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A clinical and histopathological study of Darier's disease.

Byline: Neerja Puri

Abstract

Background Darier's disease is an uncommon inherited skin disease transmitted in autosomal dominant pattern characterized by brownish keratotic papules particularly dense in the seborrheic areas of the body, palmar pits and nail dystrophy .The disease is often exacerbated by sun exposure, perspiration and heat.

Patients and methods

We selected 30 patients of Darier's disease from the dermatology OPD for the study. The histopathological examination was performed in all the patients.

Results Yellow brown crusted greasy papules were the commonest clinical feature seen in 100% patients, cobblestoning of palate was seen in 86.6% patients, palmar pits in 83.3% patients and keratotic papules were seen in 73.3% patients. Regarding the nail changes alternating red and white bands were seen in all the patients (100%) and V shaped nicking at the free margins of nails was seen in 93.3% patients. The histopathological feature noted were hyperkeratosis (100%), suprabasal acantholysis (90%), acantholytic cells (86.6%) and corps ronds and grains (83.3%).

Conclusion Cutaneous changes, clinical and histopathological, in Darier's disease are similar to that described in the literature.

Key words

Darier's disease, keratosis follicularis, dyskeratosis.

Introduction

Darier disease (DD) or Darier-White disease, also known as keratosis follicularis, is an autosomal dominantly inherited genodermatosis characterized by greasy hyperkeratotic papules in seborrheic regions, nail abnormalities, and mucous membrane changes.1,2 The disease was first reported independently by Darier and White in 1889. White was first to recognize the genetic nature of keratosis follicularis (Darier disease) by noticing that a mother and her daughter were affected.3

Mutations in the gene ATP2A2 cause DD. ATP2A2, located on 12q23-24.1, encodes the sarcoplasmic/endoplasmic reticulum Ca2+-ATP isoform 2 protein (SERCA2), which is a calcium pump.4 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 113 familial and sporadic mutations in ATP2A2 have been identified in DD patients, attempts at genotype-phenotype correlation have not been successful.5,6 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 DD. Abnormal keratinocyte-keratinocyte adhesion and aberrant epidermal keratinization are the primary histologic features of DD.

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.7,8 The mechanism by which decreased activity of the SERCA2 calcium pump leads to these changes is still under investigation.

The study was undertaken to examine the epidemiology and clinical profile and histopathological characteristics of Darier's disease.

Patients and methods

30 patients of DD from the dermatology OPD were selected for the study. Written informed consent was taken from all the patients. Prior approval of hospital ethical committee was taken before the start of the study. Routine investigations of all the patients were performed before the study including complete blood count, fasting blood sugar, ESR, urine complete examination, liver function tests and kidney function tests. The histopathological examination was performed in all the patients.

The clinical and histopathological characteristics were recorded on a pro forma.

The data was tabulated and the results were analysed.

Results

The demographic and clinical data of patients is shown in Table 1. The commonest age group of patients was 11-20 years (50% patients). Males outnumbered females and male:female ratio was 2:1. Family history was positive in 53.3% patients. Yellow brown crusted greasy papules were the commonest clinical feature seen in 100% patients (Figures 1 and 2), cobblestoning of palate was seen in 86.6% patients, palmar pits in 83.3% patients (Figure 3) and keratotic papules were seen in

Table 1 Demographic and clinical characteristics of patients with Darier's disease (n=30)###

Characteristic N (%)

Age distribution (years)

0-10###1 (3.3)

11- 20###15 (50)

21-30###10 (33.3)

31-40###2 (6.6)

41-50###1 (3.3)

51- 60###1 (3.3)

Sex

Male###20 (66.7)

Female###10 (33.3)

Family history

Positive###16 (53.3)

Negative###14 (46.6)

Clinical features

Yellow brown crusted###30 (100)

greasy papule

Palmar pits###25 (83.3)

Cobblestoning of palate 26 (86.6)

Keratotic papules###22 (73.3)

Nail changes

Red and white bands###30 (100)

V-shaped nicking at free 28 (93.3)

margin

Sites of involvement

Trunk###30 (100)

Retroauricular region###28 (93.3)

Forehead###25 (83.3)

Inguinal region###21 (79)

Table 2 Histopathological changes in Darier's disease (n=30)

Sr. No###Histopathological feature###N (%)

1.###Hyperkeratosis###30 (100)

2.###Suprabasal acantholysis###27 (90)

3.###Corps ronds and grains###25 (83.3)

4.###Acantholytic cells###26 (86.6)

5.###Papillomatosis###18 (60)

73.3% patients.

Regarding the nail changes alternating red and white bands were seen in all the patients (100%) [Figure 4] and V-shaped nicking at the free margins of nails was seen in 93.3% patients. Trunk was the commonest site of involvement seen in 100% patients, followed by retroauricular region in 93.3%, forehead in 83.3% and inguinal region in 70% patients.

None of the patients had any neuropsychiatric symptoms.

Table 2 shows the histopathological changes seen. The commonest histopathological feature was hyperkeratosis seen in 100% patients, suprabasal acantholysis was seen in 90% patients, acantholytic cells were seen in 86.6% patients and corps ronds and grains were seen in 83.3% patients.

Discussion

In our study, the commonest age group of patients was 11-20 years (50% patients), 33.3% patients were between 21-30 years; 6.6% patients were between 31-40 years and 3.3% patients were between 41-50 years, 51-60 years and 0-10 years each. The male: female ratio was 2:1. Positive family history was seen in 53.3% patients. Our results in terms of age of onset and sex distribution are similar to the previous data.

Yellow brown crusted greasy papules were the commonest clinical feature seen in 100% patients, cobble stoning of palate was seen in 86.6% patients, and palmar pits in 83.3% patients and keratotic papules were seen in 73.3% patients. Regarding the nail changes alternating red and white bands were seen in all the patients (100%) and V-shaped nicking at the free margins of nails was seen in 93.3% patients. The trunk was the commonest site of involvement seen in 100% patients, retroauricular region was involved in 93.3% patients, forehead involvement was seen in 83.3% patients and inguinal region was involved in 70% patients.

The commonest histopathological feature was hyperkeratosis seen in 100% patients, suprabasal acantholysis was seen in 90% patients, acantholytic cells were seen in 86.6% patients and corps, ronds and grains were seen in 83.3% patients. These results are consistent with previous studies.9-12

DD most commonly manifests from age of 6 to 20 years; however, patients have presented as early as age 4 years and as late as age 70 years.9 Notably, the first case of congenital DD was diagnosed by histopathology in a child with a significant positive family history for DD, in which at least the 3 preceding generations were affected.10 Most patients with DD have a family history of the disease. The pattern of inheritance is autosomal dominant.

However, some patients, up to 47% in one series, had no clear family history. These cases may represent sporadic mutations, or may have family members with mild disease who were not recognized.11

The first skin lesions typically occur in the teenage and are frequently associated with pruritus. Heat, sweat, humidity, sunlight, UVB exposure, lithium, oral corticosteroids, and mechanical trauma have been reported to exacerbate this condition. Some females report flares around menstruation. Even though the severity of the disease fluctuates over time, DD is a chronic, unremitting condition. In one study, one third of patients noted improvement with age; however, another one third of patients showed worsening of the disease with age.2,12 Although neuropsychiatric abnormalities such as epilepsy, mental impairment, and mood disorders have been associated with DD, no evidence indicates that mutations in ATP2A2 are associated with these disorders. One study suggested that a susceptibility locus for bipolar disorder co- segregates with DD region, but it is distinct from mutations causing DD.

The lesions 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. Approximately 80% of patients have mild flexural involvement with scattered papules in the groin, axillae, or, in women, submammary skin. In less 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.13 Involvement of the hands is very common (approximately 95%). Lesions on the palms include punctate keratoses (80%), palmar pits (80%), and hemorrhagic macules ( less than 10%). Acrokeratosis verruciformis-like lesions (warty flat-topped papules on the dorsal hands) are present in approximately half the patients.

Interestingly, several patients with acrokeratosis verruciformis of Hopf (who have dorsal hand lesions only) have been found to harbor mutations in ATP2A2, suggesting this condition may actually be a localized form of DD.

Nail changes provide important diagnostic clues. White and red longitudinal bands, 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 patients with DD.14 These changes on the hands can also occur on the feet, albeit less commonly. Mucosal lesions are detected in approximately 15% of patients, and these appear as white papules with a central depression. These cobblestone lesions are most commonly found in the mouth, but they also may occur on the anogenital mucosa. At times, oral lesions may affect the salivary glands and cause obstruction.15 Clinical variants of DD include hypertrophic and vesicobullous types.16 Linear or segmental keratosis follicularis (Darier disease) has been shown in some cases to result from genetic mosaicism of ATP2A2.

References

1. Burge SM. Darier's disease, keratins and proteases: a review. J R Soc Med 1989; 82: 673-6.

2. Burge SM, Wilkinson JD. Darier-White disease: A review of the clinical features in 163 patients. J Am Acad Dermatol 1992; 27: 40-50.

3. Munro CS. The phenotype of Darier's disease: Penetrance and expressivity in adults and children. Br J Dermatol 1992; 127: 702-11.

4. Sakuntabhai A, Burge S, Monk S et al. Spectrum of novel ATP2A2 mutations causes segmental Darier's disease. Hum Mol Genet 1999; 8: 1611-9.

5. Sakuntabhai A, Dhitavat J, Burge S. Mosaicism for ATP2A2 mutations causes segmental Darier's disease. J Invest Dermatol 2000; 115: 1144-7.

6. MacLennan DH, Brandl CJ, Korczak B. Amino acid sequence of a Ca2++Mg2+- dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from its complementary DNA sequence. Nature 1985; 316: 696-700.

7. Garrod D, Merritt A, Nie Z. Desmosomal cadherins. Curr Opin Cell Biol 2002; 14:537.

8. Green KJ, Jones JC. Desmosomes and hemidesmosomes: structure and function of molecular components. Faseb J 1996; 10: 871-6.

9. Cooper SM, Burge SM. Darier's disease: epidemiology, pathophysiology, and management. Am J Clin Dermatol 2003; 4: 97-105.

10. Inada M, Shimizy H, Yamada S et al. Three cases of Darier's disease in a family showing marked heterogeneous clinical severity. Dermatology 1999; 198: 167-70.

11. Beck AL, Finochio AF, White JP. Darier's disease: a kindred with a large number of cases. Br J Dermatol 1977; 97: 335-9.

12. Rand R, Baden HP. Commentary: Darier- White disease. Arch Dermatol 1983; 119: 81-3.

13. Getzler NA, Flint A. Keratosis follicularis. A study of one family. Arch Dermatol 1996; 132: 545-9.

14. Zaias N, Ackerman AB. The nail in Darier-White disease. Arch Dermatol 1973; 107: 193-9.

15. Byrge S. Darier's disease- the clinical features and pathogenesis. Dermatology 1999; 199: 365-368.

16. Telfer NR, Burge SM, Ryan TB. Vesiculo-bullous Darier's disease. Br J Dermatol 1990; 122: 831-4.

Consultant Dermatologist, Punjab Health Systems Corporation, Ludhiana, Punjab, India

Address for correspondence, Dr. Neerja Puri, C/O Dr Asha Puri, House No. 626, Phase Ii, Urban Estate, Dugri Road, Ludhiana, Punjab, India, Email: neerjaashu @ rediffmail.com Ph# 0091-98146-16427
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Author:Puri, Neerja
Publication:Journal of Pakistan Association of Dermatologists
Article Type:Disease/Disorder overview
Geographic Code:9PAKI
Date:Jun 30, 2012
Words:2048
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