Keratosis Follicularis (Darier Disease) 

  • Author: Pui-Yan Kwok, MD, PhD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: May 14, 2010
 

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.

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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, 3]

The mechanisms by which specific ATP2A2 mutations impact the function of the ATP2A2 protein have been investigated using an in vitro model.[4] 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.[5] However, a significant correlation exists between the clinical presentation of keratosis follicularis (Darier disease) and the intensity of histologic features.[6]

Some preliminary studies of keratosis follicularis (Darier disease) have suggested that alterations in calcium regulation may affect the synthesis, folding, or trafficking of desmosomal proteins.[7] 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.[8, 9] 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.[9]

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Epidemiology

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 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 simplexvirus and poxvirus infections. Initial misdiagnosis of keratosis follicularis (Darier disease) may lead to undertreatment of such infections and may lead to fatal outcomes.[10, 11] However, 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 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.[12]

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Contributor Information and Disclosures
Author

Pui-Yan Kwok, MD, PhD  Henry Bachrach Distinguished Professor, Department of Dermatology and Cardiovascular Research Institute, University of California, San Francisco

Pui-Yan Kwok, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Dermatological Association, American Society of Human Genetics, Dermatology Foundation, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Tina Bhutani, MD  Clinical Research Fellow, Department of Dermatology, University of California School of Medicine, San Francisco

Tina Bhutani, MD is a member of the following medical societies: American Association of Physicians of Indian Origin, American Medical Association, American Medical Women's Association, Indian Medical Association, and National Psoriasis Foundation

Disclosure: Nothing to disclose.

Wilson Liao, MD  Assistant Professor, Department of Dermatology, University of California at San Francisco

Wilson Liao, MD is a member of the following medical societies: American Academy of Dermatology, National Psoriasis Foundation, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

James W Patterson, MD  Professor of Pathology and Dermatology, Director of Dermatopathology, University of Virginia Medical Center

James W Patterson, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Society of Dermatopathology, Royal Society of Medicine, Society for Investigative Dermatology, and United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Michael J Wells, MD  Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Rosalie Elenitsas, MD  Herman Beerman Associate Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Rosalie Elenitsas, MD is a member of the following medical societies: American Academy of Dermatology and American Society of Dermatopathology

Disclosure: Lippincott Williams Wilkins Royalty Textbook editor; DLA Piper Consulting fee Consulting

Joel M Gelfand, MD, MSCE  Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

Dirk M Elston, MD  Director, Department of Dermatology, Geisinger Medical Center

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

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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-shaped nicks. Courtesy of Susan Mallory, MD, Director of Pediatric Dermatology, Washington University School of Medicine.
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).
 
 
 
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