Type 2 segmental Darier disease

ARTICLE

Darier disease is an autosomal dominant skin disorder (OMIM 124 200) caused by mutations in the ATP2A2 gene that encodes an intracellular Ca²⁺ pump [1]. This defect of the Ca²⁺-signalling pathway results in a disturbed adhesion of keratinocytes that gives rise to characteristic histopathological changes in the form of acantholysis and dyskeratosis [2]. Clinical features consist of disseminated brownish and pruritic papules with an affinity to the seborrheic areas of the body. The disease may be exacerbated by sun exposure or perspiration. The gene locus has been assigned to a 2-cM region on 12q23-q24.1 [1,3-5].

Segmental forms of Darier disease have been reported, since the beginning of this century, in more than 50 cases [6]. The arrangement has been described as localized, zosteriform, linear, segmental or unilateral, or as an "acantholytic dyskeratotic epidermal nevus" [7, 8]. Usually the segmental lesions show a degree of severity similar to that found in the non-mosaic phenotype. Sometimes their manifestation is triggered by ultraviolet radiation [9]. Such cases can be best explained as examples of mosaicism originating from a postzygotic mutation at the Darier locus [8].

Recently, however, a rule of dichotomous types of segmental involvement of autosomal skin disorders has been delineated [10]. The type 1 reflects a clonal outgrowth of mutant cells heterozygous for the underlying gene, in an otherwise healthy embryo. In this well-established type of mosaicism, the involved area shows lesions of an ordinary degree of severity. This type of segmental manifestation may herald gonadal mosaicism and, therefore, the following generation may feature a diffuse, non-mosaic involvement [11]. Such familial constellation has so far not been described in Darier disease. Remarkably, however, two diffusely affected brothers with healthy parents have been reported, suggesting the presence of gonadal mosaicism in one of the progenitors [12]. Molecular proof of a type 1 segmental involvement with transmission of the underlying gene to the next generation has been provided in various other autosomal dominant skin disorders. For example, a mutation within the keratin 10 gene was found in an epidermal nevus of the epidermolytic type but not in the surrounding normal skin, whereas the same mutation was documented in the patient's son who suffered from epidermolytic hyperkeratosis of Brocq [13]. By contrast, the type 2 segmental involvement originates in a heterozygous embryo from postzygotic loss of the corresponding normal allele. In this type, the segmental lesions are far more pronounced and, in general, superimposed on the corresponding ordinary trait. Clinical examples suggesting a type 2 segmental involvement have been found in reports on neurofibromatosis 1, cutaneous leiomymatosis, multiple syringomas, epidermolytic hyperkeratosis of Brocq, Darier disease, Hailey-Hailey disease, and disseminated superficial actinic porokeratosis [14]. Sometimes, coexisting bands of either excessive or absent involvement, representing a particular form of twin spotting, may occur [15].

We describe here an unusual case of Darier disease suggesting a type 2 segmental involvement.

Case report

A 45-year-old man presented with a chronic skin disorder that involved mainly the left side of his body. At the age of 27 years, a diagnosis of Darier disease was established both clinically and histopathologically. When he was 44 years old, he had noted an accentuation of the disorder on the left side of his body. The patient appeared to be of rather low intelligence. He was married but had no children. He had 13 siblings. One of his 7 sisters suffered from epileptic seizures, and two other sisters were affected with Darier disease in the form of acrokeratosis verruciformis-like lesions involving the dorsal aspect of their hands. The parents were not available for examination.

Physical examination of the propositus showed typical lesions of Darier disease involving both sides of his body in the form of greasy, brownish, keratotic papules (Fig. 1). The scalp, the retroauricular and clavicular regions as well as the extensor surfaces of the forearms were preponderantly affected. Multiple hyperpigmented papules were also present on his abdomen. The nails of both hands showed longitudinal ridging and V-shaped notches. Numerous interruptions of rete ridges were noted on the palms and fingers on both hands. Examination of the oral cavity revealed velvety plaques on the hard palate. Remarkably, in some areas of his body an asymmetric involvement was noted (Figs. 2 and 3). On the left side, the retroauricular, scapular, pectoralis major and lumbar regions as well as the forearm showed a systematized linear arrangement of excessively pronounced papules (Fig. 4). Histopathological examination of one of the linear lesions excised from the left forearm showed prominent features of Darier disease. There was extensive hyperkeratosis, elongation of rete ridges, suprabasal acantholysis and marked dyskeratosis in the form of corps ronds and grains (Fig. 5).

Discussion

Numerous cases of segmental Darier disease have been described [6-9, 16-22]. In general, they can be categorized as examples of a type 1 manifestation.

On the other hand, we have so far found in the available literature only two cases suggesting a type 2 segmental involvement. In 1959, Chester and Brown [23] published a case of "Darier's disease resembling linear verrucous epidermal nevus". The 24-year-old woman had systematized linear lesions on the right side of her body. During her four pregnancies she had noted exacerbations with appearance of bilateral lesions. In a discussion of this case, Gross [24] noted that "in addition to the nevus-like lesions on the right side of the back, the patient has scattered lesions on the rest of the trunk and typical lesions in the frontal hairline resembling seborrheic dermatitis". For this reason it seems justified to categorize this case as an example of type 2 segmental Darier disease. In 1995, Esche et al. [25] presented a 53-year-old man with Darier disease showing a unilateral systematized linear involvement of the face and the trunk. In addition to these pronounced segmental lesions, the authors noted the presence of disseminated papules symmetrically involving the axillary regions, the groins, the external auditory canal, and the hard palate. The palmar and plantar rete ridges showed multiple punctate interruptions. Histopathological examination of a segmental lesion showed pronounced acantholysis and dyskeratosis with abundant corps ronds and grains.

The present case can be taken as an additional example of type 2 segmental Darier disease. In addition to the excessively pronounced linear and unilateral lesions, the patient showed a diffuse symmetrical involvement as usually seen in this trait. Moreover, two of his sisters showed acrokeratosis verruciformis-like lesions suggestive of the presence of Darier disease.

It should be noted that, as long as molecular proof of the proposed concept is lacking, one cannot rule out alternative possibilities. For example, in an embryo heterozygous for a Darier mutation an additional postzygotic mutation involving another gene locus may result in clonal outgrowth of cells that give rise to exaggerated Darier disease, in the form of a genetically determined Köbner phenomenon. We feel, however, that the pronounced band-like lesions of this patient can be best explained as originating from an event of loss of heterozygosity that occurred during early embryogenesis. Future studies may show whether this concept can be confirmed at the molecular level.

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