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Therapeutics in Dermatology
A reference textbook in dermatology
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Darier disease

11 June 2012, by El FEKIH N. , KHARFI M. & KAMOUN M.R.

1 - BACKGROUND

Darier disease is a rare genodermatosis caused by abnormal adhesion between keratinocytes. It is transmitted in an autosomal dominant pattern, with almost total penetrance and variable expressivity. The disease is caused by a mutation in the ATP2A2 gene located on chromosome 12 q23-24.1 [1, 2, 3] that disrupts the regulation of intracellular calcium levels and affects the intercellular adhesion system and/or the organisation of the cytoskeleton. This abnormal keratinocyte adhesion is thought to be connected to abnormalities of the dendritic cells, which are involved in local immune response [4]. 

1.1 -  CLINICAL PICTURE

Onset is usually between the ages of two and six, and frequency peaks at puberty. Clinically, the site and appearance of the lesions is often typical.

The primary lesion is a small, yellowish papule covered with a sticky, greyish crust. These characteristic “warty papules” are found on the peripheries of the affected areas. They coalesce to form brownish, keratotic, papular plaques, which give the skin a dirty and greasy appearance and often exude an unpleasant odour secondary to maceration and microbial proliferation. These skin lesions can cause severe social difficulties.

These plaques present symmetrically are especially common in the seborrheic areas of the face, the temples, the lateral aspects of the neck, the scalp, the flanks, the sacral area and the flexural regions. Verruca-like lesions may be seen on the backs of the hands and feet. Typical palmar-plantar lesions are punctuate keratosis with tiny pits. The nails are widened and present longitudinal ridges, with alternating light and dark bands. Subungual hyperkeratosis and notches in the free margin of the nail complete the clinical picture. These palmar, plantar and nail lesions are typical and highly suggestive of this diagnosis [5].

There are mucosal lesions in approximately 20% of cases. These are confluent whitish or pinkish papules with a central depression. They can affect the mucous membranes in the mouth, oesophagus, rectum or the ano-genital mucosa.

Atypical clinical forms are rare. They may be unusual in terms of:

— Lesion distribution: linear, unilateral or localised lesions. The organised linear form was termed the type 1 segmental form by Happle [6].

— Lesion appearance: vesicobullous lesions and vegetative plaques. Rarer still are the forms involving dyschromia (leucoderma-type macules) or haemorrhage, or those that are nonspecific with symptoms such as keratosis pilaris, or when there are only a few nail lesions.

— Comorbidities: neurological disorders (cerebral atrophy, epilepsy, learning difficulties or psychiatric disorders); various other conditions (affecting the genito-urinary system, thyroid system, lungs, cornea or vasculature) [5].

1.2 -  HISTOLOGICAL FEATURES

Histology is very suspicious but nonspecific. It shows clefts caused by acantholysis below the stratum basale of the epidermis and dyskeratotic cells consisting of “corps ronds” formed by groups of keratinocytes and “grains” within the stratum corneum.

1.3 -  ULTRASTRUCTURE

Examination by electron microscope highlights the primary changes in the desmosome-tonofilament complex. It shows detached tonofilaments that are no longer connected to the desmosomes, forming a halo around the nucleus.

1.4 -  DIAGNOSIS

A suggestive clinical picture often leads to suspicion of Darier disease, and it can easily be confirmed due to its characteristic histological features. Diagnostic electron microscopy is rarely called upon.

This diagnosis may nonetheless sometimes be considered in the following conditions:

— Familial benign pemphigus or Hailey-Hailey disease, which is the main differential diagnosis. However, onset is earlier in this disease and the skin lesions often affect only the flexural folds, sparing the nails. Another similarity is that acantholysis is also present on histological examination but it is more intense and it is not combined with dyskeratotic cells.

— Grover’s disease can mimic Darier disease clinically and histologically, and it is the most difficult diagnosis to distinguish. Onset is usually after age 40 and it progresses in transient episodes.

— Pemphigus vegetans, which can be easily eliminated due to negative DIF.

— Acantholytic dyskeratotic epidermal hamartoma in rare linear forms.

1.5 -  PROGRESSION

This is a chronic condition that lasts throughout life. In one third of cases symptoms improve with age. Flare-ups mainly occur during hot seasons, triggered by the heat, sweating and exposure to the sun. The disease can be exacerbated by lithium carbonate or systemic corticosteroids. Women may find their symptoms worsen around menstruation [7]. The contraceptive pill has been reported to have a beneficial effect [8]. 

Complications result from an unusual sensitivity to viral infections (HSV1 or 2, poxvirus) and superinfections caused by bacteria or mycoses are common, probably secondary to a local immune deficiency [4].

1.6 - PROGNOSIS

Darier disease is chronic and entails a risk of superinfections, although these are fortunately often localised and benign. The most important factor for prognosis is that it is aesthetically disfiguring and this has an impact on the patient’s social and professional relationships, as well as their quality of life.

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