DISEASE CARD

Definition

Mutilating palmoplantar keratoderma (PPK) with deafness, is a rare autosomal dominant disorder of keratinization, characterized by honeycomb-like keratoderma associated with annular constrictions around digits (pseudoainhum) and sensorineural deafness. The disease is caused by mutations in the GJB2 (gap junction beta-2) gene encoding connexin (Cx26).¹

Clinical Description

Shiny or translucent papular hyperkeratosis on the palms and soles are usually the first signs in childhood. Gradually, those lesions become confluent and transgredient (extending beyond palmoplantar skin) and frequently cause discomfort and pain. The edges of the keratoderma at the wrists and Achilles tendon usually consist of spiky digitate hyperkeratotic projections onto normal skin, sometimes showing Koebnerization (new skin lesions appear at sites of trauma/injuries). Warty papules on the knuckles and other extensor sites (toes, knees) coalesce into starfish-like acral keratosis or show a striate pattern. Multiple keratoses on digits produce circumferential hyperkeratosis predisposing to the formation of cicatricial bands (pseudoainhum), in the childhood sometimes resulting in autoamputation. The little finger and toe are most commonly affected. This can result in impaired manual dexterity and impaired mobility. A high-frequency sensorineural hearing loss is occasionally present from birth, but is mostly relatively subtle and not progressive.^1-3

A variant of Vohwinkel syndrome is associated with generalized ichthyosis and honeycomb PPK with pseudoainhum but lacks deafness. This type is associated with loricrin gene mutations.^{4, 5}

Pathogenesis

Connexins are the building blocks of gap junctions, which are plasma membrane complexes facilitating and regulating the passage of small molecules between cells. Mutations in connexin genes are now known to cause several inherited human disorders, whose phenotype at least in part reflects the distribution and inferred function of the affected genes. A recurrent point mutation in the GJB2 gene, leading to the amino acid substitution D66H, has been found in a number of unrelated families with mutilating Vohwinkel PPK with deafness. This mutation occurs at a highly conserved residue in the first extracellular domain of the Cx26 molecule, and may exert its effects by interfering with assembly into connexons, docking with adjacent cells or gating properties of the gap junction, thus impairing epidermal differentiation as well as inner ear function.^{6, 7}

Diagnosis

The diagnosis is based on clinical history and examination. Formal audiometry may be required to document the hearing loss. Histopathologic analysis of skin reveals unspecific findings like orthohyperkeratosis and papillomatosis. Molecular analysis of the GJB2 gene may confirm the diagnosis.⁸

Treatment

Keratolytics as well as mechanical debridements may be helpful for (milder) keratoderma. Oral retinoids (acitretin, isotretinoin) are indicated in more severe cases. The pseudoainhum may require surgical reconstruction to prevent autoamputation. Long-term outcome of full thickness grafts however seems to be unfavourable, if not taken from unaffected areas. ^{2, 8-12}

References

^{1. Maestrini E, Korge BP, Ocaña-Sierra J, et al. A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families. Hum Mol Genet. 1999;8(7):1237-1243.}

^{2. Zhang M, Song K, Ding N, Shu C, Wang Y. Using a Distant Abdominal Skin Flap to Treat Digital Constriction Bands: A Case Report for Vohwinkel Syndrome. Medicine (Baltimore). 2016;95(6):e2762.}

^{3. Lee JR, White TW. Connexin-26 mutations in deafness and skin disease. Expert Rev Mol Med. 2009;11:e35.}

^{4. O'Driscoll J, Muston GC, McGrath JA, Lam HM, Ashworth J, Christiano AM. A recurrent mutation in the loricrin gene underlies the ichthyotic variant of Vohwinkel syndrome. Clin Exp Dermatol. 2002;27(3):243-246.}

^{5. Reinehr CPH, Peruzzo J. Vohwinkel syndrome: ichthyosiform variant in a family. 2018;93(5):723-725.}

^{6. Serrano Castro PJ, Naranjo Fernandez C, Quiroga Subirana P, Payan Ortiz M. Vohwinkel Syndrome secondary to missense mutation D66H in GJB2 gene (connexin 26) can include epileptic manifestations. Seizure. 2010;19(2):129-131.}

^{7. 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(6):503-508.}

^{8. Sinha M, Watson SB. Keratoderma hereditarium mutilans (Vohwinkel syndrome). J Hand Surg Eur Vol. 2009;34(2):235-237.}

^{9. Wang B, Zhang Z, Huang X, Lin X, Qu W, Zhou Y. Successful treatment of mutilating palmoplantar keratoderma with acitretin capsule and adapalene gel: a case report with review of the literature. J Eur Acad Dermatol Venereol. 2016;30(1):169-172.}

^{10. Bassetto F, Tiengo C, Sferrazza R, Belloni-Fortina A, Alaibac M. Vohwinkel syndrome: treatment of pseudo-ainhum. Int J Dermatol. 2010;49(1):79-82.}

^{11. Nico MMS, Fernandes JD. Low-dose isotretinoin prevents digital amputation in loricrin keratoderma (Vohwinkel syndrome with ichthyosis). J Dtsch Dermatol Ges. 2017;15(6):665-667.}