Vohwinkel syndrome

Vohwinkel syndrome is a disorder with classic and variant forms, both of which affect the skin.

In the classic form of Vohwinkel syndrome, affected individuals have thick, honeycomb-like calluses on the palms of the hands and soles of the feet (palmoplantar keratoses) beginning in infancy or early childhood. Affected children also typically have distinctive starfish-shaped patches of thickened skin on the tops of the fingers and toes or on the knees. Within a few years they develop tight bands of abnormal fibrous tissue around their fingers and toes (pseudoainhum); the bands may cut off the circulation to the digits and result in spontaneous amputation. People with the classic form of the disorder also have hearing loss.

The variant form of Vohwinkel syndrome does not involve hearing loss, and the skin features also include widespread dry, scaly skin (ichthyosis), especially on the limbs. The ichthyosis is usually mild, and there may also be mild reddening of the skin (erythroderma). Some affected infants are born with a tight, clear sheath covering their skin called a collodion membrane. This membrane is usually shed during the first few weeks of life.

Vohwinkel syndrome is a rare disorder; about 50 cases have been reported in the medical literature.

The classic form of Vohwinkel syndrome is caused by mutations in the GJB2 gene. This gene provides instructions for making a protein called gap junction beta 2, more commonly known as connexin 26. Connexin 26 is a member of the connexin protein family. Connexin proteins form channels called gap junctions that permit the transport of nutrients, charged atoms (ions), and signaling molecules between neighboring cells that are in contact with each other. Gap junctions made with connexin 26 transport potassium ions and certain small molecules.

Connexin 26 is found in cells throughout the body, including the inner ear and the skin. In the inner ear, channels made from connexin 26 are found in a snail-shaped structure called the cochlea. These channels may help to maintain the proper level of potassium ions required for the conversion of sound waves to electrical nerve impulses. This conversion is essential for normal hearing. In addition, connexin 26 may be involved in the maturation of certain cells in the cochlea. Connexin 26 also plays a role in the growth, maturation, and stability of the outermost layer of skin (the epidermis).

The GJB2 gene mutations that cause Vohwinkel syndrome change single protein building blocks (amino acids) in connexin 26. The altered protein probably disrupts the function of normal connexin 26 in cells, and may interfere with the function of other connexin proteins. This disruption could affect skin growth and also impair hearing by disturbing the conversion of sound waves to nerve impulses.

The variant form of Vohwinkel syndrome, sometimes called loricrin keratoderma, is caused by mutations in the LORICRIN gene. This gene provides instructions for making a protein called loricrin, which is involved in the formation and maintenance of the epidermis, particularly its tough outer surface (the stratum corneum). The stratum corneum, which is formed in a process known as cornification, provides a sturdy barrier between the body and its environment. Each cell of the stratum corneum, called a corneocyte, is surrounded by a protein shell called a cornified envelope. Loricrin is a major component of the cornified envelope. Links between loricrin and other components of the envelopes hold the corneocytes together and help give the stratum corneum its strength.

Mutations in the LORICRIN gene change the structure of the loricrin protein; the altered protein is trapped inside the cell and cannot reach the cornified envelope. While other proteins can partially compensate for the missing loricrin, the envelope of some corneocytes is thinner than normal in affected individuals, resulting in ichthyosis and the other skin abnormalities associated with the variant form of Vohwinkel syndrome.

Genetic Testing Information

• Genetic Testing Registry: Loricrin keratoderma
• Genetic Testing Registry: Mutilating keratoderma

Genetic and Rare Diseases Information Center

• Keratoderma hereditarium mutilans

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• VOHWINKEL SYNDROME; VOWNKL
• VOHWINKEL SYNDROME, VARIANT FORM

Scientific Articles on PubMed

• PubMed

• de Zwart-Storm EA, van Geel M, Veysey E, Burge S, Cooper S, Steijlen PM, Martin PE, van Steensel MA. A novel missense mutation in GJB2, p.Tyr65His, causes severe Vohwinkel syndrome. Br J Dermatol. 2011 Jan;164(1):197-9. doi: 10.1111/j.1365-2133.2010.10058.x. Citation on PubMed
• Drera B, Tadini G, Balbo F, Marchese L, Barlati S, Colombi M. De novo occurrence of the 730insG recurrent mutation in an Italian family with the ichthyotic variant of Vohwinkel syndrome, loricrin keratoderma. Clin Genet. 2008 Jan;73(1):85-8. doi: 10.1111/j.1399-0004.2007.00914.x. Epub 2007 Oct 22. No abstract available. Citation on PubMed
• Elias PM, Williams ML, Crumrine D, Schmuth M. Inherited disorders of corneocyte proteins. Curr Probl Dermatol. 2010;39:98-131. doi: 10.1159/000321086. Epub 2010 Sep 14. No abstract available. Citation on PubMed
• Gedicke MM, Traupe H, Fischer B, Tinschert S, Hennies HC. Towards characterization of palmoplantar keratoderma caused by gain-of-function mutation in loricrin: analysis of a family and review of the literature. Br J Dermatol. 2006 Jan;154(1):167-71. doi: 10.1111/j.1365-2133.2005.06995.x. Citation on PubMed
• Lee JR, White TW. Connexin-26 mutations in deafness and skin disease. Expert Rev Mol Med. 2009 Nov 19;11:e35. doi: 10.1017/S1462399409001276. Citation on PubMed
• Maestrini E, Monaco AP, McGrath JA, Ishida-Yamamoto A, Camisa C, Hovnanian A, Weeks DE, Lathrop M, Uitto J, Christiano AM. A molecular defect in loricrin, the major component of the cornified cell envelope, underlies Vohwinkel's syndrome. Nat Genet. 1996 May;13(1):70-7. doi: 10.1038/ng0596-70. Citation on PubMed
• 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 May;27(3):243-6. doi: 10.1046/j.1365-2230.2002.01031.x. Citation on PubMed
• Schmuth M, Fluhr JW, Crumrine DC, Uchida Y, Hachem JP, Behne M, Moskowitz DG, Christiano AM, Feingold KR, Elias PM. Structural and functional consequences of loricrin mutations in human loricrin keratoderma (Vohwinkel syndrome with ichthyosis). J Invest Dermatol. 2004 Apr;122(4):909-22. doi: 10.1111/j.0022-202X.2004.22431.x. Citation on PubMed
• Schmuth M, Gruber R, Elias PM, Williams ML. Ichthyosis update: towards a function-driven model of pathogenesis of the disorders of cornification and the role of corneocyte proteins in these disorders. Adv Dermatol. 2007;23:231-56. doi: 10.1016/j.yadr.2007.07.011. Citation on PubMed or Free article on PubMed Central
• Sinha M, Watson SB. Keratoderma hereditarium mutilans (Vohwinkel syndrome). J Hand Surg Eur Vol. 2009 Apr;34(2):235-7. doi: 10.1177/1753193408098901. Epub 2009 Mar 12. Citation on PubMed
• van Steensel MA. Gap junction diseases of the skin. Am J Med Genet C Semin Med Genet. 2004 Nov 15;131C(1):12-9. doi: 10.1002/ajmg.c.30030. Erratum In: Am J Med Genet C Semin Med Genet. 2006 Feb 15;142(1):58. Citation on PubMed
• Xu J, Nicholson BJ. The role of connexins in ear and skin physiology - functional insights from disease-associated mutations. Biochim Biophys Acta. 2013 Jan;1828(1):167-78. doi: 10.1016/j.bbamem.2012.06.024. Epub 2012 Jul 13. Citation on PubMed or Free article on PubMed Central