Keratosis Follicularis (Darier Disease)

Updated: Jul 11, 2017

Author: Pui-Yan Kwok, MD, PhD; Chief Editor: Dirk M Elston, MD

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.
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 Ca+ -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 -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 ATP2A2gene 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
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 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 verruciformislike 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.
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.

Complications
Renal disease has been reported. [40]

Differential Diagnoses
Acrokeratosis Verruciformis of Hopf
Familial Benign Pemphigus (Hailey-Hailey Disease)
Seborrheic Dermatitis
Transient Acantholytic Dermatosis

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 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 & Management

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, [42, 43] tazarotene gel
0.01%, [44, 45] tretinoin [46] ) 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. [47, 48]
Tacalcitol lotion and sunscreen combination therapy has been reported for localized
Darier disease. [49]
Topical pimecrolimus has been reported to be successful in case reports. [50]
A Spanish group reported the use of the COX inhibitor diclofenac sodium 3% gel
successfully in two patients. [51]
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. [52]
Systemic medications
Oral retinoids (eg, acitretin, isotretinoin, [46] etretinate, alitretinoin [53, 54] ) 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. [55]
Acitretin is effective at 0.6 mg/kg/d. The starting dose is 10-25 mg/d, which is gradually
increased as tolerated.
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. [56]
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. [53, 54]
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. [57]
Surgical Care
Dermabrasion has been used to smooth the hyperkeratotic lesions of keratosis
follicularis (Darier disease), with acceptable results. [58]
Electrosurgery [59] 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, [60, 61, 62] 2 with Er:YAG lasers, [63] and 2 with pulsed-
dye lasers. [64] 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. [65, 66]
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. [67]
Electron beam therapy has been used successfully for localized, recalcitrant Dariers
disease in a 51-year-old female. [68]
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. [69, 70]
Surgical excision of hypertrophic intertriginous keratosis follicularis has been described
in one case report. [71]
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 Administrationmandated 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.

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