of the colon cancer gene (DCC) on chromosome 18, and a mutation in the TP53 gene located on chromosome 17.[20][21][22] The inheritance pattern of Gardner syndrome follows autosomal dominant inheritance with near-complete penetrance.[23]

The prevalence of Gardner syndrome varies across multiple studies, but recent studies indicate it affects approximately 1 in 7000 to 1 in 30,000 births. Due to its near-complete penetrance through autosomal dominant inheritance, albeit with variable expressivity in extraintestinal manifestations, Gardner syndrome is thought to affect men and women equally.[14] Up to 30% of patients may develop the condition without a family history. However, this data is drawn from the broader spectrum of diseases within familial adenomatous polyposis, of which Gardner syndrome represents 1 entity.[18]

The APC gene, located on the long arm of chromosome 5, is a tumor suppressor gene responsible for producing a protein that plays a significant role in cell division, regulation, and growth.[24][25] Specifically, it controls the frequency of cell division, how cells attach to other cells within the tissue, cell polarization, and the morphology of certain structures.[26] The gene also determines a cell’s mobility and direction during chromosomal movement in cell division. The protein beta-catenin, controlled by the APC gene, prevents the excessive activation of proteins that stimulate cell division, thereby preventing cell overgrowth and proliferation.[27] In cancerous cells, the inactivation of the APC gene and subsequent loss of function in beta-catenin are often observed.[28][29][30]

Histopathological evaluations of lesions in Gardner syndrome should include an assessment of each type of lesion, both intestinal and extraintestinal, that may manifest as a part of this disease.[14] Special attention is warranted for desmoid tumors, as they have been linked to increased morbidity due to mass effect or erosion of surrounding structures.[31]

Due to the genetic heterogeneity of Gardner syndrome, there can be diverse phenotypic expressions. However, the classic symptoms of familial adenomatous polyposis, such as hundreds or thousands of polyps, are often observed.[18] While the disease is frequently detected during malignancy workups or routine screenings, specific physical examination findings may hint at extraintestinal manifestations. Patients may report diarrhea, cramping, rectal pain or bleeding, constipation related to an obstruction, or vomiting as intestinal manifestations.[32][33] Extraintestinal manifestations can include osteomas (frequently found in the mandible, cranium, and long bones), lipomas, epidermal inclusion cysts, desmoid tumors (eg, soft tissue growths), dental abnormalities (eg, supernumerary teeth), fibromatosis, pilomatricomas (with the presence of ≥6 lesions associated with Gardner syndrome), adrenal adenomas (potentially linked to hyperaldosteronism), and congenital hypertrophy of the retinal pigment epithelium.[34][35][36][37][38][39][40][41] Radioopaque lesions in the mandible are believed to occur in 93% of patients with Gardner syndrome.[35][38][42] While many findings in Gardner syndrome are typically benign, the association with various malignancies necessitates ongoing physical examination and evaluation. Colorectal cancer often manifests early in patients with this syndrome and might be the initial factor leading to a diagnosis of Gardner syndrome.[2] Desmoid fibromatosis, a nonmetastastic soft tissue neoplasm, requires further evaluation due to its potential implications.[43] Other major malignancies associated with Gardner syndrome include thyroid cancer, rectal adenocarcinoma, common bile duct adenomas, and medulloblastomas.[44][45][46][47][48]

Diagnosing and evaluating Gardner syndrome is challenging due to its wide range of intestinal and extraintestinal manifestations. While nearly all patients exhibit colorectal polyposis, the diagnosis is often identified through its extraintestinal manifestations, making careful evaluation essential.[2] These manifestations can emerge as early as 2 months of age or as late as 70 years, with the majority appearing during the teenage years. A diagnosis can be confirmed when major extraintestinal involvement is suspected, combined with clinical suspicion prompting genetic testing.[2] When evaluating a patient for Gardner syndrome, it is essential to consider the following measures:[14][49] Skin: Conduct a thorough examination with histopathologic analysis of multiple epidermal inclusion cysts, fibromas, lipomas, leiomyomas, or pilomatricomas, as necessary.[2][7][37] Soft Tissue: Desmoid tumors are high-risk lesions in patients with Gardner syndrome, necessitating active surveillance with imaging techniques such as magnetic resonance imaging (MRI) and ultrasound if there is a risk to local structures.[31] Thyroid: Perform a comprehensive examination and annual ultrasound to monitor for abnormalities.[50] Eye: Regular slit-lamp and ophthalmoscopic examinations are essential to evaluate for congenital hypertrophy of the retinal pigment epithelium.[51] Neurologic: Regularly assess for changes in neurologic symptoms to identify any neurological manifestations associated with the syndrome promptly.

Although there is no cure for Gardner syndrome, prevention is the primary approach for individuals aware of the familial inheritance or once the condition is discovered. A preventative protocol often includes maintaining a healthy diet, especially considering the proposed environmental and diet-related triggers associated with this condition.[52] Additionally, nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac, can help inhibit the growth of polyps in the colon. This is particularly important since individuals with Gardner syndrome have a higher risk of developing colon cancer, and NSAIDs have demonstrated anti-inflammatory effects, reducing this risk.[53] Surveillance through lower gastrointestinal (GI) endoscopies is strongly recommended to monitor polyp growth and development and to identify any transformation into malignant tumors. If 30 or more polyps are present, colon removal may be recommended to significantly reduce the risk of colon cancer development.[36][54][55][56][57]

Gardner syndrome, familial adenomatous polyposis, Turcot syndrome, and other attenuated forms of familial polyposis are the primary phenotypes associated with APC gene mutation.[14][18] Molecular studies indicate that these 4 types share a common mutation on chromosome 5q21. However, Gardner syndrome stands out due to its distinct features, including polyps in the colon, osteomas, and abnormalities in the retinal epithelium. Gardner syndrome and Turcot syndrome may exhibit skin manifestations, but the former is more commonly associated with epidermoid cysts, whereas cafe-au-lait spots characterize the latter.

If 30 or more polyps are present, it may be recommended to consider removing the colon to reduce the risk of developing colon cancer. This procedure might also involve the removal of other intestinal structures, depending on the individual case and the extent of polyp growth.[57]

There is no standardized staging system for Gardner syndrome, unlike many other types of cancers. Instead, clinicians consider factors such as the number of polyps present, the severity of symptoms, and the transformation of benign tumors into malignant cells to assess the progression and management of the disease.

There is currently no cure for Gardner syndrome. The prognosis for an individual diagnosed with this condition varies; however, those with an APC gene mutation are highly likely to develop colon cancer by around the age of 40 if surgery is not undertaken and polyp growth is not controlled.[23] Effective management involves surveillance and symptom control. Regular examinations and evaluations play a crucial role in identifying concerning developments early, enabling timely intervention that may significantly improve the prognosis.

The primary complication of Gardner syndrome is the high likelihood of developing colon cancer, which is strongly associated with significant morbidity and mortality in affected individuals.[58] While the polyposis associated with mutations in the 5q21 region of chromosome 5 within the APC gene can often be asymptomatic, the onset of colorectal cancer is nearly inevitable in patients with Gardner syndrome.[23] Colorectal cancer can manifest at an early age and may lead to substantial morbidity or mortality, particularly if coupled with other aspects of the disease, such as fibromatosis or desmoid fibromatosis.[43][59] Treatment-related complications, like perforation of internal structures, can further exacerbate morbidity.[60] Additionally, the extraintestinal manifestations of Gardner syndrome may progress, causing disfigurement or other symptomatic concerns, leading to decreased quality of life and increased morbidity.[14] Early detection, regular monitoring, and comprehensive management are crucial in mitigating these complications and improving the overall outlook for individuals with Gardner syndrome.

Consultations for Gardner syndrome are multifaceted and require a collaborative approach among various specialists. When diagnosed, patients typically consult with a gastroenterologist, who specializes in gastrointestinal disorders and can conduct necessary screenings and endoscopic procedures to monitor polyp growth. Genetic counselors play a crucial role in discussing the hereditary aspects of the condition, offering valuable insights into the familial implications and potential genetic testing options. Oncologists are essential for patients needing cancer-related treatments or interventions. Dermatologists address skin manifestations, while orthopedic surgeons manage bone-related complications like osteomas. Ophthalmologists focus on ocular issues, especially congenital hypertrophy of the retinal pigment epithelium. The interplay between these specialists is fundamental, ensuring a comprehensive and personalized approach to managing Gardner syndrome, addressing its diverse manifestations, and enhancing the patient's quality of life.

Education is pivotal in empowering patients with essential knowledge about the condition, its manifestations, and the significance of preventive measures. Patients should be educated about the importance of regular screenings, such as lower GI endoscopies, to monitor polyp growth and detect any potential malignancies at an early stage. Furthermore, they need to be informed about the role of healthy dietary choices and medications like NSAIDs in managing the condition. Genetic counseling is crucial in families with a history of Gardner syndrome, aiding individuals in understanding their genetic risk and making informed decisions about screening and preventive interventions. By fostering a strong understanding of the disease and its prevention strategies, patients are better equipped to actively participate in their healthcare, make informed lifestyle choices, and adhere to recommended screenings, ultimately enhancing their quality of life and prognosis.

Early detection of Gardner syndrome is vital due to its high likelihood of progressing to malignancy over time. Gardner syndrome is autosomal dominant and typically presents as gastrointestinal polyps, skin and soft tissue tumors, and multiple osteomas. Cutaneous presentations often include, among others, epidermoid cysts, desmoid fibromatosis, and benign lesions like lipomas. The progression from adenoma to carcinoma consists of a series of cellular events at the tyrosine kinase level of the cell cycle, which may be present in this condition. Although it is considered a variant of familial adenomatous polyposis, Gardner syndrome manifests in areas beyond the colon.

Gardner syndrome has no cure, and effective management involves an interprofessional team, including the primary care clinician, gastroenterologist, genetic counselor, oncologist, pharmacists, and possibly other specialists based on extraintestinal manifestations. Patient education plays a pivotal role once the diagnosis is confirmed, and every member of the healthcare team should provide education about the benefits of prevention as the primary approach for therapy. Additionally, primary healthcare professionals, pharmacists, and nutritionists can collaborate with patients to establish personalized dietary plans, emphasizing the importance of balanced nutrition, regular exercise, and stress management techniques. By integrating these lifestyle modifications with medication management, patients can optimize their overall well-being and enhance their resilience against the challenges of Gardner syndrome. Regular surveillance through lower GI endoscopies is recommended to monitor polyp growth and development and to identify any transformation into malignant tumors. Gastroenterologists or colorectal surgeons are essential for performing these procedures and managing the condition. Other specialists, such as orthopedic surgeons, ophthalmologists, dermatologists, oncologists, and genetic counselors, can also be warranted. Coordination among these specialists is crucial to providing comprehensive and tailored care for individuals with Gardner Syndrome.