Gardner Syndrome

Ahmad Charifa; Radia Jamil; Nishad Sathe; Xuchen Zhang

Gardner Syndrome

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Continuing Education Activity

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.

Introduction

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]

Etiology

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]

Epidemiology

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]

Pathophysiology

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]

Histopathology

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]

History and Physical

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]

Evaluation

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.

Treatment / Management

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]

Differential Diagnosis

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.

Surgical Oncology

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]

Staging

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.

Prognosis

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.

Complications

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

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.

Deterrence and Patient Education

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.

Pearls and Other Issues

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.

Enhancing Healthcare Team Outcomes

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.

Details

References

[1]

Antohi C, Haba D, Caba L, Ciofu ML, Drug VL, Bărboi OB, Dobrovăț BI, Pânzaru MC, Gorduza NC, Lupu VV, Dimofte D, Gug C, Gorduza EV. Novel Mutation in APC Gene Associated with Multiple Osteomas in a Family and Review of Genotype-Phenotype Correlations of Extracolonic Manifestations in Gardner Syndrome. Diagnostics (Basel, Switzerland). 2021 Aug 28:11(9):. doi: 10.3390/diagnostics11091560. Epub 2021 Aug 28 [PubMed PMID: 34573902]

[2]

Kozan R, Taşdöven İ, Seven TE, Aydemir S, Doğan Gün B, Cömert M. Gardner's syndrome: Simultaneous diagnosis and treatment in monozygotic twins. Turkish journal of surgery. 2022 Dec:38(4):413-417. doi: 10.47717/turkjsurg.2022.4218. Epub 2022 Dec 20 [PubMed PMID: 36875267]

[3]

Tan KL, Wilson S, O'Neill C, Gordon D, Napier S. Something not quite right: Gardner syndrome diagnosed by multiple cutaneous lesions and genetic testing. The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland. 2005 Dec:3(6):412-5 [PubMed PMID: 16353862]

[4]

D'Agostino S, Dell'Olio F, Tempesta A, Cervinara F, D'Amati A, Dolci M, Favia G, Capodiferro S, Limongelli L. Osteoma of the Jaw as First Clinical Sign of Gardner's Syndrome: The Experience of Two Italian Centers and Review. Journal of clinical medicine. 2023 Feb 14:12(4):. doi: 10.3390/jcm12041496. Epub 2023 Feb 14 [PubMed PMID: 36836031]

[5]

Wollina U, Langner D, Tchernev G, França K, Lotti T. Epidermoid Cysts - A Wide Spectrum of Clinical Presentation and Successful Treatment by Surgery: A Retrospective 10-Year Analysis and Literature Review. Open access Macedonian journal of medical sciences. 2018 Jan 25:6(1):28-30. doi: 10.3889/oamjms.2018.027. Epub 2018 Jan 10 [PubMed PMID: 29483974]

Level 2 (mid-level) evidence

[6]

Maimone S, Lewis JT. Gardner Syndrome With Breast Desmoid Tumors. Mayo Clinic proceedings. 2022 Oct:97(10):1894-1896. doi: 10.1016/j.mayocp.2022.06.014. Epub [PubMed PMID: 36202497]

[7]

Aghighi M, Cloutier JM, Hoover WD Jr, Roy K, Lo AA, Brown RA. Cutaneous desmoid-type fibromatosis: A rare case with molecular profiling. Journal of cutaneous pathology. 2021 Sep:48(9):1185-1188. doi: 10.1111/cup.14058. Epub 2021 Jun 30 [PubMed PMID: 33978242]

Level 3 (low-level) evidence

[8]

Adarsh M, Chakravarthy V. Multiple Giant Skull Osteomas Associated with Gardner's Syndrome. Neurology India. 2021 May-Jun:69(3):774. doi: 10.4103/0028-3886.319210. Epub [PubMed PMID: 34169894]

[9]

Signoroni S, Piozzi GN, Collini P, Cocco IMF, Biasoni D, Chiaravalli S, Ricci MT, Vitellaro M. Gardner-associated fibroma of the neck: role of a multidisciplinary evaluation for familial adenomatous polyposis diagnosis. Tumori. 2021 Dec:107(6):NP73-NP76. doi: 10.1177/03008916211009316. Epub 2021 Apr 13 [PubMed PMID: 33849326]

[10]

Arao T, Ohishi M, Yamada M, Nakamura T. [Cutaneous-internal malignancy syndrome associated with specific skin lesions]. Gan to kagaku ryoho. Cancer & chemotherapy. 1988 Apr:15(4 Pt 2-3):1581-7 [PubMed PMID: 3382230]

[11]

Ladd R, Davis M, Dyer JA. Genodermatoses with malignant potential. Clinics in dermatology. 2020 Jul-Aug:38(4):432-454. doi: 10.1016/j.clindermatol.2020.03.007. Epub 2020 Mar 30 [PubMed PMID: 32972602]

[12]

Mokhashi N, Cai LZ, Shields CL, Benson WE, Ho AC. Systemic considerations with pigmented fundus lesions and retinal pigment epithelium hamartomas in Turcot syndrome. Current opinion in ophthalmology. 2021 Nov 1:32(6):567-573. doi: 10.1097/ICU.0000000000000798. Epub [PubMed PMID: 34456292]

Level 3 (low-level) evidence

[13]

Deibert B, Ferris L, Sanchez N, Weishaar P. The link between colon cancer and congenital hypertrophy of the retinal pigment epithelium (CHRPE). American journal of ophthalmology case reports. 2019 Sep:15():100524. doi: 10.1016/j.ajoc.2019.100524. Epub 2019 Jul 24 [PubMed PMID: 31384696]

Level 3 (low-level) evidence

[14]

Dinarvand P, Davaro EP, Doan JV, Ising ME, Evans NR, Phillips NJ, Lai J, Guzman MA. Familial Adenomatous Polyposis Syndrome: An Update and Review of Extraintestinal Manifestations. Archives of pathology & laboratory medicine. 2019 Nov:143(11):1382-1398. doi: 10.5858/arpa.2018-0570-RA. Epub 2019 May 9 [PubMed PMID: 31070935]

[15]

Larsson Wexell C, Bergenblock S, Kovács A. A Case Report on Gardner Syndrome With Dental Implant Treatment and a Long-Term Follow-Up. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2019 Aug:77(8):1617-1627. doi: 10.1016/j.joms.2019.03.002. Epub 2019 Mar 13 [PubMed PMID: 30959012]

Level 3 (low-level) evidence

[16]

Abate MS, Battle LR, Emerson AN, Gardner JM, Shalin SC. Dermatologic Urgencies and Emergencies: What Every Pathologist Should Know. Archives of pathology & laboratory medicine. 2019 Aug:143(8):919-942. doi: 10.5858/arpa.2018-0239-RA. Epub 2019 Feb 20 [PubMed PMID: 30785787]

[17]

Cai D, He F, Xu X, Xiong F, Zhang L. APC c.4621C}T variant causing Gardner's syndrome in a Han Chinese family may be inherited through maternal mosaicism. Experimental and therapeutic medicine. 2021 May:21(5):488. doi: 10.3892/etm.2021.9919. Epub 2021 Mar 16 [PubMed PMID: 33790997]

[18]

Waller A, Findeis S, Lee MJ. Familial Adenomatous Polyposis. Journal of pediatric genetics. 2016 Jun:5(2):78-83. doi: 10.1055/s-0036-1579760. Epub 2016 Mar 15 [PubMed PMID: 27617147]

[19]

Casper M, Petek E, Henn W, Niewald M, Schneider G, Zimmer V, Lammert F, Raedle J. Multidisciplinary treatment of desmoid tumours in Gardner's syndrome due to a large interstitial deletion of chromosome 5q. QJM : monthly journal of the Association of Physicians. 2014 Jul:107(7):521-7. doi: 10.1093/qjmed/hcu036. Epub 2014 Feb 18 [PubMed PMID: 24554300]

[20]

Pinto RS, Simons A, Verma R, Bateman N. Gardener-associated fibroma: an unusual cause of upper airway obstruction. BMJ case reports. 2018 Sep 28:2018():. pii: bcr-2018-225079. doi: 10.1136/bcr-2018-225079. Epub 2018 Sep 28 [PubMed PMID: 30269086]

Level 3 (low-level) evidence

[21]

Yang A, Sisson R, Gupta A, Tiao G, Geller JI. Germline APC mutations in hepatoblastoma. Pediatric blood & cancer. 2018 Apr:65(4):. doi: 10.1002/pbc.26892. Epub 2017 Dec 18 [PubMed PMID: 29251405]

[22]

Kiessling P, Dowling E, Huang Y, Ho ML, Balakrishnan K, Weigel BJ, Highsmith WE Jr, Niu Z, Schimmenti LA. Identification of aggressive Gardner syndrome phenotype associated with a de novo APC variant, c.4666dup. Cold Spring Harbor molecular case studies. 2019 Apr:5(2):. doi: 10.1101/mcs.a003640. Epub 2019 Apr 1 [PubMed PMID: 30696621]

Level 3 (low-level) evidence

[23]

Gu X, Li X, Xu J, Yang J, Li H, Wu Q, Qian J. Accumulated genetic mutations leading to accelerated initiation and progression of colorectal cancer in a patient with Gardner syndrome: A case report. Medicine. 2021 Apr 2:100(13):e25247. doi: 10.1097/MD.0000000000025247. Epub [PubMed PMID: 33787608]

Level 2 (mid-level) evidence

[24]

Song L, Jia Y, Zhu W, Newton IP, Li Z, Li W. N-terminal truncation mutations of adenomatous polyposis coli are associated with primary cilia defects. The international journal of biochemistry & cell biology. 2014 Oct:55():79-86. doi: 10.1016/j.biocel.2014.08.010. Epub 2014 Aug 21 [PubMed PMID: 25150829]

[25]

Friedrich A, Kullmann F. [Familial adenomatous polyposis syndrome (FAP): pathogenesis and molecular mechanisms]. Medizinische Klinik (Munich, Germany : 1983). 2003 Dec 15:98(12):776-82 [PubMed PMID: 14685680]

[26]

Abbott J, Näthke IS. The adenomatous polyposis coli protein 30 years on. Seminars in cell & developmental biology. 2023 Dec:150-151():28-34. doi: 10.1016/j.semcdb.2023.04.004. Epub 2023 Apr 22 [PubMed PMID: 37095033]

[27]

Yanagihara H, Morioka T, Yamazaki S, Yamada Y, Tachibana H, Daino K, Tsuruoka C, Amasaki Y, Kaminishi M, Imaoka T, Kakinuma S. Interstitial deletion of the Apc locus in β-catenin-overexpressing cells is a signature of radiation-induced intestinal tumors in C3B6F1 ApcMin/+ mice†. Journal of radiation research. 2023 May 25:64(3):622-631. doi: 10.1093/jrr/rrad021. Epub [PubMed PMID: 37117033]

[28]

Tage H, Yamaguchi K, Nakagawa S, Kasuga S, Takane K, Furukawa Y, Ikenoue T. Visinin-like 1, a novel target gene of the Wnt/β-catenin signaling pathway, is involved in apoptosis resistance in colorectal cancer. Cancer medicine. 2023 Jun:12(12):13426-13437. doi: 10.1002/cam4.5970. Epub 2023 Apr 25 [PubMed PMID: 37096864]

[29]

Groenewald W, Lund AH, Gay DM. The Role of WNT Pathway Mutations in Cancer Development and an Overview of Therapeutic Options. Cells. 2023 Mar 24:12(7):. doi: 10.3390/cells12070990. Epub 2023 Mar 24 [PubMed PMID: 37048063]

Level 3 (low-level) evidence

[30]

Zhang R, Hu M, Chen HN, Wang X, Xia Z, Liu Y, Wang R, Xia X, Shu Y, Du D, Meng W, Qi S, Li Y, Xu H, Zhou ZG, Dai L. Phenotypic Heterogeneity Analysis of APC-Mutant Colon Cancer by Proteomics and Phosphoproteomics Identifies RAI14 as a Key Prognostic Determinant in East Asians and Westerners. Molecular & cellular proteomics : MCP. 2023 May:22(5):100532. doi: 10.1016/j.mcpro.2023.100532. Epub 2023 Mar 18 [PubMed PMID: 36934880]

Level 2 (mid-level) evidence

[31]

Desmoid Tumor Working Group. The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients. European journal of cancer (Oxford, England : 1990). 2020 Mar:127():96-107. doi: 10.1016/j.ejca.2019.11.013. Epub 2020 Jan 28 [PubMed PMID: 32004793]

Level 3 (low-level) evidence

[32]

Akbulut S, Koc C, Dirican A. Unusual complication in patient with Gardner's syndrome: Coexistence of triple gastrointestinal perforation and lower gastrointestinal bleeding: A case report and review of literature. World journal of clinical cases. 2018 Sep 26:6(10):393-397. doi: 10.12998/wjcc.v6.i10.393. Epub [PubMed PMID: 30283802]

Level 3 (low-level) evidence

[33]

Alkhouri N, Franciosi JP, Mamula P. Familial adenomatous polyposis in children and adolescents. Journal of pediatric gastroenterology and nutrition. 2010 Dec:51(6):727-32. doi: 10.1097/MPG.0b013e3181e1a224. Epub [PubMed PMID: 20808249]

[34]

Ciriacks K, Knabel D, Waite MB. Syndromes associated with multiple pilomatricomas: When should clinicians be concerned? Pediatric dermatology. 2020 Jan:37(1):9-17. doi: 10.1111/pde.13947. Epub 2019 Oct 16 [PubMed PMID: 31618803]

[35]

Baldino ME,Koth VS,Silva DN,Figueiredo MA,Salum FG,Cherubini K, Gardner syndrome with maxillofacial manifestation: A case report. Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry. 2019 Jan [PubMed PMID: 30417483]

Level 3 (low-level) evidence

[36]

Willauer AN, Liu Y, Pereira AAL, Lam M, Morris JS, Raghav KPS, Morris VK, Menter D, Broaddus R, Meric-Bernstam F, Hayes-Jordan A, Huh W, Overman MJ, Kopetz S, Loree JM. Clinical and molecular characterization of early-onset colorectal cancer. Cancer. 2019 Jun 15:125(12):2002-2010. doi: 10.1002/cncr.31994. Epub 2019 Mar 11 [PubMed PMID: 30854646]

[37]

García de la Filia Molina I, Crespo Pérez L, Ríos León R, Barbado Cano A, Moreno García Del Real C, Aburto Bernardo A, Figueroa Tubio A, González Olivares C, Sánchez Aldehuelo R, Albillos Martínez A. Shadow cells in a cutaneous epidermoid cyst: searching for a polyposis syndrome. Gastroenterologia y hepatologia. 2019 Jun-Jul:42(6):386-387. doi: 10.1016/j.gastrohep.2018.06.004. Epub 2018 Jul 17 [PubMed PMID: 30029926]

[38]

Sahoo MR, Nayak AK, Pattanaik A, Gowda MS. Gardner's syndrome, a rare combination in surgical practice. BMJ case reports. 2014 May 26:2014():. doi: 10.1136/bcr-2013-008760. Epub 2014 May 26 [PubMed PMID: 24862409]

Level 3 (low-level) evidence

[39]

Panyarat C, Nakornchai S, Chintakanon K, Leelaadisorn N, Intachai W, Olsen B, Tongsima S, Adisornkanj P, Ngamphiw C, Cox TC, Kantaputra P. Rare Genetic Variants in Human APC Are Implicated in Mesiodens and Isolated Supernumerary Teeth. International journal of molecular sciences. 2023 Feb 21:24(5):. doi: 10.3390/ijms24054255. Epub 2023 Feb 21 [PubMed PMID: 36901686]

[40]

Felner EI, Taweevisit M, Gow K. Hyperaldosteronism in an adolescent with Gardner's syndrome. Journal of pediatric surgery. 2009 May:44(5):e21-3. doi: 10.1016/j.jpedsurg.2009.01.049. Epub [PubMed PMID: 19433155]

[41]

Chelaïfa K, Bouzaïdi K, Chouaïb S, Azaïz O, Messaoud MB, Slim R. Adrenal adenoma in a patient with Gardner's syndrome. A case report. Acta radiologica (Stockholm, Sweden : 1987). 2003 Mar:44(2):158-9 [PubMed PMID: 12694100]

Level 3 (low-level) evidence

[42]

Utsunomiya J, Nakamura T. The occult osteomatous changes in the mandible in patients with familial polyposis coli. The British journal of surgery. 1975 Jan:62(1):45-51 [PubMed PMID: 1111674]

[43]

Trautmann M, Rehkämper J, Gevensleben H, Becker J, Wardelmann E, Hartmann W, Grünewald I, Huss S. Novel pathogenic alterations in pediatric and adult desmoid-type fibromatosis - A systematic analysis of 204 cases. Scientific reports. 2020 Feb 25:10(1):3368. doi: 10.1038/s41598-020-60237-6. Epub 2020 Feb 25 [PubMed PMID: 32099073]

Level 1 (high-level) evidence

[44]

Surun A, Varlet P, Brugières L, Lacour B, Faure-Conter C, Leblond P, Bertozzi-Salomon AI, Berger C, André N, Sariban E, Raimbault S, Prieur F, Desseigne F, Zattara H, Guimbaud R, Polivka M, Delisle MB, Vasiljevic A, Maurage CA, Figarella-Branger D, Coulet F, Guerrini-Rousseau L, Alapetite C, Dufour C, Colas C, Doz F, Bourdeaut F. Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas. Neuro-oncology. 2020 Jan 11:22(1):128-138. doi: 10.1093/neuonc/noz154. Epub [PubMed PMID: 31504825]

[45]

Punatar SB, Noronha V, Joshi A, Prabhash K. Thyroid cancer in Gardner's syndrome: Case report and review of literature. South Asian journal of cancer. 2012 Jul:1(1):43-7. doi: 10.4103/2278-330X.96510. Epub [PubMed PMID: 24455508]

Level 3 (low-level) evidence

[46]

Cirello V. Familial non-medullary thyroid carcinoma: clinico-pathological features, current knowledge and novelty regarding genetic risk factors. Minerva endocrinology. 2021 Mar:46(1):5-20. doi: 10.23736/S2724-6507.20.03338-6. Epub 2020 Oct 12 [PubMed PMID: 33045820]

[47]

Paramythiotis D, Kyriakidis F, Karlafti E, Koletsa T, Tsakona A, Papalexis P, Ioannidis A, Malliou P, Netta S, Michalopoulos A. A Rare Case of Multiple Gastrointestinal Stromal Tumors Coexisting with a Rectal Adenocarcinoma in a Patient with Attenuated Familial Adenomatous Polyposis Syndrome and a Mini Review of the Literature. Medicina (Kaunas, Lithuania). 2022 Aug 18:58(8):. doi: 10.3390/medicina58081116. Epub 2022 Aug 18 [PubMed PMID: 36013583]

Level 3 (low-level) evidence

[48]

Yan ML, Pan JY, Bai YN, Lai ZD, Chen Z, Wang YD. Adenomas of the common bile duct in familial adenomatous polyposis. World journal of gastroenterology. 2015 Mar 14:21(10):3150-3. doi: 10.3748/wjg.v21.i10.3150. Epub [PubMed PMID: 25780319]

[49]

Besteiro B, Gomes F, Costa C, Portugal R, Garrido I, Almeida J. Importance of Extraintestinal Manifestations in Early Diagnosis of Gardner Syndrome. Case reports in gastrointestinal medicine. 2020:2020():7394928. doi: 10.1155/2020/7394928. Epub 2020 Aug 4 [PubMed PMID: 32832171]

Level 3 (low-level) evidence

[50]

Monachese M, Mankaney G, Lopez R, O'Malley M, Laguardia L, Kalady MF, Church J, Shin J, Burke CA. Outcome of thyroid ultrasound screening in FAP patients with a normal baseline exam. Familial cancer. 2019 Jan:18(1):75-82. doi: 10.1007/s10689-018-0097-z. Epub [PubMed PMID: 30003385]

[51]

Chatziralli IP, Papazisis L, Sergentanis TN. Incomplete Gardner's syndrome with blepharoptosis as the first symptom. International ophthalmology. 2014 Apr:34(2):301-3. doi: 10.1007/s10792-013-9772-0. Epub 2013 Apr 12 [PubMed PMID: 23579572]

[52]

Greenwald P, Witkin KM. Familial adenomatous polyposis: a nutritional intervention trial. Journal of the National Cancer Institute. 1989 Sep 6:81(17):1272-3 [PubMed PMID: 2549260]

[53]

Belfiore A, Ciniselli CM, Signoroni S, Gariboldi M, Mancini A, Rivoltini L, Morelli D, Masci E, Bruno E, Macciotta A, Ricci MT, Daveri E, Cattaneo L, Gargano G, Apolone G, Milione M, Verderio P, Pasanisi P, Vitellaro M. Preventive Anti-inflammatory Diet to Reduce Gastrointestinal Inflammation in Familial Adenomatous Polyposis Patients: A Prospective Pilot Study. Cancer prevention research (Philadelphia, Pa.). 2021 Oct:14(10):963-972. doi: 10.1158/1940-6207.CAPR-21-0076. Epub 2021 Jul 12 [PubMed PMID: 34253565]

Level 3 (low-level) evidence

[54]

Carr S, Kasi A. Familial Adenomatous Polyposis. StatPearls. 2024 Jan:(): [PubMed PMID: 30855821]

[55]

Cheng X, Xu X, Chen D, Zhao F, Wang W. Therapeutic potential of targeting the Wnt/β-catenin signaling pathway in colorectal cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2019 Feb:110():473-481. doi: 10.1016/j.biopha.2018.11.082. Epub 2018 Dec 6 [PubMed PMID: 30530050]

[56]

Gerner EW, Bruckheimer E, Cohen A. Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer. The Journal of biological chemistry. 2018 Nov 30:293(48):18770-18778. doi: 10.1074/jbc.TM118.003343. Epub 2018 Oct 24 [PubMed PMID: 30355737]

[57]

Perniciaro C. Gardner's syndrome. Dermatologic clinics. 1995 Jan:13(1):51-6 [PubMed PMID: 7712650]

[58]

Tulchinsky H, Keidar A, Strul H, Goldman G, Klausner JM, Rabau M. Extracolonic manifestations of familial adenomatous polyposis after proctocolectomy. Archives of surgery (Chicago, Ill. : 1960). 2005 Feb:140(2):159-63; discussion 164 [PubMed PMID: 15723997]

[59]

Cobianchi L, Ravetta V, Viera FT, Filisetti C, Siri B, Segalini E, Maestri M, Dominioni T, Alessiani M, Rossi S, Dionigi P. The challenge of extraabdominal desmoid tumour management in patients with Gardner's syndrome: radiofrequency ablation, a promising option. World journal of surgical oncology. 2014 Nov 27:12():361. doi: 10.1186/1477-7819-12-361. Epub 2014 Nov 27 [PubMed PMID: 25429890]

[60]

Li W, Zhou Y, Li Q, Tong H, Lu W. Intestinal perforation during chemotherapeutic treatment of intra-abdominal desmoid tumor in patients with Gardner's syndrome: report of two cases. World journal of surgical oncology. 2016 Jul 4:14(1):178. doi: 10.1186/s12957-016-0935-0. Epub 2016 Jul 4 [PubMed PMID: 27377916]

Level 3 (low-level) evidence