Keratosis Follicularis (Darier Disease)

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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 (see the image below), 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 by noticing that a mother and her daughter were affected.



View Image

Typical distribution of keratotic papules in seborrheic regions. Image from Susan Mallory, MD, Director of Pediatric Dermatology, Washington Universit....

Several variants of the disease have been described.

Pathophysiology

Mutations in ATP2A2, located on 12q23-24.1, cause keratosis follicularis (Darier disease).[1] ATP2A2 encodes the sarcoplasmic/endoplasmic reticulum Ca2+-ATP isoform 2 protein (SERCA2), which is a calcium pump. 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 250 mutations in ATP2A2 have been identified in patients with Darier disease,[2]  attempts at genotype-phenotype correlation have been unsuccessful. Some authors have suggested that recurrent ATP2A2 p.(Pro602Leu) mutation differentiates acrokeratosis verruciformis of Hopf from the allelic condition Darier disease.[3]

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.[4, 5]  Because the mutation may be inherited in an autosomal dominant fashion or occur sporadically, a negative family history does not exclude the disease. The expressivity of the disease is highly variable, so that a family member may have disease so subtle as to have been overlooked; this further underscores the unreliability of a negative family history.

The mechanisms by which specific ATP2A2 mutations impact the function of the ATP2A2 protein have been investigated via an in-vitro model.[6] Investigators transfected a fibroblast cell line with 51 different mutations seen in Darier disease pedigrees. 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 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. 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 remains a subject of investigation.[8] However, a significant correlation exists between the clinical presentation of Darier disease and the intensity of histologic features.[9]

Some studies of keratosis follicularis have suggested that alterations in calcium regulation may affect the synthesis, folding, or trafficking of desmosomal proteins.[10] In particular, studies revealed that Darier disease keratinocytes displayed abnormal trafficking of the desmosomal protein desmoplakin and abnormal expression of cytokeratins 10 and 14.[11, 12] One study showed that SERCA2-controlled Ca²+-dependent keratinocyte adhesion and differentiation are mediated via the sphingolipid pathway.[13]

An alternative hypothesis, based on a canine model of keratosis follicularis, is that in this disease, calcium dysregulation leads to impaired control of cell cycle checkpoints, leading in turn to increased epidermal sensitivity to skin trauma and subsequent keratinocyte apoptosis.

Two particular ATP receptors have been reported to localize abnormally in vivo in patients with keratosis follicularis, and it has been speculated that they play a role in apoptosis as well as abnormal calcium signaling.[12] Subsequently, Darier keratinocytes have been found to display a constitutive endoplasmic reticulum stress response, with immature adherens junctions and desmosomes, which results in decreased intercellular adhesion strength.[14]

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 can restore proper localization to the plasma membrane of nonmutated proteins retained in the endoplasmic reticulum supports a misfolding mechanism.[14]

Epidemiology

International statistics

Keratosis follicularis (Darier disease) occurs worldwide. Estimates of its prevalence have ranged from 1 case per 30,000 population in Scotland to 1 case per 100,000 population in Denmark.

Age- and sex-related demographics

Keratosis follicularis 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 Darier disease was diagnosed by means of biopsy in a child with a significant positive family history for the disease, in which at least the three preceding generations of family members were affected.[15]

Males and females are equally affected by keratosis follicularis.

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 Darier disease.

A serious complication associated with keratosis follicularis is increased susceptibility to cutaneous bacterial and viral infections, in particular herpes simplex virus (HSV), human papillomavirus (HPV),[16] and poxvirus infections. Initial misdiagnosis of Darier disease may result in undertreatment of such infections, potentially leading to fatal outcomes.[17, 18]  Overall, however, patients with keratosis follicularis have a life expectancy similar to that of the general population.

Neuropsychiatric abnormalities (eg, epilepsy, mental impairment, schizophrenia,[19] and mood disorders) have been associated with keratosis follicularis. Several national studies have suggested that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility to a number of neuropsychiatric disorders,[20] including bipolar disorder,[21] intellectual disability, and subclinical impairments in cognitive ability.[22]

Patient Education

Darier disease is prone to exacerbations induced by infection, heat, and friction. Adoption of measures to avoid precipitating factors is recommended where possible.

Genetic counseling is recommended so that patients are aware of the risk to potential offspring.

History

Most patients with generalized keratosis follicularis (Darier disease) have a family history of the disease, though variable expressivity is a known feature. The pattern of inheritance is autosomal dominant. However, some patients (as many as 47% in one series) have no clear family history. These cases may represent sporadic mutations, or the 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, ultraviolet B (UV-B) exposure,[23] lithium, oral corticosteroids, and mechanical trauma have been reported to exacerbate Darier disease. Some female patients report flares around menstruation.

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

Physical Examination

The lesions of keratosis follicularis 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).



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Typical distribution of keratotic papules in seborrheic regions. Image from Susan Mallory, MD, Director of Pediatric Dermatology, Washington Universit....

Approximately 80% of patients have mild flexural involvement with scattered papules in the groin, axillae, or, in women, submammary skin. In fewer 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, a significant therapeutic dilemma.

Involvement of the hands is very common (~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 dorsa of the hands) are present in approximately half the patients. The finding that several patients with acrokeratosis verruciformis of Hopf (who have dorsal hand lesions only) have harbored mutations in ATP2A2 suggests that this condition may actually be a localized form of Darier disease.

Nail changes in keratosis follicularis provide important diagnostic clues (see the image below). White and red longitudinal bands ("candy cane" nails), 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 Darier disease. These changes on the hands can also occur on the feet, albeit less commonly.



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Longitudinal ridges, red and white lines, and V-shaped nicks. Image from Susan Mallory, MD, Director of Pediatric Dermatology, Washington University S....

Mucosal lesions are detected in approximately 15% of patients, appearing as white papules with a central depression. These cobblestone lesions are most commonly found in the mouth but may also occur on the anogenital mucosa. At times, oral lesions may affect the salivary glands and cause obstruction.[24] In rare instances, a patient may present with only oral manifestions of keratosis follicularis.[25] Esophageal involvement is rare.[26]

Clinical variants of Darier disease include hypertrophic and vesicobullous types. Blaschkolinear or segmental keratosis follicularis has been shown in some cases to result from genetic mosaicism (from postzygotic mutation) of ATP2A2. Guttate leukoderma has been noted in some families.[27] Localized lesions, such as those localized only to the vulva, have been described.

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.

Histologic Findings

Acantholysis (loss of epidermal adhesions) and dyskeratosis (abnormal premature keratinization) are the two main features of 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.



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Acantholysis and dyskeratosis (abnormal keratinization) are two main features of Darier disease. Loss of epidermal adhesion with acantholysis frequent....

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.

Medical Care

Basic measures

Comorbid conditions associated with keratosis follicularis (Darier disease) may include increased cardiovascular risk and should be evaluated.  Depression may be associated with decreased quality of life.[29]

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 medium-potency topical steroid is sometimes useful for inflammation.

When bacterial overgrowth is suspected or crusting is prominent, application of antiseptics (eg, triclosan) or soaking in astringents (eg, Burrow or Domeboro solution) can be helpful.

Pharmacotherapy

Topical medications

Case reports have shown that topical retinoids (eg, adapalene,[30, 31] tazarotene gel 0.01%,[32, 33]  and tretinoin[34] ) 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.[35, 36]

Tacalcitol lotion and sunscreen combination therapy has been reported for localized Darier disease.[37]

Topical pimecrolimus has been successful in case reports.[38]

A Spanish group reported successful use of diclofenac sodium 3% gel in two patients.[39]

Treatment of malodor is frequently difficult. Transcriptome analysis of the microbiome in patients with Darier patients has revealed changes in bacterial levels in active lesions, with some levels increasing and others decreasing.[40]  Many of these bacteria are associated with odor, so that topical treatment with agents such at metronidazole in intertriginous areas may yield better results than alternative systemic therapies. The agent to be used should be selected carefully; some topically applied antibiotics (eg, clindamycin) can produce significant systemic absorption with resulting complications (eg, such as Clostridioides [Clostridium] difficile colitis).

Targeted therapy is evolving.[41]

Botulinum toxin injection

Injection of botulinum toxin type A was reported in one case to achieve significant relief of the discomforting symptoms associated with keratosis follicularis located in the submammary areas.[42]

Systemic medications

Oral retinoids (eg, acitretin, isotretinoin,[34] etretinate, and alitretinoin[43, 44] ) have been the most effective medical treatment for Darier disease, achieving some reduction of symptoms in 90% of patients. These agents reduce hyperkeratosis, smoothen papules, and reduce odor.

In a study of 11 patients, five with keratosis follicularis and six with pityriasis rubra pilaris, significant improvement occurred with isotretinoin therapy.[45] All 11 patients received isotretinoin at 0.5 mg/kg/day, increasing to a maximum dose of 4 mg/kg/day, for 16 weeks. Clinical improvement greater than 50% was observed in all five patients with keratosis follicularis and in five of the six patients with pityriasis rubra pilaris; one pityriasis rubra pilaris patient showed no clinical improvement. Upon discontinuance of therapy, relapse occurred in all but one patient with pityriasis rubra pilaris.

Acitretin is effective at 0.6 mg/kg/day. The starting dosage is 10-25 mg/day, which is gradually increased as tolerated. Long-term effects on bone should be monitored.[46]

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

Etretinate (not available in the United States) has been reported to be useful if acitretin fails.[47]

Alitretinoin (not available in the United States) at 30 mg/day has been used successfully by British and German groups for women of childbearing age because of its shorter half-life (2-10 h) as compared with acitretin; it thus serves as an alternative to isotretinoin.[43, 44]

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 antivirals may be used to treat or suppress herpes simplex virus (HSV) infection.

Oral contraceptives have been reported to help with perimenstrual keratosis follicularis flares.

Celecoxib, through cyclooxygenase-2 (COX-2) inhibition, was suggested as a possible therapeutic strategy for keratosis follicularis on the basis of one in-vitro study showing that COX-2 inhibition may restore downregulation of ATP2A2/SERCA2 expression in keratinocytes caused by ultraviolet B (UV-B) irradiation.[48]

Immunoprofiling of Darier skin lesions in some patients has demonstrated elevated levels of Th17 cells resulting in increased activity of interleukin (IL)-17 and IL-23.[49]  Use of guselkumab and secukinumab in these patients resulted in clinical improvement. Use of anti-IL-4/IL-13 monoclonal antibodies (dupilumab and tralokinumab) has also been described.[50]  Improvement in these few cases was not rapid, taking months. It is noteworthy that improvement with the use of IL-4/IL-13 monoclonal antibodies has also been described in Hailey-Hailey disease, which has similar clinical features.[51]

Apremilast has been reported to be effective in a few cases of keratosis follicularis.[52, 53]

Baracitinib was reported to be highly effective in a single patient.[54]

Radiation therapy

Radiation therapy (RT) of various modalities (eg, Grenz, superficial radiation, electron beam) has been reported to be beneficial in the treatment of refractory Darier disease.[55, 56, 57]

Surgical Care

Dermabrasion has been used to smooth the hyperkeratotic lesions of Darier disease, with acceptable results.[58]

Electrosurgery[59] and Mohs micrographic surgery have been used to treat localized keratosis follicularis areas, with good results.

Laser ablation of recalcitrant plaques has been reported. In one report, three patients were treated with carbon dioxide lasers,[60, 61, 62] two with erbium:yttrium-aluminum-garnet (Er:YAG) lasers,[63] and two with pulsed-dye lasers.[64] In all cases, treatment was successful, with only one patient developing disease recurrence in her axilla 7 months after treatment. Other reports have described resolution of disease with the use of the 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 has been reported to cause disease remission for 8 months to 2 years.[67, 68]

Electron beam therapy has been used successfully for localized recalcitrant Darier disease in a 51-year-old female.[69]

Photodynamic therapy with 5-aminolevulinic acid has been used to treat keratosis follicularis.[70, 71] In a study that included six patients, four patients showed sustained improvement or clearance over a follow-up period of 6 months to 3 years.[70, 71]

Surgical excision of hypertrophic intertriginous keratosis follicularis has been described in a case report.[72]

Complications

Patients with Darier disease have an increased risk of skin cancer, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. This risk appears to be linked to the disease and is independent of other risk factors.[73] The risk applies to localized disease as well as to generalized disease.[74]  

An association with type 1 and type 2 diabetes mellitus has been described.[75, 76]  Type 2 diabetes may be underdiagnosed in Darier patients, because these patients as they are frequently treated with retinoids, which have a known tendency to improve glycemic control.[77]  A significant association between Darier disease and psychiatric disease, especially bipolar disease and depression, has also been described. Renal disease has been reported.[78]

Variability in neuropsychiatric disease may occur, as with cutaneous disease. Administration of lithium, which worsens Darier disease, could occur if patients had not yet been diagnosed with Darier disease at the time their psychosis treatment was instituted. The resulting eruption could be mistaken for drug eruption.

Significant risk of heart failure is present. An increase of more than 50% in the risk of heart failure, without an associated increase in the risk of infarction or arrthymia, has been reported.[79]  Heart failure was noted to occur earlier in Darier patients than in matched control subjects. Females are more at risk.

Several different renal diseases, including polycystic kidney disease, have been reported to be associated with keratosis follicularis. Complications from renal disease could complicate Darier disease management affecting other systems, and treatment of the disease in other systems could aggravate underlying renal pathology.

Exacerbations of keratosis follicularis, especially when acute, may be due to herpesvirus infection (Kaposi varicelliform eruption) or other bacterial or fungal infection. In addition to barrier disruption, Darier patients have been reported to have underlying T cell dysfunction that in some cases renders them anergic.[80]

Acitretin (Soriatane (DSC))

Clinical Context: 

Isotretinoin (Absorica, Absorica LD, Amnesteem)

Clinical Context: 

Tazarotene (Arazlo, Avage, Fabior)

Clinical Context: 

Adapalene (Differin)

Clinical Context: 

Tretinoin topical (Altreno, Atralin, Avita)

Clinical Context: 

Apremilast (Otezla)

Clinical Context: 

Guselkumab (Tremfya)

Clinical Context: 

Secukinumab (Cosentyx)

Clinical Context: 

Dupilumab (Dupixent)

Clinical Context: 

Tralokinumab (Adbry, Tralokinumab-ldrm)

Clinical Context: 

Pimecrolimus (Elidel)

Clinical Context: 

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)?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)?Which conditions should be included in the differential diagnoses of keratosis follicularis (Darier disease)?What are the differential diagnoses for Keratosis Follicularis (Darier Disease)?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)?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)?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)?

Author

Edward J Zabawski, Jr, DO, MBA, Adjunct Assistant Professor, Clinical Sciences

Disclosure: Nothing to disclose.

Specialty Editors

Steven R Feldman, MD, PhD, Professor, Departments of Dermatology, Pathology and Public Health Sciences, and Molecular Medicine and Translational Science, Wake Forest Baptist Health; Director, Center for Dermatology Research, Director of Industry Relations, Department of Dermatology, Wake Forest University School of Medicine

Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbvie for consulting; Received honoraria from Galderma for speaking and teaching; Received consulting fee from Lilly for consulting; Received ownership interest from www.DrScore.com for management position; Received ownership interest from Causa Reseasrch for management position; Received grant/research funds from Janssen for consulting; Received honoraria from Pfizer for speaking and teaching; Received consulting fee from No.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Arash Taheri, MD, Research Fellow, Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine

Disclosure: Nothing to disclose.

Jillian Wong Millsop, MD, MS, Resident Physician, Department of Dermatology, University of California, Davis, School of Medicine

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Wilson Liao, MD, Associate Professor, Department of Dermatology, University of California, San Francisco, School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Sarah Fitzmaurice, MD, Jillian Wong Millsop, MD, MS, Tina Bhutani, MD, and Wilson Liao, MD, to the development and writing of this article.

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

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

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

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

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

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

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