Keratosis Follicularis (Darier Disease) 

Updated: Jul 31, 2018
Author: Pui-Yan Kwok, MD, PhD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Keratosis follicularis, also known as Darier disease (DD) or Darier-White disease, is an autosomal dominantly inherited genodermatosis characterized by greasy hyperkeratotic papules in seborrheic regions, nail abnormalities, and mucous membrane changes. See the images below. The disease was first reported independently by Darier and White in 1889. White was first to recognize the genetic nature of keratosis follicularis (Darier disease) by noticing that a mother and her daughter were affected.

Typical distribution of keratotic papules in the s Typical distribution of keratotic papules in the seborrheic regions. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.
Longitudinal ridges, red and white lines, and V-sh Longitudinal ridges, red and white lines, and V-shaped nicks. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.

Pathophysiology

Mutations in the gene ATP2A2 cause keratosis follicularis (Darier disease). ATP2A2, located on 12q23-24.1, encodes the sarcoplasmic/endoplasmic reticulum Ca2+ -ATP isoform 2 protein (SERCA2), which is a calcium pump.[1] This pump maintains a low cytoplasmic Ca2+ level by actively transporting calcium ions from the cytosol into the lumen of the endoplasmic reticulum. Although more than 120 familial and sporadic mutations in ATP2A2 have been identified in keratosis follicularis (Darier disease) patients, attempts at genotype-phenotype correlation have not been successful. Some authors have suggested that recurrent ATP2A2 p.(Pro602Leu) mutation differentiates acrokeratosis verruciformis of Hopf from the allelic condition Darier disease.[2]

Family members with confirmed identical ATP2A2 mutations can exhibit differences in the clinical severity of disease, suggesting that other genes or environmental factors affect the expression of keratosis follicularis (Darier disease).[3, 4] A wide variety of ATP2A2 mutations in Darier disease have been identified.[5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]

The mechanisms by which specific ATP2A2 mutations impact the function of the ATP2A2 protein have been investigated using an in vitro model.[22] Investigators transfected a fibroblast cell line with 51 different mutations seen in keratosis follicularis (Darier disease) pedigrees. The investigators found that the resultant transfected cells showed defects in ATP2A2 protein expression (15 mutants), ATP hydrolysis (29 mutants), calcium transport (4 mutants), and calcium binding and kinetics (3 mutants). In a different study, in which researchers systematically analyzed mutations identical to those found in patients with Darier disease, mutant SERCA2 protein aggregates were found to cause stress to the endoplasmic reticulum, subsequently inducing cell apoptosis.[7] Thus, diverse biochemical mechanisms are responsible for altered protein function.

Although expressivity is variable, penetrance of keratosis follicularis (Darier disease) is high, estimated at 95%. Because the disease-causing mutations in ATP2A2 affect functional domains of the gene, the mechanism of autosomal dominant transmission is believed to be haploinsufficiency, in which a single wild-type functioning ATP2A2 is insufficient to prevent disease. No unique phenotype for genetic homozygotes has been reported.

Abnormal keratinocyte-keratinocyte adhesion and aberrant epidermal keratinization are the primary histologic features of keratosis follicularis (Darier disease). Electron microscopy reveals loss of desmosomes (epithelial intercellular junctions formed by membrane and submembrane protein complexes), breakdown of desmosome-keratin intermediate filament attachment, and perinuclear aggregates of keratin intermediate filaments. The mechanism by which decreased activity of the SERCA2 calcium pump leads to these changes is still under investigation.[23] However, a significant correlation exists between the clinical presentation of keratosis follicularis (Darier disease) and the intensity of histologic features.[24]

Some studies of keratosis follicularis (Darier disease) have suggested that alterations in calcium regulation may affect the synthesis, folding, or trafficking of desmosomal proteins.[25] In particular, studies have revealed that keratosis follicularis (Darier disease) keratinocytes displayed abnormal trafficking of the desmosomal protein desmoplakin and abnormal expression of cytokeratins 10 and 14.[26, 27] A recent study shows that SERCA2-controlled Ca²+ -dependent keratinocyte adhesion and differentiation is mediated via the sphingolipid pathway.[28]

Alternatively, another hypothesis, based on a canine model of keratosis follicularis (Darier disease), is that keratosis follicularis (Darier disease) calcium dysregulation leads to impaired control of cell cycle checkpoints, leading to increased epidermal sensitivity to skin trauma and subsequent keratinocyte apoptosis.

Two particular ATP receptors have been reported to abnormally localize in vivo in keratosis follicularis(Darier disease) and are speculated to play a role in apoptosis as well as abnormal calcium signaling.[27] More recently, Darier keratinocytes were found to display a constitutive endoplasmic reticulum stress response, with immature adherens junctions and desmosomes, which results in decreased intercellular adhesion strength.[29]

Remarkably, an orphan drug, the α-glucosidase inhibitor miglustat, restores mature adherens junctions and desmosomes in Darier keratinocytes and increases adhesion strength. The observation that miglustat is able to restore proper localization to the plasma membrane of nonmutated proteins retained in the endoplasmic reticulum supports a misfolding mechanism.[29]

Epidemiology

Frequency

Keratosis follicularis (Darier disease) occurs worldwide. The prevalence of keratosis follicularis (Darier disease) has been estimated to range from 1 case in 30,000 population in Scotland to 1 case in 100,000 population in Denmark.

Sex

Males and females are equally affected by keratosis follicularis (Darier disease).

Age

Keratosis follicularis (Darier disease) most commonly manifests from age 6-20 years; however, patients have presented as early as age 4 years and as late as age 70 years. Notably, the first case of congenital keratosis follicularis (Darier disease) was diagnosed by biopsy in a child with a significant positive family history for keratosis follicularis (Darier disease), in which at least the 3 proceeding generations of family members were affected.[30]

Prognosis

Patients with keratosis follicularis (Darier disease) experience pruritus and sometimes pain in the affected skin areas. Psychosocial consequences from the appearance and odor of the lesions also constitute the major morbidity of keratosis follicularis (Darier disease). A serious complication associated with keratosis follicularis (Darier disease) is increased susceptibility to cutaneous bacterial and viral infections, in particular herpes simplex virus, human papillomavirus,[31] and poxvirus infections. Initial misdiagnosis of keratosis follicularis (Darier disease) may lead to undertreatment of such infections and may lead to fatal outcomes.[32, 33] However, overall, patients with keratosis follicularis (Darier disease) have a life expectancy similar to that of the general population.

Neuropsychiatric abnormalities such as epilepsy, mental impairment, schizophrenia,[34] and mood disorders have been associated with keratosis follicularis (Darier disease). Several national studies suggest that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility for a number of neuropsychiatric disorders,[35] including bipolar disorder,[36] intellectual disability, and subclinical impairments in cognitive ability.[37]

 

Presentation

History

Most patients with keratosis follicularis (Darier disease) have a family history of the disease. The pattern of inheritance is autosomal dominant. However, some patients, up to 47% in one series, have no clear family history. These cases may represent sporadic mutations, or these patients may have family members with mild disease that was not recognized.

The first skin lesions typically occur in the teenage years and are frequently associated with pruritus.

Heat, sweat, humidity, sunlight, UVB exposure,[38] lithium, oral corticosteroids, and mechanical trauma have been reported to exacerbate keratosis follicularis (Darier disease). Some females report flares around menstruation.

Even though the severity of keratosis follicularis (Darier disease) fluctuates over time, keratosis follicularis (Darier disease) is a chronic, unremitting condition. In one study, one third of patients noted improvement of the condition with age; however, another one third of patients showed worsening of the disease with age.

Physical Examination

The lesions may first appear as skin-colored or yellow-brown papules with a greasy, warty texture. These lesions are especially common in seborrheic areas such as the forehead, scalp, margin of the scalp, nasolabial folds, ears, chest, and back (see the image below).

Typical distribution of keratotic papules in the s Typical distribution of keratotic papules in the seborrheic regions. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.

Approximately 80% of patients have mild flexural involvement with scattered papules in the groin, axillae, or, in women, submammary skin. In less than 10% of patients, flexural disease predominates, with large, warty, vegetative plaques in the axillae, groin, or perineum. These large flexural lesions are especially bothersome to patients because of their malodor.

Involvement of the hands is very common (approximately 95%). Lesions on the palms include punctate keratoses (80%), palmar pits (80%), and hemorrhagic macules (< 10%). Acrokeratosis verruciformis–like lesions (warty flat-topped papules on the dorsal hands) are present in approximately half the patients. Interestingly, several patients with acrokeratosis verruciformis of Hopf (who have dorsal hand lesions only) have been found to harbor mutations in ATP2A2, suggesting this condition may actually be a localized form of keratosis follicularis (Darier disease).

Nail changes in keratosis follicularis (Darier disease) provide important diagnostic clues (see the image below). White and red longitudinal bands, longitudinal nail ridges, longitudinal splitting, and subungual hyperkeratosis are frequently found. A sandwich of red and white longitudinal bands, often with a V-shaped nick at the free margin of the nail, is the most pathognomonic nail finding in persons with keratosis follicularis (Darier disease). These changes on the hands can also occur on the feet, albeit less commonly.

Longitudinal ridges, red and white lines, and V-sh Longitudinal ridges, red and white lines, and V-shaped nicks. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.

Mucosal lesions are detected in approximately 15% of patients, and they appear as white papules with a central depression. These cobblestone lesions are most commonly found in the mouth, but they also may occur on the anogenital mucosa. At times, oral lesions may affect the salivary glands and cause obstruction.[39]

Clinical variants of keratosis follicularis (Darier disease) include hypertrophic and vesicobullous types. Linear or segmental keratosis follicularis (Darier disease) has been shown in some cases to result from genetic mosaicism of ATP2A2. Guttate leukoderma has been noted in some families.[40]

Complications

Renal disease has been reported.[41]

 

DDx

Diagnostic Considerations

Also consider acantholytic dermatosis of the vulva.[42]

Differential Diagnoses

 

Workup

Other Tests

With the discovery that mutations in ATP2A2 cause keratosis follicularis (Darier disease), gene sequencing can be used to confirm the diagnosis.

Procedures

A skin biopsy is helpful in confirming the diagnosis of keratosis follicularis (Darier disease).

Histologic Findings

Acantholysis (loss of epidermal adhesions) and dyskeratosis (abnormal premature keratinization) are the 2 main features of keratosis follicularis (Darier disease). Acantholysis frequently results in the formation of characteristic suprabasal clefts (lacuna) (see the image below). The underlying dermal papillae, covered by a single layer of epithelium (stratum basale), project into these clefts and form villuslike structures. A large keratin plug, often showing focal parakeratosis, overlies each lesion. Hyperkeratosis is also common.

Acantholysis and dyskeratosis (abnormal keratiniza Acantholysis and dyskeratosis (abnormal keratinization) are the 2 main features of Darier disease. Loss of epidermal adhesion with acantholysis frequently results in the formation of suprabasal clefts (lacunae).

Two types of dyskeratotic cells are present: corps ronds and grains. Corps ronds are predominantly located in the stratum spinosum and the stratum granulosum. Corps ronds are characterized by an irregular eccentric and sometimes pyknotic nucleus, a clear perinuclear halo, and a brightly eosinophilic cytoplasm. Grains are mostly located in the stratum corneum, and they consist of oval cells with elongated cigar-shaped nuclei and abundant keratohyalin granules. Diagnostic histologic changes are often focal, necessitating a careful search.

 

Treatment

Medical Care

Basic measures

Sunscreen, cool cotton clothing, and avoidance of hot environments can help prevent flares, especially during the summer.

Moisturizers with urea or lactic acid can reduce scaling and hyperkeratosis.

A low- or mid-potency topical steroid is sometimes useful for inflammation.

When bacterial overgrowth is suspected or crusting is prominent, application of antiseptics such as triclosan or soaks in astringents such as Burrow or Domeboro solution can be helpful.

Topical medications

Case reports have shown that topical retinoids (adapalene,[43, 44] tazarotene gel 0.01%,[45, 46] tretinoin[47] ) can reduce hyperkeratosis in 3 months. However, irritation is a limiting factor.

Emollients and topical corticosteroids can be used in combination with topical retinoids to reduce irritation.

Topical 5-fluorouracil (5-FU) has been used effectively in some patients.[48, 49]

Tacalcitol lotion and sunscreen combination therapy has been reported for localized Darier disease.[50]

Topical pimecrolimus has been reported to be successful in case reports.[51]

A Spanish group reported the use of the COX inhibitor diclofenac sodium 3% gel successfully in two patients.[52]

Botulinum toxin type A

Injection of botulinum toxin type A was reported in one case to significantly relieve the discomforting symptoms associated with keratosis follicularis (Darier disease) located in the submammary areas.[53]

Systemic medications

Oral retinoids (eg, acitretin, isotretinoin,[47] etretinate, alitretinoin[54, 55] ) have been the most effective medical treatment for keratosis follicularis (Darier disease), achieving some reduction of symptoms in 90% of patients. They reduce hyperkeratosis, smoothen papules, and reduce odor. In a study of 11 patients, 5 with keratosis follicularis (Darier disease) and 6 with pityriasis rubra pilaris, significant improvement occurred with isotretinoin therapy. All 11 patients received isotretinoin at 0.5 mg/kg/d, increasing to a maximum dose of 4 mg/kg/d, for a period of 16 weeks. Greater than 50% improvement occurred in all 5 patients with keratosis follicularis (Darier disease) and in 5 of 6 patients with pityriasis rubra pilaris. One patient showed no clinical improvement. Upon discontinuation of therapy, relapse occurred in all but 1 patient with pityriasis rubra pilaris.[56]

Acitretin is effective at 0.6 mg/kg/d. The starting dose is 10-25 mg/d, which is gradually increased as tolerated. Long-term effects on bone should be monitored.

[57]

Isotretinoin at 0.5-1 mg/kg/d is especially useful in females of childbearing age because pregnancy need only be avoided for 1 month after stopping treatment. Unfortunately, prolonged remissions, such as those noted with isotretinoin for severe acne, are not seen in keratosis follicularis (Darier disease).

Etretinate (not available in the United States) has been reported useful if acitretin fails.[58]

Alitretinoin (not available in the United States) at 30 mg/d has been used successfully by British and German groups for women of childbearing age because of its shorter half-life (2-10 h) compared with acitretin and is therefore an alternative to isotretinoin.[54, 55]

Prolonged use of oral retinoids is limited by their significant adverse effects, including mucosal dryness, photosensitivity, hyperlipidemia, transaminitis, and skeletal hyperostosis. Oral retinoids are teratogenic, and appropriate counseling and contraception must be given.

Oral antibiotics are often necessary to clear secondary bacterial superinfection. They may also be used as prophylaxis to prevent infection.

Oral acyclovir may be used to treat or suppress herpes simplex virus infection.

Oral contraceptives have been reported to help with perimenstrual keratosis follicularis (Darier disease) flares.

Celecoxib, through cyclooxygenase-2 (COX-2) inhibition, was suggested as a possible therapeutic strategy based on one in vitro study which showed that COX-2 inhibition may restore downregulation of ATP2A2/SERCA2 expression in keratinocytes caused by ultraviolet B (UVB) irradiation.[59]

Surgical Care

Dermabrasion has been used to smooth the hyperkeratotic lesions of keratosis follicularis (Darier disease), with acceptable results.[60]

Electrosurgery[61] and Mohs micrographic surgery have been used to treat localized keratosis follicularis (Darier disease) areas, with good results.

Laser ablation of recalcitrant plaques has been reported. In one report, 3 patients were treated with carbon dioxide lasers,[62, 63, 64] 2 with Er:YAG lasers,[65] and 2 with pulsed-dye lasers.[66] In all of these cases, treatment was successful, with only one patient developing disease recurrence in her axilla 7 months after treatment. Other reports describe resolution of disease using 1550-nm erbium-doped fractional fiber laser and other fractionated resurfacing devices.[67, 68]

Carbon dioxide laser ablation with adjunctive dermabrasion, curettage, and shave excision in various combinations have also been reported to cause disease remission for 8 months to 2 years.[69]

Electron beam therapy has been used successfully for localized, recalcitrant Darier’s disease in a 51-year-old female.[70]

Photodynamic therapy with 5-aminolevulinic acid was used to treat keratosis follicularis (Darier disease) lesions in 6 patients, with 4 patients showing sustained improvement or clearance for a follow-up period of 6 months to 3 years.[71, 72]

Surgical excision of hypertrophic intertriginous keratosis follicularis has been described in one case report.[73]

 

Medication

Medication Summary

The goals of pharmacotherapy for keratosis follicularis (Darier disease) are to reduce morbidity and prevent complications.

Retinoid-like Agents

Class Summary

These agents decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce potential for malignant degeneration. They also modulate keratinocyte differentiation.

Adapalene (Differin)

Adapalene modulates cellular differentiation, inflammation, and keratinization. It may be tolerated by individuals who cannot tolerate tretinoin creams. It is available as 0.1% gel or solution.

Tazarotene (Avage, Tazorac)

Tazarotene is a retinoid prodrug whose active metabolite modulates differentiation and proliferation of epithelial tissue; it may also have anti-inflammatory and immunomodulatory properties.

Tretinoin topical (Avita, Renova, Retin-A, Tretin X)

Tretinoin inhibits microcomedo formation and eliminates lesions present. It makes keratinocytes in sebaceous follicles less adherent and easier to remove. It is available as 0.025, 0.05, and 0.1% creams or 0.01 and 0.025% gels.

Acitretin (Soriatane)

Acitretin is a metabolite of etretinate and is related to retinoic acid and retinol (vitamin A). The mechanism of action is unknown but it is thought to exert a therapeutic effect by modulating keratinocyte differentiation, hyperproliferation, and tissue infiltration by inflammatory cells. Its mechanism of action on keratosis follicularis (Darier disease) is unknown.

Isotretinoin (Amnesteem, Claravis, Sotret)

Isotretinoin is an oral agent that treats serious dermatologic conditions. It is a synthetic 13-cis isomer of the naturally occurring tretinoin (trans-retinoic acid). Both agents are structurally related to vitamin A. Isotretinoin decreases sebaceous gland size and sebum production. It may inhibit sebaceous gland differentiation and abnormal keratinization.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

 

Questions & Answers

Overview

What keratosis follicularis (Darier disease)?

What is the pathophysiology of keratosis follicularis (Darier disease)?

What is the role of calcium regulation in the pathophysiology of keratosis follicularis (Darier disease)?

What is the prevalence of keratosis follicularis (Darier disease)?

What are the sexual predilections of keratosis follicularis (Darier disease)?

Which age groups have the highest prevalence of keratosis follicularis (Darier disease)?

What is the prognosis of keratosis follicularis (Darier disease)?

Presentation

Which clinical history findings are characteristic of keratosis follicularis (Darier disease)?

Which physical findings are characteristic of keratosis follicularis (Darier disease)?

What are the possible complications of keratosis follicularis (Darier disease)?

DDX

Which conditions should be included in the differential diagnoses of keratosis follicularis (Darier disease)?

What are the differential diagnoses for Keratosis Follicularis (Darier Disease)?

Workup

How is a diagnosis of keratosis follicularis (Darier disease) confirmed?

What is the role of biopsy in the diagnosis of keratosis follicularis (Darier disease)?

Which histologic findings are characteristic of keratosis follicularis (Darier disease)?

Treatment

How is keratosis follicularis (Darier disease) treated?

What is the role of topical medications in the treatment of keratosis follicularis (Darier disease)?

What is the role of botulinum toxin type A in the treatment of keratosis follicularis (Darier disease)?

What is the role of oral medications in the treatment of keratosis follicularis (Darier disease)?

What is the role of surgery in the treatment of keratosis follicularis (Darier disease)?

Medications

What is the goal of drug treatment for keratosis follicularis (Darier disease)?

Which medications in the drug class Retinoid-like Agents are used in the treatment of Keratosis Follicularis (Darier Disease)?