eMedicine Specialties > Dermatology > Papulosquamous Diseases

Keratosis Follicularis (Darier Disease)

Author: Pui-Yan Kwok, MD, PhD, Henry Bachrach Distinguished Professor, Department of Dermatology and Cardiovascular Research Institute, University of California, San Francisco
Coauthor(s): Sarah Fitzmaurice, BS, MS, University of California Davis School of Medicine; Wilson Liao, MD, Assistant Professor, Department of Dermatology, University of California at San Francisco
Contributor Information and Disclosures

Updated: Feb 25, 2009

Introduction

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. 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.

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 113 familial and sporadic mutations in ATP2A2 have been identified in keratosis follicularis (Darier disease) patients, attempts at genotype-phenotype correlation have not been successful. 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).²

The mechanisms by which specific ATP2A2 mutations impact the function of the ATP2A2 protein have been investigated using an in vitro model.³ 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). 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.⁴

Some preliminary studies have suggested that alterations in calcium regulation may affect the synthesis, folding, or trafficking of desmosomal proteins.⁵ 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.^6,7 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 recently 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.⁷

Frequency

International

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.

Mortality/Morbidity

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 this condition. A serious complication associated with keratosis follicularis (Darier disease) is increased susceptibility to cutaneous bacterial and viral infections, in particular herpes simplex virus and poxvirus infections. Overall, patients with keratosis follicularis (Darier disease) have a life expectancy similar to that of the general population.

Sex

Males and females are equally affected.

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.⁸

Clinical

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,⁹ lithium, oral corticosteroids, and mechanical trauma have been reported to exacerbate this condition. 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.
• Although neuropsychiatric abnormalities such as epilepsy, mental impairment, and mood disorders have been associated with keratosis follicularis (Darier disease), no evidence indicates that mutations in ATP2A2 are associated with these disorders.¹⁰ One study¹¹ suggests that a susceptibility locus for bipolar disorder co-segregates with the keratosis follicularis (Darier disease) region, but it is distinct from the keratosis follicularis (Darier disease) – causing mutation.

Physical

• 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 Media File 1). 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 provide important diagnostic clues (see Media File 2). 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.
• 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.
• 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.

Causes

See Pathophysiology.

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