Darier's Disease Research Articles

A novel ATP2A2 mutation in Darier and genotype phenotype: correlation analysis.

Darier's disease (DD) is a skin disorder caused by mutations in the ATP2A2 gene. Researchers have been investigating the correlation between genotype and phenotype in DD. Understanding the genotype-phenotype relationship in DD can enhance our comprehension of the genetic background and phenotypic characteristics of the condition, as well as the relationship between its systemic and localized manifestations. This study aimed to investigate the molecular pathogenesis of DD in a Chinese family, and to elucidate the genotype-phenotype correlation in DD by summarizing relevant literature. Gene mutations associated with DD were screened by whole-exome sequencing and verified using Sanger sequencing. Genetic analysis assessed the potential impact of these mutations. Genotype-phenotype correlation was obtained by chi-square analysis using literature search test. (1) A novel ATP2A2 Missense mutation, c.2560T>C (p.W854R), was identified and confirmed by Sanger sequencing. Annotation analysis with the ANNOVAR tool indicated that this mutation disrupts normal protein function and is linked to DD clinical manifestations. (2) Genotype-phenotype analysis showed a significant correlation between the prevalence of DD-related mental disorders and geographic regions (P = 0.00), but no association between mutation type and mental disorder prevalence (P = 0.324). The age of onset varied between sporadic and familial cases (P = 0.032), averaging 33years in sporadic cases and 16years in familial cases. By analyzing the genotype-phenotype correlation, we aim to enhance our understanding of the genetic basis of DD. This research could improve early diagnosis, intervention, and the development of personalized long-term health management plans.

Carbon dioxide laser treatment for Darier disease

Carbon dioxide laser treatment for Darier disease

A Rare Case of Darier Disease Flaring Up During Pregnancy

A Rare Case of Darier Disease Flaring Up During Pregnancy

Microbial imbalance in Darier disease: Dominance of various staphylococcal species and absence of Cutibacteria

Darier disease (DD) is a rare autosomal dominant genodermatosis characterized by erythematous papules and plaques mainly involving sebaceous areas, such as the face, chest and back. Skin microbiome plays an essential role in maintaining skin homeostasis. A disturbed skin microbiome may contribute to the exacerbation of DD. We investigated the bacterial composition of two predilectional sites in DD patients and healthy individuals. We also measured the microbiome composition of deeper skin layers, where diversity was significantly reduced compared to the superficial layer of the skin from the same area. The microbiome of DD patients at lesional sites differed from that of non-lesional skin areas; moreover, non-lesional sites were different from those of the controls. Lesional areas were dominated by Staphylococcus species, such as S. aureus, S. epidermidis, S. hominis, S. sciuri, and S. equorum. However, levels of Cutibacterium acnes (formerly Propionibacterium acnes) and C. acnes subspecies defendens were significantly lower in lesional sites than in non-lesional sites. A significant decrease was measured in the levels of these two bacteria between non-lesional and control samples. Our findings may indicate that alterations in the skin microbiome could contribute to the inflammation of skin lesions in DD.

The unusual suspect: Inverted follicular keratosis of eyelid simulating a malignant lesion

The unusual suspect: Inverted follicular keratosis of eyelid simulating a malignant lesion

The use of photodynamic therapy in the management of darier disease and Hailey-Hailey disease: a systematic review.

Darier disease and Hailey-Hailey disease are rare autosomal dominant genodermatoses that negatively impact patient quality of life. In addition, they pose challenges to dermatologists who manage these diseases. There is currently no treatment that reliably induces remission for either disease, leaving patients dependent on symptom management. Oral and topical retinoids are the most commonly used therapies but have numerous side effects that often lead to discontinuation or inability to tolerate long-term treatment (Burge and Wilkinson in J Am Acad Dermatol 27:40-50, 1992). Due to the rarity of these diseases, there are no clinical trials investigating treatment options for the persistent flares patients experience. In light of this, dermatologists have tried various methods used in the management of other inflammatory disorders including photodynamic therapy (PDT). A systematic review was conducted to investigate this treatment option which yielded a total of 12 studies that had reported the use of photodynamic therapy (PDT) as a treatment option for Darier or Hailey-Hailey disease. Though results showed that PDT can induce disease remission for up to several months or years, there are many unanswered questions that need to be addressed before adopting PDT as a leading treatment option for those genodermatoses. In particular, cost, tolerability, and efficacy and safety in patients who are skin of color need to be further studied. Lastly, recommendations on treatment duration, number of sessions, photosensitizing agents, lasers, and continuation or discontinuation of topical and systemic medications need to be appraised before formal recommendations can be made.

Acantholytic Dyskeratoses of the Vulva: Clinicopathologic Characterization of 16 Cases and Review of the Literature.

The vulva and perineum are rarely involved by acantholytic dyskeratoses, including Hailey-Hailey disease, Darier disease, papular acantholytic dyskeratosis of the genitocrural area, acantholytic dyskeratotic acanthoma, and warty dyskeratoma. These entities show broad histomorphologic overlap, generally requiring clinical correlation for definitive classification. This institutional series aims to better characterize vulvar acantholytic dyskeratoses and provide a practical literature review and diagnostic aid for gynecologic pathologists. Our institutional archives contained 16 vulvar acantholytic dyskeratoses diagnosed between 1990 and 2023. Affected patients were 36 to 79 (mean, 58) years old and presented with one or more asymptomatic (n = 9) or pruritic (n = 6) lesions involving the vulva (predominantly the labia majora), with additional perineal involvement in 2. Four patients have known Hailey-Hailey disease. Eleven cases comprised singular, raised, erythematous, or skin-colored papules, measuring 0.2 to 0.6 (mean, 0.3) cm. Two patients had oligofocal (both with known Hailey-Hailey disease) vulvar lesions, and 2 had multifocal vulvar lesions (one with known Hailey-Hailey disease). Histologically, all showed acantholysis and dyskeratoses (abundant in 8, focal in 8, with corps ronds generally more conspicuous than corps grains). Additional features included suprabasal clefting (n = 14), dermal papillomatosis (n = 12), and acanthosis (n = 8). Adnexal involvement was rare (n = 1). No histologic features reliably distinguished sporadic versus syndromic acantholytic dyskeratoses. Sporadic lesions were cured by local excision. Patients with Hailey-Hailey disease were variably responsive to corticosteroids. Neither our series nor the literature indicate a significant correlation between sporadic or syndromic acantholytic dyskeratosis and squamous cell carcinoma. Important differential diagnoses include pemphigus vulgaris and pemphigus vegetans, for which direct immunofluorescence may be performed, when indicated.

Dantrolene corrects cellular disease features of Darier disease and may be a novel treatment

Darier disease (DD) is a rare severe acantholytic skin disease caused by mutations in the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2). SERCA2 maintains endoplasmic reticulum calcium homeostasis by pumping calcium into the ER, critical for regulating cellular calcium dynamics and cellular function. To date, there is no treatment that specifically targets the disease mechanisms in DD. Dantrolene sodium (Dl) is a ryanodine receptor antagonist that inhibits calcium release from ER to increase ER calcium levels and is currently used for non-dermatological indications. In this study, we first identified dysregulated genes and molecular pathways in DD patient skin, demonstrating downregulation of cell adhesion and calcium homeostasis pathways, as well as upregulation of ER stress and apoptosis. We then show in various in vitro models of DD and SERCA2 inhibition that Dl aided in the retention of ER calcium and promoted cell adhesion. In addition, Dl treatment reduced ER stress and suppressed apoptosis. Our findings suggest that Dl specifically targets pathogenic mechanisms of DD and may be a potential treatment.

Successful treatment of Darier's disease with apremilast and review of reported cases.

Darier's disease (DD) is a rare autosomal dominant genetic disorder caused by a mutation in ATP2A2, which encodes calcium (Ca2+) ATPase pumps in the endoplasmic reticulum. In this report, we present the first documented case in Japan successfully treated with apremilast. An 18-year-old female presented with red or brown hyperkeratotic papules and plaques on her head, neck, and chest. Histopathological examination revealed a hyperkeratotic, acanthotic epidermis, along with suprabasal acantholysis characterized by corps ronds and grains. Exome sequencing of DNA from peripheral blood mononuclear cells identified a missense mutation in ATP2A2. Based on the above results, we diagnosed her with DD despite the absence of a family history. Given the effectiveness of apremilast, a phosphodiesterase 4 inhibitor, in treating Hailey-Hailey disease (HHD), a genetically related disorder involving ATPases in epidermal calcium channels, we opted for apremilast therapy. Eight weeks post-initiation, significant improvement was observed in the patient's skin lesions on the head, neck, and chest. In this paper, we discuss the successful treatment of DD and HHD cases with apremilast, providing insights into its therapeutic potential, and offer a comprehensive review.

Dariers Disease with Oral Manifestations : A Clinical Rarity : Case Report

Darier disease (DD), also known as keratosis folicularis and White disease , is an inherited autosomal dominant genodermatosis. DD often develops in childhood, persists through adolescence and causes small papules predominantly in seborrheic areas such as the face , chest and back. The oral lesions are asymptomatic and comprise multiple white papules in the buccal mucosa and the soft and hard palate , giving a cobblestone appearance. Histologically , DD is characterized by corps ronds and grains in addition to suprabasal cleavage. There are no currently validated curative treatments available for DD, with the majority of cases treated symptomatically. This is a case report of DD with varied manifestations intraorally and extraorally. Diagnosis was established on the basis of clinical , histopathological and dermatological findings. Patient reported to the OPD with a chief complaint of loose teeth. A holistic treatment approach was carried out based on clinical and histological findings. Functional and esthetic demands were met with satisfactory results.

Unmet Needs in Darier's Disease from a Patient's Perspective: Lessons Learnt from the German Registry.

The MDHHgermany registry was initiated to characterize the "real-life" situation of affected individuals with Darier's disease (DD; Morbus Darier, MD) and Hailey-Hailey disease (HH), including their treatment and healthcare. To gain deeper insights into medical care of patients with DD, various aspects such as demographics, subjective symptoms, patient satisfaction with medical care, past and current therapies were explored. Patients with diagnosed DD were included. Subjective symptoms such as itch, pain and burning sensation were assessed. Individual therapy goals were recorded and patients assessed previous/current therapies along with satisfaction of medical care and treatment. A total of 55 patients were recruited; 47 patients were eligible for the analysis. Pruritus was rated the most bothersome symptom. Some 42.6% had not received systemic treatment so far or systemic therapies were rated ineffective (32.6%). Most commonly oral retinoids were prescribed, followed by corticosteroids. Patient satisfaction with medical care and treatment proved to be mediocre. This "real-life" data show an alarming unmet need regarding patients' satisfaction with medical care and treatment, evidenced by the reported lack of disease control. Further studies and interventions are needed to improve the spectrum of available therapies. MDHHgermany provides a foundational platform for future clinical trials, epidemiological studies, and pathophysiological analyses.

Comorbidities and Treatment Options for Acne Keloidalis Nuchae

Acne keloidalis nuchae (AKN) is a condition that involves chronic inflammation of the hair follicles on the occipital scalp and posterior neck that often progresses to keloid-like plaques. AKN has most commonly been reported to affect postpubertal males of African descent. The cause of AKN has not been definitively described; however, it is likely an inflammatory response to trauma or infection of the scalp. AKN is associated with chronic scalp folliculitis, hidradenitis suppurativa, folliculitis decalvans, acne mechanica, keratosis follicularis spinulosa decalvans, cutis verticis gyrata, metabolic syndrome, acanthosis nigricans, and hypothyroidism. Treatment for AKN begins with topicals, antibiotics, and intralesional steroid injections. Refractory cases are treated with laser and surgery. Isotretinoin, cryotherapy, phototherapy, electrosection, and radiotherapy have also been effective in treating AKN but are less commonly used. In this review, we describe the existing understanding of AKN with a focus on comorbid conditions and available treatment options.

Proliferating inverted follicular keratosis of genital skin: Case series of a challenging variant.

Inverted follicular keratosis (IFK) is a benign cutaneous epithelial tumor typically presenting as a small papule on the head and neck. We have encountered deep endophytic tumors on genital skin with some characteristics of IFK but also atypical features, raising concern for squamous cell carcinoma (SCC). Four such tumors were identified in our database. Histopathologic analysis and ancillary studies were performed. All patients were young women who presented with a solitary 0.5-1.0 cm lesion on the vulva, perineum, or inner buttock. Each showed a squamous proliferation arising from the epidermis, with endophytic growth that was deep and bulbous but not infiltrative. The tumor lobules contained eosinophilic keratinocytes, forming numerous squamous eddies. Small irregular spaces and dyskeratotic cells were frequently found. Nuclear pleomorphism was minimal to absent. All demonstrated wild-type p53 expression and lack of p16 block positivity. In situ hybridizations for human papillomavirus were negative. None of the three cases with follow-up data showed evidence of recurrence. The absence of infiltrative growth or significant pleomorphism, the presence of numerous squamous eddies, the reassuring immunoprofile, and the lack of evidence of recurrence support a variant of IFK and speak against SCC. We propose the term "proliferating IFK" to highlight the florid squamous proliferation. Recognition of this unusual variant would avoid overdiagnosis of SCC.

Inverted Follicular Keratosis in the Post-Auricular Region: A Case Report

Inverted Follicular Keratosis in the Post-Auricular Region: A Case Report

Kaposi’s Varicelliform Eruption in a Patient with Darier’s Disease: A Rare Case Report

Darier's disease is a rare autosomal dominant disorder, characterized clinically by the appearance of multiple, pruritic, discrete, and scaly papules affecting seborrheic areas coupled with palmar pits, nail changes, and mucosal involvement. Histologically, the lesions show supra-basal clefts with acantholytic and dyskeratotic cells. Kaposi's varicelliform eruption (KVE) is the dissemination of the herpes simplex virus in the setting of preexisting skin disease, presenting with disseminated vesico-pustules. Darier's disease presenting as KVE is a rare occurrence. If misdiagnosed or left untreated can increase the rate of mortality. Here, we report the case of a 25-year-old male patient who presented with multiple vesicles and crusted lesions over the face, neck, chest, and upper back. After thorough cutaneous examination, he was found to have multiple hyperkeratotic, dirty-warty papules over seborrheic areas, present since childhood. With detailed clinical and laboratory evaluation, we arrived at the diagnosis of KVE with underlying Darier disease.

Persistent Cutaneous Lesions of Darier Disease and Second-Hit Somatic Variants in ATP2A2 Gene

Darier disease (DD) is a rare genetic skin disorder caused by heterozygous variants in the ATP2A2 gene. Clinical manifestations include recurrent hyperkeratotic papules and plaques that occur mainly in seborrheic areas. Although some of the lesions wax and wane in response to environmental factors, others are severe and respond poorly to therapy. To investigate the molecular mechanism underlying the persistency of skin lesions in DD. In this case series, DNA was extracted from unaffected skin, transient and persistent lesional skin, and blood from 9 patients with DD. Genetic analysis was used using paired-whole exome sequencing of affected skin and blood or by deep sequencing of ATP2A2 of affected skin. Chromosomal microarray analysis was used to reveal copy number variants and loss of heterozygosity. All variants were validated by Sanger sequencing or restriction fragment length polymorphism. Paired whole-exome sequencing and deep sequencing of ATP2A2 gene from blood and skin samples isolated from persistent, transient lesions and unaffected skin in patients with DD. Germline and somatic genomic characteristics of persistent and transient cutaneous lesions in DD. Of 9 patients with DD, all had heterozygous pathogenic germline variants in the ATP2A2 gene, 6 were female. Participant age ranged from 40 to 69 years on enrollment. All 11 persistent skin lesions were associated with second-hit somatic variants in the ATP2A2 gene. The somatic variants were classified as highly deleterious via combined annotation-dependent depletion (CADD) scores or affect splicing, and 3 of them had been previously described in patients with DD and acrokeratosis verruciformis of Hopf. Second-hit variants in the ATP2A2 gene were not identified in the transient lesions (n = 2) or the normal skin (n = 2). In this study, persistent DD lesions were associated with the presence of second-hit somatic variants in the ATP2A2 gene. Identification of these second-hit variants offers valuable insight into the underlying mechanisms that contribute to the lasting nature of persistent DD lesions.

Darier disease is associated with neurodegenerative disorders and epilepsy

Darier disease (DD) is a rare monogenetic skin disorder with limited data on its potential association with neurological disorders. This study aimed to investigate the association between DD and neurological disorders, specifically Parkinson's disease, dementias, and epilepsy. Using Swedish national registers in a period spanning between 1977 and 2013, 935 individuals with DD were compared with up to 100 comparison individuals each, randomly selected from the general population based on birth year, sex, and county of residence at the time of the first diagnosis of DD. Individuals with DD had increased risks of being diagnosed with Parkinson's disease (RR 2.1, CI 1.1; 4.4), vascular dementia (RR 2.1, CI 1.0; 4.2), and epilepsy, (RR 2.5, CI 1.8; 3.5). No association of DD with other dementias were detected. This study demonstrates a new association between DD and neurodegenerative disorders and epilepsy, underlining the need for increased awareness, interdisciplinary collaboration, and further research to understand the underlying mechanisms. Early identification and management of neurological complications in DD patients could improve treatment strategies and patient outcomes. The findings also highlight the role of SERCA2 in the pathophysiology of neurological disorders, offering new targets for future research and potentials for novel treatments.

Darier disease: Histopathology revisited.

Darier disease (DD) is a rare genodermatosis. Literature on this topic is overwhelmingly dominated by case reports with rare clinical presentations, which have mentioned the histopathologic features briefly. The aim of this study was to document the histopathology of DD. Skin biopsies diagnosed as Darier disease based on clinicopathologic correlation over 12 years were reviewed for various epidermal and dermal features. There were 16 patients included, who most commonly presented in the third decade, with slight female predilection. The most common clinical presentation was hyperpigmented, hyperkeratotic, papules and plaques (91%), with 69% affecting the trunk. In addition to the classic suprabasal acantholytic clefts, we noted some unusual features: absence of parakeratosis (19%), a cornoid lamella-like pattern (62%), follicular acantholysis (13%) and multiple foci of involvement within a single biopsy (63%). Features such as the presence of dyskeratotic cells and minimal dermal lymphocytic infiltrates were concordant with previous literature. The limitation of this study was the small sample size. To conclude, pathologists must be aware of the variations in histopathology of Darier's disease, especially when challenged with atypical clinical presentations. The Darier-like pattern is met within several acantholytic diseases, and clinicopathologic correlation has the last word in arriving at a diagnosis.

First report of ATP2A2 somatic mosaicism occurring during embryogenesis in transient acantholytic dermatosis

AbstractTransient acantholytic dermatosis (TAD) is a relatively common skin disease that typically affects older individuals, which shows clinical and histologic similarities to autosomal dominant Darier disease. TAD was recently shown to be caused by somatic ATP2A2 damaging variants. In this study, we performed Sanger sequencing and droplet digital PCR (ddPCR) in a Japanese elderly male with TAD to identify ATP2A2 somatic mosaicism occurring during embryogenesis for the first time and mutant allelic fraction (MAF). Sanger sequencing revealed a known heterozygous substitution c.1645C>T, p.Arg549* in ATP2A2 from blood and the affected skin containing the epidermis and dermis, whereas the signals of the mutated allele were weaker, suggesting that discrepancy of signal intensities demonstrates the presence of somatic mosaicism. By ddPCR, the normal and mutant allele were identified in genomic DNAs and the MAFs were 20.1% (affected skin) and 14.7% (blood), respectively. In the present case, somatic mosaicisms observed in ectodermal (epidermis) and mesodermal (dermis and blood) origin DNA can be explained by a mutational event during the early‐stage differentiation of embryonic epiblast in embryogenesis, and mutant embryonic cells somewhat preferentially differentiate to form the epidermis, rather than the dermis and blood. Disrupted intracellular Ca2+ homoeostasis through clinical deterioration together with ATP2A2 somatic mosaicism in this patient might result in transient skin eruptions.

Bacterial Skin Dysbiosis in Darier Disease

Introduction: Darier disease is a rare inherited disease with dominant skin manifestations including keratotic papules and plaques on sebaceous and flexural areas. Secondary infection of skin lesions is common, and Staphylococcus aureus commonly colonizes these lesions. The aim of the study was to characterize the bacterial microbiome of cutaneous Darier lesions compared to normal-looking skin and disease severity. Methods: All patients with a history of Darier followed up at Emek Medical Center were invited to participate in the study. Patients that did not use antibiotics in the past month and signed informed consent had four skin sites sampled with swabs: scalp, chest, axilla, and palm. All samples were analyzed for bacterial microbiome using 16S rDNA sequencing. Results: Two hundred and eighty microbiome samples obtained from lesional and non-lesional skin of the scalp, chest, axilla, and palm of 42 Darier patients were included in the analysis. The most abundant bacterial genera across all skin sites were Propionibacterium, Corynebacterium, Paracoccus, Micrococcus, and Anaerococcus. Scalp and chest lesions featured a distinct microbiome configuration that was mainly driven by an overabundance of Staphylococci species. Patients with more severe disease exhibited microbiome alterations in the chest, axilla, and palm compared with patients with only mild disease, driven by Peptoniphilus and Moryella genera in scalp and palmar lesions, respectively. Conclusion: Staphylococci were significantly associated with Darier lesions and drove Darier-associated dysbiosis. Severity of the disease was associated with two other bacterial genera. Whether these associations also hold a causative role and may serve as a therapeutic target remains to be determined and requires further investigation.