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1192 SHORT COMMUNICATION Keratoderma-Deafness-Mucocutaneous Syndrome Associated with Phe142Leu in the GJB2 Gene Liliana GUERRA 1 , Fabio BERGAMO 2 , Maria Rosaria D’APICE 3 , Francesco ANGELUCCI 4 , Stefano DI GIROLAMO 5 , Letizia CAMEROTA 6 , Rosanna MONETTA 1,6 , Giorgio ANNESSI 7 , Daniele CASTIGLIA 1 , Giuseppe NOVELLI 3 , Mauro PARADISI 8 and Francesco BRANCATI 1,6 * Laboratory of Molecular and Cell Biology, 2 Dermatology Division and 7 Laboratory of Dermopathology, IDI-IRCCS, Rome, Italy, 3 Laboratory of Medical Genetics, Tor Vergata University Hospital, Rome, 4 Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, 5 Department of Otorhinolaryngology, University of Rome Tor Vergata, Rome, 6 Medical Genetics Division, Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Piazzale Salvatore Tommasi 1, IT-67100 – Coppito (AQ), and 8 Campus Bio- Medico Medical School, Rome, Italy. E-mail: [email protected] 1 Accepted Aug 12, 2019; E-published Aug 13, 2019 Gap junctions are aggregates of intercellular channels al- lowing direct cell–cell transfer of ions and small molecules (1). Connexin-26 (Cx26), encoded by the GJB2 gene, plays a role in gap junction formation in the epithelia of epidermis, skin appendages, cochlea and cornea. Its function is crucial for exchange of electrical signals and recycling of potas- sium ions during auditory transduction and contributes to epidermal homeostasis, barrier function and integrity (2). Heterozygous GJB2 mutations cause a spectrum of dif- ferent, partly overlapping conditions known as palmoplan- tar keratoderma (PPK) with sensorineural hearing loss, Vohwinkel syndrome (VS), Bart-Pumphrey syndrome (BPS), keratitis-ichthyosis-deafness (KID) and Clouston- like syndrome (3–5). Here, we describe a 41-year-old woman exhibiting mucocutaneous manifestations with periorificial erythe- matous patches, angular cheilitis and scaly erythematous psoriasiform plaques affecting different body parts. Palmoplantar keratoderma, papulopustular acne and sensorineural hearing loss manifested with age. Genetic investigations revealed a c.426C>A heterozygous vari- ant in GJB2 leading to p.Phe142Leu missense change localized in the 3 rd transmembrane helix of Cx26. In the literature, we identified 4 subjects from 3 families with the Phe142Leu displaying similar features, supporting distinct genotype-phenotype correlation in GJB2-pathies (6–8). CASE REPORT A 41-year-old woman was seen for chronic recurrent dermatitis mainly characterized by erythema, papules and plaques that healed leaving cicatricial sequelae, associated to bilateral high- frequency sensorineural hearing loss. At age 3 days, she had been hospitalized for diffuse severe erythematous lesions over the face (cheeks), lower limbs, inguinal and intergluteal skinfolds asso- ciated to severe erythema of the oral mucosa (especially the hard palate) and perianal region. She was discharged with a diagnosis of maculopapular exanthema. Recurrent episodes of intermittent angular cheilitis were registered during childhood and adol­scence together with intermittent eruptions of scaly erythematous pla- ques, the most affected areas being neck, trunk, pubis and the inguinal and axillary folds. Cyclosporine therapy was started after a diagnosis of psoriasis with dramatic worsening of the disease. Premature loss of permanent teeth was recorded at 25 years. At age 33 years, erythematous, scaly and oedematous lesions with clearly defined borders were noticed in the pubic area and inguinal folds, while erythematous papules and pustules involved the trunk. A skin biopsy of a plaque in the area of the mons pubis revealed doi: 10.2340/00015555-3291 Acta Derm Venereol 2019; 99: 1192–1194 epidermal hyperplasia, hyperkeratosis with focal parakeratosis and a dermal infiltrate rich in lymphocytes and neutrophils, with numerous spores, hyphae and pseudo-hyphae in the horny layer. Candida albicans was cultured from this specimen and antimy- cotic therapy (itraconazole 100 mg/day) was started with limited improvement of lesions attributable to candidiasis. Laboratory analyses revealed lymphocytopenia with decreased T-lymphocytes CD4, CD8 and natural killer cells. At last examination, aged 41 years, she showed papulopustular acne lesions on the face (Fig. 1a,b), erythematous papules on the trunk (Fig. 1c,d), focal plantar keratoderma (Fig. 1e) that contiguously extends to the Achille tendon region (transgrediens) (Fig. 1f) and minimal hyperkeratosis on the palmar aspect of the first interdigital spaces (Fig. 1g, h). Hair, nails and sweating were not affected. Due to the association of keratoderma and hearing loss, Sanger sequencing analysis of the GJB2 gene was started in the proband and revealed a single heterozygous nucleotide substitu- tion c.426C>A, absent in her parents supporting its de novo origin (Fig. S1 1 ). This variant (rs397516877 in dbSNP) was absent in gnomAD database (http://gnomad.broadinstitute.org/) and caused the p.Phe142Leu change scored as “pathogenic” by prediction sys- tems such as MutationTaster, PolyPhen2 and Mutation Assessor. The clinical and genetic features of our patient, as compared to those of previously reported families mutated Phe142Leu, are shown in Table SI 1 . DISCUSSION Here, we report a 41-year-old patient displaying the as- sociation of a distinct mucocutaneous phenotype with hearing loss, heterozygote for the Phe142Leu mutation in the GJB2 gene. In the literature, 3 additional families with 4 patients harbouring this missense change existed: two families had a c.424T>C nucleotide substitution and one the same c.426C>A variant identified in our patient (6–8). At clinical comparison, phenotypic overlap was evident especially at neonatal age (Table SI 1 ). Indeed, most of the patients are described as neonates or infants, when the phe- notype is particularly manifested with unusual cutaneous and mucous manifestations resembling mucocutaneous candidiasis being constantly seen. Dermatologic lesions were variably described as psoriasiform dermatitis, eryt- hematous macules, patches and plaques. Angular cheilitis was recorded in all patients. Some individuals had inflam- mation of oesophageal mucosa. Squamous cell carcinoma of the hard palate was registered once. Susceptibility to https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-3291 1 This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.