Vohwinkel Syndrome

Are You Confident of the Diagnosis?

Vohwinkel syndrome, also referred to as keratoderma hereditaria mutilans, is a rare autosomal dominant skin disorder resulting in a mutilating keratoderma of the hands and feet. Two types have been characterized that differ in clinical presentation and distinct gene mutations.

What you should be alert for in the history

Classic Vohwinkel syndrome: The classic form of Vohwinkel syndrome presents with sensorineural hearing loss and palmoplantar hyperkeratosis that begins in infancy or early childhood. These patients also have hyperkeratosis on the dorsal aspect of their hands and feet and occasionally on their knees. Over time these patient develop fibrous constricting bands (pseudo-ainhum) over the digits of their hands and toes, which lead to progressive strangulation and auto-amputation. Patients may complain of pain in these digits due to neurovascular compromise. A number of associations have occurred sporadically including seizures, mental retardation, alopecia, cleft lip, or palate and facial asymmetry.

Variant form Vohwinkel syndrome: Loricrin keratoderma, Camisa’s variant, or the ichthyosis type of Vohwinkel syndrome clinically manifests with palmoplantar hyperkeratosis and eventual formation of pseudo-ainhum with auto-amputation. Patients with this variant also demonstrate mild widespread ichthyosis with erythroderma that is especially apparent on the limbs. Some babies with this disorder may be born encased in a collodion membrane, usually shed within the first two weeks of life. Patients with the variant form of Vohwinkel syndrome do not have the sensorineural hearing loss that is associated with the classic form.

Characteristic findings on physical examination

The palmoplantar hyperkeratosis appears in a distinct honeycomb pattern. The hyperkeratosis on the dorsum of hands and feet may appear as starfish-like patches of thickened skin in both the classic and variant form. The fibrous bands, or pseudo-ainhum, appear as fibrous scar tissue that completely encircle the affected digit and cause a local narrowing and constriction of the digit. These bands most commonly occur on the fifth digit of hands and feet. In variant form Vohwinkel syndrome patients also have generalized noninflammatory ichthyosiform dermatitis with fine scaling and occasionally with larger scaling on the arms and legs. Patients may have mild erythroderma in the affected areas.

Expected results of diagnostic studies

The work up for Vohwinkel syndrome may include audiometry studies, histologic examination of skin biopsies, and serial lab studies to rule out other disorders. Serial laboratory studies are usually normal in Vohwinkel syndrome, though serum beta-glucuronidase activity was found to be elevated in some case reports. Audiometry studies in classic Vohwinkel syndrome may show hearing impairment ranging from high frequency hearing loss to complete deafness. Histologic examination is nonspecific and the initial diagnosis is based more on clinical presentation. Histologic findings include acanthosis, hypergranulosis, and hyperkeratosis with retained nuclei in the stratum corneum. Light microscopy in the variant form also shows intranuclear granules in the upper cells of the stratum granulosum. Immunoelectron microscopy show that these granules are composed of loricrin.

Diagnosis confirmation

There are many types of palmoplantar keratosis that are clinically categorized into localized palmoplantar keratosis or diffuse palmoplantar keratosis. These syndromes are then further categorized based on their associated diseases. Both the classical form and variant form of Vohwinkel syndrome present with diffuse palmoplantar keratosis and auto-amputation of digits. The differential diagnosis for this presentation includes:

Olmsted syndrome: Distinguished from Vohwinkel syndrome by presence of perioral and/or perinasal keratotic plaques. It has been associated with mutations in the TRPV3 gene.
Mal de Meleda disease: Distinguished from Vohwinkel syndrome with hyperhidrotic, macerated, and malodorous keratoderma and perioral erythema. Nail abnormalities may also exist. It has been associated with mutations in the SLURP1 gene.

The classical form of Vohwinkel syndrome can be confused with other diseases that have palmoplantar keratoderma and deafness. There is debate if these three diseases would be better classified as variants of a single disorder with a heterogeneous phenotype. This theory is supported by molecular genetics and identical gene mutations in GJB2. The differential diagnosis for this presentation includes:

Bart-Pumphrey syndrome: An autosomal dominant palmoplantar keratoderma. The presence of leukonychia and the absence of digital constrictions distinguish this syndrome from Vohwinkel syndrome, though they are both due to GJB2 gene mutations.
Keratitis-ichthyosis-deafness (KID) syndrome: An autosomal dominant disorder that is characterized by palmoplantar keratitis and generalized ichthyosis with erythrokeratoderma and keratitis. Auto-amputation is not associated with this syndrome. This syndrome is also due to a mutation in the GJB2 gene.
Diffuse palmoplantar keratoderma with deafness: This disorder has diffuse palmoplantar keratosis and deafness without auto-amputation of digits and with less severe hearing loss. It can be due to the GJB2 gene mutation or in some cases it has been linked to a mitochondrial gene mutation.

Diagnostic confirmation for Vohwinkel syndrome can be done with mutation analysis. The classic type can be diagnosed with genetic testing looking for mutations in the GJB2 gene on chromosome 13. The variant form of Vohwinkel syndrome can be diagnosed with genetic testing looking for mutations in the loricrin gene on chromosome 1. For health care providers, information on laboratory providers for genetic testing can be found in the Genetic Testing Registry through NCBI.

Who is at risk of developing this disease?

Vohwinkel syndrome is inherited in an autosomal dominant fashion, so patients with a parent with this disease have a fifty percent chance of inheriting it. While most cases are familiar, some cases may arise de novo from a sporadic mutation of the gene. Some studies note an increased prevalence in Caucasian females.

What is the cause of this disease?

Etiology

Classic Vohwinkel syndrome: The classic form of Vohwinkel syndrome is caused by a variety of different amino acid substitutions in GJB2, a gene which encodes for connexin 26. Connexin proteins combine to form gap junctions, which are intercellular channels that allow for exchange of ions, nutrients, and signaling molecules between adjacent cells. Connexin 26 is found throughout the body, including the cochlea and the skin.

Variant form Vohwinkel syndrome: The variant form of Vohwinkel syndrome is due to a mutation in the loricrin gene. Loricrin is a small protein synthesized by the granular layer of the epidermis and is a major constituent of the cornified cell envelope. Links between loricrin and other proteins of the cellular membrane keep the stratum corneum together and maintain its strength. The loricrin gene mutation results in an extension in the gene which contains a nuclear localization signal. Instead of the protein product being incorporated into the cornified cell envelope, it translocates to the nucleus where it is trapped.

Pathogenesis

Classic Vohwinkel syndrome: Gap junctions in the cochlea help to recycle endolymphatic potassium ions that pass through sensory cells during auditory transduction and is necessary for normal hearing. Loss of these gap junctions through the connexin 26 gene mutation is responsible for the hearing loss associated with this syndrome. Communication by gap junctions by the cells in the epidermis mediate growth and differentiation of the cells in the epidermis. It is hypothesized that loss of this communication leads to decreased epidermal differentiation and subsequent palmoplantar epidermal hyperproliferation seen in this syndrome.

Variant form Vohwinkel syndrome: The pathogenesis of the variant form of Vohwinkel syndrome is still not well understood but recent research has elucidated certain transcription and growth factors implicated in this disease.

A transcription factor named AP1 has been implicated in this disease. This transcription factor is expressed in the suprabasal epidermis near the transition zone. The cells in the transition zone between the stratum corneum and stratum granulosum undergo extensive enzymatic remodeling resulting in covalent crosslinking of proteins and formation of a mature stratum corneum. Achieving this morphological alteration requires an alteration in gene transcription, guided by transcription factors that interact with DNA to increase the transcription of certain genes. AP1 is a transcription factor that induces genes responsible for controlling the differentiation of epidermal keratinocytes and the release of cytokines and chemokines involved in this process.

It has been shown that suppression of the AP1 transcription factor in the suprabasal epidermis in a mouse with a normal wild type loricrin gene produces a phenotype identical to variant form Vohwinkel syndrome with palmoplantar keratosis, auto-amputation of the digits, and generalized mild ichthyosis. It is hypothesized that the accumulation of the mutant loricrin protein in the nucleus may alter intracellular signaling leading to a suppression of AP1 in the suprabasal epidermis. It is thought that this suppression of this transcription factor leads to the delayed differentiation in the epidermis with this disease.

A separate study has shown that there is increased VEGF, TGF-alpha, and EGFR in the epidermis of patients with the loricrin mutation, which the study hypothesized accounted for the hyperproliferation seen in this disease.

These studies show that an alteration in the control of mediators of epidermal differentiation and proliferation in the epidermis is responsible for the phenotype in the variant from of Vohwinkel syndrome, instead of a mechanical defect due to loss of the crosslinking loricrin protein.

Systemic implications and complications

The major complication of Vohwinkel syndrome is the pseudo-ainhum leading to auto-amputation. These fibrous encircling bands usually occur on the fifth digit of the toes and hands. The pseudo-ainhum cause pain, neurological defects, and vascular compromise with skin ulcerations from tissue ischemia. They may even cause decreased mobility of the hand.

Some case reports on Vohwinkel syndrome show the occurrence of skin cancers in affected areas. The skin cancers implicated include basal cell carcinoma and squamous cell carcinoma.

Treatment

Oral retinoids enhance the differentiation of epidermal tissues and are the mainstay treatment of this disorder. Although they are the most effective treatment option, they do not work in every patient with Vohwinkel syndrome and treatment may have to be tailored to the individual. Relapse occurs upon discontinuation of retinoids and they must be prescribed judiciously due to risks associated with their toxicity and teratogenicity.

Keratolytic agents can be used for symptomatic control of palmoplantar keratoderma. Keratolytic agents include salicylic acid in concentrations of 12% to 17.6% and urea in preparations of 10% to 30%.

Optimal surgical management of pseudo-ainhum is based on a limited number of case reports. Surgical management is only indicated in symptomatic pseudo-ainhum and when there is neurovascular compromise, as it provides only short-term benefit with high rates of reoccurrence. Surgical options tried include local split- or full-thickness skin grafts, Z-plasties, and local flaps. These have all led to relapse within 1 month to 3 years. There is one case report of surgical management with full thickness skin graft harvested from the patient’s groin cleft. The skin retained the characteristics of its donor site, and local recurrence had not occurred at 16 months follow-up. The suggested reasoning for this was that the diseased skin was permanently modified by replacement with nondiseased skin in a different area of the body. Longer-term follow up was still needed, but a full-thickness skin graft from a remote site may hold promise for longer term viability.

Optimal therapeutic approach for this disease

The optimal therapeutic approach for this disease involves oral retinoids using a risk-benefit analysis for minimizing toxicity and preventing teratogenicity. Symptomatic treatment of the palmoplantar keratoderma includes topical keratolytic agents such as salicylic acid and urea. Hearing aids and speech therapy can be helpful in patients who have hearing loss.

Patient Management

Regular follow-up with a dermatologist is recommended with these patients, with referral to plastic surgery if pseudo-ainhum develops. Patients with palmoplantar keratosis should be screened for hearing impairment, due to the strong association of these two conditions. Those with evidence of hearing impairment on the newborn hearing screen or later in life should be referred to audiologists and speech therapists. Genetic counseling should be done with patients to discuss the risk of having affected offspring.

Unusual clinical scenarios to consider in patient management

The variant form of Vohwinkel syndrome can result in a clinical entity called a collodion membrane. Collodion babies are born encased in a tight, shiny clear membrane. Most often the presence of the membrane indicates an underlying ichthyotic disease. The collodion membrane can produce many complications that can impact the health of the child. Cracking of this skin before desquamation can lead to skin barrier defects resulting in infection, dehydration, and temperature instability. The collodion membrane can cause physical constraints on underlying tissue that can result in difficulty breathing, suckling, and feeding, as well as reduced blood flow to limbs. It can also cause a condition called ectropion in which the outer eyelids turn outside, away from the eyeballs.

Management for this condition requires referral to the NICU, where the baby is placed in an incubator and given other supportive treatments such as IV fluid and tube feeding. The aim of treatment is to keep the skin soft and reduce peeling. Treatment options include emollients, mild topical steroids to reduce inflammation, pain relief medication, and artificial tears if there is severe ectropion. Oral retinoids are recommended soon after delivery to promote accelerated shedding of the hyperkeratotic plaques and improvement of ectropion.

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Vohwinkel Syndrome