The first Danish family reported with an AQP5 mutation presenting diffuse non-epidermolytic palmoplantar keratoderma of Bothnian type, hyperhidrosis and frequent Corynebacterium infections: a case report

Palmoplantar keratodermas (PPKs) comprise a clinically and genetically heterogenous group of hereditary disorders of the skin characterized by thickening of the stratum corneum of the palms and soles. In some cases the skin lesions are accompanied by associated diseases [1]. Based on the clinical presentation, PPKs are divided into four subtypes, including diffuse, punctate, focal and striate PPK [2]. Diffuse PPK can be further subdivided histopathologically into epidermolytic and non-epidermolytic forms depending on the presence or absence of cytolysis in the upper spinous and granular layers of the epidermis. Diffuse non-epidermolytic PPK of Bothnian type (PPKB), is not accompanied by associated diseases and was initially described in two Swedish families [3]. PPKB (OMIM 600231) is autosomal dominantly inherited and initial studies linked the underlying gene defect to chromosome 12q11-q13 [3, 4]. In 2013, the genetic cause of PPKB was established as due to mutations in the AQP5 gene, located at 12q13.12 [5]. In the northernmost region of Sweden the condition is relatively common with a reported prevalence of 0.3−0.55 % [3].

The clinical presentation of PPKB include diffuse palmoplantar hyperkeratosis with a yellowish tint over the whole of the palms and soles and acral hyperhidrosis [5]. The symptoms usually presents in early childhood, in some cases as young as three months of age [6]. Secondary dermatophyte infections are frequent. A distinctive feature of this type of PPK is a whitish spongy appearance of the skin following exposure to water. The phenotypic apperarence of PPKB varies and in some individuals, clinical signs of the condition are only seen after exposure to water [5].

A large four-generation Caucasian family was ascertained, including 14 affected individuals, as seen in Fig. 1. The proband was a 36-year-old male, affected since childhood by palmoplantar keratoderma, pronounced hyperhidrosis and recurrent secondary dermatophyte infections on affected skin. Examination of the skin revealed a mild, yellow tinted diffuse keratoderma of palms and soles, pitted keratolysis and erythematous keratotic plaques with a clear demarcation on the margins of the hands and feet, as seen in Fig. 2. Sparing of the skin was seen in the arches of the planta pedis. Physical examination was non-contributory. The skin lesions were periodically foul-smelling and the patient suffered from recurrent tinea pedis and onychomycosis caused by dermatophyte infections. Thirteen additional family members presented with a similar phenotype. Initially, the diagnosis epidermolytic palmoplantar keratoderma was suspected. Mutational screening of KRT1, KRT9 and KRT16 genes provided negative results.

The biopsy showed a markedly thickened stratum corneum with a prominent stratum granulosum and a moderate acanthosis, as seen in Fig. 3. The acrosyringial ducts were remarkably dilated as well in the epidermis as in the stratum corneum. The distal part of the eccrine ducts in the papillary dermis, however, were without recognizable dilatation. Focally, changes like those seen in miliaria rubra with spongiosis and exocytosis of lymphocytes around the intraepidermal acrosyringial channels were noted. The lymphocytic infiltration extended into the papillary dermis around and into the distal parts of the dermal sweat ducts, but the hyperkeratotic plugging, often seen in miliaria rubra above the spongiosis, was not present in this biopsy. The proximal part of the sweat ducts and the secretory coil appeared normal. Spores and hyphae indicating a dermatophytosis were demonstrated in the stratum corneum. Corynebacteria, however, were not seen.

Water immersion test revealed aquagenic wrinkling, also known as “hand-in-the-bucket-sign”, as translucent white papules and a whitish spongy appearance due to swelling of the stratum corneum was observed after three minutes exposure to water, as seen in Fig. 4. The aquagenic wrinkling lead to suspicion of transient reactive papulotranslucent acrokeratoderma [7] or aquagenic syringeal acrokeratoderma [8] but the proper diagnosis was not established until the report by Blaydon et al. [5] raised the suspicion of PPKB.

Interestingly, the dermatophyte infection of the plantar skin was complicated by a superinfection with Corynebacterium. Examination in Woods light showed massive coral red fluorescence in interdigital areas of planta pedis, as seen in Fig. 5. The Corynebacterium infection was treated with clindamycin and chlorhexidine with satisfactory effect.

We present the first Danish family diagnosed with autosomal dominant PPKB resulting from c.562C>T, p.Arg188Cys in the AQP5 gene. According to the Human Gene Mutation Database a total of six missense mutations in the AQP5 gene associated with PPKB have been reported to this date [9] in families of Swedish, British, Scottish and Han Chinese descent [2, 5]. The condition has also been reported in a patient from India [10].

The AQP5 gene encodes aquaporin 5, a cell-membrane protein that allows osmotic movement of water across the cell membrane independently of solute transport [11]. Aquaporin 5 is situated in the apical plasma membrane of cells of the sweat glands, salivary glands, lacrimal gland, lung, cornea [11] and in the palmoplantar epidermis [5]. The study by Blaydon et al. reported that the expression of AQP5 in the stratum granulosum was not affected by mutations in the gene [5]. Hence, at the genetic level, mutations associated with PPKB most likely induce increased expression of the gene or excert a gain-of-function effect leading to accelerated keratinocyte water uptake. This likely explains the swelling of the stratum corneum of the epidermis following water exposure.

The notion of increased function of aquaporin 5 in PPKB is supported by the fact that immunolocalization experiments involving Sjögrens syndrome, which is characterized by hypohidrosis, revealed reduced expression of AQP5 in sweat glands from patients with Sjögrens compared to normal skin [12]. Thus, the hypohidrosis observed in Sjögrens syndrome may result from reduced expression of AQP5 and correspondingly, the hyperhidrosis of PPKB may result from an increased function of the gene product. From a clinical perspective, the hyperhidrosis characterizing PPKB entails notable discomfort to the patient and most likely is a contributing factor to the recurrent Corynebacterium infections. Conversely, it has recently been hypothesized that hyperhidrosis may be exacerbated by bacterial infection [13].

The histopathologic unspecific features of hyperkeratosis and acanthosis are in agreement with the findings in PPKB. In addition, however, we found focal changes around the intraepidermal sweat ducts as seen in conditions like miliaria rubra, also known as heat rash. To our knowledge, this has not been described in PPKB. It is possible that the biopsy was taken during an episode of hyperhidrosis, but the inflammatory changes of miliaria rubra typically do not accompany ordinary hyperhidrosis. It seems likely that the changes of stratum corneum in PPKB may obstruct the sweating and induce the miliaria rubra like changes. It certainly would be of interest to study biopsies from larger series of PPKB to assess the specificity of this feature.

Whether the pitted keratolysis results from the palmoplantar keratoderma, the hyperhidrosis or the Corynebacterium infection is not established. Treatment options for PPKB include salicylic acid 4−6 % in petrolatum, urea- or salicylic acid-containing creams and lotions and avoidance of too much moisture. The hyperhidrosis may respond to aluminum chloride-containing products or other therapeutic options of hyperhidrosis. Treatment of secondary dermatophyte infections and superinfections with bacteria like Corynebacterium is of extreme importance for optimal patient care.

The “hand-in-the-bucket-sign” is not pathonomonic of PPKB as aquagenic wrinkling of the palms following exposure to water is observed in several conditions including transient reactive papulotranslucent acrokeratoderma and aquagenic syringeal acrokeratoderma and is suggested to be more frequent than previously assumed [14]. In accordance with the PPKB genotype-phenotype correlation, aberrant expression of aquaporin 5 has been reported to be associated with aquagenic wrinkling of the palms [15]. Conversely, aquagenic keratoderma has also been suggested to be associated with mutations in the CFTR gene involved in cystic fibrosis [16, 17].

Though increasing evidence suggests a gain-of-function effect of AQP5 mutations related to PPKB, the exact mechanisms by which mutations in AQP5 lead to defective epidermal-water-barrier function remains to be elucidated. Conclusively, we have yet to arrive at a final understanding and characterization of conditions of disturbed water permeability of the palmoplantar epidermal cells.

The present manuscript adds a Danish family with PPKB to the literature and emphasizes that Corynebacterium superinfections may complicate the condition.

PPK, Palmoplantar keratoderma; PPKB, Diffuse non-epidermolytic PPK of Bothnian type