19/04/2019 Keratosis Follicularis (Darier Disease): Background, Pathophysiology, Epidemiology

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Keratosis Follicularis (Darier

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

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 seborrheic regions. Courtesy of Susan Mallory, MD, Director of Pediatric
Dermatology, Washington University School of Medicine.

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19/04/2019 Keratosis Follicularis (Darier Disease): Background, Pathophysiology, Epidemiology

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

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19/04/2019 Keratosis Follicularis (Darier Disease): Background, Pathophysiology, Epidemiology

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]

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19/04/2019 Keratosis Follicularis (Darier Disease): Background, Pathophysiology, Epidemiology

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]

Clinical Presentation

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