Nevoid Basal Cell Carcinoma Syndrome with Nystagmus and Immobile First Digit Interphalangeal Joints: Expanding the Phenotype of PTCH1 Duplications - Abstract
Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) is an autosomal dominant condition caused by mutations in the PTCH1 gene. It is characterized by distinct skeletal and craniofacial anomalies with an increased risk for basal cell carcinomas. We present a 5-year-old male with a family history of NBCCS, found to have a previously unreported 2.7kb partial duplication in the PTCH1 gene. The patient has several classical craniofacial findings of NBCCS (macrocephaly and frontal bossing), but he also displays additional manifestations of nystagmus and immobile first digit interphalangeal joints due to hypoplastic flexor muscles with underlying normal bony anatomy. Pathogenic mutations are typically protein truncating due to deletions or missense mutations; there have only been three previous reports of duplications in PTCH1. Although nystagmus is frequently listed as an eye anomaly associated with NBCC, it has been reported in just 3 members of the same family (all with rotary nystagmus). Hand abnormalities such as polydactyly, metacarpal shortening, and cutaneous 2,3 syndactyly have been reported, but thumb abnormalities are rare, and there are no reports of immobile thumbs due to hypoplastic flexor muscles. This patient’s novel genetic duplication and combination of classical and uncommon features of NCBBS offer the opportunity for both expansion of the NBCCS phenotype and further genotype-phenotype correlations. This case also reiterates the importance of copy number analysis for both duplication and deletion events in the PTCH1 gene.