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

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.     

The management of Darier's disease

Darier's disease (keratosis follicularis) is a rare, dominantly inherited condition which is characterised by the presence of warty papules and plaques on the trunk, scalp and flexures. Diagnostic nail changes are present in most patients. Suprabasal clefting, acantholysis and dyskeratosis are present in involved skin and the diagnosis may be confirmed by a skin biopsy. The disease never remits. Exacerbating factors such as heat, sweating and ultraviolet light should be avoided. Topical therapy with emollients, moderately potent corticosteroids and antimicrobials may provide some symptomatic relief, but have no effect on the progress of the disease. Oral retinoids are effective in most patients. Complications such as cutaneous infections, blistering and salivary gland obstruction may occur in some patients.     

Darier's disease in Singapore

BACKGROUND: Darier's disease is a rare, dominantly inherited genodermatosis. Although it has been well studied in caucasians, very little is known about the clinical spectrum of this disorder among Asians. OBJECTIVES: To determine the demographic and clinical profile of Asian patients with Darier's disease. METHODS: This is a retrospective study of all new cases of Darier's disease seen in our centre over a 20-year period (1982-2002). Results Twenty-four nonrelated cases of Darier's disease were studied. The incidence rate was 3.1 per million per decade. The gender distribution was 19 males and five females, and the ethnic origin was 21 Chinese, two Malays and one Nepalese. The peak age of onset was between 11 and 20 years. Sun exposure exacerbated the disease in 13 of the patients, and three had neuropsychiatric disorders. The disease affected predominantly seborrhoeic areas in 19 patients, flexural in three, acral in one and was segmental in one patient. Hand involvement was common and included palmar pits in nine patients, acrokeratosis verruciformis in four and nail changes in 12 patients. Haemorrhagic macules were not seen. Rare features included oral mucosal lesions (two patients) and guttate leucoderma (three patients). Pathogens involved in cutaneous infections included herpes simplex virus, Staphylococcus aureus, Streptococcus species and Morganella morgani. All patients treated with oral retinoids had improvement of clinical signs. In contrast, the response to topical retinoids was poor. CONCLUSIONS: Compared with western studies, our results show a similar incidence rate, age of onset, distribution of disease patterns and association with neuropsychiatric disorders. Features that differ include co-occurrence of guttate leucoderma, rarity of acrokeratosis, absence of haemorrhagic macules and poor response to topical retinoids.     

Treatment of Darier's disease with photodynamic therapy

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.     

Clinical improvement in Darier's disease with photodynamic therapy

We report a patient with Darier's disease successfully treated with photodynamic therapy. She had previously been recalcitrant to treatment with emollients, topical corticosteroids and retinoids. Photodynamic therapy was trialled with significant clinical improvement in her cutaneous symptoms and signs that was maintained for over 27 months.     

Combined treatment of psoriasis with etretinate plus hydroxyurea

Nineteen patients with extensive, therapy-resistant psoriasis received combined treatment with etretinate plus hydroxyurea. The individual components were given at a reduced dosage and hydroxyurea was administered intermittently. During 12 weeks of treatment, complete remission or marked improvement was observed in 16 patients (84%). The combination of etretinate and hydroxyurea in the above-mentioned regimen was both effective and well-tolerated.     

Localized Darier's disease in a Blaschkoid distribution: two cases of phenotypic mosaicism and a review of mosaic Darier's disease

Darier's disease is a rare autosomal dominant genodermatosis. Characteristic skin and nail changes consist of bilateral crusted red-brown papules and plaques in a seborrheic distribution, and V-shaped nicking or longitudinal ridging of the nails. In limited cases, a segmental distribution of this disease may be present in which localized lesions, found along the lines of Blaschko, are otherwise indistinguishable from those of generalized Darier's disease. Genomic mosaicism in localized lesions of Darier's disease is a new concept that was recently demonstrated in individuals of mosaic phenotypes. Both type 1 and type 2 mosaic phenotypes have been reported. We report two cases of type 1 localized Darier's disease in a Blaschkoid distribution and review the genetic implications of phenotypic mosaicism within the field of Darier's disease.     

Darier's disease complicated by Kaposi's varicelliform eruption due to herpes simplex virus

Darier's disease is an autosomal dominant dermatosis. It may rarely be complicated by localized or widespread cutaneous viral infections. We describe a case of Kaposi's varicelliform eruption due to herpes simplex virus type 1 presenting in a patient with Darier's disease.     

Histological characterization of Darier's disease in Tunisian families

Background  Darier's disease (OMIM 124200) is an autosomal-dominant skin disorder characterized by warty papules and plaques in seborreheic areas, palmo-plantar pits and distinctive nail abnormalities. The disease has complete penetrance in adults and variable expressivity. It is caused by mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca²⁺ ATPase type 2 isoform (SERCA2).
Objective  We report histological investigations of six unrelated Tunisian families including 15 affected individuals with Darier's disease mutations.
Results  The typical histological features of Darier's disease have been observed in the 15 patients. Variable histological features have been observed among Tunisian patients ranging from mild to moderate lesions of Darier's disease. A significant correlation has been observed between the clinical presentation of the Darier's disease (mild or moderate) and the intensity of the histological features. Isolated acral form of Darier's disease was seen in one case. Two distinct original associations have been observed: Darier's disease/pemphigus vulgaris in one patient and Darier's disease/ichtyosis in the other patient.
Conclusion  Our findings confirmed the clinical heterogeneity of Darier's disease on the basis of histological study. The intensity of the histological features could be closely correlated to the severity of Darier's disease clinical presentation.     

Topical treatment of ichthyoses and Darier's disease with 13-cis-retinoic acid

In a bilaterally paired double-blind comparison study, a cream containing 0.1% 13-cis-retinoic acid (13-cis-RA) and cream base only were applied over 4 weeks in seven patients with non-erythrodermic lamellar ichthyosis (NELI), two patients with Darier's disease and one patient with autosomal dominant ichthyosis vulgaris (ADIV). In two patients with NELI and two patients with Darier's disease a half-side effect was observed in favour of the side treated with 13-cis-RA. In three patients an induction of cytokeratin-4, and in one of these patients expression of cytokeratin-13, were observed after therapy. Topical 13-cis-RA-appears to be a promising approach in the treatment of disorders of keratinization. The selective modulation of the cytokeratin pattern may provide an immunohistochemical tool to investigate the mode of action of retinoids.     

Linear Darier's disease in a patient with recurrent carcinoma of the bladder reflects cutaneous mosaicism

We report a case where occurrence of linear Darier's disease along Blaschko's lines followed radiotherapy due to the subject's recurrence of a longstanding carcinoma of the bladder. Scattered papules on the chest and hack preceded the exacerbation of the disease. In this case, localised linear disease may he triggered on a background of a more disseminated disease which raises the possibility that linear keratosis follicularis is a separate entity of cutaneous mosaicism for the mutation responsible for Darter's disease.     

The behaviour of Bcl-2, Bax and Bcl-x in Darier's disease

BACKGROUND: Darier's disease (DD) is a rare autosomal dominant disorder of keratinization caused by a mutation of the ATP2A2 gene. There is little information on the behaviour of Bcl-2, Bax and Bcl-x in DD. OBJECTIVES: To investigate the dynamic control and the behaviour of Bax, Bcl-2 and Bcl-x in DD. We asked whether members of the Bcl-2 family might manifest their effects through modulation of intracellular calcium signalling or whether the gene that encodes the sarco/endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2) modulates the Bcl-2 family in the regulation of apoptosis in DD. Methods Immunohistochemical methods were used. RESULTS: There was no immunoreactivity for Bcl-2 and Bcl-x in epidermal keratinocytes in lesional epidermis. Staining for Bax was evident in the cells of the perilesional uninvolved skin, but decreased in the epidermal cells of lesional involved skin. CONCLUSIONS: The decrease or absence of Bcl-2 and Bcl-x and the imbalance of Bax in the epithelial cells of affected DD skin is likely to be an important control point determined by the genetic mutation of SERCA2, which modifies the programme of the antiapoptotic proteins. The consequent imbalance of the factors controlling apoptosis in keratinocytes underlines another apoptotic pathway responsible for the dyskeratotic cells in DD.     

Mutation analysis of the ATP2A2 gene in Taiwanese patients with Darier's disease

BACKGROUND: Darier's disease (DD) is an autosomal dominant skin disorder characterized by abnormal keratinization and acantholysis. Pathogenic mutations in the ATP2A2 gene encoding SERCA2, a calcium pump of the sarco/endoplasmic reticulum, have recently been identified. OBJECTIVES: To identify mutations of the ATP2A2 gene in Taiwanese patients with DD. METHODS: Mutation analysis of genomic DNA was performed on five families with DD and two sporadic cases. All 21 exons and the flanking intron boundaries were amplified and followed by direct sequencing. Restriction fragment analysis or direct sequencing in each family and in normal controls further verified the mutations. RESULTS: Mutations in the functional domains of the ATP2A2 gene were identified and verified in all seven pedigrees. They consisted of four mis-sense mutations (R131Q, P680L, G703S, G807R), one altered splice-site mutation (2980 + 5insA) and one frameshift deletion mutation (1457-1458delAG). Of these, R131Q, which was reported twice previously, was detected in two unrelated families. The remaining five were novel mutations. CONCLUSIONS: Six pathogenic mutations in the ATP2A2 gene were identified in seven Taiwanese DD pedigrees. The results confirmed that most mutations in the ATP2A2 gene are private and of the mis-sense type.     

毛囊角化病九例ATP2A2基因突变研究

目的:检测9例毛囊角化病(Darier's disease,DD)患者的基因突变.方法:提取1家系中2例患者、7例散发患者及100名正常对照外周血基因组DNA,用Sanger测序检测9例DD患者ATP2A2的致病突变.对不携带ATP2A2突变的患者,应用全外显子组测序(WES)寻找可能导致该疾病的其他变异.364名健康...     

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

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.     

毛囊角化病一家系及三例散发患者ATP2A2基因突变研究

目的：对毛囊角化病（Darier's disease, DD）一家系及三例散发患者进行ATP2A2基因的突变分析。方法：收集先证者及其家系成员、散发病例的临床资料和外周血,采用PCR技术扩增ATP2A2基因所有编码区及侧翼序列,用Sanger法测序检测潜在的突变,选取与患者无亲缘关系的100例健康人作为对照,同时对已报道的ATP2A2基因突变进行文献回顾。结果：家系中三例患者均检测出ATP2A2基因第5号外显子c.380 G>A(p.G127D)新发错义突变;散发患者S1检测出第13号外显子C.1676G>A(p.R559Q)错义突变,散发患者S2检测出第14号外显子c. 2001C>T(p.D667D)同义突变,散发患者S3未检测出突变。结论：本研究中共发现三个突变,其中c.380G>A(p.G127D)在中国人群中首次报道,拓展了ATP2A2的基因突变谱。     

Calcium pumps and keratinocytes: lessons from Darier's disease and Hailey-Hailey disease

Darier's disease and Hailey-Hailey disease are autosomal dominantly inherited skin disorders in which desmosomal adhesion between keratinocytes is abnormal. ATP2A2 and ATP2C1 have been identified as the causative genes for Darier's disease and Hailey-Hailey disease, respectively. ATP2A2 encodes the sarco(endo)plasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2) pump, while ATP2C1 encodes a secretory pathway Ca(2+)/Mn(2+)-ATPase (SPCA1) found in the Golgi apparatus. We review recent work into the function of these pumps in human keratinocytes and discuss how mutations in these genes might cause these diseases by altering the formation or stability of desmosomes.     

Identification of mutations in the ATP2A2 gene in patients with Darier's disease from Hungary

Mutation analysis in the ATP2A2 gene had been performed in eight Hungarian patients with Darier's disease (DD), to get more information about phenotype-genotype relations. All patients had moderate to severe skin symptoms. Polymerase chain reaction (PCR) amplification of the entire coding region of ATP2A2 was performed. Mutation detection strategies included heteroduplex scanning by conformation-sensitive gel electrophoresis (CSGE) and direct nucleotide sequencing. We found distinct, heterozygous mutations (five missense, one nonsense, one deletion, and one insertion), six of which were novel. In a 31-year-old DD woman with learning difficulties we disclosed a previously described missense mutation (D702N) in exon 15. A 44-year-old DD woman had a novel T insertion at nucleotide 559 in exon 7 of the ATP2A2 gene, which resulted in a premature termination codon (PTC) at codon 192. A woman, whose skin symptoms developed unusually late, at the age 50, had a new T deletion (1320delT) in exon 11 resulting in a PTC at codon 448. Our most severe case had a known missense mutation N39T, resulting in a non-conservative amino acid change at the upstream stalk region. Three new missense mutations (A161D, R164S, and Q790P) affected conservative regions of the SERCA2 protein within the activation (A)-domain and the M6 transmembrane region. A further new nonsense mutation (C909X) was detected in the M8 transmembrane domain. Our data suggest that differences in DD phenotypes are probably also related to factors different from the type of causative mutation.     

Genetic epidemiology of Darier's disease: a population study in the west of Scotland

BACKGROUND: Darier's disease has a world-wide distribution, but estimates of prevalence have varied. The discovery that the disease is due to mutations in ATP2A2 provides the opportunity to study the genetic epidemiology of the disease in localized populations. OBJECTIVES: To survey the prevalence of Darier's disease in the west of Scotland and look for founder effects in this population. METHODS: We ascertained cases of Darier's disease in the west of Scotland and used genealogy and mutational analysis to seek common ancestry. RESULTS: Seventy-eight current cases were identified, giving a prevalence of approximately 1 : 30 000. While 63 cases gave a history of Darier's disease in previous generations, conventional genealogy identified only two pairs of two family groups with common ancestry within the last 180 years. Eleven patients (14%; three of whom had in total four affected children) had probable de novo mutations. Causative mutations in ATP2A2 have been identified in 11 of 15 pedigrees screened for mutation, but no two share the same mutation. CONCLUSIONS: High estimates of prevalence are likely to be due to intensive ascertainment, rather than founder effects. Darier's disease is likely to be more common than has been recognized in other populations.