BACKGROUND: Hereditary palmoplantar keratodermas (hPPKs) comprise a heterogeneous group of skin disorders characterized by persistent palmoplantar hyperkeratosis. Loss-of-function variants in a serine peptidase inhibitor, SERPINA12, have recently been implicated in autosomal recessive diffuse hPPK. The disorder appears to share similarities with another hPPK associated with protease overactivity, namely Nagashima-type PPK (NPPK) caused by biallelic variants in SERPINB7.
OBJECTIVE: The aim of this study was to enhance the understanding of the clinical and genetic characteristics of serine protease-related hPPKs caused by variants in SERPINA12 and SERPINB7.
METHODS: Whole-exome sequencing (WES) was performed for hPPK patients. Haplotype analysis was completed for the patients with identified recessive SERPINA12 variants and their available family members. In addition, the current literature of SERPINA12- and SERPINB7-related hPPKs was summarized.
RESULTS: The phenotype of SERPINA12-related hPPK was confirmed by reporting three new SERPINA12 patients, the first of European origin. A novel SERPINA12 c.1100G>A p.(Gly367Glu) missense variant was identified confirming that the variant spectrum of SERPINA12 include both truncating and missense variants. The previously reported SERPINA12 c.631C>T p.(Arg211*) was indicated enriched in the Finnish population due to a plausible founder effect. In addition, SERPINA12 hPPK patients were shown to share a similar phenotype to patients with recessive variants in SERPINB7. The shared phenotype included diffuse transgradient PPK since birth or early childhood and frequent palmoplantar hyperhidrosis, aquagenic whitening and additional hyperkeratotic lesions in non-palmoplantar areas. SERPINA12 and SERPINB7 hPPK patients cannot be distinguished without genetic analysis.
CONCLUSIONS: Recessive variants in SERPINA12 and SERPINB7 leading to protease overactivity and hPPK produce a similar phenotype, indistinguishable without genetic analysis. SERPINA12 variants should be assessed also in non-Asian patients with diffuse transgradient PPK. Understanding the role of serine protease inhibitors will provide insights into the complex proteolytic network in epidermal homeostasis.

Nagashima-type palmoplantar keratoderma (NPPK) is the most prevalent hereditary palmoplantar keratoderma (PPK) in China, but there is a paucity of epidemiological data on the Chinese population. To explore the clinical and genetic characteristics, evaluate the demographic distribution, and estimate the burden of disease of NPPK. A total of 234 Chinese patients with NPPK were enrolled from two medical centers and an online PPK support group. Next-generation sequencing and Sanger sequencing were performed to screen out and confirm pathogenic mutations in SERPINB7. Clinical features and quality of life (QOL) were evaluated using self-completed questionnaires. In total, 14 pathogenic mutations were identified in SERPINB7 from the cohort. The top four recurrent mutations were c.796C>T (355, 75.9%), c.522dupT (66, 14.1%), c.650_653delCTGT (24, 5.1%), and c.455G>T (12, 2.6%), accounting for 97.6% of Chinese NPPK patients. Other mutations (11, 2.4%) include c.455-1G>T, c.336+2T>G, c.635delG and seven novel mutations c.2T>C, c.434delG, c.455-16A>G, c.656T>C, c.745-553T>G, c.832C>T, c.1036G>T. The estimated prevalence of NPPK in China was found to be 0.975/10 000 based on Chinese databases. Clinically, there were no apparent genotype-phenotype correlations in NPPK patients. Pediatric patients mainly presented with palmoplantar peeling, while adults presented with scale (p < 0.001). The most common comorbidities in NPPK patients were onychomycosis (40.0%), eczema (36.8%), and tinea pedis (30.3%). As for burden of disease, NPPK patients\' QOL was decreased by a moderate degree. In this study, pathogenic mutations\' allele frequencies in SERPINB7 were updated, and prevalence of NPPK in China was estimated. This large-scale cohort study provides evidence-based recommendations for patient management. Identification of new mutations are important for timely diagnosis of NPPK. Palmoplantar peeling in children can be used as a hallmark for early recognition of NPPK.

Nagashima-type palmoplantar keratoderma (NPPK) is characterized by non-progressive, diffuse, and cross-gradient hyperkeratosis caused by mutations in the SERPINB7 gene on chromosome 18q21.33. Chromosome 18q deletion syndrome (18q- syndrome) is a terminal deletion or microdeletion syndrome characterized by intellectual disability and congenital malformations. This paper describes an 18-year-old man with palmoplantar keratoderma and diffuse white matter abnormalities in the brain. Trio-based exome sequencing (ES) revealed a suspected mosaic compound heterozygous mutation for c.796C>T (p.Arg266∗) in exon 8 inherited from the mother and a de novo exons 4-6 deletion of SERPINB7. Additional copy number variant (CNV) analysis of the ES data indicated a heterozygous gross deletion of 18q22.3-q23. The two SERPINB7 gene variants were verified by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Finally, low-coverage whole-genome sequencing (WGS) confirmed the 18q22.3-q23 deletion and additionally detected a mosaic 18q21.33-q22.3 deletion, together explaining NPPK and the neurological phenotypes of the proband. The gross deletion of all exons of SERPINB7 was revealed for the first time. More rarely, c.796C>T (p.Arg266∗) was likely to be mosaic, while the exon deletion was mosaic. In conclusion, the combination of multiple molecular genetic testing methods provides comprehensive informative molecular findings and promotes the diagnosis of complex diseases, as in this case.

BACKGROUND: Herein we present a case of palmoplantar keratoderma (PPK) in a young adopted girl of Chinese origin living in France.
METHODS: The patient, aged six years, had presented transgressive PPK since birth, as well as erythema progressing in congestive inflammatory episodes, palmoplantar hyperhidrosis and progressive characteristics (moderate hyperkeratosis in areas of rubbing other than the palms and soles, namely the elbows and knees). Histopathological examination of a skin biopsy revealed a thick epidermis with lengthening and thickening of crests. The epithelium displayed a thick granular layer. Electron microscopy showed hyperorthokeratosis with hypergranulosis and loss of lamellar structure of the keratinosomes, as well as cleavage between corneocytes. Molecular studies showed the presence of two composite heterozygous mutations of the SERPINB7 gene, enabling a diagnosis of Nagashima-type PPK (NPPK) to be made.
CONCLUSIONS: NPPK is an autosomal recessive disease caused by a mutation in the SERPINB7, a member of the superfamily of serine protease inhibitors. It was described by Nagashima in 1977 with molecular characterisation by Kubo following in 2013. It is the most widespread form of PPK in Asia (with a prevalence of 1.2/10,000 in Japan and 3.1/10,000 in China). It is distinguished from the other PPKs in terms of transgressive soft hyperkeratosis, inflammatory episodes and hyperhidrosis, as well as by its non-progressive nature. In the present case, while the clinical presentation was characteristic, diagnosis was only made thanks to sequencing of a panel of over 50 genes responsible for PPK. The disease is effectively little-known in Europe. This study highlights the increasing importance of diagnostic investigation methods involving the use of gene panels.