Vohwinkel syndrome, also known as keratoderma hereditarian mutilans, is classified as palmoplantar keratoderma (PPK). 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. 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 the affected digit(s).
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.
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. Of note, this gene is also mutated in keratitis-ichthyosis-deafness (KID) and Bart-Pumphrey syndromes. 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 LOR mutations; this is the gene on the epidermal differentiation complex (EDC) on chromosome 1q21 that encodes loricrin. 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.
Vohwinkel syndrome is extremely rare, with less than 50 reported cases in the literature. Males and females are equally affected.
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. The channels formed by connexin 26 are responsible for transporting potassium ions that convert sound waves into electoral nerve impulses and, therefore, normal hearing.
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. 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. 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.
There are no specific histologic findings in Vohwinkel disease. Nonspecific findings include prominent orthohyperkeratosis (pertaining to the PPK), as well as papillomatosis.
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. Patients also present with starfish-shaped “knuckle pads,” 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 the autoamputation of digits. 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 scarring alopecia.
The loricrin variant presents as mild, generalized ichthyosis with accentuation of the ichthyosis in flexural surfaces.
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.
The hyperkeratotic callus-like lesions (PPK) are often improved with oral retinoids such as isotretinoin. 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. 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. Hearing testing is indicated in any patient with Vohwinkel syndrome features, and cochlear implants are often performed.
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 as well as the honeycomb pattern to the PPK.
The prognosis of Vohwinkel syndrome carries a normal lifespan.
Autoamputation of digits and lifelong keratoderma are potential complications.
Dermatology, hand surgery, and otolaryngology (ENT) are should be involved in the care of patients with Vohwinkel syndrome.
The condition is inherited in an autosomal dominant pattern. Patients may want to consider genetic counseling.
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 enhance treatment outcomes. It may be prudent for the patient to establish care at a 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.
|||Avshalumova L,Fabrikant J,Koriakos A, Overview of skin diseases linked to connexin gene mutations. International journal of dermatology. 2014 Feb [PubMed PMID: 23675785]|
|||Kallini JR,Sadeghani K,Khachemoune A, Paraneoplastic palmoplantar keratoderma secondary to metastatic uterine adenocarcinoma. Cutis. 2017 Mar [PubMed PMID: 28398428]|
|||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. 2016 Feb [PubMed PMID: 26871826]|
|||Ainhum - A Rare Case Report., Prabhu R,Kannan NS,Vinoth S,Praveen CB,, Journal of clinical and diagnostic research : JCDR, 2016 Apr [PubMed PMID: 27190888]|
|||Vohwinkel syndrome: ichthyosiform variant in a family., Reinehr CPH,Peruzzo J,Cestari T,, Anais brasileiros de dermatologia, 2018 Sep-Oct [PubMed PMID: 30156625]|
|||Ozturk S,Can I,Eser B,Yazici H, A Deletion Mutation of the Connexin 26 (Gjb2) Gene in a Turkish Patient with Vohwinkel Syndrome . Genetic counseling (Geneva, Switzerland). 2016 [PubMed PMID: 29485809]|
|||Mammano F, Inner Ear Connexin Channels: Roles in Development and Maintenance of Cochlear Function. Cold Spring Harbor perspectives in medicine. 2018 Sep 4 [PubMed PMID: 30181354]|
|||Khalil S,Daou L,Hayashi R,Abbas O,Nemer G,Saadeh D,Shimomura Y,Kurban M, Identification of a novel mutation in the LOR gene in an Iraqi patient with loricrin keratoderma resembling epidermolytic hyperkeratosis. Journal of the European Academy of Dermatology and Venereology : JEADV. 2017 Mar [PubMed PMID: 27520397]|
|||Stypczyńska E,Placek W,Zegarska B,Czajkowski R, Keratinization Disorders and Genetic Aspects in Palmar and Plantar Keratodermas. Acta dermatovenerologica Croatica : ADC. 2016 Jun [PubMed PMID: 27477171]|
|||Moscato S,Cabiati M,Bianchi F,Vaglini F,Morales MA,Burchielli S,Botta L,Sabbatini ARM,Falleni A,Del Ry S,Mattii L, Connexin 26 Expression in Mammalian Cardiomyocytes. Scientific reports. 2018 Sep 18 [PubMed PMID: 30228305]|
|||Wertz PW, Lipids and the Permeability and Antimicrobial Barriers of the Skin. Journal of lipids. 2018 [PubMed PMID: 30245886]|
|||Murphrey MB,Zito PM, Histology, Stratum Corneum null. 2018 Jan [PubMed PMID: 30020671]|
|||Sinha M,Watson SB, Keratoderma hereditarium mutilans (Vohwinkel syndrome). The Journal of hand surgery, European volume. 2009 Apr [PubMed PMID: 19282408]|
|||Dippold S,Butsch F,Schopf R,Keilmann A, [Vohwinkel syndrome. Hearing loss and keratoderma on the hands and feet]. HNO. 2013 Jul [PubMed PMID: 23247752]|
|||Camisa C,Rossana C, Variant of keratoderma hereditaria mutilans (Vohwinkel's syndrome). Treatment with orally administered isotretinoin. Archives of dermatology. 1984 Oct [PubMed PMID: 6237617]|
|||Low-dose isotretinoin prevents digital amputation in loricrin keratoderma (Vohwinkel syndrome with ichthyosis)., Nico MMS,Fernandes JD,, Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 2017 Jun [PubMed PMID: 28591443]|
|||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. Journal of the European Academy of Dermatology and Venereology : JEADV. 2016 Jan [PubMed PMID: 25200571]|
|||Behera B,Chandrashekar L,Singh N,Thappa DM,Gochhait D, Lamellar ichthyosis associated bilateral pseudoainhum of fingers and toes successfully treated with tazarotene. Dermatologic therapy. 2017 Sep [PubMed PMID: 28730635]|
|||Hyman CH,Cohen PR, Report of a family with idiopathic knuckle pads and review of idiopathic and disease-associated knuckle pads. Dermatology online journal. 2013 May 15 [PubMed PMID: 24011277]|
|||Choi JY,Kim SE,Lee SE,Kim SC, Olmsted Syndrome Caused by a Heterozygous p.Gly568Val Missense Mutation in TRPV3 Gene. Yonsei medical journal. 2018 Mar [PubMed PMID: 29436206]|
|||Mohanty P,Dash G,Mohapatra L,Puhan MR, Olmsted syndrome in three sisters in a family. Indian journal of dermatology, venereology and leprology. 2018 Jul-Aug [PubMed PMID: 28799532]|
|||Bukharia A,Komal S,Sudhanan VM,Chaudhary SS, Olmsted Syndrome: Rare Occurrence in Four Siblings. Indian journal of dermatology. 2016 May-Jun [PubMed PMID: 27293270]|
|||Xie W,Wang Q,Zhou F,Zhao X,Zhu C, [Diffuse palmoplanta keratoderma: a pedigree with 23 cases]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2018 Apr 10 [PubMed PMID: 29653014]|
|||Pisoh T,Bhatia A,Oberlin C, Surgical correction of pseudo-ainhum in Vohwinkel syndrome. Journal of hand surgery (Edinburgh, Scotland). 1995 Jun [PubMed PMID: 7561409]|