Clinicopathologic findings of guttate leukoderma in Darier disease: A helpful diagnostic feature

Abstract

Darier disease (DD), also known as keratosis follicularis or Darier-White disease, is a rare autosomal dominant genodermatosis attributed to a mutation in the ATP2A2 gene. DD affects both males and females worldwide, with high penetrance (95%) and variable expressivity, allowing for varied clinical manifestations and disease severity among affected families and individuals.1Sehgal V.N. Srivastava G. Darier's (Darier-White) disease/keratosis follicularis.Int J Dermatol. 2005; 44: 184-192Crossref PubMed Scopus (64) Google Scholar The characteristic feature of DD is the presence of firm, greasy, skin-colored to yellow-brown, hyperkeratotic papules distributed in seborrheic areas, such as the scalp, face, and trunk. Other classic findings include flat, wart-like papules over the dorsal hands and feet (acrodermatitis verruciformis of Hopf); flexural vegetative lesions; palmoplantar pitting; cobblestone appearance of the oral mucosa; and V-shaped scalloping of the distal nail plate.2Cooper S.M. Burge S.M. Darier's disease: epidemiology, pathophysiology, and management.Am J Clin Dermatol. 2003; 4: 97-105Crossref PubMed Scopus (137) Google Scholar Confetti-like hypopigmented macules in association with DD were described by Goodall and Richmond, and this manifestation was termed guttate leukoderma (GL).3Goodall J.W. Richmond Q.M. A case of Darier's disease.Br J Clin Pract. 1965; 19: 475-476PubMed Google Scholar This unique feature is considered distinct from postinflammatory changes that can be seen at sites of healed lesions in darkly pigmented skin. Since the initial description, this manifestation has been sparsely reported and might be infrequently recognized as a diagnostic feature of this genodermatosis.4Terrom M. Dhaille F. Baltazard T. et al.Guttate leukoderma in Darier disease: case report and review.J Eur Acad Dermatol Venereol. 2016; 30: e205-e209Crossref PubMed Scopus (6) Google Scholar Herein, we report GL as a helpful identifying clinical finding in a case of previously unrecognized DD and, in addition, describe the histopathology of this dyschromia. A 55-year-old black man requested evaluation of a pruritic, papular eruption on his back of 1-month duration. His condition was aggravated with sweating. He also noted the appearance of asymptomatic hypopigmented macules over his neck, arms, chest, abdomen, and back since the first decade of life. Over the years, the lesions increased in number and became more prominent. Family history revealed that his maternal grandmother, 4 siblings, and daughter had the same leukoderma and onset of findings. Physical examination revealed widespread involvement of multiple 1-4 mm discrete and coalescing hypopigmented macules scattered over his central chest, abdomen, and back (Fig 1, A; Fig 2, A and B), with less prominent involvement of his neck and 4 extremities. Examination of his fingernails revealed subungual hyperkeratosis and V-shaped scalloping of several of the distal nail plates (Fig 1, B). On the lower back, there were multiple firm, greasy, hyperkeratotic, brown papules (Fig 2, A and B).Fig 2A and B, Back with multiple hypopigmented macules admixed with multiple hyperkeratotic brown papules.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Histopathologic evaluation of a biopsy taken from a papular lesion on the back revealed verrucous epidermal hyperplasia with suprabasilar clefting, as well as numerous dyskeratotic cells forming corp ronds and grains; follicular involvement was evident (Fig 3, A and B). Examination of a hypopigmented macule demonstrated papillomatosis without acanthosis, thinned epidermis and rete ridges, and maintained basilar pigmentation of the rete ridges (Fig 3, A); these features contrasted starkly to the patient's nonlesional skin (Fig 3, D). In addition, immunoperoxidase for SOX-10 and a Fontana Masson special stain highlighted a focal absence of pigmentation and melanocytes, with preservation of melanization at the base of rete ridges. Pigment incontinence and dermal melanophages were absent (Fig 4, A-D).Fig 4A, Immunostaining for SOX-10 within a hypopigmented macule demonstrates an overall reduction in the number of melanocytes at the dermoepidermal junction, with preservation of melanocytes at the base of rete ridges and acrosyringium and absence within the epidermis overlying dermal papillae. B, A corresponding near absence of melanization is also demonstrated between rete ridges, while basilar pigment is preserved at the ends of rete ridges and the acrosyringium. Pigment incontinence is absent. C and D, For comparison, the patient's adjacent nonlesional skin features a normal complement of melanocytes and complete melanization. (A and C, SOX-10 stain; B and D, Fontana Masson stain; original magnification: ×100.)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Given the family history, onychodystrophy, and cutaneous clinical and histologic morphology, a diagnosis of Darier disease was made. Sequencing analysis for ATP2A2 gene mutations was recommended but was deferred by the patient due to financial constraints. Fewer than 30 cases of GL in DD have been documented in the literature. While the majority of cases have been reported in dark-skinned individuals of African descent, there have been cases reported in fair-skinned Japanese patients as well.4Terrom M. Dhaille F. Baltazard T. et al.Guttate leukoderma in Darier disease: case report and review.J Eur Acad Dermatol Venereol. 2016; 30: e205-e209Crossref PubMed Scopus (6) Google Scholar The pathogenesis of GL has not yet been fully elucidated. Several features support GL as a manifestation of the disease itself, rather than secondary postinflammatory change. In 70% of patients with DD, keratotic or verrucous papules first present during 6-20 years of age, with peak onset during the second decade of life in the peripubertal period.5Burge S.M. Wilkinson J.D. Darier-White disease: a review of the clinical features in 163 patients.J Am Acad Dermatol. 1992; 27: 40-50Abstract Full Text PDF PubMed Scopus (383) Google Scholar Given the patient's history of recent onset of keratotic papules, transient acantholytic dermatosis (Grover disease) was considered. However, transient acantholytic dermatosis is not associated with a family history consistent with a hereditary process, GL, or the characteristic onychodystrophy described herein. Lesions of GL typically appear simultaneously or, more commonly, years before the development of papular lesions; only 1 previously reported case described subsequent onset of macular lesions.6Fangman W.L. Selim M.A. Murrary J.C. Diffuse hypopigmented macules.Arch Dermatol. 2006; 142: 235-240Crossref PubMed Scopus (3) Google Scholar In the patient presented here, the hypopigmented macules developed several decades before the keratotic papules, without evolution into classic lesions of DD. Unlike keratotic papules of DD, GL is not limited to sebaceous areas, but is widespread with involvement of the extremities and sometimes face and scalp.4Terrom M. Dhaille F. Baltazard T. et al.Guttate leukoderma in Darier disease: case report and review.J Eur Acad Dermatol Venereol. 2016; 30: e205-e209Crossref PubMed Scopus (6) Google Scholar In addition, while treatment with systemic retinoids typically leads to clinical improvement in keratotic lesions, no effective treatment has been reported for GL. Previously described histologic features of GL are a decrease in the density of basal epidermal melanocytes, with variable dyskeratosis and acantholysis.4Terrom M. Dhaille F. Baltazard T. et al.Guttate leukoderma in Darier disease: case report and review.J Eur Acad Dermatol Venereol. 2016; 30: e205-e209Crossref PubMed Scopus (6) Google Scholar, 6Fangman W.L. Selim M.A. Murrary J.C. Diffuse hypopigmented macules.Arch Dermatol. 2006; 142: 235-240Crossref PubMed Scopus (3) Google Scholar, 7Goh B.K. Kumarasinghe S.P. Ng S.K. Two Singaporean cases of guttate leucoderma in Darier's disease.Clin Exp Dermatol. 2004; 29: 313-314Crossref PubMed Scopus (18) Google Scholar In the case described here, the histopathologic features are notably similar to that of confluent and reticulated papillomatosis, with an attenuated epidermis, slender rete ridges, and absence of acanthosis.8Lim J.H. Tey H.L. Chong W.S. Confluent and reticulated papillomatosis: diagnostic and treatment challenges.Clin Cosmet Investig Dermatol. 2016; 9: 217-223Crossref PubMed Scopus (23) Google Scholar Furthermore, the skip melanization observed here is similar to that described in idiopathic guttate hypomelanosis (IGH), but this pattern has not been reported previously for GL of DD. Distinction from IGH is supported by the epidermal changes observed; epidermal atrophy is typical of IGH.9Joshi R. Skip areas of retained melanin: a clue to the histopathological diagnosis of idiopathic guttate hypomelanosis.Indian J Dermatol. 2014; 59: 571-574Crossref PubMed Scopus (10) Google Scholar Evidence of postinflammatory pigment alteration (pigment incontinence and melanophages) was absent. Taken together with the unique histologic findings, the historical and clinical findings of GL support this manifestation as a distinct clinicopathologic feature of DD. Several proposed mechanisms exist regarding the underlying pathogenesis of GL. Goh et al proposed that mutations in ATP2A2 are directly responsible. In DD, mutations in the ATP2A2 gene lead to the dysfunction of SERCA-2, a calcium pump of the sarcoplasmic endoplasmic reticulum. This results in disruption of intracellular calcium levels, ultimately leading to loss of cell-cell adhesion (acantholysis) and induction of apoptosis (dyskeratosis).2Cooper S.M. Burge S.M. Darier's disease: epidemiology, pathophysiology, and management.Am J Clin Dermatol. 2003; 4: 97-105Crossref PubMed Scopus (137) Google Scholar, 4Terrom M. Dhaille F. Baltazard T. et al.Guttate leukoderma in Darier disease: case report and review.J Eur Acad Dermatol Venereol. 2016; 30: e205-e209Crossref PubMed Scopus (6) Google Scholar E-cadherin is a calcium-dependent transmembrane glycoprotein that functions within adherens junctions to mediate epithelial intercellular adhesion. E-cadherins also play a pivotal role in the adhesion of melanocytes to keratinocytes, and formation of melanocyte dendrites requires this direct keratinocyte contact. Defective E-cadherins disrupt melanocyte-keratinocyte adhesion, resulting in impaired dendrite formation and melanin transfer. Melanocyte apoptosis consequently follows, suggesting the underlying pathophysiology of GL in DD.7Goh B.K. Kumarasinghe S.P. Ng S.K. Two Singaporean cases of guttate leucoderma in Darier's disease.Clin Exp Dermatol. 2004; 29: 313-314Crossref PubMed Scopus (18) Google Scholar Given the rarity of GL in DD, dermatologists and dermatopathologists might be unaware of this unique feature. However, it is both important and helpful to recognize this manifestation: GL often precedes the onset of keratotic papules, thereby serving as an early marker of DD. This finding might also be useful in dark-skinned patients without classic keratotic papules in a seborrheic distribution. In addition, the histology of GL, including findings that might simulate confluent and reticulate papillomatosis and the skip melanization of IGH, may prompt consideration of DD when evaluating a leukoderma. Awareness of the clinicopathologic features of this unusual manifestation could allow earlier diagnosis and appropriate counseling to patients and family members with this genodermatosis.