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ISSN: 2155-9554
Journal of Clinical & Experimental Dermatology Research
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Comedonal Darier’s Disease: A Rare Variant and a Common Misdiagnosis

Magda Assaf1 and Eman Salah2*

1Professor of Pathology, Faculty of Medicine, Zagazig University, Egypt

2Lecturer of Dermatology and Venereology, Faculty of Medicine, Zagazig University, Egypt

*Corresponding Author:
Eman Salah
Professor of Pathology
Faculty of Medicine
Zagazig University, Egypt
Tel: +201003348972
E-mail: [email protected]

Received Date: January 08, 2015; Accepted Date: January 22, 2015; Published Date: January 29, 2015

Citation: Assaf M, Salah E (2015) Comedonal Darier’s Disease: A Rare Variant and a Common Misdiagnosis. J Clin Exp Dermatol Res 6:261. doi: 10.4172/2155-9554.1000261

Copyright: ©2015 Magda Assaf et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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Abstract

Comedonal Darier’s disease is an extremely rare variant demonstrating unique clinical and histopathological findings; however, it is commonly misdiagnosed. Herein, we report a case of comedonal Darier’s disease and discuss its different diagnostic and therapeutic challenges.

Keywords

Darier’s disease; Comedones; Acne vulgaris; Dyskeratosis; Isotretinoin

Abbreviations

DD: Darier’s disease; F: Female; M: Male; NM: Not mentioned; NMSC: Non melanoma skin cancers; UK: United Kingdom; -ve: Negative; +ve: Positive

Case Report

A 19-year-old male presented with three years duration of multiple disfiguring acneform lesions on the face. Skin examination revealed multiple white and black-heads, soft nodules, oily skin and ice-pick scars (Figure 1).

clinical-dermatology-dirty-brown

Figure 1: Comedonal Darier’s disease: Classic and comedonal lesions. Diffuse dirty brown keratotic papules affecting the trunk associated with typical nodulo-cystic acne-like facial appearance.

Moreover, there were brown keratotic papules affecting the neck, trunk, axillae, ears and scrotum. Careful inspection of these papules revealed surmounted black-heads. Palmar pits and V-shaped distal notching of the nails were also found. The patient was otherwise healthy with no family history of similar condition. Microscopic examination of one papule demonstrated a cup-shaped invagination with keratotic plug, dyskeratosis, suprabasal acantholysis with prominent villi (Figure 2) and mild dermal lymphocytic infiltrate.

clinical-dermatology-dyskeratotic-cells

Figure 2: Comedonal Darier’s disease: Histopathological findings from a papular lesion. A cup shaped epidermal invagination filled with keratotic plug and some dyskeratotic cells, suprabasal acantholysis with lacunae, prominent villi and surrounding dermal lymphocytic infiltrate (H&E, original magnification × 10).

Furthermore, microscopic findings of one nodular lesion revealed a markedly dilated hair follicle cyst with acantholysis and dyskeratosis (Figure 3). Finally a diagnosis of comedonal Darier's disease was established and surgical excision of the largest facial cystic lesions was done for cosmetic purpose. Isotretinion (40 mg/day for 8 weeks) was given with unsatisfactory response, so it was terminated upon patient request.

clinical-dermatology-nodular-lesion

Figure 3: Comedonal Darier’s disease: Histopathological findings from a nodular lesion. A markedly dilated hair follicle cyst with acantholysis and prominent dyskeratosis involving the wall of the cyst (Arrow) (H&E, original magnification × 40).

Discussion

Darier’s disease (DD) is a rare genodermatosis including classic and atypical variants. Comedonal DD is an extremely rare variant with unique presentation. It was first described by Derrick et al. in 19953 and since then only 14 cases have been reported including the presented one with different demographic features. Surprisingly, it is a diagnostic pitfall for two decades evidenced by the time lag between onset of symptoms and final diagnosis (Table 1).

Reference No. Of Cases Country Age Sex Family History Sites Associations Treatment Response
      Of Onset Of Diagnosis     Comedones Open &/or Closed Classic Darier’s Disease      
Derrick et al, 1995 [3] 2 UK 61 65 M Negitive *Face,Scalp Nails, Palms Pruritus Topical steroid, Emolients Initial improvement then recurrence
10s 55 M Positve Face,Trunk Nails,Palms,Trunk Scalp nodules Etretinate 50mg/day Improved, except for persistent scalp nodules
Song et al, 1997 [6] 1 Korea 16 43 M Negitive Face, Scalp,Trunk Trunk,Nails None Etretinate 30mg/day Improved
Lee et al, 2002 [5] 2 Korea 25 47 M Negitive Face,Trunk Trunk, Face Greasy skin, Pruritus, Facial ice-pick scars & nodules  with a leonine appearance Oral Isotretinion 30 mg/day Stopped  after 4 weeks due to side effects
24 34 M Negitive Face None Facial nodules Minocyclin No response after several months
Aliagaoglu et al, 2006 [9] 1 Turkey 18 42 M Negitive Face,Neck, Trunk,Legs None Cornifying& hypertrophic variants Acitretin 1mg/kg/day No response after 4 months
Long-term antibiotics No response
Topical adapalene for comedonal&cornifying lesions No response after 4 months
Yegin et al, 2007 [7] 1 Turkey 7 42 M Negitive Face,Scalp Trunk Face,Scalp Trunk, Palms, Soles, Nails, Oral Scalp syringocyst-adenoma papilliferum& scarring alopecia, Pitted scars on face, scalp, trunk, Malodor Isotretinion 1mg/kg/day for 3 months Poor response
Tsuruta et al, 2010 [4] 1 Japan 10s 22 M Negitive Face,Trunk None Ice-pick scars on face Oral: biotin, Korean ginseng, anti-histamins No response
Topical: bufexamac, calcipotriol, steroid No response
Etretinate 10 mg/day & topical adapalene Mostly improved
Chung et al, 2011 [1] 1 Korea Late 20s 31 F Positve Face None Greasy skin Oral minocycline & Topical tacrolimus Little improvement
Goel et al, 2012 [8] 1 India 66 70 M Negitive Face Scalp, Palms None NM NM
Buchanan & Strutton , 2013 [13] 1 Australia 22 52 M Negitive Not defined NMSC NM NM
              Face,Neck,Chest,Abdomen,Back      
Lora et al, 2013 [11] 2 Italy NM 46 M Negitive Scalp Trunk, Palms NM NM NM
      25 68 F Negitive Face, Trunk Palms NM NM NM
Our case 1 Egypt 16 19 M -ve Face,Trunk Trunk, Scrotum, Palms, Nails Greasy skin, Ice-pick scars, Facial nodules Surgical removal of large nodulo-cystic facial lesions & then oral Isotretinion 40 mg/day Improved cosmetic results after removal of the nodules. No response after 2 months

Table 1: Summary of the reported cases of comedonal Darier’s disease

Note: NM: not mentioned; NMSC: non-melanoma skin cancer; UK: United Kingdom; M: male; F: female; *Face involvement is almost a constant finding. N.B: None of the 14 cases showed neurological or infectious complications and only two cases reported a positive family history.

The hallmark of comedonal DD is prominent comedones invariably involving the face however, other sites can be also affected (Table 1) [1-4]. Greasy skin, nodulo-cystic lesions and even ice-pick scars have been reported [4]. Furthermore, these acne-like lesions may or not be associated with characteristic warty papules of classic DD representing a real diagnostic challenge [4,5]. Also, nails, palms and mucous membranes lesions of classic DD may or not be found (Table 1) [3,6-8]. Other associated cutaneous manifestations include pruritus, leonine face, syringocystadenoma papilliferum and even other Darier variants [9].

In contrast to classic DD, all reported comedonal DD patients did not show any neurological disorders or increased susceptibility to bacterial/or viral infections [10]. This may be explained by the paucity of the reported cases or by different underlying pathogenic mechanisms.

Acantholytic dyskeratosis is the main histiopathologic picture in DD [5]. However, comedonal DD is characterized by prominent follicular involvement and marked elongation of dermal villi with papillary projections which may be surrounded by dermal lymphocytes and plasma cells resembling warty dyskeratoma [4,9].

Classic DD is an autosomal dominant trait with a high penetrance, however, in comedonal DD there are only two genetic studies in the literature [10]. First, Tsuruta et al. [4] by direct sequencing of ATP2A2 in patient’s genomic DNA, revealed a heterozygous three-base deletion in exon 2 leading to deletion of leucine at the 41st amino acid residue from the amino terminus. However recently, Lora et al. [11] found no evidence of pathogenic mutations in the ATP2A2 gene in their patient suggesting that other genes may be implicated. In agreement with that we noticed that almost all reported patients (12 out of 14 as shown in Table 1) were males which raise the possibility for an X-linked pattern of transmission, an observation that deserves further genetic studies. Furthermore, familial comedonal DD was reported only in two patients [1]. Additionally, Kurokawa et al. [12] demonstrated that keratin and filaggrin expression pattern in comedonal DD has similar characteristics to classic DD rather than acne vulgaris.

In addition to differentiating comedonal DD from classic DD (Table 2), acne vulgaris and familial dyskeratotic comedone are the main clinical differential diagnoses while warty dyskeratoma is the main histopathological mimicker [13]. So, careful history taking and clinical examination of the whole skin, mucous membranes and nails in any suspected case is critical for the diagnosis of comedonal DD and proceeding to histopathological examination in doubtful cases is a must.

Items ComedonalDarier’s disease Classic Darier’s disease
Incidence Extremely rare Rare
Demographics
Age of onset Ranges from 10s to 66 2nd decade usually
Sex Predominantly in males Equal in both sexes
Geographic distribution Asia, East & Middle East Worldwide
Aetiology
Defective Gene ATP2A2 ATP2A2
Reported mutation types Deletion [only one report] Missense & splicing [many reports] & others e.g. deletions
Mode of inheritance Autosomal dominant with a possible X-linked inheritance Autosomal dominant
Clinical Manifestations
Comedonal lesions (Open & / or Closed) Must be present Absent
Facial ice-pick scars May be present Absent
Dirty warty papules / plaques May be absent Must be present
Palmar pits / keratoses May be present May be present
Nail changes May be present May be present
Mucosal lesions May be present May be present
Associations
Neurological disorders None reported Higher liability
Susceptibility to infections None reported Increased susceptibility
Histopathological Findings
Acantholyticdyskeratosis Invariably present Invariably present
Follicular involvement  Present & prominent Present
Villi & papillary projections Markedly elongated Elongated
Course
Chronicity Chronic Chronic
Remissions Not reported Spontaneous remission rarely reported
Exacerbations by sun, heat & lithium Absent Present

Table 2: Key differentiating features between comedonal and classic Darier’s disease

Like classic DD, treatment options for comedonal variant are largely unsatisfactory. Topical treatments (emolients, steroids, retinoids, calcipotriol, tacrolimus and bufexamac) and systemic therapies (etretinate, isotretinion, acitretin, antibiotics, biotin, Korean ginseng and anti-histamines) have all showed guarded success (Table 1) [1,3-5,7,9].

In the present report, no response was associated with the use of isotretinion for 2 months. Lee et al. [5] were the first to introduce oral isotretinion (30 mg/day) for their patient but it was stopped after just 4 weeks due to uncomfortable chelitis and xerosis. Similarly, Yegin et al. [7] used systemic isotretinion for their case (1 mg/kg/day) for 3 months with a poor response.

On the other hand, surgical excision of large nodulo-cystic lesions can enhance cosmetic results and patients’ satisfaction as in the presented case. However, this should be considered before initiating systemic retinoids to avoid the possibility of a complicating hypertrophic scarring.

The clinical course of comedonal DD is unpredictable1, which can be explained by the extreme rarity of the condition. In comparison to classic DD, lacking of associated neurological or infectious complications may provide patients with comedonal DD with a better quality of life. However, recently Buchanan and Strutton [13] reported non-melanoma skin cancers in one patient

In conclusion, we reported a new patient with comedonal DD. Because of the extreme rarity of the reported cases, and the closely similar clinical features with acne vulgaris, comedonal Darier’s disease represents a real diagnostic challenge. Treatment options for comedonal variant are largely unsatisfactory, as for classic DD. We hope that the presentation of this report and future similar cases would help dermatologists to minimize missing of patients that may be responsible for paucity of reports. Finally this should provide comedonal DD patients with the proper therapeutic and prognostic information.

References

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