Content » Vol 99, Issue 12

Short communication

Keratoderma-Deafness-Mucocutaneous Syndrome Associated with Phe142Leu in the GJB2 Gene

Liliana Guerra1, Fabio Bergamo2, Maria Rosaria D’Apice3, Francesco Angelucci4, Stefano Di Girolamo5, Letizia Camerota6, Rosanna Monetta1,6, Giorgio Annessi7, Daniele Castiglia1, Giuseppe Novelli3, Mauro Paradisi8 and Francesco Brancati1,6*

1Laboratory of Molecular and Cell Biology, 2Dermatology Division and 7Laboratory of Dermopathology, IDI-IRCCS, Rome, Italy, 3Laboratory of Medical Genetics, Tor Vergata University Hospital, Rome, 4Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, 5Department of Otorhinolaryngology, University of Rome Tor Vergata, Rome, 6Medical Genetics Division, Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Piazzale Salvatore Tommasi 1, IT-67100 – Coppito (AQ), and 8Campus Bio-Medico Medical School, Rome, Italy. E-mail:

Accepted Aug 12, 2019; E-published Aug 13, 2019


Gap junctions are aggregates of intercellular channels allowing 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 potassium ions during auditory transduction and contributes to epidermal homeostasis, barrier function and integrity (2).

Heterozygous GJB2 mutations cause a spectrum of different, partly overlapping conditions known as palmoplantar 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 erythematous 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 variant in GJB2 leading to p.Phe142Leu missense change localized in the 3rd 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).


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 associated 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 adolescence together with intermittent eruptions of scaly erythematous plaques, 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 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 antimycotic 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 substitution c.426C>A, absent in her parents supporting its de novo origin (Fig. S1). This variant (rs397516877 in dbSNP) was absent in gnomAD database ( and caused the p.Phe142Leu change scored as “pathogenic” by prediction systems 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.

Fig. 1. Clinical findings. (a, b) Papulopustular acne lesions on the face. (c, d) Erythematous papules on the trunk. (e, f) Focal plantar keratoderma contiguously extending to the tendon regions (transgrediens). (g, h) Minimal hyperkeratosis of the first interdigital spaces.


Here, we report a 41-year-old patient displaying the association 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). Indeed, most of the patients are described as neonates or infants, when the phenotype is particularly manifested with unusual cutaneous and mucous manifestations resembling mucocutaneous candidiasis being constantly seen. Dermatologic lesions were variably described as psoriasiform dermatitis, erythematous macules, patches and plaques. Angular cheilitis was recorded in all patients. Some individuals had inflammation of oesophageal mucosa. Squamous cell carcinoma of the hard palate was registered once. Susceptibility to infections was common although laboratory investigations, when conducted, excluded immune deficiencies. Interestingly, in our patient we recorded lymphocytopenia with decreased CD4, CD8 and natural killer cells, which can at least in part contribute to such susceptibility.

Despite a number of common features observed among Phe142Leu mutated patients, some differences exist. In fact, palmoplantar keratoderma and papulopustular acne have never been reported before. Although this may be due to very early age of previously described cases, interestingly in skin and mucosa biopsies of two other Phe142Leu patients, hyperkeratosis was recorded (6–8), while severe nodulo-cystic acne was described in KID (9).

Most GJB2 variants causative of KID syndrome map to IC1, TM1 and EC1 domains of Cx26, involved in channel gating and regulation, and rarely to TM2 domain (1). In contrast, variants underlying VS, BPS and PPK with Deafness (Table SII) mostly map to EC1 and to transition zone between EC1 and TM2, with sporadic cases affecting EC2 and IC2 domains (10). The Phe142 residue lies at the beginning of TM3 (residues 129–159) with its side chain protruding into the membrane bilayers and being about 30 Å distant from the pore shrinkage (Fig. S2a). Notably, closely located mutations such as Thr135Ala or Val153Ile, also with side-chains buried in the membrane bilayers and far from functional sites of the hemichannel, are associated to non-syndromic hearing loss. As the Phe142Leu, these changes preserve the hydrophobic features of TM3 and are not predicted to differently affect channel architecture and stability; accordingly, more subtle conformational alterations might explain the different phenotypic consequences. We speculate that distinct mutations in TM3 helix may differentially influence the conformation of IC2, connecting TM2 and TM3 and altering the interactions with its substrates. In particular, Phe142 is in contact with Pro87, which belongs to TM2 and disrupts its H-bond array inducing a bent of this structural element (Fig. S2b). Consequently, a loosen interaction due to the Phe142Leu substitution may both alter the relative orientation of TM2-TM3 and, indirectly, the IC2 conformational states. Notably, this structural feature mediates the majority of protein-protein interactions of a connexin hemichannel, including those with kinases (fundamental to regulate its open-to-close transition) and with other proteins necessary for anchoring to cytoskeleton (11).

In conclusion, we outlined the phenotype resulting from Phe142Leu in GJB2 characterized by mucocutaneous lesions with erythematous patches, angular cheilitis, scaly erythematous psoriasiform plaques and hearing loss. The cutaneous phenotype is particularly evident and severe at birth. Palmoplantar keratoderma, papulopustular acne and teeth defects are possible additional age-related characteristics. More data are needed to confirm such genotype-phenotype correlation in GJB2-pathies.


Supported by the Italian Ministry of Health, Ricerca Corrente 2018-2020 and GR-2013-02356227 to FB.

The authors have no conflicts of interest to declare.

  1. García IE, Prado P, Pupo A, Jara O, Rojas-Gómez D, Mujica P, et al. Connexinopathies: a structural and functional glimpse. BMC Cell Biol 2016; 17 (Suppl 1): 17.
    View article    Google Scholar
  2. Lilly E, Sellitto C, Milstone LM, White TW. Connexin channels in congenital skin disorders. Semin Cell Dev Biol 2016; 50: 4–12.
    View article    Google Scholar
  3. Guerra L, Castori M, Didona B, Castiglia D, Zambruno G. Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – diagnostic algorithm and principles of therapy. J Eur Acad Dermatol Venereol 2018; 32: 899–925.
    View article    Google Scholar
  4. Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol 2010; 63: 607–641.
    View article    Google Scholar
  5. van Steensel MA, Steijlen PM, Bladergroen RS, Hoefsloot EH, van Ravenswaaij-Arts CM, van Geel M. A phenotype resembling the Clouston syndrome with deafness is associated with a novel missense GJB2 mutation. J Invest Dermatol 2004; 123: 291–293
    View article    Google Scholar
  6. Brown CW, Levy ML, Flaitz CM, Reid BS, Manolidis S, Hebert AA, et al. A novel GJB2 (connexin 26) mutation, F142L, in a patient with unusual mucocutaneous findings and deafness. J Invest Dermatol 2003; 121: 1221–1223.
    View article    Google Scholar
  7. Rednam S, Hicks J, Levy ML, Pappo AS. Metastatic squamous cell carcinoma of the oropharynx in a child with a mutation in the Connexin 26 gene. J Pediatr Hematol Oncol 2011; 33: 387–389.
    View article    Google Scholar
  8. Ibáñez MM, Alcalde MM, Jiménez MR, Muñoz MD, Díez-Delgado FJ. An unusual mucocutaneous syndrome with sensorineural deafness due to connexin 26 mutations. Pediatr Dermatol 2013; 30: e138–142.
    View article    Google Scholar
  9. Lazic T, Li Q, Frank M, Uitto J, Zhou LH. Extending the phenotypic spectrum of keratitis-ichthyosis-deafness syndrome: report of a patient with GJB2 (G12R) connexin 26 mutation and unusual clinical findings. Pediatr Dermatol 2012; 29: 349–357.
    View article    Google Scholar
  10. Iossa S, Marciano E, Franzé A. GJB2 Gene mutations in syndromic skin diseases with sensorineural hearing loss. Curr Genomics 2011; 12: 475–785.
    View article    Google Scholar
  11. Hervé JC, Bourmeyster N, Sarrouilhe D. Diversity in protein-protein interactions of connexins: emerging roles. Biochim Biophys Acta 2004; 1662: 22–41.
    View article    Google Scholar
  12. Bennett BC, Purdy MD, Baker KA, Acharya C, McIntire WE, Stevens RC, et al. An electrostatic mechanism for Ca(2+)-mediated regulation of gap junction channels. Nat Commun 2016; 7: 8770.
    View article    Google Scholar
Supplementary content
Table SI
Table SII
Figure S1
Figure S2