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 Table of Contents  
Year : 2016  |  Volume : 3  |  Issue : 1  |  Page : 46-48

Inheritance pattern of hypopigmented macules associated with familial Darier's disease

1 Department of Dermatology, Government Medical College, Amritsar, Punjab, India
2 Department of Pathology, Government Medical College, Amritsar, Punjab, India

Date of Web Publication17-Jun-2016

Correspondence Address:
Dr. Nidhi Sharma
207, Basant Avenue, Amritsar, Punjab
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2349-5847.184268

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Hypopigmented macules or guttate leukoderma is a rarely reported association of Darier's disease largely reported in dark colored individuals. So far, the pathogenesis of hypopigmented macules has been only partially explained by varying hypotheses such as post inflammatory phenomenon, an early or subclinical variant of disease, and genetic mosaicism. We describe a case of a 32-year-old male of Indian origin suffering from multigenerational Darier's disease associated with hypopigmented macules over the trunk. Classical warty papules and plaques were present in three generations thus highlighting autosomal dominant inheritance of the disease. The hypopigmented macules were found only in the proband thereby signifying its nonfamilial manner of inheritance.

Keywords: Darier's disease, depigmented macules, familial, guttate leukoderma

How to cite this article:
Sharma N, Aggarwal Y, Malhotra S K, Chahal K S. Inheritance pattern of hypopigmented macules associated with familial Darier's disease. Pigment Int 2016;3:46-8

How to cite this URL:
Sharma N, Aggarwal Y, Malhotra S K, Chahal K S. Inheritance pattern of hypopigmented macules associated with familial Darier's disease. Pigment Int [serial online] 2016 [cited 2022 Dec 5];3:46-8. Available from: https://www.pigmentinternational.com/text.asp?2016/3/1/46/184268

  Introduction Top

Darier's disease is an autosomal dominant disorder of keratinization with a prevalence rate of 1/36,000–1/100,000.[1] Classically, it presents as malodorous, greasy, crusted, hypertrophic papules, and plaques over seborrheic sites mainly scalp, forehead, nasolabial folds, chest, groin, and natal cleft. Its histopathology shows distinctive dyskeratotic cells (corps, ronds, and grains) and suprabasal cleavage due to acantholysis.[1] Although Darier's disease was originally described in 1889, guttate leukoderma in association with Darier's disease was first described by Goodall and Richmond in 1965.[2] Since then, about 20 cases have been reported in world literature.[3] We are reporting this case because of this rare association of Darier's disease as well as to highlight the nonfamilial nature of etiopathogenesis of guttate leukoderma.

  Case Report Top

The proband was a 32-year-old male who presented with asymptomatic, multiple, dirty, crusted, greasy papules on face, scalp, and upper back which developed insidiously over a period of 10 years [Figure 1]. Their course was marked with remission and relapses with aggravation in summers. Discrete, asymptomatic, skin-colored papules were present on the dorsum of his hands and feet since the age of 5 years [Figure 2]. On further examination, numerous asymptomatic, persistent, perifollicular, nonatrophic, hypopigmented macules [Figure 3] ranging in size from 1 to 5 mm were noticed in a bilaterally symmetrical fashion over previously normal skin of the chest and abdomen. They had substantially increased in number over a period of 5 years. The palms and soles were thickened with innumerable closely set asymptomatic papules. Numerous minute pits were also noted in the hypothenar area of both the palms. All mucosal surfaces and hair had unremarkable changes. Nail examination revealed a characteristic longitudinal, subungual red streaks and triangular nicking of free margins. There was no history of consanguinity among parents. Other family members including his grandfather, father, paternal uncle, sister [Figure 4] reportedly had similar dirty warty papules and plaques, but guttate leukoderma was not present in any of the other family members. Systemic examination was within normal limits.
Figure 1: Multiple dirty warty greasy papules in seborrheic distribution on face

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Figure 2: Perifollicular hypopigmented macules over the trunk

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Figure 3: Acrokeratosis verruciformis of bilateral dorsa of feet and pathognomonic V-shaped nicking of the distal end of the nails

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Figure 4: Pedigree chart of three generation family showing autosomal dominant pattern of inheritance

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Routine laboratory investigations were within normal limits. The histopathology of papules revealed corps and ronds with suprabasal cleft [Figure 5], but histopathology of hypopigmented macule exhibited normal looking epidermis with few melanocytes but without any dyskeratotic cells. KOH examination of the skin scrapings of hypopigmented macules was negative. The patient was advised strict sun protection and topical retinoids on the face at night.
Figure 5: Histopathology of papule shows “corps ronds” along with dyskeratosis in the upper layers of the epidermis (H and E, ×40)

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  Discussion Top

Darier's disease, also known as keratosis follicularis, was first described by Morrow in 1886 and subsequently in 1889 by Darier and White in an independent manner.[1],[4] Besides papillomatous and vegetating papules and plaques in seborrheic and flexural areas, acrokeratosis verruciformis such as discrete hyperkeratotic papules over hands and feet, palmer, and plantar pits are pathognomonic clinical features seen in Darier's disease. Mucosal lesions are uncommon, but palate may show cobble-stone papules resembling nicotinic stomatitis. Characteristic nail changes include red or white longitudinal bands often ending in a notch at the free margin of the nail.[2]

The etiopathogenesis of leukodermic macules has not been well understood even after 50 years of its first report. There are conflicting opinions regarding the clinical and histological relationship between warty papules and leukoderma. Initially, hypopigmented macules were considered to be postinflammatory in nature developing subsequently to warty papules.[5] In most of the reports, the hypopigmented lesions had appeared de novo and were not preceded by keratotic papules; conversely, the classical papular lesions on the remission did not leave residual hypopigmentation.[4] The histology of these leukodermic lesions showed basal hypomelanosis and decreased number of melanocytes. Berth-Joneset al. suggested it to be a form of a subclinical variety of Darier's disease and coined the term “guttate leukoderma” as he reported the histopathological findings of hypopigmented macules similar to classical Darier's disease.[6] However, this hypothesis is being questioned as the hypopigmented macules had not evolved into keratotic papules in any case reports. These observations suggest that the leukoderma is neither a result of postinflammatory changes nor a representative of an early lesion.

Darier's disease is a genetic disorder determined by an autosomal dominant gene; although some sporadic cases due to de novo mutation have been reported. Penetrance of Darier's disease is complete in adults; expressivity may be variable with significant interfamilial phenotypic variability.[1] In a case report, genetic mosaicism due to somatic mutations during embryogenesis leading to two distinct genetic cell population was considered to be responsible for the coexistence of Darier's disease with guttate leukoderma.[7] In our case report, characteristic warty papules were present in three generations (grandfather, father, paternal uncle, and sister) thereby endorsing the autosomal dominant pattern of inheritance in Darier's disease. The hypopigmented macules were noticed only in the proband out of all the affected family members; thereby furnishing corroborative evidence against the hypothesis of genetic pathomechanisms of guttate leukoderma.

Another possible way of the etiopathogenesis of macular hypopigmentation is erroneous keratinocyte–melanocyte interactions, which interfere with the transfer of melanosomes to keratinocytes leading to disruption of the functioning of “Epidermal Melanin Unit.”[8] Darier's disease is due to mutations in ATP2A2 gene at chromosome 12q23-24 which encodes the Sarco-endoplasmic reticulum Ca2+ ATPase type 2.[9] Disturbances in intracellular calcium have been shown to disrupt the formation of adhesion molecules in epithelial cells. In Darier's disease, proteolysis or conformational change of the adhesion molecule leads to loss of extracellular domains of E-cadherin in acantholytic cells. E-cadherin is a calcium-dependent, transmembrane glycoprotein localized in adherens junctions and mediates epithelial cell–cell contacts.[10] It helps in melanocyte adhesion to keratinocytes thereby promoting the formation of dendrites in melanocytes and melanosome transfer to keratinocytes.[3] This theory is unable to explain the sporadic nature of the development of hypopigmented macules associated with the Darier's disease.

Hypopigmented perifollicular macules may mimic tinea versicolor, lichen sclerosus, idiopathic guttate hypomelanosis or follicular vitiligo.

This case is being reported to highlight the bleak possibility of the role of genetics in the etiopathogenesis of hypopigmented macules associated with the Darier's disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Sehgal VN, Srivastava G. Darier's (Darier-White) disease/keratosis follicularis. Int J Dermatol 2005;44:184-92.  Back to cited text no. 1
Peterson CM, Lesher JL Jr., Sangueza OP. A unique variant of Darier's disease. Int J Dermatol 2001;40:278-80.  Back to cited text no. 2
Goh BK, Kumarasinghe SP, Ng SK. Two Singaporean cases of guttate leucoderma in Darier's disease. Clin Exp Dermatol 2004;29:313-4.  Back to cited text no. 3
Cornelison RL, Smith EB, Knox JM. Guttate leukoderma in Darier's disease. Arch Dermatol 1970;102:447-50.  Back to cited text no. 4
Cattano AN. An unusual case of keratosis follicularis. Arch Dermatol 1968;98:168-74.  Back to cited text no. 5
Berth-Jones J, Hutchinson PE. Darier's disease with peri-follicular depigmentation. Br J of Dermatol 1989;120:827-30.  Back to cited text no. 6
Gupta S, Shaw JC. Unilateral Darier's disease with unilateral guttate leukoderma. J Am Acad Dermatol 2003;48:955-7.  Back to cited text no. 7
Sornakumar L, Srinivas CR. Darier'S disease with perifollicular hypopigmentation. Indian J Dermatol 2010;55:299-300.  Back to cited text no. 8
[PUBMED]  Medknow Journal  
Craddock N, Dawson E, Burge S, Parfitt L, Mant B, Roberts Q, et al. The gene for Darier's disease maps to chromosome 12q23-q24.1. Hum Mol Genet 1993;2:1941-3.  Back to cited text no. 9
Dassoni F, Abebe Z, Morrone A, Padovese V. Darier's disease in Ethiopia: Report of two cases. Int J Dermatol 2015;54:e160-2.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

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