Novel clinical and molecular findings in Spanish patients with Nevoid Basal Cell Carcinoma Syndrome

Abstract

Background

Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is an autosomal dominant disorder characterised by developmental alterations and multiple basal cell carcinomas. Mutations in PTCH1, a membrane receptor for Sonic Hedgehog, are associated with the development of the disease. Most of them produce a truncated protein which is unable to supress Smoothened protein and continuously activates the downstream pathway

Objectives

We aimed to characterize 22 unrelated Spanish subjects with NBCCS, the largest cohort of Gorlin syndrome reported to date in Spain

Methods and results

We reported for the first time two young patients with uterus didelphys and ganglioneuroma, within the context of NBCCS. One patient showing a severe phenotype of the disease developed basal cell carcinomas since the childhood. Sanger sequencing of PTCH1 gene in this cohort identified 17 novel truncating mutations (11 frameshift, 5 nonsense and one mutation affecting an exon-intron splicing site) and 2 novel missense mutations that were predicted to be pathogenic. Patients showed a great clinical variability and inconsistent genotype-phenotype correlation, as seen in relatives carrying similar mutations

Conclusion

This study contributes to increase the pool of clinical manifestations of the NBCCS, as well as increasing the number of pathogenic mutations identified in PTCH1 predisposing to the condition. The inconsistencies found between phenotype and genotype suggest the involvement of other modifying genetic/epigenetic or environmental.

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