Novel Mutation in APC Gene Associated with Multiple Osteomas in a Family and Review of Genotype-Phenotype Correlations of Extracolonic Manifestations in Gardner Syndrome

Abstract

Gardner syndrome is a neoplasic disease that associates intestinal polyposis and colorectal adenocarcinoma with osteomas and soft tissue tumors determined by germline mutations in the APC gene. The early diagnosis and identification of high-risk individuals are important because patients have a 100% risk of colon cancer. We present the case of a family with Gardner syndrome. Cephalometric, panoramic X-rays and CBCT of the proband and her brother showed multiple osteomas affecting the skull bones, mandible and paranasal sinuses. The detailed family history showed an autosomal dominant transmission with the presence of the disease in the mother and maternal grandfather of the proband. Both had the typical signs of disease and died in the fourth decade of life. Based on these aspects the clinical diagnosis was Gardner syndrome. By gene sequencing, a novel pathogenic variant c.4609dup (p.Thr1537Asnfs*7) in heterozygous status was identified in the APC gene in both siblings. We reviewed literature data concerning the correlation between the localization of mutations in the APC gene and the extracolonic manifestations of familial adenomatous polyposis as well as their importance in early diagnosis and adequate oncological survey of patients and families based on abnormal genomic variants.

Osteoma of the Jaw as First Clinical Sign of Gardner’s Syndrome: The Experience of Two Italian Centers and Review

“…The average age at GS diagnosis ranges between 13 and 31 years, while common symptoms related to colonic polyps include intermittent mucous discharge with defecation, rectal bleeding, diarrhea, constipation, and abdominal pain. As stated by Antohi et al [ 13 ], the extracolonic manifestation of GS could be divided into non-malignant and malignant. Regarding the oral and maxilla facial regions, prevalent signs are represented by osteoma, dental abnormalities, CHRPE, benign cutaneous lesions, desmoid tumors, and adrenal masses.…”

“…Oral osteomas are found in 60–80% of FAP patients and 50% of all oral osteomas occur in FAP. This incidence is remarkable, especially if compared to the normal occurrence of osteomas in the healthy population, which is approximately 1–2% [ 13 ]. In particular, Capodiferro et al, 2005 [ 14 ] suggested that dentomaxillofacial lesions in the early stage could be an indicator of GS not yet diagnosed.…”

Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision

“…Due to the high incidence of osteomas in FAP patients 38 , 237 and especially oral osteoma 237 compared to the general population, genetic testing should be considered in those with oral or facial osteomas 237 , 238 .…”

“…Due to the high incidence of osteomas in FAP patients 38 , 237 and especially oral osteoma 237 the diagnosis of FAP should be considered, when compared to the normal occurrence of osteoma in the healthy population, the diagnosis of FAP should be considered 237 , 238 .…”

Multiple osteomas of paranasal sinuses

“…Множественные остеомы верхнечелюстных пазух в доступной литературе описаны в контексте синдрома Гарднера и проявляющейся симптоматики со стороны желудочно-кишечного тракта и челюстно-лицевых аномалий [24,25]. Данные об их встречаемости малочисленны, в до- ступной литературе найдено единичное сообщение о множественных остеомах при выполнении компьютерной томографии околоносовых пазух 0,13% [26].…”