Dermatology Online Journal

A new variant of Vohwinkel syndrome: A case report
Hassan Seirafi MD¹, Somayeh Khezri MD¹, Saeid Morowati MD², Kambiz Kamyabhesari MD³, Mehdi Mirzaeipour MD¹, Farzaneh Khezri MD⁴
Dermatology Online Journal 17 (3): 3

1. Department of Dermatology, Razi skin hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
2. Research Center for Human Genetics, Baqiyatallah University of Medical Sciences, Tehran, Iran
3. Department of Dermatopathology, Razi skin hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
4. Department of Dermatology, Mayo Clinic, Rochester, Minnesota

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Abstract

Vohwinkel syndrome (mutilating and diffuse palmoplantar keratoderma) is associated with various extracutaneous features including icthyosis and deafness. Its mode of inheritance is autosomal dominant with mutation in loricrin and connexin 26 genes. Here we report a mutilating and focal palmoplantar keratoderma in two siblings with congenital hypotrichosis and probably autosomal recessive inheritance that appears to be a new variant of Vohwinkel syndrome.

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Introduction

Palmoplantar Keratoderma (PPK) is a heterogeneous group of hereditary and acquired skin diseases [1]. Hereditary keratodermas are mostly autosomal dominant and their genetic defects have been identified in some groups. Extra cutaneous features are often reported in these cases. Because of the rarity of hereditary PPKs, our knowledge is often based on case reports. One of the inherited keratodermas is Vohwinkel syndrome (classic and variant form) [1, 2, 3]. Here we report a new sub-type of Vohwinkel syndrome, its extracutaneous features, and the associated genetic studies. To our knowledge, no previous similar case report exists.

Case presentation

Two adult siblings, one male and one female, were referred to the dermatology outpatient clinic of Razi hospital, Tehran, Iran in January 2010. They were born of a fourth degree consanguineous marriage.

The affected woman is the first child and the affected man is the last one. There is another healthy daughter as the second child.

The affected woman, aged 34 years, had sparse, fine, dry, brittle, and hypopigmented scalp hair, which rarely exceeded more than 8 centimeters in length, from birth. The eyebrows, eye lashes, and pubic hair were also sparse. By the age of one, when she started to walk, a marginal hyperkeratosis of the palms and soles appeared. A clear-cut transgredient border with a reddish inflammatory halo on the dorsal surfaces of the hands and feet was present around the hyperkeratosis. A constricting band developed around the distal interphalangeal joint of the third finger of the right hand by the age of 4. Nails, teeth, and mucous membranes were normal (Figures 1a, 1b, 1c, and 1d).

Figure 1a	Figure 1b
Figure 1a. Hypotrichosis of the scalp in sister Figure 1b. Focal striate keratoderma of the palms in sister (Note the constricting band.)

Figure 1c	Figure 1d
Figure 1c. Focal keratoderma of the soles in sister Figure 1d. Transgredient margins with erythematous halo in sister

The affected man, aged 20 years, was apparently normal at birth. The scalp hair was shed during the first 12 months of his life and never adequately replaced. At the age of 20 years, it remains sparse and fine like his sister. The eyebrows, eye lashes, beard, mustache, and pubic hair were sparse as well. During early childhood, focal keratoderma (keratoderma striata) developed on the pressure points of the toes and heels bilaterally. Later, it became transgredient with spiky digitate hyperkeratotic projections at the border. Like his sister, an erythematous halo was noted around the transgredient hyperkeratosis of the palms and soles. By the age of 5 years, constriction bands had developed around the distal interphalangeal joint of the second and third fingers of the right hand. The nails, teeth, and mucous membranes were normal except for nail clubbing. The patients complained of pain in the affected fingers caused by congestion (Figures 2a, 2b, 2c, and 2d). They did not have any history of deafness or ichthyotic skin and all the other musculoskeletal features were normal. The patients had used various keratolytics plus emollients with transient and partial relief of the keratoderma. The family history of similar disease is negative.

Figure 2a	Figure 2b
Figure 2a. Hypotrichosis of the scalp in brother Figure 2b. Constricting band of the second and third fingers (Note the congestion of the same finger tips.)

Figure 2c	Figure 2d
Figure 2c. Transgredient margins with erythematous halo in brother Figure 2d. Focal striate keratoderma of the soles in brother

Additional investigations are listed below:

1. The tissue samples taken from plantar skin in both patients showed the same histopathological features, dense hyperkeratosis with a layer of spotty parakeratosis, hypergranulosis, and regular acanthosis of epidermis (Figure 3).
2. The trichograms from the scalp hair of our patients were the same and except the variability in hair shaft diameters, the bulbs of hair shaft and the proportions of the catagen, and telogen to anagen hair were normal (about 10%).
3. Audiometries of the patients were also normal.
4. Genetic study with the purpose of the detection of the two known genes for Vohwinkel syndrome (loricrin and connexin 26 genes), was done.

The methods and results of genetic analysis are shown below:

Figure 3	Figure 4
Figure 3. Photomicrograph of the plantar keratoderma biopsy. Note the dense hyperkeratosis, spotty parakeratosis, regular acanthosis, and preserved granular layer (H&E, x40) Figure 4. PCR amplified a 201-bp product, which contained a part of coding region of the loricrin gene: 1) Father, 2) Mother, 3) Affected brother, 4) Affected sister, 5) Normal sib

Genomic DNA was prepared from the patients, their parents, and the other sibling. High-molecular weight DNA was isolated from peripheral leucocytes, using standard phenol/chloroform extraction method. For mutation identification in the loricrin gene, a fragment of exon 2 of the loricrin gene from genomic DNA was amplified by polymerase chain reaction (PCR) (Figure 4). A G residue insertion at codon 230-231 in this part of the loricrin gene has been previously reported in Vohwinkel syndrome [4]. For mutation identification in connexin 26 gene, the coding sequence of the connexin 26 gene was PCR amplified. A missense mutation in connexin 26 (GJB2), D66H, has been previously reported in Vohwinkel syndrome [5]. PCR products were purified on agarose gel and directly sequenced with the same PCR primers.

Briefly, direct sequencing analysis of PCR product of the coding region of the loricrin gene did not show the mutation in our patients, their parents, and sibling.

Another investigation was direct sequencing analysis of PCR product of the coding region of connexin 26 gene, which showed a heterozygote silent mutation 257-258GC-CG (code for the same amino acid) in connexin 26 gene of our patients.

The patients were advised to use topical keratolytics with emollients (10% urea in eucerin). The male patient who had painful constricting bands around his right second and third fingers was referred to a hand surgeon for surgical correction.

Discussion

Vohwinkel reported a mutilating and diffuse palmoplantar keratoderma in a 24 year-old woman in 1929 [6]. Since then, various reports have clarified the classification, genetic defects, and clinical details of this syndrome. These studies have included genetic analysis. The following table summarizes the characteristics of our patients and the two subgroups of Vohwinkel syndrome (classic and variant form) (Table 1).

Other reported findings of classic Vohwinkel syndrome are deafmutism, congenital alopecia universalis, pseudopelade type alopecia, acanthosis nigricans, spastic paraplegia, myopathy, nail changes, mental retardation, bullous lesions on the soles, and seizures [1, 2, 3, 7].

Because of the transgredient PPK with the onset in infancy, pseudoainhum and reddish border of keratoderma in our patients it is highly probable that they have Vohwinkel syndrome (classic or variant form).

Similar to the reports of Arfan Ul Bari and Mir Mubashir Ali, our patients did not show the common associations of the two forms of Vohwinkel syndrome (deafness and icthyosis) [8, 9]. Instead, they had congenital hypotrichosis, which to our knowledge has never been reported before. We decided to investigate the two known mutations in the connexin 26 and loricrin genes in our patients. Surprisingly, the loricrin gene was normal and a silent mutation, but not a missense, was detected in the connexin 26 gene. Because our patients also have diffuse and congenital hypotrichosis, we should also consider the ectodermal dysplasia syndromes with PPK, especially Clouston syndrome, which is characterized by nail dystrophy, diffuse hypotrichosis, and PPK.

The key feature of Clouston syndrome is nail dystrophy, not seen in our patients. In addition, Clouston syndrome has orthohyperkeratosis with a normal granular layer in the histopathological study of PPK. With normal nails and hyper-granulosis in our patients, we can rule out Clouston syndrome [10, 11].

In conclusion we report a mutilating keratoderma with 1) striate pattern and reddish border, 2) congenital hypotrichosis, and 3) likely autosomal recessive inheritance in two siblings that can be considered as another subgroup of Vohwinkel syndrome. To our knowledge there are no similar reports. We are proceeding with further gene analysis to find the responsible mutation.

References

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6. Vohwinkel k. Keratoma hereditaria mutilans. Arch Dermatol Syphilol 1929; 158:354-64.

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8. ul Bari A. Keratoderma hereditarium mutilans (Vohwinkel syndrome) in three siblings. Dermatol Online J. 2006;12(7):10. [PubMed]

9. Ali MM, Upadya GM. Variant of Vohwinkel's syndrome. Indian Journal of Dermatology, Venereology and Leprology. Nov/Dec 2006;72(6):449-51. [PubMed]

10. Burns T, Breathnach S, Cox N, Griffiths c. Ectodermal dysplasias. Rook's Textbook Of Dermatology. Seventh ed 2004. p. 43.

11. Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ. Ectodermal Dysplasias. Fitzpatrick's Dermatology In General Medicine. Seventh ed2008. p. 1342-3.

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