Itchy, Smelly Lesions and Streaked Nails in a Teenager
A 17-year-old male presented with a 4-year history of greasy, hyperkeratotic papules and plaques on his chest, abdomen, and upper extremities. The lesions were pruritic and had a foul odor, especially during summertime. His 45-year-old father had had similar papules and plaques on his neck, abdomen, and back for years.
Physical examination revealed reddish brown papules and plaques with a verrucous texture, primarily on the chest, abdomen, and upper extremities. He also had white and red longitudinal bands on his fingernails, as well as some flat-topped papules in the periungual areas. The rest of the examination findings were unremarkable.
What’s your diagnosis?
(Answer and discussion on next page)
Answer: Darier disease
Darier disease, also known as Darier-White disease and keratosis follicularis, is a rare genodermatosis. The disease is characterized histologically by acantholysis, dyskeratosis, and hyperkeratosis and clinically by warty papules and plaques in seborrheic areas.1
The condition was described independently by Ferdinand Jean Darier and James White in 1889, and the disease now bears their names.2,3 The name Darier disease, nevertheless, seems to be more popular and is now in common usage.
EPIDEMIOLOGY, ETIOLOGY, PATHOGENESIS
The disease is inherited as an autosomal dominant disorder with a high penetrance, although expressivity is variable.4,5 The prevalence has been estimated to be 1 in 30,000 to 100,000.1,6 Both sexes are equally affected, although males tend to be more severely affected than females. Typically, patients present between 6 and 20 years of age, with onset peaking between 11 and 15 years of age.7
The disease is caused by mutations in the ATP2A2 (ATPase, Ca2+ transporting, slow twitch 2) gene that encodes a sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase isoform 2 protein (SERCA2).1,4 This calcium ATPase pump plays an essential role in intercellular calcium signaling.1 Mutations in ATP2A2 have been shown to cause severe disruption in calcium homeostasis, leading to depletion of calcium stores in the keratinocytes with resultant formation of hyperkeratotic papules and/or plaques.4 The ATP2A2 gene is located on chromosome 12q23-24.1.5
Exacerbating factors include sunlight, heat, sweating, mechanical trauma, menstruation, and stress.7,8 The disease can also be precipitated by oral lithium carbonate, as well as phenol and ethyl chloride sprays.9
Histopathologic examination of the lesion shows loss of intercellular adhesion (acantholysis) between epidermal cells with corps ronds and suprabasal cleavage as a result of acantholysis, abnormal keratinization (dyskeratosis), and hyperkeratosis in the epidermis.8,10
Skin changes are characterized by greasy discrete, flat-topped, hyperkeratotic papules and plaques that occur in seborrheic areas such as the trunk, lateral sides of the neck, scalp, limbs, and forehead.4 The distribution is often symmetric.
Lesions are itchy; are yellow-brown, brown, or skin-colored; and feel like coarse sandpaper. Lesions may have a foul odor if secondary infection or colonization is present. In flexural areas, lesions may present as large, malodorous, fleshy, exuberant growths.7 On the palms and soles, lesions often appear as hyperkeratotic papules and centrally depressed pits.1,10 Lesions resembling acrokeratosis verruciformis might be seen on the dorsa of hands. Other cutaneous features include café au lait spots and leukodermic macules.11,12
More than 95% of patients have nail changes that can include white and red longitudinal stripes, splinter hemorrhages, subungual hyperkeratosis, distal notches, and triangular nicking of the distal nail plate; these changes may precede other signs of the disease.10 While red longitudinal stripes are characteristic of Darier disease, the combined “sandwich” of white and red longitudinal stripes with a peripheral notch or split is pathognomonic.1,7
Papules, fissures, and ulcers may develop on the palate, buccal mucosa, or tongue. The gingiva may assume a cobblestone appearance. Oral manifestations are present in approximately 50% of patients with Darier disease.13 Intermittent parotid gland swelling is an infrequent but notable feature.7,10 Presumably, the parotid swelling results from metaplasia of the parotid ductal lining with resultant obstruction to the salivary flow.1
Affected patients often have dry eye syndrome with or, more often, without Sjögren syndrome, keratotic plaques on the eyelid, corneal opacities, and focal keratinization in the limbal conjunctiva.14,15 Other ocular features such as cataract, corneal ulceration, corneal sub-basal nerve involvement, subnormal dark adaption, and retinitis pigmentosa have been described in patients with Darier disease.14,15
Clinical variants such as linear Darier disease, comedonal Darier disease, and vesiculobullous Darier disease are extremely rare. Linear Darier disease is a mosaic cutaneous form of Darier disease characterized by unilateral skin lesions conforming to linear, zosteriform, or localized patterns located on Blaschko lines.16 Comedonal Darier disease differs from classic Darier disease in that there is prominent follicular involvement with formation of large comedones, while other features of classic Darier disease also are present.17 In vesiculobullous Darier disease, vesicles and bullae are present in addition to other features seen in classic Darier disease.18,19
Affective disorder, mental retardation, epilepsy, psychosis, bipolar disorder, suicidal tendency, and schizophrenia are more common in patients with Darier disease.1,5,20
The diagnosis is mainly a clinical one. A skin biopsy should be considered if the diagnosis is in doubt and is generally recommended.
Darier disease should be differentiated from seborrheic dermatitis, Hailey-Haley disease, Grover disease, pemphigus vegetans, and confluent and reticulated papillomatosis.
The lesions may be cosmetically unsightly and socially embarrassing if they occur in an exposed area. Secondary infection or colonization by bacteria is common, followed by fungi and viruses.5,7
The unsightly appearance, pruritus, irritation, and malodor have an adverse effect on the quality of life.21 Squamous cell carcinoma arising from Darier disease, although rare, has been reported.22
The disease runs a chronic course characterized by remissions and relapses throughout life.
The environment should be kept cool. Patients should be advised to wear comfortable cotton clothing and to use sunscreens and emollients. Emollients with urea or lactic acid can reduce scaling and hyperkeratosis. Treatment often is difficult and unsatisfactory. Therapeutic options include topical corticosteroids, topical calcineurin inhibitors, topical 5-fluorouracil, topical retinoids, oral retinoids, dermabrasion, excision, electrodessication, cryosurgery, ablative laser therapy, electron beam therapy, and photodynamic therapy with 5-aminolevulinic acid.8,23
In general, oral retinoids are the most effective treatment for generalized or severe Darier disease.8 Side effects such as mucosal dryness, epistaxis, skin fragility, hypercholesterolemia, hypertriglyceridemia, teratogenicity in women of childbearing age, depression, and suicidal attempts are drawbacks and preclude its routine long-term use. Use of topical and/or oral antibiotics may be necessary for secondary bacterial infection and odor. Affected patients may benefit from genetic counseling.
This patient was treated with a topical antibiotic and hydrocortisone combination, along with oral retinoids, with moderate improvement of the lesions after 3 months.
1.Chacon GR, Wolfson DJ, Palacio C, Sinha AA. Darier’s disease: a commonly misdiagnosed cutaneous disorder. J Drugs Dermatol. 2008;7(4):387-390.
2.Darier J. Psorospermose folliculaire végétante. Ann Dermatol Syphiligr. 1889;10:597-612.
3.White JC. A case of keratosis (ichthyosis) follicularis. J Cutan Genitourin Dis. 1889;7:201-209.
4.Green EK, Gordon-Smith K, Burge SM, et al. Novel ATP2A2 mutations in a large sample of individuals with Darier disease. J Dermatol. 2013;40(4):259-266.
5.Metze D. Darier disease. In: Lang F, ed. Encyclopedia of Molecular Mechanisms of Disease. Berlin, Germany: Springer-Verlag; 2009:495-496.
6.Tavadia S, Mortimer E, Munro CS. Genetic epidemiology of Darier’s disease: a population study in the west of Scotland. Br J Dermatol. 2002;146(1):107-109.
7.Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27(1):40-50.
8.Pérez-Carmona L, Fleta-Asín, Moreno-García-Del-Real C, Jaén-Olasolo P. Successful treatment of Darier’s disease with topical pimecrolimus. Eur J Dermatol. 2011;21(2):301-302.
9.Ngo J, Haber R. Exacerbation of Darier disease by lithium carbonate. J Cutan Med Surg. 2010;14(2):80-84.
10.Sehgal VN, Srivastava G. Darier’s (Darier-White) disease/keratosis follicularis. Int J Dermatol. 2005;44(3):184-192.
11.Bleiker TO, Burns DA. Darier disease with hypopigmented macules. Br J Dermatol. 1998;138(5):913-914.
12.Soroush V, Gurevitch AW. Darier’s disease associated with multiple café-au-lait macules. Cutis. 1997;59(4):193-195.
13.Cardoso CL, Freitas P, Taveira LA, Consolaro A. Darier disease: case report with oral manifestations. Med Oral Patol Oral Cir Bucal. 2006;11(5):e404-e406.
14.Lagali N, Dellby A, Fagerholm P. In vivo confocal microscopy of the cornea in Darier-White disease. Arch Ophthalmol. 2009;127(6):816-818.
15.Mielke J, Grüb M, Besch D, Schlote T. Recurrent corneal ulcerations with perforation in keratosis folliculitis (Darier-White disease). Br J Ophthalmol. 2002;86(10):1192-1193.
16.Dogan S, Karaduman A, Erkin G, Gokoz O. Effective treatment of linear Darier’s disease with topical retinoids: case report and review of the literature. Acta Dermatovenerol Croat. 2011;19(3):206-209.
17.Lora V, Cota C, Grammatico P, Pedace L, Kerl H, Cerroni L. Comedonal Darier disease: report of 2 cases. J Am Acad Dermatol. 2013;69(6):e307-e309.
18.Clover GB, Gawkrodger DJ. Vesiculo-bullous Darier’s disease. Br J Dermatol. 1992;126(4):416-417.
19.Kakar B, Kabir S, Garg VK, Bhushan P. A case of bullous Darier’s disease histologically mimicking Hailey-Hailey disease. Dermatol Online J. 2007;13(3):28.
20.Tang C, Chan M, Lee J, Hariram J. Darier’s disease and schizophrenia. East Asian Arch Psychiatry. 2010;20(4):190-192.
21.Dodiuk-Gad, Cohen-Barak E, Ziv M, et al. Health-related quality of life among Darier’s disease patients. J Eur Acad Dermatol Venereol. 2013;27(1):51-56.
22.Matsui K, Makino T, Nakano H, Furuichi M, Sawamura D, Shimizu T. Squamous cell carcinoma arising from Darier’s disease. Clin Exp Dermatol. 2009;34(8):e1015-e1016.
23.Letulé V, Herzinger T, Ruzicka T, Molin S. Treatment of Darier disease with oral alitretinoin. Clin Exp Dermatol. 2013;38(5):523-525.