OBJECTIVE: describing the clinical features of twelve Egyptian patients with Papillon-Lefever syndrome (PLS). Five novel mutations in the cathepsin C (CTSC) gene are introduced and the phenotype of the syndrome is expanded by the identification of new clinical features.
METHODS: the clinical, oro-dental data of twelve Egyptian patients from seven unrelated families are described. Sequence analysis of the CTSC gene was performed to identify the causative mutaions.
RESULTS: Typical PLS features were presented in all patints but with variable severity. One patient showed atypical dental features including dental structural defect, minimal periodontitis, severe gingivitis, and delayed closure of root apices. Another patient presented with arachnodactyly, dystrophic nails, and buphthalmos in the right eye secondary to uncontrolled congenital glaucoma. Mutational analysis of CTSC gene revealed seven distinct homozygous variants including five novel ones: c.285_286delGT (p.Leu96GlufsTer2), c .302 G>C (p.Trp101Ser), c.622_628delCACAGTC (p.H208Efs*11), c.1331delinsAAAAA (p.G444Efs*4) and c .1343 G>A (p.Cys448Tyr). The previously reported missense variant c .757 G>A (p.Ala253Thr) was found in one patient. This variant is very close to the splice region and by functional studies, we proved that it results in exon skipping and early protein truncation (p.R214Sfs*46).
CONCLUSIONS: We report five novel CTSC variants and describe rare and unusual associated clinical and dental findings such as dental structural defects, delayed closure of root apices, and congenital glaucoma. Therefore, our results expand both the phenotypic and mutational spectrum of PLS.

Haim-Munk syndrome (HMS) and Papillon-Lefevre syndrome (PLS) are phenotypic variants of palmoplantar keratoderma (PPK) with progressive early-onset periodontitis and dental caries. HMS and PLS have been associated with homozygous or compound heterozygous mutations in the lysosomal protease gene Cathepsin C (CTSC). There have been only a few documented cases of CTSC mutations in patients from South-East Asia. We report the clinical findings of two Cambodian brothers who presented with diffuse, demarcated PPK with transgrediens extending to the elbows and knees, as well as pachyonychia and dental caries. Arachnodactyly and periodontitis were also found in the older brother. Next-generation sequencing unveiled a homozygous missense variant in CTSC (NM_001814.5: c.1337AC: p.(Asp446Ala)) in both brothers. Both parents were heterozygous for the variant, while an unaffected older brother was homozygous for the wild-type allele. Our study adds to the spectrum of mutations and associated clinical presentations for this rare genodermatosis.

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