Dyskeratosis follicularis Q82.8

Rare, genetically determined, chronic progressive or chronic relapsing, diffuse or localized, also segmental or as cutaneous mosaic in Blaschko lines occurring skin and mucous membrane disease with acantholytically disturbed keratinization. The skin changes occur especially in seborrheic areas. Nail deformities are frequently observed.

Family clusters. Prevalence (Denmark): 1/50 000-100 000 inhabitants; 1/36 000 (England). Incidence: 4/1 million inhabitants/10 years. The expression of the disease varies greatly among Darier families.

Autosomal-dominantly inherited mutations of the ATP2A2 gene located on chromosome 12q23-24. The ATP2A2 gene encodes the calcium-pumping ATPase (also known as SERCA2 = sarco(endo)plasmic reticulum Ca2+-ATPase 2) in the sarco and endoplasmic reticulum. Mutations of the gene lead to defective enzyme formation and secondarily to inadequate replenishment of the calcium stores of the endoplasmic reticulum. This results in the expression of altered calcium-dependent adhesion molecules (desmosomal cadherins). These proteins are necessary for adhesion processes of epithelial cells. Their impaired biological function leads to loss of adhesion, acantholysis and apoptosis of keratinocytes.

Mostly in children, more often peripubertal. In about 70% of patients, the disease begins between the ages of 6 and 20 with a peak of the disease during puberty. It typically progresses in relapses with phases of extensive lack of symptoms. Complete remissions are rare.

Mainly seborrheic areas of the face and trunk, hairy head, anogenital region, palmae, plantae and nails. Mucosal lesions (primarily on the hard palate) are found in about 15% of patents. Occasionally occurring more intensely in exposed areas!

Rarely arranged along the Blaschko lines (in Anglo-American literature called "segmental Darier`s disease"). Here the genetic connection with the common diffuse phenotype has been proven.

• Initially glass pinhead-sized, isolated standing, reddish to brownish, mostly non follicular papules (naming incorrect). Brown, firmly adherent keratoses confluent to beet-like, verrucous or macerated areas. The affected areas show a dirty-brownish aspect; mostly unpleasant body odour. The patients appear unkempt. Occasionally severe itching. The skin changes are often provoked by light (appearance in the area of the exposed areas). Triggered also by heat and sweating.
• Characteristic roundish or bizarrely configured interruptions of the papillary lines on the palms of the hands and soles of the feet (" pits"). These sometimes widen into pits with hyperkeratosis. In addition, isolated or aggregated 3-5 mm yellow-brownish horn papules are found on palms and/or soles of the feet. More rare are flat keratoderma.
• Typical papules on the cheek mucosa, palate, esophageal mucosa, rectal and genital mucosa. Small spotted leukoderms, often attached to the follicle orifice.
• The hand and toenails show grooved dystrophies, also longitudinal erythronychia with saw-tooth border, splinter hemorrhages, subungual hyperkeratosis, disal onycholysis.
• Also cystic bone changes, possibly schizoid features.
• Clinical special forms:
  • Vesicular-bullous variants: mainly in fever and heavy sweating; widening of suprabasal clefts to intraepithelial blisters.
  • Intertriginous acantholytic dyskeratosis: acquired, intertriginously localized (groin, submammary, genitals) papular lesions with histological features of follicular dyskeratosis.
  • Unilateral, zosteriform Darier: Striiform papules arranged in the Blaschko lines with the clinical and histological aspect of Darier's disease (see mosaic, cutaneous).
  • Actinic comedones: formation of comedones in actinically exposed skin showing signs of focal acantholytic dyskeratosis. In very rare cases this "comedone variant" may occur as a monsymptomatic form of Darier's disease (v. Köckritz A 2018).
  • Acral verruciform papules: Disseminated, flat papules on the back of the hand and foot. Histological signs of acantholytic dyskeratosis.

• Moderate to distinct acanthosis, with hyperkeratosis and focal, mostly columnar parakeratosis. Mostly clearly protruding suprabasal cleft formation. In the stratum spinosum and granulosum dyskeratotic elements. These rounded keratinocytes isolated from the cell structure are called "corps rond". Above this, a columnar parakeratosis zone with individual dyskeratotic cells (grains) develops.
• Electron microscopy: absence or greatly reduced number of desmosomes, disturbances in the desmosome-keratin fibre attachment to the desmosomes and perinuclear aggregates of intermediate filaments (keratin).

• In mild cases external treatment with keratolytic topicals such as 0.05-0.1% Vit A acid cream/gel (e.g. Isotrex cream or gel; Cordes VAS cream, R256 ), 3-5% salicylic acid-containing topicals (e.g.Salicylvaseline Lichtenstein, Squamasol Gel) and caring hydrating preparations with 2-10% urea (e.g. Excipial U Lipo-Lotio, Eucerin 5% Urea Cream, R104 R102 ).
• In case of beginning superinfection body care with disinfecting soaps (e.g. Betaisodona washing solutions), baths with potassium permanganate (light pink). By means of a defined therapy (< 7 cm2) with 5-fluorouracil (e.g. Efudix, every 2 days for 1-2 weeks) a remission lasting for weeks to months can be achieved in exposed areas.
• In severe cases external therapy is usually of little help, external retinoids can sometimes cause unpleasant skin irritation in such cases.

In severe cases, systemic administration of acitretin (Neotigason) initially 10-20 mg/day p.o. until significant improvement, maintenance dose: < 5 mg/day depending on clinical outcome. With discontinuation of acitretin, the skin symptoms flare up again.

Alternative: In individual cases the success of alitretinoin in usual dosage (30mg/day p.o).has been reported.

Short-term administration of systemic glucocorticoids such as prednisolone (e.g. Decortin H) 100-150 mg/day and subsequent rapid dose reduction only in cases with a highly inflammatory, eczematous component.

In case of superinfection, antibiosis according to antibiogram.

1. Barfield RL et al (2002) Pruritic linear papules on a 75-year-old woman: a case of localized Darier-White disease. Cutis 70: 225-228
2. Barnstedt SE (2012) Successful therapy of Darier's disease with alitretinoin. Dermatologist 63:139-141
3. Burge SM et al (1995) Topical isotretinoin in Darier's disease. Br J Dermatol 133: 924-928
4. Darier FJ (1889) De la psorospermose folliculaire végétante. Étude anatomo-pathologique d'une affection cutanée non décrite ou comprise dans le groupe des acnés sebacées, cornées, hypertrophiantes, des kératoses (ichtyoses) folliculaires. Ann Dermatol Syphil (Paris) 10: 597-612
5. Dhitavat J et al (2004) Calium pumps and keratinocytes: lessons from Darier`s disease and Hailey-Hailey disease. Br J Dermatol 150: 821-828
6. Goh BK et al (2005) Darier's disease in Singapore. Br J Dermatol 152: 284-288
7. Itin PH et al (2000) Segmental manifestation of Darier disease. What is the genetic background in type 1 and type 2 mosaic phenotypes? Dermatology 200: 254-257
8. Jorg B et al (2000) A hemorrhagic acral form of dyskeratosis follicularis Darier. dermatologist 51: 857-861
9. Knulst AC et al (1995) Topical 5-fluorouracil in the treatment of Darier's disease. Br J Dermatol 133: 463-466
10. Köckritz v. A (2018) Treatment resistant comedones (comedone variant of Darier's disease): J Dtsch Derrmatol 16: 493-495
11. Oster-Schmidt C, Stucker M, Altmeyer P (2000) Follicular dyskeratosis: successful treatment with local retinoid. dermatologist 51: 196-199
12. Wada T et al (2003) A Japanese case of segmental Darier`s disease caused by mosaicism for the ATPA2 mutation. Br J Dermatol 149: 185-188
13. White JC (1889) A case of keratosis (ichtyosis) follicularis. Journal of Cutaneous and Genitourinary Diseases (Chicago) 7: 201-209