A novel missense mutation in the PTCH1 gene in a premature case of nevoid basal cell carcinoma syndrome

ARTICLE

Auteur(s) : Motonobu Nakamura, Yoshiki Tokura

Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan

Nevoid basal cell carcinoma syndrome (NBCCS; Gorlin syndrome; MIM 109400) is an autosomal dominant disease, characterized by a mixture of multiple basal cell carcinomas (BCCs), skeletal anomalies, palmoplantar pits, odontokeratocysts of the jaw and a variety of other tumors [1, 2]. The phenotype is variable, and affected individuals may exhibit a combination of several features. Mutations in the patched homolog 1 (PTCH1) gene underlie NBCCS as well as BCCs in non-NBCCS patients [3]. Here we report a woman who showed palmoplantar pits and odontokeratocysts without apparent BCC. The patient had a novel PTCH1 missense mutation in the second transmembrane domain.

A 21-year-old Japanese female was referred to us for evaluation of palmar pits. The palmar and plantar pits occurred at the age of 10 years. She was diagnosed as having multiple jaw cysts by a dentist and underwent surgery in the jaw a month previously. Both her brother and sister also suffered from multiple jaw cysts and received surgery. Her brother had palmar and plantar pits, while her sister had no pits on the palms or soles. There was no consanguinity in her family and there was no relative who suffered from basal cell carcinoma. Physical examination revealed multiple pits both on the palms and soles. Limb development and facial appearance were apparently normal. Although our close inspection disclosed that she had no skin tumor, we collectively diagnosed her as having NBCCS.

A molecular analysis of the PTCH1 gene, responsible for NBCCS, was performed after obtaining informed consent from the patient. Genomic DNA was extracted from the patient’s blood [4]. The exons of the PTCH1 gene were amplified by polymerase chain reaction (PCR) using the specific primers described previously [5]. PCR products were purified and directly sequenced. The sequence analysis revealed a missense mutation in exon 9: V442E (1325T→A). We could not obtain her consent for further analysis of DNA from her parents, brother, or sister.

The PTCH1 protein is a multipass transmembrane protein and serves as a receptor for Hedgehog (Hh) [6]. To date, 80 different kinds of mis/nonsense mutations of the PTCH1 gene have been reported. The mutation in our patient was a novel mutation that has not been reported in the literature or the SNP database network in Japan (http://snpnet.jst.go.jp/top_e.html). The PTCH1 mutations reported thus far in patients with NBCCS were scattered over the entire gene without hot spots [5]. No correlation was observed between the clinical features of NBCCS and the nucleotide positions of mutations in the PTCH1 gene [5]. Although Japan is a genetically closed island and founder effects are observed in some inherited diseases, there were no preferred mutation sites in the PTCH1 gene among Japanese NBCCS patients in an extensive genetic study [5] (figure 1).

Clinically, palmoplantar pits and odontokeratinocysts may be observed before BCC development. Since ultraviolet (UV) light irradiation is supposed to be one of the most high-risk factors for BCC development in NBCCS [5], we advised our patient to protect her skin from sun exposure and to use daily sunscreens. The early diagnosis of NBCCS by genetic examination before the occurrence of BCCs, and the subsequent UV protection, might prevent tumor development later on, in the forties to fifties.

In summary, we identified a novel missense mutation in the second transmembrane domain of the PTCH1 gene in a young NBCCS patient and advised her to refrain from sun exposure to avoid the future development of BCCs.

Acknowledgements

References

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