INTRODUCTION

Inherited palmoplantar keratodermas (PPKs) constitute a heterogeneous group of diverse diseases causing hyperkeratosis of the palms and soles, and often clinically confusing branch of genodermatosis. PPKs are primarily caused by mutations in keratins, loricrin, desmosomes, cathepsins, and connexins.¹ A number of PPKs occur within an inherited syndrome with genetic predisposition to other conditions, including hearing loss (HL) and cardiomyopathy.²

Vohwinkel’s syndrome (VS) is a rare autosomal dominant variant of PPKs characterized by honeycomb-like surface, juxta-articular starfish-shaped hyperkeratotic papules and pseudoainhum of the digits resulting in spontaneous amputation.³ Two variants of VS have been reported, namely classic VS associated with deafness and caused by dominant mutations in GJB2 gene encoding the protein connexin 26,⁴ and the ichthyosis variant of VS caused by loricrin gene mutations.⁵

Mutations in other connexin genes, including GJB3, GJB4, GJB6, and GJA1, are responsible for various dermatological syndromes, sometimes in combination with HL.⁶ In a number of pedigrees with variable expressivity of PPKs and progressive HL, cosegregation of the mitochondrial mutation A7445G has been demonstrated.⁷

We report the clinical and genetic characteristics of the first variant of PPK and sensorineural HL with an autosomal recessive inheritance pattern in three siblings of consanguineous parents from the Republic of Chad.

CASE REPORTS

Three siblings, 18 and 12 years of age (one sister and two dizygotic twin brothers), from a large family of 11 siblings, presented HL and skin lesions affecting palms and soles. A common ancestor from five or six generations ago was reported by the unaffected parents. Other family members presented no skin or HL problems.

Soon after the first year of life, affected siblings started to manifest delayed speech attributed to HL. Thickening and cracking of the skin of the soles started at the age of two. Soon thereafter, the process started to affect the palms. The three siblings were deafmute but not intellectually disabled.

On examination, the female patient (case 1) showed bilateral symmetrical diffuse plantar waxy yellowish hyperkeratosis, associated with deep fissures and cracks all over the sole (Figure 1). The hyperkeratosis was asymmetrically striate and focal in both palmer surfaces (Figure 1).

Figure 1 Hands and feet of the patient 1. A Bilateral symmetrical diffuse planter waxy yellowish hyperkeratosis of the feet, more severe in pressure sites, less severe in the plantar arch, and associated with deep fissures and cracks all over the sole. B Asymmetrically striate and focal hyperkeratosis in both palmar surfaces without significant nail changes 

The twin brothers (case 2, 3) presented bilateral symmetrical diffuse waxy yellowish hyperkeratosis with cracks in both plantar aspects of the soles (Figures 2 and 3). Warty papules and dystrophic nail changes were present on the dorsum of the foot (Figures 2 and 3).

Figure 2 Hands and feet of the patient 2. A - Bilateral symmetrical diffuse waxy yellowish hyperkeratosis with cracks in both plantar aspects of the soles. B - Warty papules on the knuckles of the dorsal aspect of the big toes. Note the dystrophic nail changes in the form of onychographosis (hyperkeratotic and grossly thickened nail plates) which was more severe in both big toes, but less severe in the small toes. C - Bilateral asymmetrical hyperkeratosis in the form of punctate keratoderma and focal warty keratotic papules in the palmar surface of the fingers, mainly against the interphalangeal and metacarpophalangeal joints. D - Deformed nails of both hands (non-specific nail changes) 

Figure 3 Hands and feet of the patient 3. A - Soles and toes with characteristics similar to patient 2 (see fig. 2 for description). B - Hyperkeratotic projections onto normal skin at the medial aspect of big toe and first web space. C - Bilateral asymmetrical hyperkeratosis in the form of warty keratotic papules in the palmar surface of both hands and fingers 

Bilateral asymmetrical hyperkeratosis was present at the palmar surface of the fingers (Figure 2). The nails in the same patient were deformed (Figure 2). In case 3, the edge of the keratoderma consisted of hyperkeratotic projections onto normal skin and bilateral asymmetrical hyperkeratosis was noticed on both hands and fingers (Figure 3).

Features suggesting epidermolytic hyperkeratosis, any other form of dyskeratosis, fungal infections, and other abnormalities were not found in any of the 3 patients. All patients received treatment with oral retinoids (isotretinoin) along with topical keratolytics combined with emollients (10% salicylic acid in emulsifying ointment), which was effective in improving their skin condition.

A PPK-HL syndrome was suspected and the work-up included audiometry and skin biopsy. Audiometry demonstrated bilateral, moderate to severe sensorineural HL in the 3 siblings. Skin biopsy taken from plantar skin in all patients showed massive hyperkeratosis with parakeratosis, acanthosis, and a sparse perivascular inflammatory infiltrate. Moreover, extensive genetic analysis, included mutation analysis of GJB2 and GJB6, and the mitochondrial A7445G by Sanger sequencing and Whole Exome Sequencing (WES) (Table 1) of potential candidate genes.

Analysis of GJB2, GJB6, and the mitochondrial A7445G mutation could not reveal the disease causing mutation for PPKs-HL syndrome in the family. The coverage analysis of the 20 potential candidate genes, revealed that respectively 89.81% and 74.32% of the target bases were covered at least 10x and 30x (Table 1). The coverage of KRT1, KRT16, and 79 other regions by WES detected 3 homozygous and 16 compound heterozygous variants (Table 2). Segregation analysis of all Sanger validated variants excluded all WES identified variants.

DISCUSSION

This article presents the first report of a unique syndrome characterized by a rare form of PPKs and sensorineural HL segregating in an autosomal recessive mode, which has not been reported before in patients with PPKs-HL syndromes. The patients presented some exclusive features, including the presence of a diffuse bilateral symmetrical non-epidermolytic non-transgradient hyperkeratosis on the soles in all patients and asymmetrically focal, striate, or punctuate hyperkeratosis on the palmer surface of both hands with dystrophic nail changes in the twin brothers. Mutation analysis by Sanger sequencing did not reveal gene mutations in GJB2 and GJB6, or the mitochondrial A7445G mutation associated with other known PPKs-HL syndromes. This is in line with the autosomal recessive inheritance pattern in our family, as the reported syndromes affecting the skin caused by GJB2 and GJB6 are dominantly inherited, and the A7445G mutation is maternally inherited.

Classic VS, ichthyotic variant of VS, Bart-Pumphrey syndrome, the keratitis-ichthyosis deafness, Clouston syndrome, hystrix-like ichthyosis deafness syndromes and PPKs with deafness could be excluded, since commonly described clinical characteristics and mutations in genes for these syndromes were absent in all patients (Table 1). ⁸

Although PPK in Unna Thost is usually not syndromic, PPK in association with deafness has been reported. However, Unna Thost disease is inherited in an autosomal dominant manner and is characterized by the presence of erythema gradually progressing to sharply demarcated hyperkeratotic scaling plaques over palms and soles.⁹ Based on the absence of these two features and failure to detect the most commonly mutated genes for Unna Thost, namely KRT1 and KRT16, the diagnosis of Unna Thost could be ruled out.

Other forms of keratoderma with HL, such as Olmsted syndrome, Mal de Meleda, and Papillon-Lefevre syndrome were excluded by the absence of characteristic clinical features and failure to detect gene mutations known to be associated with these syndromes (Table 1).¹⁰