Vohwinkel Syndrome

Article Author:
Dahlia Saleh
Article Editor:
Laura Tanner
Updated:
10/27/2018 12:31:59 PM
PubMed Link:
Vohwinkel Syndrome

Introduction

Vohwinkel syndrome, also known as keratoderma hereditarian mutilans, is classified as a palmoplantar keratoderma (PPK).[1] PPKs exist on a spectrum from inherited to acquired and can range in their presentation. A PPK may be an isolated finding or part of a syndrome with extracutaneous involvement. Rarely, a PPK can be drug-induced or part of a paraneoplastic process.[2] The classic Vohwinkel syndrome is a hereditary PPK associated with “starfish” keratoses on the knuckles, a PPK in a “honeycomb” pattern, hearing impairment and mutilating digital constriction bands (pseudoainhum) that often lead to autoamputation of affected digit(s).[3][4]

A variant of Vohwinkel syndrome, loricrin keratoderma, presents as a honeycomb PPK with pseudoainhum with the addition of ichthyosis; deafness is not a feature of this ichthyosiform variant.[5]

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] Of note, this gene is also mutated in keratitis-ichthyosis-deafness (KID) and Bart-Pumphrey syndromes.[7][1] Connexin proteins are ubiquitous throughout the human body, including the cochlea of the inner ear, and responsible for forming gap junctions, or transport channels for signaling molecules between cells. There are several human connexin disorders caused by mutations in gap junction proteins that result in deafness.

Loricrin keratoderma, the ichthyosiform variant of Vohwinkel syndrome, is caused by mutations in LOR; the gene on the epidermal differentiation complex (EDC) on chromosome 1q21 that encodes loricrin.[8][9] 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. Because there is no gap junction protein mutation, deafness is not a feature of this variant.

Epidemiology

Vohwinkel syndrome is extremely rare with less than 50 reported cases in the literature. Males and females are equally affected.

Pathophysiology

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 the transportation of nutrients, ions, and neurotransmitters from cell to cell. Specifically, connexin 26 is found in the epidermis of palmoplantar skin, sweat glands, and cochlea.[10] The channels formed by connexin 26 are responsible for the transport of potassium ions that convert sound waves into electoral nerve impulses and therefore normal hearing.[7]

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 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 transepidemal water loss and a 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]

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 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 “knucklepads”, or plaques of thick skin 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 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 the potential finding is a scarring alopecia.

The loricrin variant presents as a mild, generalized ichthyosis with accentuation of the ichthyosis in flexural surfaces.[9]

Evaluation

This is a clinical diagnosis based on the typical findings of PPK and sensorineural hearing loss. Hearing testing is indicated in Vohwinkel syndrome. Genetic testing is available to identify the gene 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 the application of a keratolytic agent (urea, lactic acid, and salicylic acid-containing creams and lotions) under occlusion is often helpful. Another major aspect of treatment is aimed at releasing the digital constriction bands found in pseudoainhum. Historically, surgery to release these digital constriction bands 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] Hearing testing is indicated in any patient who has features of Vohwinkel syndrome, and cochlear implants are often performed.

Differential Diagnosis

The differential diagnosis for classic Vohwinkel syndrome includes other PPKs with hearing impairment. These include Bart-Pumphrey syndrome, which presents with as a nonmutilating PPK with deafness, knucklepads, and leukonychia. Bart-Pumphrey syndrome lacks the starfish-shaped keratoses as well as the honeycomb pattern to the PPK.[14][19]

The differential diagnosis for mutilating PPKs (PPKs with digital constriction bands) includes Olmsted syndrome, Papillon-Lefevre syndrome, Loricrin keratoderma, and Mal de Meleda.[20][21][22][23]

Prognosis

The prognosis of Vohwinkel syndrome carries a normal lifespan.[24]

Complications

Autoamputation of digits and a lifelong keratoderma are potential complications.[3]

Consultations

Dermatology, hand surgery, and otolaryngology (ENT) are should be involved in the care of patients with Vohwinkel syndrome.

Enhancing Healthcare Team Outcomes

Interprofessional collaboration is an essential component of care for any syndromic disease that presents with a constellation of findings. A primary care doctor, dermatologist, surgeon, and ENT often work together to provide Vohwinkel patients with the best possible outcome and to enhance treatment outcomes. It may be prudent for the patient to establish care at multispecialty care clinic to ease coordination of care, access to laboratory data and encounter notes between healthcare professionals, and convenience for the patient leading to a better quality of life. Multispecialty “hubs” have been linked to lower hospital admission rates, higher patient satisfaction, and improved quality of care overall.