The Analysis Of Clinical Characteristics And Gene Mutation In The Familial Benign Chronic Pemphigus And Mal De Meleda

PurposeTo investigate the clinical characteristics and molecular genetic pathogenesis of patients in one family with familial benign chronic pemphigus and one family with Mal de Meleda,as well as the correlation between clinical phenotypes and genotypes of the two diseases.Methods1.All patients in one family with familial benign chronic pemphigus and one family with Mal de Meleda were examined with detailed medical history and physical examination.The samples of skin lesions were taken for histopathological examination and blood samples were collected for genetic analysis.2.Use Sanger sequencing to detect pathogenic gene mutations in the two families,and use the DNAMAN tool for sequence alignment,and then use softwares such as mutation taster and HSF（The Human Splicing Finder）to predict whether the discovered mutation sites may cause disease.3.Whole-genome sequencing was used to expand the scope of sequencing when Sanger sequencing did not find mutation sites,and the phenotype tags of the HPO（The Human Phenotype Ontology;https://hpo.jax.org/app/）database were combined with Exomiser（https://exomiser.monarchinitiative.org/exomiser/）tool to annotate and filter suspicious variants and get results.And use the patient combined with 10controls’ whole exome sequencing results for verification,and finally use next-generation sequencing to verify.4.The literatures in PUBMED and CNKI in the last 10 years were searched and summarized to explore the association between genotype and phenotype of familial benign chronic pemphigus and Mal de Meleda.Results1.Familial benign chronic pemphigus: The proband was a 24-year-old male with itchy genital and perianal rash for more than 7 years.Physical examination showed multiple bright red verrucous papules in pubic mound,bilateral groin,scrotum,perineum and perianal area.Histopathology of a biopsy from his right groin showed epidermal hyperkeratosis,parakeratosis,downward proliferation with a finger-like protrusion,and acantholysis with the appearance of a dilapidated brick-wall as well as the formation of a blister in the epidermis.In addition,there were vascular dilatation in the dermal papilla and infiltration of lymphocytes and eosinophils in the dermis.Her mother had recurrent mild erythema in her armpit for many years.The proband was diagnosed as familial benign chronic pemphigus.Sanger sequencing demonstrated that both the proband and his mother had a novel heterozygous mutation in ATP2C1 gene c.900-1G>C（NM＿001001486.1）.The skin lesions of proband quickly subsided after the therapy of antibiotics.The clinical phenotypes of familial benign chronic pemphigus were varied,and no correlation was found between the clinical phenotype and genotype.2.Mal de Meleda: The proband is a 26-year-old male with onset of illness at about the age of 1.Physical examination showed diffuse erythema on both palms and plantar surfaces with thickened keratinization and a thick layer of waxy yellow scales in a "glove and sock" pattern.A large erythematous patch with mild scales was present on his buttocks.Nails are noticeably thickened.Histopathological examination of the palm showed hyperkeratosis of the epidermis,hypergranulosis,acanthosis,hyperplasia of small vessels in the superficial dermis,accompanied by a few inflammatory cells.We used second generation sequencing,combined with HPO clinical phenotypic database and analysis software,and identified a homozygous mutation C.256G>A（NM＿020427.3）in SLURP1 gene.The patient was diagnosed as Mal de Meleda.No correlation was observed between clinical phenotype and genotype.Conclusions1.The proband presented with condyloma acuminatum-like lesions,and had a novel heterozygous mutation in ATP2C1 gene in the family with familial benign chronic pemphigus.The curative efficacy of anti-infective treatment is remarkable.Its clinical phenotype is varied,and there is no association between genotype and phenotype in the disease.2.The patient presented with diffuse erythema covered with heavy scales on both palms and soles,as well as a large erythematous patch on his buttocks,and had a homozygous mutation C.256G>A in SLURP-1 gene in this case of Mal de Meleda disease.Its clinical phenotype is single and there is no association between genotype and phenotypein the disease.