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Background

This blistering disorder is more appropriately placed in an acantholytic dyskeratosis. It is an autosomal dominantly inherited trait although sporadic cases have been reported. These lesions are characterized by small papules with a scale crust occurring on the seborrheic areas of the face, scalp, and trunk. The nails may be involved with characteristic red and white longitudinal bands and a V-shaped notching of the edge of the nail. Rarely, the oral cavity may be involved.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS Keratosis follicularis

DISEASE ASSOCIATIONS CHARACTERIZATION
ALOPECIA AREATA  
Alopecia areata in Darier disease and clinical findings in five affected family members.

Kerman University of Medical Sciences, Afzalipoor Hospital, Kerman, Iran.

Dermatol Online J. 2005 Dec 1;11(3):23. Abstract quote

A 32-year-old man known to have keratosis follicularis presented with a new problem of alopecia areata involving his scalp. His Darier disease had been present for 24 years and was manifested by pruritic eruptions that were more severe in the summer months.

Other family members, including his father, brother, and two sisters suffered from similar skin manifestations.
PARANEOPLASTIC  

Darier's disease associated with an underlying neoplasm in combination with a nodular fibroproliferative disease.

Dortzbach KL, Seykora JT, Werth VP.
J Am Acad Dermatol. 2003 Nov;49(5 Suppl):237-9 Abstract quote


Darier's disease is an autosomal dominant disease that typically arises during the first or second decades of life. It involves the abnormal keratinization of the epidermis, mucosa, and nails.

We describe a 74-year-old man with metastatic carcinoma in whom fibroproliferative disease and an acquired variant of Darier's disease developed, both of which may have been paraneoplastic processes.

 

PATHOGENESIS CHARACTERIZATION
ATP2A2 GENE MUTATIONS
(CA-ATPase)

Hum Mol Genet 1993;2:1763-1764

Disease has been mapped to this gene
Chromosome 12q23-24

Five mutations of ATP2A2 gene in Chinese patients with Darier's disease and a literature review of 86 cases reported in China.

Institute of Dermatology and Department of Dermatology, No: 1 Hospital, Anhui Medical University, 69 Meishan Road, 230032, Hefei, Anhui, China

Arch Dermatol Res. 2006 Jul;298(2):58-63. Abstract quote

Darier's disease (DD) is an autosomal dominantly inherited skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization.

To date, at least 140 mutations in the ATP2A2 gene have been identified as the genetic basis of DD. Here we reported three familial and two sporadic Chinese DD patients totally with four missense mutations (N767D, M494I, M494L, C318F) and one splice-site mutation (1288-6A-->G) in ATP2A2 gene, and presented a literature review of DD cases reported in China since 1989.

Our data add new variants to the repertoire of ATP2A2 gene in DD and confirms that most mutations in the ATP2A2 gene are private and missense type. Likewise, the literature review indicates that DD is not uncommon in China and presents more information about genotype-phenotype correlations.

Mutations in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase isoform cause Darier's disease.

Dhitavat J, Dode L, Leslie N, Sakuntabhai A, Lorette G, Hovnanian A.

The Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.
J Invest Dermatol. 2003 Sep;121(3):486-9. Abstract quote  

Darier's disease is an autosomal dominantly inherited skin disorder, characterized by loss of adhesion between epidermal cells and abnormal keratinization. ATP2A2 encoding the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA)2 has been identified as the defective gene in Darier's disease. All mutations previously reported occur in the region of ATP2A2 encoding both SERCA2a and SERCA2b isoforms. These isoforms result from alternative splicing of exon 20, with SERCA2b being the major isoform expressed in the epidermis.

In this report, we studied a family affected with Darier's disease and identified a deletion (2993delTG) in a region of exon 20 of ATP2A2, which is specific for SERCA2b. This heterozygous mutation predicts a frameshift with a premature termination codon (PTC+32aa) in the eleventh transmembrane domain of SERCA2b. It segregates with the disease phenotype in the family members tested, and functional analysis shows a drastic reduction of the expression of the mutated protein in comparison with the wild-type SERCA2b.

Our result suggests that the mutated allele causes the disease phenotype through loss of function of SERCA2b isoform. This finding indicates that SERCA2b plays a key role in the biology of the epidermis, and its defects are sufficient to cause Darier's disease.


A Japanese case of segmental Darier's disease caused by mosaicism for the ATP2A2 mutation.

Wada T, Shirakata Y, Takahashi H, Murakami S, Iizuka H, Suzuki H, Hashimoto K.
Br J Dermatol. 2003 Jul;149(1):185-8. Abstract quote  

Darier's disease is an autosomal dominant skin disorder that is characterized by multiple keratotic papules, focal loss of adhesion and abnormal keratinization. Mutations in the ATP2A2 gene encoding sarco/endoplasmic reticulum calcium pumping ATPase type 2 have been identified as the molecular basis of Darier's disease.

Segmental Darier's disease is a rare type of Darier's disease in which there is characteristic localization of the keratotic papules in a linear pattern following Blaschko's lines. In this study we examined ATP2A2 mutations in a Japanese patient with segmental Darier's disease. The samples from affected skin, unaffected skin and peripheral leucocytes were subjected to polymerase chain reaction (PCR). Direct sequencing of the PCR products was performed. Sequence analysis revealed that the patient had 160A-->G substitution mutation which predicts I54V.

This novel mutation was present in the affected skin, but not in the unaffected skin or peripheral leucocytes. This is the first report of segmental Darier's disease caused by mosaicism for an ATP2A2 mutation in Japan.
Bcl-2  
Reduced expression of the antiapoptotic proteins of Bcl-2 gene family in the lesional epidermis of patients with Darier's disease.

Department of Dermatology, University of Patras, Patras, Greece.

 

J Cutan Pathol. 2007 Mar;34(3):234-8. Abstract quote

Background: Dyskeratotic cells in Darier's disease (DD) are thought to represent apoptotic keratinocytes. Bcl-2 gene family proteins play a major role in the regulation of apoptosis of epidermal keratinocytes and reveal pleiotropic interactions with intracellular Ca(2+) homeostasis. The latter is impaired in DD because of mutations of ATP2A2 gene that encodes the type 2 isoforms of the sarcoplasmic/endoplasmic reticulum (ER) Ca(++) ATPase 2 (SERCA2) pump. Methods: The expression of Bcl-2, Bax, and Bcl-x(L) proteins was investigated in the epidermis of 11 patients with DD and of 11 sex- and age-matched healthy controls by immunohistochemistry.

Results: The expression of Bcl-2 and Bcl-x(L) was clearly reduced in the lesional epidermis of the patients, as compared with the normal epidermis of healthy controls, whereas the expression of Bax remained unaltered.

Conclusions: The alterations in the expression of Bcl-2 gene family proteins could be a crucial event for the activation of the apoptotic process in the lesional epidermis of DD patients and for the occurrence of the characteristic dyskeratotic keratinocytes. The question as to whether these alterations are associated with the ER Ca(2+) depletion in DD or represent secondary phenomena unrelated to the genetic defect of this genodermatosis remains to be elucidated.
P-CADHERIN  

Upregulation of P-cadherin expression in the lesional skin of pemphigus, Hailey-Hailey disease and Darierís disease

Megumi Hakuno, etal.

Journal of Cutaneous Pathology 2001; 28 (6): 277-281 Abstract quote

Background: Autoimmune blistering diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are known to be caused by binding of autoantibodies to the desmosomal cadherins, desmoglein 3 and desmoglein 1, respectively. Recently, mutations in the genes coding Ca2+ pumps leads to inherited blistering diseases, Hailey-Hailey disease (HHD) and Darierís disease (DD). Cadherins are a family of Ca2+-dependent cell adhesion molecules and P-cadherin is one of the major cadherins expressed in the epidermis. Although detailed mechanisms of acantholysis of these blistering diseases have not been fully clarified, abnormal expression of cadherins caused by altered Ca2+ concentration due to the binding of autoantibodies to cell surface or by mutations in Ca2+ pumps is suggested to be involved in mechanisms of acantholysis of these atuoimmune and inherited blistering diseases. The purpose of the present study was to determine whether altered P-cadherin expression is present in these diseases.

Method: Distribution patterns of P-cadherin in skin specimens from patients with PV (n=2), PF (n=2), HHD (n=4) and DD (n=3), were examined with confocal laser scanning microscopy using two anti-P-cadherin antibodies, 6A9 and NCC-CAD-299.

Results: In normal control skin, P-cadherin expression was restricted to the basal layer. In contrast, positive immunostaining of P-cadherin was observed not only in the basal cells, but also in the suprabasal cells in lesional skin of all the acantholytic diseases.

Conclusions: The present results clearly demonstrated that upregulation of P-cadherin expression occurs in the acantholysis in all the four blistering diseases PV, PF, HHD and DD. Upregulation of P-cadherin may be involved in the pathomechanism of both the autoimmune blistering diseases and the inherited blistering diseases.

TRCP1  
Up-Regulation of TRPC1 following SERCA2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease.

Departments of Biochemistry and Molecular Biology and Internal Medicine, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202; Department of Oral Biology, Korea 21 Project for Medical Science, Yonsei University College of Dentistry, Seoul 120-752, Korea; Department of Dermatology, Mayo Clinic College of Medicine, Rochester, MN 55905; Department of Functional Genetics of Epithelial Diseases, INSERM U563, 31024 Toulouse Cedex 3, France; Secretory Physiology Section, Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892

Mol Biol Cell. 2006 Aug 9 Abstract quote

We investigated the distribution and function of TRPC in epidermal skin cells. DD patient's demonstrated upregulation of TRPC1, but not TRPC3, in the squamous layers. Ca(2+) influx was significantly higher in keratinocytes obtained from DD patients and showed enhanced proliferation than normal keratinocytes. Similar upregulation of TRPC1 was also detected in epidermal layers of SERCA2(+/-) mice. HaCaT cells expressed TRPC1 in the plasma membrane. Expression of SERCA2 si-RNA in HaCaT cells increased TRPC1 levels and thapsigargin-stimulated Ca(2+) influx, which was blocked by SOCE inhibitors. Thapsigargin-stimulated intracellular Ca(2+) release was decreased in DD cells. DD Keratinocytes exhibited increased cell survival upon thapsigargin treatment. Alternatively, overexpression of TRPC1 or SERCA2-siRNA in HaCaT cells demonstrated resistance to thapsigargin-induced apoptosis.

These effects were dependent on external Ca(2+) and activation of NF-kappaB. Isotretinoin reduced Ca(2+) entry in HaCaT cells and decreased survival of HaCaT and DD keratinocytes. These findings put forward a novel consequence of compromised SERCA2 function in DD where upregulation of TRPC1 augments cell proliferation and restrict apoptosis.

We suggest that the anti-apoptotic effect of TRPC1 could potentially contribute to abnormal keratosis in DD.

 

CLINICAL VARIANTS CHARACTERIZATION
ORAL  
Darier disease: case report with oral manifestations.

Department of Stomatology (Oral Pathology), Bauru Dental School, University of Sao Paulo, Bauru, Sao Paulo, Brazil.

 

Med Oral Patol Oral Cir Bucal. 2006 Aug 1;11(5):E404-6. Abstract quote

Darier disease, also known as keratosis follicularis or dyskeratosis follicularis, is a rare autosomal dominant genodermatosis. It is clinically manifested by hyperkeratotic papules primarily affecting seborrheic areas on the head, neck and thorax, with less frequent involvement of the oral mucosa. When oral manifestations are present, they primarily affect the palatal and alveolar mucosa, are usually asymptomatic, and are discovered in routine dental examination.

Histologically, the lesions present suprabasal clefts in the epithelium with acantholytic and dyskeratotic cells represented by corps ronds and corps grains. This paper reports a case of an adult male patient presenting clinical signs of Darier disease in the palatal mucosa and skin on the neck and upper limbs. Intraoral biopsy of the affected area, analysis of family history and evaluation by a multidisciplinary team led to the diagnosis of Darier disease.

Dental professionals and pathologists should be aware of these lesions to allow correct diagnosis and proper management of this disease.

HISTOLOGICAL TYPES CHARACTERIZATION
General

Acantholytic keratinocytes are present forming corp ronds and corp grains, usually within a suprabasilar position

Hyperkeratosis, parakeratosis, follicular plugging, and irregular acanthosis may be present

VARIANTS  
Comedonal, cornifying and hypertrophic Darier's disease in the same patient: a Darier combination.

Department of Dermatology, Numune State Hospital, Turkey.

 

J Dermatol. 2006 Jul;33(7):477-80. Abstract quote

Our 42-year-old patient had comedonal Darier's disease (DD) on the face, comedonal cornifying DD on the upper back, and hypertrophic DD on both legs.

Biopsies taken from face, upper back and medial sides of the legs were found to be compatible with these clinical subtypes. The comedonal type was in the classical place, but the hypertrophic and cornifying types were not in the usual sites.

In addition to the classic histopathology of DD, we noted multiple, warty dyskeratoma-like structures in the comedonal type, marked compact hyperkeratosis in the cornifying type, and marked papillomatosis in the hypertrophic type.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
CONGENITAL ACANTHOLYTIC DYSKERATOTIC DERMATOSIS  

Congenital acantholytic dyskeratotic dermatosis: localized Darier disease or disseminated benign papular acantholytic dermatosis?

Bergua P, Puig L, Fernandez-Figueras MT, Baselga E, Alomar A.

Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Pediatr Dermatol. 2003 May-Jun;20(3):262-5. Abstract quote  

Acantholytic dyskeratosis is a histopathologic pattern defined by a hyperkeratotic and parakeratotic epidermis with intraepidermal clefts containing acantholytic and dyskeratotic keratinocytes.

These typical features are distinctive but not entirely pathognomonic of Darier disease, since they may occur at cutaneous and mucocutaneous sites in other conditions such as Grover disease, acantholytic and dyskeratotic epidermal nevus (nevus of Starink), warty dyskeratoma, or acantholytic papular dermatosis localized to the vulvocrural area.

We report a newborn girl who had congenital erosive papules and plaques located on the left thigh, left ankle, and right side of the neck. Histopathologic examination of a punch biopsy specimen disclosed findings typical of acantholytic dyskeratosis. In the absence of any family history or other manifestations of Darier disease, we propose the descriptive term "congenital acantholytic dyskeratotic dermatosis."

This descriptor characterizes our patient's disease on the basis of the clinical and histopathologic findings and facilitates recognition of this condition until a putative genetic mutation can be demonstrated or ruled out.

 

TREATMENT CHARACTERIZATION
PHOTODYNAMIC THERAPY  

Treatment of Darier's disease with photodynamic therapy.

Exadaktylou D, Kurwa HA, Calonje E, Barlow RJ.

Department of Histopathology, St John's Institute of Dermatology, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
Br J Dermatol. 2003 Sep;149(3):606-10 Abstract quote.  

BACKGROUND: Photodynamic therapy (PDT) using topical 5-aminolaevulinic acid (5-ALA) as a photosensitizer has been reported in the treatment of both neoplastic and benign cutaneous disorders.

OBJECTIVES: To evaluate the efficacy of photodynamic therapy in selected patients with Darier's disease (keratosis follicularis).

METHODS: Six patients with Darier's disease were assessed before and after treatment with PDT using 5-ALA and mean fluence rates of 110-150 mW cm-2.

RESULTS: Of the six patients, one was unable to tolerate the treatment. Of the remaining five, all experienced an initial inflammatory response that lasted two to three weeks. In four of the five patients, this was followed by sustained clearance or improvement over a followup period of six months to three years. Three of these four patients were on systemic retinoids and the fourth had discontinued acitretin prior to PDT. In the fifth patient partial improvement was followed by recurrence after etretinate therapy was discontinued. Biopsy specimens taken immediately after the procedure in two patients demonstrated a mild inflammatory cell infiltrate in the dermis. A biopsy obtained eighteen months after PDT from a successfully treated area showed no signs of Darier's disease and a subtle increase of collagen in the upper dermis.

CONCLUSIONS: Photodynamic therapy can be viewed as a potential adjunctive modality for Darier's disease but should not be considered as a substitute for retinoids in patients who require systemic treatment.
TACROLIMUS  
A case of Darier's disease successfully treated with topical tacrolimus.

Department of Clinical Medicine and Immunological Sciences, Section of Dermatology, University of Siena, Italy

J Eur Acad Dermatol Venereol. 2006 Jan;20(1):84-7. Abstract quote

Tacrolimus is a macrolide that inhibits T-cell activation. The most extensive experience with topical tacrolimus has been in treating atopic dermatitis but it has been used in various skin diseases, including Hailey-Hailey disease, with encouraging results.

We report a case of extensive Darier's disease successfully treated with topical tacrolimus, after suspension of oral isotretrinoin due to major depression.
TAZAROTENE  
Linear Darier's disease successfully treated with 0.1% tazarotene gel "short-contact" therapy.

Department of Human and Hereditary Pathology, Institute of Dermatology, University of Pavia, IRCCS Policlinico S. Matteo, Pavia, Italy.

Eur J Dermatol. 2006 Jan-Feb;16(1):59-61. Abstract quote

We report the case of a 25 year old man affected by linear Darier's disease. The patient presented with brownish keratotic papules involving the trunk in a linear pattern. These lesions were successfully treated within 6 weeks with 0.1% tazarotene gel "short contact".

The good response that was obtained suggests that the use of "short contact" tazarotene could be useful in the treatment of linear Darier's disease.

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