An Update on the Cutaneous Manifestations of Darier Disease

Abstract

Background

Knowledge about the clinical features of Darier disease, an orphan autosomal-dominant genetic disorder, is sparse and has been evaluated only in few studies.

Objectives

To investigate the clinical features of a large group of patients with Darier disease, and to explore for associations between disease characteristics and severity of the disease.

Methods

Seventy-six individuals with Darier disease were evaluated utilizing a structured questionnaire-based interview, a physical examination, and a retrospective assessment of their medical records.

Results

The most frequent locations of lesions were hands (99%) and fingernails (93%). Wart-like lesions on the hands were more visible after soaking them in water for 5 minutes, we therefore named this phenomenon the “wet hand sign”. Oral involvement was found in 43% of patients, while 48% of women and 16% of men showed genital lesions. Patients with severe Darier disease had a tenfold greater risk of developing genital lesions than those with mild disease (P = .01). Most patients (88%) in our study exhibited a combination of the four types of the disease patterns of distribution (flexural, seborrheic, nevoid, and acral).

Conclusions

Documentation of disease on the hands and fingernails provides a highly sensitive means to aid in the diagnosis of Darier disease. It is important to evaluate mucosal lesions including genital and oral mucosa.

Keywords

Darier disease clinical manifestations keratosis folicullaris

Introduction

Darier-White disease (DD) was initially described independently in 1889 by the two legendary dermatologists; Professor Jean Darier (1856-1938), and Professor James C White (1833-1916).^1,2

DD is an autosomal-dominant disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization (dyskeratosis, “corps ronds,” and “grains”).^3

-6 Exact figures of prevalence are unknown but there are estimates of around 1 in 55,000. Penetrance is complete and delayed, onset is usually before the third decade, and expressivity varies.⁷

The gene ATP2A2 on chromosome 12q23-24.1 was recognized as the causative gene for DD by Sakuntabhai et al. in 1999.⁸ ATP2A2 encodes the sarco/endoplasmic reticulum Ca2 +ATPase isoform 2 (SERCA2), which plays a central role in intracellular calcium signaling.⁹

Clinical features include brown, keratotic papules, often associated with itching and malodor.¹⁰ Acral involvement is very common and includes punctate depressions on the palms and soles (palmoplantar pits) and wart-like lesions on back of hands and feet.⁷ Nail involvement is highly common and include red or white longitudinal bands, V-shaped notches at the free margin, longitudinal ridging, and subungual hyperkeratotic debris.⁷

The disease is historically classified according to patterns of distribution (flexural, seborrheic, nevoid, and acral).¹¹

Few clinical studies have been conducted to define the various aspects of DD.^7,12

-15

The most comprehensive one, carried out in England in 1992 on 163 patients from 107 unrelated families, described various clinical manifestations.¹¹

In this descriptive study, we aimed to comprehensively characterize the various clinical manifestations of DD in skin and mucous membranes, to explore for associations between disease characteristics and severity of the disease and to learn from patients’ knowledge and experience on the disease by studying in-depth a large sample of patients with DD.

Materials and Methods

Study Population

Seventy-six patients with DD from 34 families were recruited for the study from dermatology department at Emek Medical Center and other hospitals along with community dermatology clinics in Israel (Table 1). Inclusion criteria were age above 18 years, biopsy-proven diagnosis of DD and at least one of the classical lesions of DD (keratotic papules, acral pits, and acral wart-like lesions). In order to apply these inclusion criteria, each participant was assessed by an experienced dermatologist (the primary investigator (PI), R.P.D-G) prior to enrollment in the study. Exclusion Criteria: Age under 18 years and pregnancy.

Table 1

Clinical and Demographic Characteristics of 76 Patients With Darier Disease (DD).

Parameter	Number
Age (years)	44.0 ± 15.5 (19, 88)
Gender
Females	38 (50%)
Males	38 (50%)
DD Severity^a
Mild	25 (33%)
Moderate	37 (49%)
Severe	13 (18%)
Family History of DD (%)	67 (88 %)
Percent of Skin Area Affected	20.5 ± 14.7 (0.20, 70)
Age of DD onset (years)	17.0 ± 9.1 (5, 50)
Time Until Diagnosis (years)	6.4 ± 9.4 (0, 50)
BMI (kg/m²)^b	28.3 ± 5.4 (18, 40)
Ethnic Origin
Jewish, Caucasian	68 (90%)
Other, Caucasian	8 (10%)
Smoking	16 (21%)
Currently in Medical Follow-up
Yes	25 (33%)
No	50 (67%)

^aDisease severity was classified at entry to the study according to Sakuntabhai et al. as mild, moderate, or severe.¹⁶

^bBMI, body mass index.

Study Design

Participants were invited individually to a meeting with the study supervisor, during which inclusion criteria were verified, the study was explained, and signed informed consent was obtained. An interview was conducted based on a structured questionnaire (Supplemental Appendix 1), and a physical examination (Supplemental Appendix 2) was performed, which included being photographed. Medical information was also gathered by retrospective assessment of patient’s medical records.

The study protocol was approved by the institutional ethics committee at Emek Medical Center.

Instruments

Questionnaire

The highly comprehensive questionnaire (27-pages with over 300 items) designed for the study, gathered the following information: personal and family demography and medical history, family tree, initial manifestations of DD, its course, triggering factors, medical follow-up and hospitalizations, disease symptoms, location of the lesions, and involvement of nail, oral, and genital regions (Supplemental Appendix 1). The questionnaire was completed by the study investigator during a medical interview, which took approximately 60 minutes per participant.

Physical examination

A thorough cutaneous examination of the skin, hair, nails, oral mucus membranes, and external genitalia was performed by the primary investigator (R.P.D-G) to determine the skin findings, areas involved, disease severity, and classification of the disease.^11,16 Height and weight were also recorded. Disease severity was classified as mild, moderate, or severe according to the criteria of Sakuntabhai et al.¹⁶ Mild—keratotic papules scattered sparsely over the trunk or flexures, or disease limited to one or two areas. Moderate—more extensive papular lesions or localized verrucous plaques. Severe—coalescent verrucous plaques involving most of the trunk or grossly hypertrophic flexured disease.¹⁶

The examination was conducted according to a form designed for the study (Supplemental Appendix 2), and took approximately 25 minutes to complete.

Photography

Skin and mucous membranes were photographed by a professional medical photographer.

Statistical Analysis

Data were analyzed with SAS statistical software, version 9.4 (SAS Institute, Cary, NC, USA); significance was set at P < .05. Demographic and clinical data are presented as frequencies and percentages for categorical variables and by mean ± SD for continuous variables. Wilcoxon’s two sample test was applied to compare patients with severe and mild disease by age of onset. Spearman’s rank correlation coefficient was used to determine the relationship between body surface area (BSA) (as continuous variable) and age of onset of the disease. Logistic regression model was used to explore the association between severity of disease or BSA (as categorical variable) and several categorical variables.

Results

Disease Characteristics

Initial onset

Average age of onset of the disease was 17 ± 9 years (5-50); and time from onset of cutaneous symptoms to diagnosis was 6 ± 9 years (0, 50).

The disease appeared in the summer in 53 patients (83%), in the spring in 8 patients (13%), in the winter in 2 patients (3%), and in the fall in 1 patient (1%). Twelve patients could not recall the season in which the disease first appeared.

Only 6 patients (8%) stated that the disease was triggered by a sunburn.

Exacerbating factors

Exacerbation of the disease was reported by 67 patients (88%) during the summer and while sweating, by 56 patients (74%) following exposure to sunlight, by 45 (59%) at times of mental distress, by 33 (43%) following contact with wool, and by 23 (30%) during febrile illness.

Exacerbation of the disease was reported by 21 patients (28%) following surgical procedures and by 26 patients (34%) following skin injury. Twenty patients (26%) reported being hospitalized due to disease exacerbation.

Of the 38 females in the study, 18 (47%) reported disease onset prior to menarche, 15 (39%) reported change in disease course during pregnancy, 9 (60%) of whom described amelioration of symptoms. Twenty-five (67%) reported no effect of oral contraceptive pills on the disease.

Clinical Features

Distribution

Seventy-five of the 76 patients agreed to a physical exam. The most frequently involved areas were the palms (99%) and nails (93%). Other areas involved were the chest (77%), neck (71%), ears (69%), feet (69%), and body folds (67%). The most severely involved areas were the chest (28%), neck (24%), and body folds (24%). The areas most lightly involved were the upper extremities (18%), abdomen (15%), lower extremities (15%), and back (12%). Most of the patients (88%) exhibited a combination of the patterns suggested by Burge et al with no clear dominance of a specific location.¹¹ One patient exhibited a linear pattern of lesions on the trunk.

Morphology

The most frequent primary lesion was a keratotic papule, found in 95% of patients (Figure 1a), mostly on the trunk. The most frequent lesions on the hands were wart-like papules and pits (Figure 1b and 1c), and on the fingernails were red and white lines, ridging, V-shaped notches, and subungual hyperkeratosis (Figure 1d). The wart-like lesions on the hands were more visible after soaking in water for 5 minutes. This phenomenon was noted in 58 of 59 patients in the physical examination and could be termed the “wet hand sign.” (Figure 2)

Figure 1

Classical lesions of Darier disease in the skin and nails. (a) Keratotic papules scattered on the trunk, some with central erosion and hemorrhagic crust. (b) Wart-like papules on the dorsum of the hands. (c). Palmar pits—palmar papules with centeral depression. (d) Nail abnormalities: V-shaped notches at free edge of nail and longitudinal red and white lines, ridging and splitting.

Figure 2

The “wet hand” sign. Heightened wart-like lesions on the hands following soaking in water for 5 minutes.

Rare skin findings included palmar keratoderma in six patients (8%) from three families, plantar keratoderma in 11 patients (15%) from six families (Figure 3a), leukodermic macules in five patients (7%) from four families (Figure 3b), numerous giant comedones in one patient (1%) (Figure 3c), keloid-like vegetations in body folds in six patients (8%) from four families (Figure 3d), and blisters on plantar area and small black hemorrhagic macules with jagged borders on the palms in five patients (7%) from two families (Figure 3e and f).

Figure 3

Non-classical lesions of Darier disease (variants of DD) (a) Plantar keratoderma. (b) Leukodermic macules. (c) Giant comedones. (d) Vegetations. (e and f). Blisters (Hemorrhagic and non-hemorrhagic).

The patient with giant comedones and two patients with hemorrhagic bullae also had acral keratoderma.

Mucous membranes and nails

Oral involvement was found in 30/69 (43%) of patients. Examination of the genitalia in 50 patients (25 men and 25 women) revealed lesions in 12 women (48%) and 4 men (16%). Nail involvement was found in 67/72 patients (93%). The objective and subjective findings are presented in Table 2.

Table 2

Oral, Genital, and Nail Findings in Patients With Darier Disease.

	Objective	Subjective
Oral Findings	Multiple minute white and red papules affecting gingiva and hard palate (30%) (Figure 4a) Whitish papules of varying size with a central depression, giving the mucosa a rough texture (12%) Papules on the tongue (6%)	N/A
Genital Findings	Pink-red papules with central erosion (Figure 4b)	Pruritus (69%)Secretions (42%)Burning (25%)
Nail Findings (Figure 1d)	Red lines or white lines (82%) Longitudinal ridging (76%) V-shaped notches (61%) Subungual hyperkeratosis (56%)	Pain (26%)

N/A not available.

Figure 4

Manifestations of Darier disease in oral and genital mucous membranes. (a) White papules on hard palate (arrow). (b) Pink papules, a few with central erosions on labia minor and clitoris (arrow).

Correlation to Disease Severity

There was a statically significant difference between severity of disease and age of onset. Patients with severe disease were younger at onset (average 13.7 ± 11.4 years) than patients with mild disease. (average 18.6 ± 10.0 years, P = .01).

Disease severity influenced the probability of having genital and oral lesions. Patients with severe DD had 10 times greater chance of having genital lesions than patients with mild disease (95% CI 1.61-60.24, P = .01). Female patients with severe DD had 22 times greater chance of having genital lesions than those with mild disease (95% CI 1.54-314.27, P = .03). There was a clear trend toward the association of disease severity and having oral lesions: patients with severe DD had a 4.5 greater chance of having oral involvement than patients with mild disease (95% CI 0.85-24.11, P = .07).

Not surprisingly, disease severity was correlated with the probability of being under dermatological medical follow-up and having been hospitalized for treatment of DD. Patients with severe DD had nine times greater odds of being supervised under follow-up care than patients with mild disease (95% CI 1.78-43.49, P = .01), and 38 times greater chances of being hospitalized than patients with mild disease (95% CI 3.88-379.69, P = .002)

Discussion

Darier disease is an orphan disease, which accounts for the meager number of studies describing the clinical manifestations of the disease on large cohorts of patients.^15,17
-19 The largest cohort on DD was studied by Burge et al. and published in 1992.¹¹ In accordance with the results of this study, we found the hands to be the most common location of the disease. Indeed, 100% of our patients had cutaneous and/or nail involvement of hands. Thus, assessment of the skin on the hands for wart-like lesions, pits, and even keratoderma, and of the fingernails for red/white lines, ridging, V-shape notches and subungual hyperkeratosis in a patient with suspected DD offers a sensitive diagnostic approach.

The “wet hand sign” found in our study can also assist in diagnosis (Figure 2). This discovery was made thanks to the patients who reported that the wart-like papules on their hands become prominent after soaking in water for several minutes.

We found high percentage of oral involvement (43%) (Figure 4a) as previously documented in studies and case reports.^20,21

We also found high percentage of genital lesions: pink-red papules with central erosion. (Figure 4b) These lesions, reported previously only in rare case reports, were a common finding in our study, especially in female patients (48% of female patients and 16% of male patients).^22,23

Genital lesions were significantly more common in patients with a severe disease. Interestingly, patients with a severe disease also experienced younger age of onset of their disease.

Burge et al. suggested classifying the disease into four cutaneous categories according to the location of the lesions: seborrheic (predominantly scalp, face, and trunk with mild flexural involvement), flexural (predominantly flexural with mild involvement elsewhere), nevoid (unilateral zosteriform involvement), or hands only.¹¹ We found it problematic to apply this classification to our patients, since most of them (88%) exhibited a combination of the patterns suggested by Burge et al.¹¹ with no clear dominance of a specific location.

We found that the cutaneous manifestations of DD can be easily divided into two types of lesions; classical and non-classical. The classical lesions—keratotic papules, acral pits and acral wart-like lesions—are common and characterize the disease (Figure 1), whereas the non-classical lesions—acral keratoderma, leukodermic macules, giant comedones, kelloid-like vegetations, and acral hemorrhagic blisters—are rare and appear only in patients with DD variants (Figure 3).

In our study, all patients (100%) had at least one of the classical lesions and 33% of patients had non-classical lesions of DD.

Limitation of the study is collection of some of the data by interview, a technique which is subject to recall bias. There may be bias due to non-response when data are missing. Differential recall bias is also possible as patients diagnosed with DD know the reported exacerbation risk factors and may be more likely to report them (eg, onset in summer in 80% may be real vs may be suspected by the patient as they know UVR leads to disease exacerbation). Differential exposure ascertainment was minimized since questionnaire and physical examination were performed by same PI.

Darier disease is a debilitating and chronic condition, with both cutaneous and systemic manifestations, which can have a severe impact on patients’ general health and quality of life. Therefore, prompt and accurate diagnosis and treatment are crucial. This study, which follows our previous research on DD,^9,24
-26 sheds new light on the clinical aspects of DD; a novel skin manifestation (the “wet hand” sign), prominent genital involvement found to be more frequent in patients with severe disease, and combination of previously suggested disease patterns (flexural, seborrheic, nevoid, and acral) in most of our patients (88%), indicating that there may be a need to re-evaluate the classification of DD.

Further studies on this rare disease should be conducted to better characterize its full magnitude and develop improved treatment modalities.

Supplemental Material

Supplementary Material 1 - Supplemental material for An Update on the Cutaneous Manifestations of Darier Disease

Supplemental material, Supplementary Material 1, for An Update on the Cutaneous Manifestations of Darier Disease by Algit Yeshurun, Michael Ziv, Eran Cohen-Barak, Shiraz Vered, Dganit Rozenman, Muhammad Sah, Morad Khayat, Olga Polyakov, Boaz Amichai, Abraham Zlotogorski, Stavit Shalev and Roni P. Dodiuk-Gad in Journal of Cutaneous Medicine and Surgery

Supplemental Material

Supplementary Material 2 - Supplemental material for An Update on the Cutaneous Manifestations of Darier Disease

Supplemental material, Supplementary Material 2, for An Update on the Cutaneous Manifestations of Darier Disease by Algit Yeshurun, Michael Ziv, Eran Cohen-Barak, Shiraz Vered, Dganit Rozenman, Muhammad Sah, Morad Khayat, Olga Polyakov, Boaz Amichai, Abraham Zlotogorski, Stavit Shalev and Roni P. Dodiuk-Gad in Journal of Cutaneous Medicine and Surgery

Footnotes

Acknowledgments

We thank the patients for their participation in this study; Hadas Baumgarten, the study coordinator, and the dermatologists and other health professionals for their assistance in recruiting participants; Inbar Bizinski, Efrat Yaskil, and Rita Yuval for assistance in designing the study; Sandra Trumper and Yael Meshulam for photography of patients; and Dr Naama Schwartz and Paula Herer for assistance with the statistics. We wish to express our deepest gratitude to Dr Orna Blondheim, the CEO of Emek Medical Center, for her full support in our study in all of its stages. We are indebted to the Harold Grinspoon Foundation for funding the study; their support played no role in the design, methods, data collection, analysis or interpretation of the results, and its publication was not contingent on their approval.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a grant from the Harold Grinspoon Foundation.

ORCID iD

Algit Yeshurun

Supplemental Material

Supplemental material for this article is available online.

References

. Psorospermose folliculare vegetante. Ann Dermatol Syphilol. 1889;10

White

. A case of keratosis (ichthyosis) follicularis. J Cutan Genito-Urin Dis. 1889;7:201-209.

Savignac

Edir

Simon

Hovnanian

. Darier disease : a disease model of impaired calcium homeostasis in the skin. Biochim Biophys Acta. 2011;1813(5):1111-1117.doi:10.1016/j.bbamcr.2010.12.006

21167218

Ahn

Lee

MG.

Kim

KH.

Muallem

. Multiple effects of SERCA2b mutations associated with Darier's disease. J Biol Chem. 2003;278(23):20795-20801.doi:10.1074/jbc.M301638200

12670936

Pani

Singh

. Darier’s disease: a calcium-signaling perspective. Cell Mol Life Sci. 2008;65(2):205-211.doi:10.1007/s00018-007-7397-z

18049860

Zeglaoui

Zaraa

Fazaa

et al. Dyskeratosis follicularis disease: case reports and review of the literature. J Eur Acad Dermatol Venereol. 2005;19(1):114-117.doi:10.1111/j.1468-3083.2004.01096.x

15649206

Cooper

SM.

Burge

. Darier's disease: epidemiology, pathophysiology, and management. Am J Clin Dermatol. 2003;4(2):97-105.doi:10.2165/00128071-200304020-00003

12553850

Sakuntabhai

Ruiz-Perez

Carter

et al. Mutations in Atp2a2, encoding a Ca2+ pump, cause Darier disease. Nat Genet. 1999;21(3):271-277.doi:10.1038/6784

10080178

Dodiuk-Gad

RP.

Cohen-Barak

Khayat

et al. Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects. Br J Dermatol. 2016;174(3):562-568.doi:10.1111/bjd.14220

26471493

10.

Takagi

Kamijo

Ikeda

. Darier disease. J Dermatol. 2016;43(3):275-279.doi:10.1111/1346-8138.13230

26945535

11.

Burge

SM.

Wilkinson

. Darier-white disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27(1):40-50.doi:10.1016/0190-9622(92)70154-8

1619075

12.

Sehgal

VN.

Srivastava

. Darier's (Darier-White) disease/keratosis follicularis. Int J Dermatol. 2005;44(3):184-192.doi:10.1111/j.1365-4632.2004.02408.x

15807723

13.

Amichai

Karpati

Goldman

Peleg

. Novel mutations in two families with Darier’s disease. Int J Dermatol. 2007;46(1):64-67.doi:10.1111/j.1365-4632.2006.03049.x

17214724

14.

Klausegger

Nischler

Wagner

RN.

Pletschacher

Hintner

Bauer

. Seven novel mutations in the ATP2A2 gene of Austrian patients with Darier’s disease. Arch Dermatol Res. 2011;303(5):371-374.doi:10.1007/s00403-011-1148-6

21519848

15.

Bchetnia

Benmously

Ben Brick

et al. New mutations of darier disease in Tunisian patients. Arch Dermatol Res. 2009;301(8):615-619.doi:10.1007/s00403-009-0963-5

19488774

16.

Sakuntabhai

Burge

Monk

Hovnanian

. Spectrum of novel ATP2A2 mutations in patients with Darier’s disease. Hum Mol Genet. 1999;8(9):1611-1619.doi:10.1093/hmg/8.9.1611

10441323

17.

Macleod

RI.

Munro

. The incidence and distribution of oral lesions in patients with Darier’s disease. Br Dent J. 1991;171(5):133-136.doi:10.1038/sj.bdj.4807636

1931295

18.

Godic

Korosec

Miljković

Kansky

Glavac

. Four novel ATP2A2 mutations in Slovenian patients with Darier disease. J Am Acad Dermatol. 2010;62(5):819-823.doi:10.1016/j.jaad.2009.07.031

20223560

19.

Ren

Y-Q.

Gao

Liang

Y-H

et al. Five mutations of ATP2A2 gene in Chinese patients with Darier's disease and a literature review of 86 cases reported in China. Arch Dermatol Res. 2006;298(2):58-63.doi:10.1007/s00403-006-0658-0

16552539

20.

Suryawanshi

Dhobley

Sharma

Kumar

. Darier disease: a rare genodermatosis. J Oral Maxillofac Pathol. 2017;21(2):321.doi:10.4103/jomfp.JOMFP_170_16

28932054

21.

Cardoso

CL.

Freitas

Taveira

LAdeA.

Consolaro

. Darier disease: case report with oral manifestations. Med Oral Patol Oral Cir Bucal. 2006;11(5):E404-406.16878056

22.

Stefanaki

Rozakou

Antoniou

et al. Genital Darier’s disease mimicking genital warts. Acta Obstet Gynecol Scand. 2010;89(3):409-410.doi:10.3109/00016340903545017

20109016

23.

Ferizi

Begolli-Gerqari

Luzar

Kurshumliu

Ferizi

. A rare clinical presentation of Darier's disease. Case Rep Dermatol Med. 2013;2013:419797 doi:10.1155/2013/419797

23573430

24.

Dodiuk-Gad

Cohen-Barak

Ziv

et al. Health-related quality of life among Darier’s disease patients. J Eur Acad Dermatol Venereol. 2013;27(1):51-56.doi:10.1111/j.1468-3083.2011.04355.x

22121995

25.

Dodiuk-Gad

Cohen-Barak

Ziv

et al. Bacteriological aspects of Darier’s disease. J Eur Acad Dermatol Venereol. 2013;27(11):1405-1409.doi:10.1111/jdv.12025

23078077

26.

Dodiuk-Gad

Lerner

Breznitz

et al. Learning disabilities in Darier’s disease patients. J Eur Acad Dermatol Venereol. 2014;28(3):314-319.doi:10.1111/jdv.12103

23410204

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.18 MB

0.05 MB