Clinical and genetic findings in 103 individuals in Norway with basal cell naevus syndrome

Abstract

Background Basal cell naevus syndrome (BCNS) is a rare autosomal dominant condition characterized by early onset and multiple basal cell carcinomas (BCCs), skeletal and ocular abnormalities, and extracutaneous tumours and cysts. In most cases, BCNS is caused by a pathogenic variant in the tumour suppressor gene PTCH1. Pathogenic variants in SUFU account for a minority of cases. No clear genotype-phenotype associations between different PTCH1 variants have been established. Objectives To identify all individuals with BCNS in Norway, characterize their clinical and genetic profiles, and investigate possible genotype-phenotype associations. Methods In this cross-sectional study, we approached all individuals with BCNS registered at the Department of Dermatology at Oslo University Hospital and two national resource centres for rare medical conditions. Dermatologists, dentists and geneticists across Norway were contacted in order to identify additional individuals with BCNS. Data were collected from structured interviews, whole-body physical examinations, electronic medical records, radiographic imaging and molecular genetic analyses. Results We identified 109 individuals with BCNS, indicating a national prevalence of BCNS of at least 1.9 per 100 000, of whom 103 agreed to be included. Clinical findings confirmed the considerable phenotypic variation in BCNS, including BCC in 61 individuals (median number of BCCs 48, range 1-1025), odontogenic keratocysts in 72 (median number of odontogenic keratocysts 5, range 1-30) and a wide spectrum of ocular and skeletal abnormalities in 43 and 98 individuals, respectively. This study is the first to report the prevalence estimates of autism (4%) and epilepsy (7%), as well as intracranial lesions associated with epilepsy, in BCNS. Genetic analyses identified a pathogenic or probable pathogenic PTCH1 variant in 93 individuals, while 5 individuals had variants of uncertain clinical significance. Twenty-one of the pathogenic PTCH1 variants were novel. None of the individuals with PTCH1 variants in exon 1, all belonging to the same family, exhibited BCCs, odontogenic keratocysts or palmoplantar pitting. Conclusions This study expands the number of pathogenic PTCH1 variants, elucidates important clinical aspects in BCNS and reveals novel insight to genotype-phenotype associations, providing new implications for management and follow-up.