6.1.6 Dyskeratosis follicularis (Darier)

Keratosis follicularis, Darier-White disease, Darier’s disease.

Darier disease is one of the most common genodermatoses, first reported by Darier and White in 1889. The prevalence is 1:30,000-100,000 and an incidence of new cases of four per million per 10 years. The occurrence of sporadic cases is approximately 40-50%, with a high penetrance of about 95%. There is no gender difference with respect to incidence. However, the disease affects men more severely than women. It develops initially in childhood and persists throughout adolescence. The life expectancy is normal.

Dyskeratosis follicularis (Darier’s disease) is a rare autosomal dominant genodermatosis. It affects not only the skin but also the oral mucosa and nails, indicating that the term “dyskeratosis follicularis” is a misnomer. Typical clinical features are keratotic papules, predominantly on the upper trunk and on the scalp in conjunction with palmar pits and nail dystrophy.

The ATP2A2 gene maps to the long arm of chromosome 12 at 12q23-24.1 and encodes SERCA2, a calcium pump classified as a P-type calcium ATPase.

A mutation leads to defect differentiation of keratinocytes and disturbed formation of desmosomal tonofilaments, resulting in acantholysis. High temperatures, high humidity, excessive sweating, UV light, virus infections (herpes simplex), caffeine, alcohol, stress, and mechanical irritation are trigger factors.

Skin: small grayish-brown, itchy keratotic papules several millimeters in diameter; occasionally confluent, weeping, sometimes itching and foul-smelling. Papules do not always occur in the hair follicles, but often aggregate to form a verrucous lesion with keratotic crusts, leading to hair loss. Papules developing at sites of friction, such as the groin may fuse and become papillary.

Disturbances in dermatoglyphics, tiny palmoplantar pits and punctiform interruptions of the papillary strip structure on the fingers and toes, sometimes with small keratotic plugs may point to early diagnosis of Darier disease. A rare variant shows disabling palmoplantar hyperkeratosis.

Oral mucosa and hard palate: leukoplakia-like changes with small white grouped papules are found in about 15% of patients, initially on the palate, resembling cobblestones They may become very widespread. Similar lesions are seen on the genital mucosa.

Nails: Marked nail dystrophies may evolve over time in up to 90% of patients, presenting as grooves and subungual hyperkeratosis, distal notches, longitudinal ridging and splitting and longitudinal red or white lines. Fingernails and toenails may become brittle and weak.

Psycho-neurological problems, including seizure, mental retardation and psychoses. Maniac depressive illness and epilepsy are seen more frequently in patients with Darier’s disease.

Acrokeratosis verruciformis Hopf, presenting as verrucous papules on the back of the hand, also is caused by mutations in the SERCA2-ATPase gene, indicating the nosologic relationship to Darier’s disease.

Seborrheic regions: centrofacial, scalp, axillary region, central breast and back regions, inguinal region, anogenital. The nape is often the first site of involvement.

Linear and circumscribed forms exist.

Various mutations in the SERCA2-AT Pase gene are known, without evident impact on the clinical expression of the disease. Mild forms and more severe forms can be differentiated, considering the course of the disease.

Special form: Verrucous papules on the back of the hand are also referred to as acrokeratosis verruciformis Hopf.

• Dyskeratosis: defective differentiation of keratinocytes with corps ronds (eosinophilic cells in Str. spinosum) and corps grain (granular nuclear residues in Str. Granulosum) Verrucous hyperkeratosis, especially in acrokeratosis verruciformis Hopf.

• Acantholysis: suprabasal cleft formation with numerous eosinophilic granulocytes. The basal layer may be retained, producing a tombstone pattern like in pemphigus vulgaris.

• Inflammatory infiltrate in the dermis.

Chronic with progressing worsening in the first years of illness and following the impact of triggering factors, like UV-light or virus infection (herpes), which can lead to widespread flare and acute worsening. Bacterial superinfection may become a problem at intertriginous sites. Severe complications are rare.

Prevention: Avoidance of direct exposure to the sun (UV; sweating) and other triggering factors (see above).

Topical: emollient-like soap substitutes and moisturizers are usually sufficient in mild forms. Retinoids, antiseptic baths, short-term weak glucocorticosteroids.

Systemic: oral retinoids (acitretin: 0.6 mg/kg daily, increased gradually up to 10-25 mg daily; isotretinoin) are effective in up to 90% of patients. Slow tapering down necessary to find optimal maintenance dose. In case of superinfection: oral antibiotics.

Surgical: exceptionally dermabrasion, laser.