Vohwinkel Syndrome

Etiology

Classic Vohwinkel syndrome is inherited in an autosomal dominant (AD) fashion. It is caused by a mutation in the gap junction beta 2 (GJB2) gene located on chromosome 13q11-12, which encodes the protein connexin 26.[6]

Loricrin keratoderma, the ichthyosiform variant of Vohwinkel syndrome, is caused by LOR mutations; this is the gene on the epidermal differentiation complex (EDC) on chromosome 1q21 that encodes loricrin.[7][8] Loricrin is a protein component of the cornified envelope, and therefore, mutations in loricrin lead to the ichthyosis that differentiates this variant from classic Vohwinkel syndrome. Because there is no gap junction protein mutation, deafness is not a feature of this variant.

Epidemiology

Vohwinkel syndrome is extremely rare, with <50 reported cases in the literature. Males and females are equally affected between infancy and early childhood.

Pathophysiology

Two mutations of the EDC have been identified in Vohwinkel syndrome. One is a missense mutation of the GJB2 gene coding connexin-26, a gap junction protein. This mutation on chromosome 13 is associated with the classic (hearing loss–associated) Vohwinkel syndrome. The pathophysiology of classic Vohwinkel syndrome is, in part, explained by the role of connexin proteins in forming the building blocks for gap junctions. The connexin proteins that compose gap junctions are integral for transporting nutrients, ions, and neurotransmitters from cell to cell. Connexin proteins are ubiquitous throughout the human body, including the cochlea of the inner ear, and are responsible for forming gap junctions or transport channels for signaling molecules between cells. Specifically, connexin 26 is found in the epidermis of palmoplantar skin, sweat glands, and cochlea.[9] The channels formed by connexin 26 are responsible for transporting potassium ions that convert sound waves into electoral nerve impulses and, therefore, normal hearing.[10] There are several human connexin disorders caused by mutations in gap junction proteins that result in deafness. Mutations in connexin 26 are linked to Vohwinkel syndrome, keratitis-ichthyosis deafness and hystrix-like ichthyosis deafness syndromes, palmoplantar keratoderma with deafness, deafness with Clouston-like phenotype, and Bart-Pumphrey syndrome.[1]

Another mutation is an insertional mutation of the loricrin gene on the EDC on chromosome 1q21. The pathophysiology of loricrin keratoderma, a Vohwinkel variant, can be appreciated by recognizing the role that the loricrin protein plays in the cornified envelope and the importance of the cornified envelope in maintaining the integrity of the stratum corneum. The stratum corneum is the outermost layer of the epidermis that serves as a barrier to transepidermal water loss.[11] The stratum corneum is made up of corneocytes, and each corneocyte is surrounded by a cornified envelope “shell.” Loricrin is an integral protein of the cornified envelope.[12] When the LOR gene is mutated, the structure of the loricrin protein is distorted and cannot make its way into the cornified envelope. This leads to transepidermal water loss and resultant ichthyosis.

Histopathology

There are no specific histologic findings in Vohwinkel disease. Nonspecific findings include prominent orthohyperkeratosis (pertaining to the PPK), as well as papillomatosis.[13] The constricting bands consist of fibrous connective tissue resembling scars.

History and Physical

Vohwinkel syndrome is characterized by a PPK, digital constriction bands (pseudoainhum), and hearing impairment/deafness. The PPK begins within the first few years of life and appears as a callus-like thickening on the palms and soles and is often referred to as having a “honeycomb” pattern.[14] Patients also present with starfish-shaped “knuckle pads,” or thick skin plaques on the dorsal surfaces of their fingers, toes, and/or knees. They may also have linear keratoses on their elbows and knees. A characteristic (albeit not pathognomonic) feature of Vohwinkel is the development of fibrous constriction bands encasing the fingers and toes, often referred to as pseudoainhum. This pseudoainhum presents in late childhood or adulthood. Pseudoainhum is associated with the autoamputation of digits.[15][16][4] A high-frequency, nonprogressive hearing loss is also present. This hearing loss is often not appreciated until after infancy. Another less characteristic but a potential finding is scarring alopecia.

The loricrin variant presents as mild, generalized ichthyosis with accentuation of the ichthyosis in flexural surfaces.[8]

Evaluation

The diagnosis of Vohwinkel syndrome is mainly made clinically. Audiometry is indicated to evaluate the nature and extent of hearing loss and for eventual follow-up. Radiographs of the hands and feet are used to detect any abnormalities of the underlying bones. Craniofacial studies can be performed if clinical findings justify them. Histologic findings are non-specific. Genetic testing is available to identify the genetic mutation.[6]

Treatment / Management

The hyperkeratotic callus-like lesions (PPK) are often improved with oral retinoids such as isotretinoin.[17] Debridement with a blade followed by applying a keratolytic agent (urea, lactic acid, and salicylic acid-containing creams and lotions) under occlusion is often helpful.(B3)

Another major aspect of treatment is aimed at releasing the digital constriction bands found in pseudoainhum. Historically, surgery to release these digital constriction bands (Z-plasty, other methods for relaxing scars) was commonplace; however, there is increasing evidence to support the use of low-dose oral retinoids to prevent and/or treat the pseudoainhum to avoid autoamputation or surgery.[18] Low-dose isotretinoin was reported to prevent digital amputation.[16] Systemic retinoids can reverse both the keratoderma and pseudoainhum; however, relapse is the rule upon discontinuation of treatment.

Hearing testing is indicated in any patient with Vohwinkel syndrome features, and cochlear implants are often performed.

A recent study suggested that low doses of transforming growth factor β1 (TGF-β1) can improve the proliferation of Vohwinkel syndrome, providing new insights into its treatment.[19]

Differential Diagnosis

The differential diagnosis for classic Vohwinkel syndrome includes other PPKs with hearing impairment. These include Bart-Pumphrey syndrome, which presents as a non-mutilating PPK with deafness, knuckle pads, and leukonychia. Bart-Pumphrey syndrome lacks the starfish-shaped keratoses and the honeycomb pattern of the PPK.[14][20]

The differential diagnosis for mutilating PPKs (PPKs with digital constriction bands) includes Olmsted syndrome, Papillon-Lefevre syndrome, Loricrin keratoderma, and Mal de Meleda.[21][22][23][24]

The differential diagnosis for pseudoainhum includes vascular abnormalities (Raynaud disease, scleroderma, diabetes mellitus), infections (leprosy, tertiary syphilis, yaws), and scar formation following ergot poisoning. 

Prognosis

The prognosis of Vohwinkel syndrome is overall good but can have profound implications for those diagnosed with it. The prognosis of affected patients can vary widely depending on several factors, including the severity of their condition, the timing of diagnosis, and the effectiveness of the management strategies employed. While Vohwinkel Syndrome is a chronic and progressive disorder, early diagnosis and comprehensive care can significantly improve the long-term prognosis. The condition is associated with an average lifespan.[25]

The dermatological manifestations, such as palmoplantar keratoderma and pseudoainhum, can be managed with regular dermatological assessments, wound care, and topical treatments, potentially preserving hand and foot function.

Hearing impairment is a common and challenging aspect of the syndrome, often necessitating cochlear implants for effective intervention. 

Complications

Complications of Vohwinkel syndrome include the following:

• Autoamputation of digits with functional impairment of the limbs                                                             
• Persistent keratoderma[3]
• Secondary skin infections
• Hearing loss in the classic variant
• Squamous cell carcinoma has been documented in 2 cases
• Social isolation
• Psychological distress