Phenotypic dento-osseous characterization of a Brazilian family with Familial Adenomatous Polyposis

Highlights

• FAP patients have a higher prevalence of dento-osseous anomalies.

• Bone changes are more prevalent than dental changes in FAP population.

• A nonsense heterozygous mutation in the APC gene (c.1370C > G; p.Ser457*) was detected.

• FAP patients should undergo dental examination and genetic counseling.

• The screening of dento-osseus anomalies contributes to the early diagnosis.

Abstract

Objective

To perform a phenotypic characterization of the dento-osseous anomalies in a Brazilian family with Familial Adenomatous Polyposis (FAP) and to investigate the adenomatous polyposis coli (APC) causative variant.

Design

The study included a family of 14 individuals (Group A: affected; Group B: non-affected). The frequency of radiographic findings in both groups was evaluated according to the Dental Panoramic Radiograph Score (DPRS) diagnostic method. The accuracy and reproducibility of DPRS were tested. The DNA was isolated from the index patient’s saliva and submitted to whole-exome and Sanger sequencing approach.

Results

DPRS ≥ 7 was observed in 80 % of Group A but in none of Group B. The most common findings in Group A were dense bone islands (60 %), hazy sclerosis (40 %), osteomas (40 %), and supernumerary tooth (20 %). DPRS has proved to be a reliable method while DPRS ≥ 5 and DPRS ≥ 7 were taken as positive for FAP, and reproducible diagnosis test considering that the evaluators correctly identified the affected patients (Kappa agreement>0.8, p = 0.002). A nonsense heterozygous mutation in the APC gene (c.1370C > G; p.Ser457*) of the index case was detected.

Conclusion

FAP patients have a higher frequency of dento-osseous anomalies (p = 0.005). Bone abnormalities were more prevalent than dental anomalies (p = 0.001). Thus, FAP patients should be referred for dental examination and genetic counseling to perform early diagnosis of dento-osseous anomalies and evaluate the implications of the molecular findings in each particular family.

Introduction

Familial Adenomatous Polyposis (FAP- MIM175100) is an autosomal dominant inherited syndrome predisposing to colorectal cancer. FAP is caused by variants in the Adenomatous Polyposis Coli (APC) tumor suppressor gene, mapped to the long arm of chromosome 5 (5q21) band q21 (MIM 611731). Pathogenic variants in the APC gene can cause two distinct phenotypes: the classic FAP and the Attenuated Familial Adenomatous Polyposis (Knudsen et al., 2010). The encoded APC protein is a nucleus-cytoplasmic shuttling protein, known to antagonize the Wnt signaling pathway by the formation of a cytoplasmic complex that targets β-catenin for degradation (Zeineldin et al., 2014); therefore, the loss of APC function contributes to the increase of cytoplasmic β-catenin levels. The β-catenin protein is related to the process of cell adhesion and gene transcription (Amado et al., 2012). In high concentrations, β-catenin is translocated to the nucleus, where it binds to transcription factors of target genes. The dysregulated signaling pathway induces cell proliferation and the formation of intestinal adenomas, resulting in malignant transformation of normal cells (Fujii et al., 2019; Nusse and Clevers, 2017; Yang et al., 2014).

When pathogenic variants in the APC gene are not identified in FAP patients, a second gene must be investigated, the MUTYH gene (chromosome 1p34.1; MIM 604933). MUTYH pathogenic variants cause an attenuated phenotype similar to Attenuated Familial Adenomatous Polyposis that is called MAP, MUTYH-Associated Polyposis, and has an autosomal mode of inheritance (Nielsen et al., 2009; Torrezan et al.2013).

In general, FAP patients develop multiple intestinal polyps around the second decade of life. Approximately 50 % of patients with classic FAP have these colorectal adenomas by the age of 15 years, and this percentage increases to 95 % by the age of 35 years (Half et al., 2009). The attenuated form of the disease called Attenuated Familial Adenomatous Polyposis is clinically characterized by the development of less than 100 colorectal adenomatous and by a delay in the polyps’ onset, on average of up to 20–30 years (Hernegger et al., 2002). In addition to the development of adenomatous polyps in the colon and rectum, classic FAP patients may present extracolonic manifestations, including gastric and duodenal adenomas, congenital hypertrophy of the retinal pigment epithelium desmoid tumors, fibromas, and dento-osseous anomalies (odontomas, osteomas, dense bone islands, and supernumerary tooth) (Campos et al., 2015; Gardner, 1962). Although commonly noted in FAP, extraintestinal manifestations are rare in Attenuated Familial Adenomatous Polyposis patients, and affected individuals are likely to have a reduced lifetime risk of colorectal cancer, less than in 100 % of cases as in FAP (Jasperson et al., 2010). The diagnosis and follow-up of FAP are achieved by periodic colonoscopy examination and, if indicated, prophylactic or elective colectomy (Syngal et al., 2015).

The presence of both intestinal polyps and dental anomalies in patients with classic FAP were first described by Gardner (Gardner, 1951). Gardner Syndrome is a term which has been used to refer to this phenotypic characterization of FAP. Bone alterations in the jaw and dental anomalies have been reported in 65 % and 30 % of patients respectively and may precede the development of intestinal polyps and the colorectal cancer (Almeida et al., 2016; Almeida et al., 2020; Septer et al., 2018).

Thakker et al. (1995) developed a diagnostic method using panoramic radiographs to identify high-risk FAP patients called Dental Panoramic Radiograph Score (DPRS). This method has demonstrated a significant association between the presence of substantial changes and the presence of FAP, allowing the early diagnosis of the disease (Aggarwal et al., 2003; Thakker et al., 1995). Although the literature presents several studies showing the phenotypic characterization of FAP, studies still lack on showing the genotypic correlation with the clinical data of patients with FAP. Thus, the present study aimed to perform a phenotype characterization of a family with FAP in order to detail the dento-osseous anomalies using the DPRS diagnostic method to determine its diagnostic accuracy. In addition, genetic analyses using whole-exome sequencing and Sanger sequencing validation were performed.