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Table of Contents
Year : 2020  |  Volume : 38  |  Issue : 4  |  Page : 228-231

Vohwinkel syndrome associated with a p.Gly59Arg missense mutation in GJB2

1 Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan
2 Department of Otolaryngology; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
3 Department of Medical Genetics, National Taiwan University Hospital; Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
4 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
5 Department of Dermatology, National Taiwan University Hospital; Department of Dermatology, National Taiwan University College of Medicine, Taipei, Taiwan

Date of Submission16-Sep-2019
Date of Decision23-Mar-2020
Date of Acceptance14-Apr-2020
Date of Web Publication16-Dec-2020

Correspondence Address:
Dr. Yi-Hua Liao
Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan, No. 7, Chung-Shan South Road, Taipei 10002
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ds.ds_14_20

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Vohwinkel syndrome is a rare autosomal dominant disease caused by GJB2 mutations. Patients present with sensorineural deafness, pseudoainhum, stellate keratosis on knuckles, and diffuse honeycombed palmoplantar keratoderma. We present a case of a Taiwanese patient with characteristics of Vohwinkel syndrome. A heterozygous missense mutation c.175G > C (p.Gly59Arg) was identified in the GJB2 gene, encoding the gap junction protein connexin 26. Pathogenic GJB2 mutations have been implicated in a spectrum of diseases from nonsyndromic hearing loss to syndromic hearing loss with palmoplantar keratoderma. This report expands the phenotypic spectrum of the p.Gly59Arg mutation to include Vohwinkel syndrome.

Keywords: Vohwinkel syndrome; palmoplantar keratoderma; pseudoainhum; connexin 26; sensorineural hearing loss

How to cite this article:
Hsieh PC, Wu CC, Lee NC, Hsieh JH, Liao YH. Vohwinkel syndrome associated with a p.Gly59Arg missense mutation in GJB2. Dermatol Sin 2020;38:228-31

How to cite this URL:
Hsieh PC, Wu CC, Lee NC, Hsieh JH, Liao YH. Vohwinkel syndrome associated with a p.Gly59Arg missense mutation in GJB2. Dermatol Sin [serial online] 2020 [cited 2022 Dec 3];38:228-31. Available from: https://www.dermsinica.org/text.asp?2020/38/4/228/303689

  Introduction Top

Vohwinkel syndrome (OMIM# 124500), also known as keratoderma hereditaria mutilans, is characterized by sensorineural deafness, constricting bands (pseudoainhum) leading to autoamputation, stellate hyperkeratotic papules or plaques on the dorsal hands and feet, and diffuse honeycombed palmoplantar keratoderma.[1] Symptoms usually manifest neonatally and progress thereafter. It is transmitted autosomal dominantly. Mutations in GJB2 have been found to underlie Vohwinkel syndrome and related diseases.[2] Here, we present a case with features of Vohwinkel syndrome, carrying a heterozygous missense mutation p.Gly59Arg in GJB2 encoding connexin 26 (Cx26).

  Case Report Top

A 37-year-old female patient with congenital hearing loss had progressive hyperkeratosis of the palms and sole, and constriction rings on the distal interphalangeal joints of all fingers and toes since childhood. Her parents and siblings (one brother and one sister) all had normal hearing and no similar skin symptoms. Severe constriction bands at the interphalangeal joints, especially on the bilateral little fingers and right index finger, were noted at the age of 34, so she visited the plastic surgery clinic at our hospital for treatment. Under the impression of pseudoainhum, she received a series of surgeries on several fingers and toes, with incision followed by Z-plasty. She was referred to the dermatology clinic 3 years later due to dry and scaly skin on the soles.

On physical examination, there was diffuse hyperkeratosis and scaling over bilateral palms and soles. The KOH tests on the great toenails and feet were positive for hyphae. She was treated with oral terbinafine 250 mg daily over 3 months for dermatophytosis of the toenails and soles. After treatment, the scaling improved substantially, but diffuse palmoplantar keratoderma with focal honeycomb-like pattern persisted [Figure 1]a and [Figure 1]b. Transgredient involvement of the heels, lateral foot, and dorsal toes was evident [Figure 1]c, while a well-demarcated border at the wrist was present [Figure 1]b. Knuckle pads were present at the interphalangeal joints, with stellate hyperkeratotic plaques at the dorsal hands [Figure 1]d. She had no features of ichthyosis, keratitis or nail involvement. The audiometry revealed severe bilateral sensorineural hearing loss [Figure 2]a. Taking into account her sensorineural hearing impairment, pseudoainhum, and diffuse palmoplantar keratoderma, genetic examination was suggested under suspicion of Vohwinkel syndrome. Following informed consent, DNA was extracted from the patient's peripheral blood. Sanger sequencing of the second exon of the GJB2 gene was done and revealed a heterozygous missense mutation c.175G >C (p.Gly59Arg) [Figure 2]b. The diagnosis of Vohwinkel syndrome was reached based on the constellation of symptoms and the likely pathogenic GJB2 mutation. Since both of her parents had no hearing impairment or skin lesions, a de novo mutation was most likely, however this could not be established definitively without testing of her parents' DNA.
Figure 1: (a) Diffuse plantar keratoderma with honeycombing pattern. (b) Diffuse palmar keratoderma with pseudoainhum (arrows) at the interphalangeal joints. (c) Involvement of the soles and side of foot. (d) Knuckle pads at the interphalangeal joints and stellate hyperkeratotic plaque at the dorsal hand

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Figure 2: (a) Audiogram showing severe bilateral sensorineural hearing loss. Air conduction results are plotted with circles (O, right ear) and crosses (X, left ear). Bone conduction results are plotted with angle brackets (<, right ear) (>, left ear). Arrows represent no response to the loudest tone. (b) DNA sequence of the patient's GJB2 gene shows a heterozygous missense mutation c.175G > C (p.Gly59Arg) (red arrow), and the corresponding nucleotide in a control subject (arrowhead)

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  Discussion Top

To our knowledge, this report first expanded the phenotypic spectrum of the p.Gly59Arg mutation of the GJB2 gene to Vohwinkel syndrome. The GJB2 gene located on chromosome 13q12 encodes the protein Cx26. Connexins are components of gap junctions, which facilitate electric and chemical coupling between cells. Each gap junction is composed of hemichannels from neighboring cells, while each hemichannel, termed a connexon, is formed by six identical or different connexin subunits.[3] Different connexins have different tissue expression patterns, and Cx26 is expressed most notably in the inner ear and skin.[4],[5] While its function remains incompletely understood, it is postulated that Cx26 is important for maintaining inner ear function,[6] and regulating keratinocyte proliferation and differentiation in the skin.[7] Correspondingly, pathogenic GJB2 mutations manifest as various phenotypes, ranging from nonsyndromic deafness (hearing loss without other organ system deficiencies) to syndromic deafness (hearing loss associated with other features).[2] Recessive GJB2 mutations are the most common genetic cause of nonsyndromic deafness. All syndromic diseases linked to GJB2 mutations share the common features of sensorineural deafness and palmoplantar keratoderma, but differ in other characteristics. Aside from Vohwinkel syndrome described above, Bart-Pumphrey syndrome (OMIM# 149200) is heralded by palmoplantar keratoderma, knuckle pads, and leukonychia.[8] Keratosis-ichthyosis-deafness (KID) syndrome (OMIM# 148210) presents with erythrokeratoderma, marked ichthyosis, and vascularizing keratitis leading to progressive visual acuity deterioration.[9] The p.Gly45Glu and p. Ala88Val mutations additionally cause multi-organ abnormalities and even lethality in infancy.[10] Hystrix-like ichthyosis deafness syndrome (OMIM# 602540) is characterized by generalized spiky hyperkeratosis, and has been reported to be genetically identical to KID syndrome.[2] Finally, patients with palmoplantar keratoderma with deafness syndrome (OMIM# 148350) have variable severity of palmoplantar keratoderma and may display knuckle pads.[2]

Structurally, connexins are composed of four transmembrane domains, two extracellular loops, and three intracellular domains.[2] The majority of mutations causing deafness and palmoplantar keratoderma map to the first extracellular domain of Cx26. By contrast, the mutations causing KID are mostly localized to the first 50 amino acids (spanning the first intracellular, first transmembrane, and part of the first extracellular domains), and appear to disrupt calcium homeostasis.[3] Despite these suggestive patterns, an exact one-to-one correspondence between specific GJB2 mutations and clinical symptoms does not exist, as patients with the same mutation may display highly different phenotypes. For example, p.Gly130Val was linked to Vohwinkel syndrome in one report, but only caused hearing loss with mild palmoplantar keratoderma in another.[11],[12] Similarly, mutations of Gly59 have been reported in palmoplantar keratoderma with deafness, Vohwinkel syndrome, and Bart-Pumphrey syndrome. The pathogenic mutation in our case, p.Gly59Arg in GJB2 gene, caused only hearing loss, striate palmoplantar keratoderma, and knuckle pads, without evidence of pseudoainhum in a previous report.[13] It was also identified in a large-scale study of GJB2 and GJB6 mutations in North American individuals with hearing loss.[14] A different mutation at the same amino acid, p.Gly59Ser, was linked to both Vohwinkel syndrome and Bart-Pumphrey syndrome.[15],[16],[17] Members of a Taiwanese family with the p.Gly59Ala mutation were reported to have palmoplantar keratoderma with deafness and knuckle pads.[18] Traditionally, diseases were classified based on their clinical and pathological features. However, in the postgenomic era, genotype-phenotype discrepancies have highlighted the limitations of such classification schemes. Divergent clinical expressions of the same genetic mutation suggest the presence of additional factors affecting disease development. Further investigation would be valuable to decipher such additional genetic or environmental contributions. In the future, a taxonomy synthesizing genetic and phenotypical features may better segregate disease entities. In the current scheme, owing to the distinct feature of pseudoainhum, our case is probably still best classified as Vohwinkel syndrome.

Notably, the extracellular domains are highly conserved among connexins, and a patient with a p.Gly59Arg mutation in the GJB6 gene, encoding connexin 30 (Cx30), was identified.[19] This patient had palmoplantar keratoderma with knuckle pads and pseudoainhum, resembling Vohwinkel syndrome and Bart-Pumphrey syndrome. The remarkably similar clinical features caused by the same mutation at a conserved codon hints at interactions between Cx26 and Cx30. Indeed, Cx26 and Cx30 form heteromeric junctions in both the skin and inner ear. In vitro studies demonstrated that Cx26 mutations had a dominant negative effect on Cx30.[20] Thus, the possibility of GJB6 mutations should be considered in cases of palmoplantar keratoderma with hearing loss with no identified pathogenic GJB2 mutation. Other studies have demonstrated that the A7445G mitochondrial DNA mutation can also cause inherited palmoplantar keratoderma with deafness.[21]

Left untreated, pseudoainhum can progress to autoamputation. Thus, surgical treatments including the cross-finger flap, Z-plasty, distant abdominal flap, and excision of constriction bands have been reported.[1],[22],[23] However, recurrences may occur with disease progression, as in our case. As in general principles of treatment of palmoplantar keratoderma, dermatophytes or other secondary infections should be managed appropriately.[24] Oral retinoids, such as acitretin or etretinate, may be considered and have been demonstrated to improve keratoderma and pseudoainhum in case reports.[25],[26] Finally, patients with genetic diseases may wish to have children and may worry about passing the mutation to their children. Genetic counseling is an essential resource, and should be offered to patients of reproductive age.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Iossa S, Marciano E, Franzé A. GJB2 gene mutations in syndromic skin diseases with sensorineural hearing loss. Curr Genomics 2011;12:475-785.  Back to cited text no. 2
Lilly E, Sellitto C, Milstone LM, White TW. Connexin channels in congenital skin disorders. Semin Cell Dev Biol 2016;50:4-12.  Back to cited text no. 3
Goliger JA, Paul DL. Expression of gap junction proteins Cx26, Cx31.1, Cx37, and Cx43 in developing and mature rat epidermis. Dev Dyn 1994;200:1-3.  Back to cited text no. 4
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Richard G, Brown N, Ishida-Yamamoto A, Krol A. Expanding the phenotypic spectrum of Cx26 disorders: Bart-Pumphrey syndrome is caused by a novel missense mutation in GJB2. J Invest Dermatol 2004;123:856-63.  Back to cited text no. 8
Yang CY, Chen YJ, Shen JL. Keratitis, ichthyosis and deafness syndrome – A case report and literature review. Dermatol Sinica 2008;26:151-6.  Back to cited text no. 9
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Bondeson ML, Nyström AM, Gunnarsson U, Vahlquist A. Connexin 26 (GJB2) mutations in two Swedish patients with atypical Vohwinkel (mutilating keratoderma plus deafness) and KID syndrome both extensively treated with acitretin. Acta Derm Venereol 2006;86:503-8.  Back to cited text no. 16
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Sevior KB, Hatamochi A, Stewart IA, Bykhovskaya Y, Allen-Powell DR, Fischel-Ghodsian N, et al. Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness. Am J Med Genet 1998;75:179-85.  Back to cited text no. 21
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