Epidermolytic palmoplantar keratoderma (Vörner type) case report and revision of literature

Abstracts

As queratodermias palmo-plantares familiares são doenças pouco comuns. As manifestações clínicas são variadas e exuberantes, atraindo a atenção dos dermatologistas. Apesar de sua maioria ser limitada à pele, algumas apresentam repercussões clínicas sistêmicas, sobretudo em derivados ectodérmicos. Devido à variabilidade clínica, bem como a mecanismos etiopatogênicos mal compreendidos, diversas classificações têm sido propostas. Nenhuma apresenta total aceitação universal, sendo comum a discordância entre os diversos autores no que diz respeito não só às classificações, mas também com relação à existência de alguns tipos de queratodermia reconhecidos ora como variantes, ora como nova entidade. Recentemente, a melhor compreensão da estrutura e dinâmica da epiderme, em especial o citoesqueleto celular, o sistema de adesão intercelular e a ultra-estrutura da membrana basal, tem permitido elucidar de forma concreta a origem de tais processos. O citoesqueleto, sobretudo as citoqueratinas, tem sido alvo freqüente de estudos e identificado como responsável por muitas das queratodermias palmo-plantares. O presente caso refere-se a paciente com queratodermia palmo-plantar difusa, não transgressiva, iniciada na infância, com diversos casos familiares. A avaliação clínico-histopatológica permitiu o diagnóstico de hiperqueratose epidermolítica de Vörner. Tal caso justifica-se pela raridade e exuberância do quadro, com associação de câncer urotelial no mesmo paciente, e destaca a importância do estudo histopatológico no diagnóstico correto das queratodermias.

Ceratodermia palmar e plantar; queratina

CASE REPORT

Epidermolytic palmoplantar keratoderma (Vörner type) case report and revision of literature^*

Alexandre Bortoli Machado^I; Rafael Lenzi Tarnowsky^II; Roberto Moreira Amorim^III; Jorge José de Souza Filho^IV; Marcelo Rigatti^IV

^IM.D. Dermatologist, Associate of the Brazilian Society of Dermatology

^IIFirst-year student of Dermatology specialization, University Hospital, Federal University of Santa Catarina

^IIICoordenador do Serviço de Dermatologia do Hospital Universitário da Universidade Federal de Santa Catarina

^IVCoordinator of the Dermatology Service, University Hospital, Federal University of Santa Catarina Titular Professor of the Dept. of Clinical Medicine, University Hospital, Federal University of Santa Catarina

^VVisiting M.D. of the Dermatology Service, University Hospital, Federal University of Santa Catarina

^{Correspondence}

SUMMARY

The family of palmoplantar keratodermas are relatively uncommon diseases. The clinical manifestations are varied and exuberant, attracting the dermatologists' attention. Although the majority are limited to the skin, some present systemic clinical repercussions, above all in the ectodermal derivatives. Due to the clinical variability, as well as to the poorly understood etiopathogenic mechanisms, several classifications have been proposed. However, none has attained total universal acceptance, such that disagreement is common between the various authors with regard not only to the classifications, but also regarding the existence of some types of keratoderma that are sometimes considered as variants, while other times as new entities.

Recently, better understanding of the structure and dynamics of the epidermis, especially the cellular cytoskeleton, intercellular adhesion system and ultra-structure of the basal membrane, has enabled a concrete clarification of the origin of such processes. The cytoskeleton and above all the cytokeratins, have been the frequent subject of studies and identified as responsible for many of the palmoplantar keratodermas.

The present case refers to a patient with a non-transgressing diffuse palmoplantar keratoderma, with onset in childhood and several familial cases. The clinical-histopathological evaluation enabled the diagnosis of Vörner type epidermolytic hyperkeratosis. Such a case report is justified by the rarity and exuberance of the picture, with association of urothelial cancer in the same patient, and it underscores the importance of the histopathological evaluation for the correct diagnosis of keratodermas.

Key words:keratoderma, palmoplantar; keratin.

INTRODUCTION

Palmoplantar keratoderma constitutes a complex group of diseases, presenting epidermal thickening of the respective areas and may or may not be associated to other systemic manifestations, that can comprise the main alteration in the clinical picture, due to possible associated morbidity and mortality. They present several classifications, given the diversity in the genetic, morphotopographic and associated systemic manifestations and, more recently, the related molecular alterations. They can also be acquired, such as manifestations of several diseases (Table 1)¹ or associated to other genodermatoses (Table 2).¹

CASE REPORT

Patient aged 49 years, male, motorist, natural and resident in Tijucas, Santa Catarina State. He reported a history of lesions in the hands and feet, with onset in the second month of life that coursed with stabilization of the picture in childhood. He denied local symptoms, such as hyperhidrosis and appearance of vesicles or erosions. He was interned for treatment of vesicular carcinoma, presenting a clinical picture of frequency urinary stream and lumbar pain. He underwent radical cystectomy and ureteroileostomy. Histopathology demonstrated aggressive urothelial carcinoma. Smoker of some 30 cigarettes a day, since approximately 17 years of age. He did not present other comorbidity.

Dermatological exam (Figures 1 to 3) showed diffuse keratoderma, with a yellowish, irregular surface and several fissures. Such alterations were limited to the palms and soles, without compromising other topographies. An erythematous halo was noticed delimiting the periphery of the lesions. The mucous membranes and cutaneous enclosures were unaffected.

   

The patient referred similar cases in the family, as can be observed in the hereditary chart below. Involvement of other generations was observed, with autosomal dominant inheritance. The presence of consanguinity is apparently coincidental.

Some of the relatives were examined (according to the hereditary chart Þ II 6, II 9-12, III 2, III 13-16), and a similar clinical picture, onset and course were verified.

Histopathological exam of the biopsy (Figures 4 and 5) collected from the plantar surface demonstrated intense compact orthokeratosis, hypergranulosis and acanthosis, together with vacuolar degeneration of the superior part of the corneum stratum and granular layer. The laboratory exams were normal.

The patient opted to just continue under dermatological observation, without any local or systemic treatment.

DISCUSSION

Classifications of the palmoplantar keratodermas are mainly based on the morphologic and topographical characteristics and associated systemic alterations. There are several classifications (Tables 3 and 4), which is justified by the diverse clinical characteristics, as well as the fact that there are still diseases whose mechanism remains little understood and with controversy between authors. Regarding the morphology, they can present as diffuse, focal and punctate. In terms of topography, they can be restricted to the palmoplantar surfaces or involve extensor areas, such as the back of hands and feet, as well as knees and elbows (transgressing). They can also present a stable course or worsen with age (progressive). The presence of other alterations characterizes the also denominated ectodermic palmoplantar dysplasias, with diverse manifestations, usually associated to the structures derived from the ectoderm (Table III).¹

The present case concerns epidermolytic palmoplantar keratoderma, described initially by Vörner, in 1901.³

The manifestations begin in the first weeks of life. Most of the cases present autosomal dominant inheritance;⁴ however, new familial cases4 (mutations) have been reported (Table 5).

The clinical picture^5-6is characterized by presenting marked palmoplantar keratoderma, with a yellowish coloration, well-delimited borders and often an erythematous halo outlining the lesion. The affected surface presents an aspect of snakeskin and there can be formation of blisters. The occurrence of hyperhidrosis is marked in some cases, sometimes associated to fungal infections, which is an important characteristic to be evaluated during therapeutics. The lesions rarely extend to the lateral surface of the fingers, as well as knuckle pad-like lesions.^1,7,8 Minimal involvement of the elbows and knees can occur.^1,7 ACutaneous annexes, as well as mucous surfaces, are unaffected. The course of the disease is stable, without progression throughout the patient's life. The existence of other diseases (Table 5) in the patient with keratoderma of Vörner type, above all neoplasias,^9,10 probably arises due to multiple phenomena or segregation of oncogenes.^2,11,12 In the present case the patient had a prior diagnosis of urothelial carcinoma, while the cutaneous picture was considered a chance finding. However this clinical aspect does not reduce the relevance of keratoderma in such patients, because it is these that will probably benefit from the futures tests of genetic investigation.

The histopathological alterations¹¹ are restricted to the epidermis. There is orthokeratoderma, hypergranulosis, acanthosis and vacuolar alterations of the granular layers and superior part of the corneum stratum. Such vacuolar alterations are characterized by the presence of clear perinuclear spaces, accompanied by slightly pink-colored, reticular cytoplasmatic material, as well as abundant and irregular keratohyalin granules. The dermis remains unaffected.

Histopathological exam is indispensable for the diagnosis, since it is the only means of differentiating keratoderma of Vörner type from Unna-Thost type keratoderma, which present similar clinical alterations and form of inheritance, as well as in benign cases, or that is, those with minimum transgression, related to keratoderma of Greither type (Sybert).¹² Due to the existence of several cases diagnosed only on the basis of the clinical pattern and without a histopathological evaluation, some authors question the real frequency of keratoderma of Vörner type.¹³ Several studies have demonstrated its rarity; with rare cases described, however, for the above-mentioned reasons, such disease is probably little notified,¹³ and even considered by some authors to be the most common form of palmoplantar keratoderma.¹³ The real significance of the epidermolysis, however, is still uncertain and does not occur exclusively in this variant, but also in other keratodermas, as well as other congenital and acquired diseases (Table 6).⁴

Electron microscopy reveals^5,14 a rarefaction of the tonofilaments in the areas with vacuolar degeneration and the grouping of these around the nucleus. The desmosomes are unaffected. The keratin granules are enlarged and present as of the spinous layer.

Genetic analysis of the cases of epidermolytic palmoplantar keratoderma presents alterations in the gene of cytokeratin K9, located in chromosome 17.^15,16Such an alteration generally occurs in the non variable central area of the cytokeratin and above all in segment 1A. Surprisingly alterations in areas other than the cytokeratin have been reported, although without phenotypic differences.¹⁷

Cytokeratin K9, the molecular weight of which is 54Kda and isoelectric point (pHi) of 5.4, is found exclusively in the palmoplantar surfaces.¹⁸ Such a characteristic is the main aspect that enables the differentiation of Vörner type keratoderma as a singular entity, differentiating it not only from the other keratodermas, but also from other diseases with a similar histopathological pattern. The identification of the cytokeratins and their respective functions has allowed a better characterization of several diseases, for which they are responsible or associated. It also renders unlikely the hypothesis of clinical mosaics of epidermolysis as the cause of several diseases with an epidermolytic pattern, discarding, for instance, the hypothesis that Vörner type keratoderma is a localized form of bullous congenital ichthyosiform erythroderma.³ Cytokeratin K9 is part of the proteins of intermediate filaments (PIF), molecules whose main function is to provide the cell structure with mechanical strength and cellular adhesion.^19,20 They are closely related to the desmosomes and cellular nucleus. Such a denomination is due to the intermediate size (10nm) between the microfilaments of actin (6nm) and the microtubules (25nm). PIFs belong to a large family of structural proteins, divided into six groups,¹ according to their sequence of amino acids and tissular specificity. Types I and II are constituted by the cytokeratins, predominant in squamous stratified epithelia, mainly the epidermis. According to the molecular weight and isoelectric point (pHi), the cytokeratins are divided into two groups:

Type I - acidic - pKi 4.5/5.5 Þ smaller in size, (40 - 56.5KDa), comprising keratins 9 to 20 (K9 - K20). The genes of these keratins are located in chromosome 17q 12 - q21.

Type II - basic or neutral - pKi 5.5/7.5 Þ larger in size (52 - 67KDa), comprising keratins 1 to 8 (K1 - K8). The genes are located in chromosome 12q11-q13.

All of the cytokeratins, as well as PIFs, present a central homologous structure (1A, 1B, 2A, 2B) constituted in a-helix by approximately 310 amino acids, separated by short non-helical segments (L1, L1-L2, L2) responsible for the spatial conformity (molecular). They also present variable external structures (head and tail), supposedly responsible for the interaction between PIFs and other cellular structural proteins, besides the cellular polymerization.

The cytokeratins become polymerized by means of non-parallel arrangements of molecules and progressive interaction one with another, successively forming protofilaments (2-3nm), protofibrils (4.5nm) and fibrils (10nm).

The cytokeratins are a means for epidermal, pilar and unguinal differentiation. They are present in variable proportion according to the differentiation and cellular function (basal keratinocytes 10% - corneocytes 85%). Control of gene regulation of the cytokeratins is little understood, but apparently takes place in the initial phases of transcription of the DNA. It is known that in keratinopathies, the retinoids present therapeutic efficacy after this point.^20,21 However, it is underscored that other altered cellular structures can be responsible for the onset of keratodermas, such as alterations in the envelope of the corneocyte (loricrin) in Vohwinkel's syndrome (mutilating keratoderma),²² modifications in the desmosomes in Brunauer-Fuhs-Siemens type keratoderma²³ and biochemical alterations (tyrosine aminotransferase enzyme) in Richner-Hanhart type keratoderma,²⁴ as well as defects which have yet to be clarified.

The therapeutic resources are scarce. Treatment is mainly symptomatic. Topical keratolytic, such as salicylic acid, as well as topical retinoids, can aid in reducing the epidermal thickness, however with transitory results. The use of topical calcipotriol has been described as a therapeutic alternative, although again with transitory results.^26,27 The use of systemic retinoids,^1,4-25,28-21 etretinate and currently acitretin, has demonstrated a reduction in the keratoderma within several weeks; however, due to pain and greater tactile sensitivity as well as an increase in cutaneous fragility, this therapy is usually discontinued by the patients. The use of gene therapy continues limited, given the autosomal pattern of the disease, which hinders the success of the intervention. Even with techniques that overcome the epidermal barrier and allow the gene insert into the keratinocytes, the transformed allele persists in expressing itself. The ideal answer would be to repair the transformed allele, but such a technique presents extreme difficulties. Such that possible steps would be inhibition of the expression of the transformed genes or an increase in the expression of the unaltered allele.²

REFERENCES

Received in October, 20th of 2000.

Approved by the Consultive Council and accepted for publication in March, 10th of 2002.

*Work done at "Ambulatório de Dermatologia do Hospital Universitário da Universidade Federal de Santa Catarina".

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Publication Dates

• Publication in this collection
  12 May 2006
• Date of issue
  Oct 2002

History

• Accepted
  10 Mar 2002
• Received
  20 Oct 2000