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Novel clinical and molecular findings in Spanish patients with naevoid basal cell carcinoma syndrome
N Alonso1,2, J Cañueto3,4, S Ciria1
1Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain.
Background:
Naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental alterations and multiple basal cell carcinomas. Mutations in PTCH1, which encodes 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 suppress Smoothened protein and continuously activates the downstream pathway.
Objectives:
We aimed to characterize 22 unrelated Spanish patients with NBCCS, the largest cohort with Gorlin syndrome reported to date in Spain.
Methods:
Genomic analysis of PTCH1 was performed in patients with NBCCS and controls, and mutations were analysed using bioinformatics tools.
Results:
We report for the first time two young patients, one each with uterus didelphys and ganglioneuroma, within the context of NBCCS. One patient showing a severe phenotype of the disease had developed basal cell carcinomas since childhood. Sanger sequencing of PTCH1 in this cohort identified 17 novel truncating mutations (11 frameshift, five nonsense and one mutation affecting an exon-intron splice site) and two novel missense mutations that were predicted to be pathogenic. The patients showed great clinical variability and inconsistent genotype-phenotype correlation, as seen in relatives carrying similar mutations.
Conclusions:
This study contributes to increase the pool of clinical manifestations of 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 factors, genetic, epigenetic or environmental.
Insights
Naevoid basal cell carcinoma syndrome (NBCCS) involves developmental issues and multiple skin tumors due to PTCH1 gene mutations. This study identified new mutations and rare associated conditions, highlighting genetic variability in Gorlin syndrome.
Area of Science:
- Genetics
- Dermatology
- Oncology
Background:
- Naevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant disorder, is linked to developmental abnormalities and multiple basal cell carcinomas.
- Mutations in the PTCH1 gene, encoding a Sonic Hedgehog pathway receptor, are implicated in NBCCS pathogenesis, often leading to a continuously active signaling cascade.
Purpose of the Study:
- To characterize 22 unrelated Spanish patients with NBCCS, forming the largest reported cohort in Spain.
- To identify and analyze PTCH1 gene mutations in patients with NBCCS.
- To document clinical variability and genotype-phenotype correlations within the Spanish NBCCS cohort.
Main Methods:
- Genomic analysis of the PTCH1 gene was conducted on patients with NBCCS and control individuals.
- Bioinformatics tools were employed to analyze identified mutations.
- Sanger sequencing was used to detect mutations in the PTCH1 gene.
Main Results:
- Seventeen novel truncating PTCH1 mutations (11 frameshift, 5 nonsense, 1 splice site) and two novel pathogenic missense mutations were identified.
- Two young patients presented with rare co-occurring conditions: uterus didelphys and ganglioneuroma within the NBCCS context.
- Significant clinical variability and inconsistent genotype-phenotype correlations were observed among patients, including within families.
Conclusions:
- This study expands the known clinical manifestations associated with NBCCS and adds to the spectrum of pathogenic PTCH1 mutations.
- The observed inconsistencies between genetic mutations and clinical presentation suggest the influence of additional genetic, epigenetic, or environmental modifying factors.
