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AUTHOR AND EDITOR INFORMATION

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Author: Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School

Robert A Schwartz is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Coauthor(s): Borys Savchyk, MD, PhD, Director, Molecular Biology Institute, Medical University of Lviv, Ukraine; Alexander Zajchenko, MD, Head, Professor, Department of Skin and Venereal Diseases, Medical University of Lviv, Ukraine

Editors: Mark A Crowe, MD, Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey; Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System

Author and Editor Disclosure

Synonyms and related keywords: Dowling-Degos disease, dark dot disease, Dowling Degos Ossipowski disease, DDD

INTRODUCTION

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Background

Dowling1 first delineated this genodermatosis as a distinct entity in 1938. In 1954, Degos and Ossipowski2 described a patient with a similar case. Few patients with reticulate pigmented anomaly, also known as Dowling-Degos disease (DDD), have been reported.

DDD is characterized by flexural pigmented reticulate macules and sometimes comedolike papules on the back and/or the neck (dark dot follicles). Some patients have pitted perioral scars. Pruritus of affected flexural areas may be the only symptom. In both male and female patients, pigmented reticulate macules may also be evident on the genitalia, where they may be seen alone. The pigmented eruption on the male external genitalia may be a cutaneous marker of underlying testicular carcinoma,3 although the association is probably fortuitous. Bilateral nephroblastoma in familial Hay-Wells syndrome has been associated with familial reticulate pigmentation of the skin,4 another possibly fortuitous association.

The disease is slowly progressive. It is characterized by pigmented filiform epidermal papules closely resembling an adenoid seborrheic keratosis, but similar proliferations also develop around the variably dilated pilosebaceous follicles.

Galli-Galli disease is a rare genodermatosis in the spectrum of reticulate hyperpigmentation probably best regarded as an acantholytic variant of DDD.5

Pathophysiology

DDD is often familial and appears to be inherited in an autosomal dominant manner.6 A gene locus believed responsible in one Chinese patient was mapped to 17p13.3.7 A genome-wide linkage analysis of 2 German families mapped this disease to 12q.8 This region includes the keratin gene cluster, which was screened for mutations. Loss-of-function mutations were identified in the keratin 5 gene (KRT5) in all affected family members and in 6 unrelated patients with DDD.

A heterozygous frameshift mutation in the V1 domain of keratin 5 was identified in a family with DDD.9 This study confirmed that haploinsufficiency for K5 causes DDD and points to a prominent role for the keratin intermediate filament cytoskeleton within basal keratinocytes in epidermal pigment biology.

Frequency

International

DDD is a rare condition.

Sex

The disease affects both sexes. Although this disorder appears to be inherited in an autosomal dominant manner,10 a female predominance has been noted in some surveys.11

Age

DDD tends to develop early in adult life, with the onset of pigmentation occurring in individuals before they are aged 24 years. A Chinese newborn with reticulate pigmented anomaly of the flexures was recently described.12


CLINICAL

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History

This rare pigmentary disorder is characterized by reticulate pigmentation of the flexures, prominent comedolike lesions and pitted scars.

  • Some patients report pruritus in the involved regions.
  • Most patients in the authors' experience report increased pigmentation in the neck, the axillae, or the groin, with an onset varying from childhood to adult life.
  • It has been described in one family as occurring together with dyschromatosis universalis hereditaria.13
  • A rare association has been described between hidradenitis suppurativa and DDD, in one case together with multiple epidermal cysts. This may reflect a single underlying defect of follicular proliferation.14

Physical

  • The flexural pigmentation has its onset from childhood to adult life. It may be intense, with a brownish black color and sometimes steel blue or navy overtones. However, if the condition is less severe, it is stippled in shades of brown.
  • No verrucous or velvety papillomatosis is present, as might be seen in acanthosis nigricans.
  • If the patches are palpable, it is because of lichenification that produces a glossy and at times somewhat wrinkled appearance.
  • The margins may show tiny pigmented comedones.
  • In some cases, comedolike papules may be present on the back and/or neck.
  • Some patients have pitted perioral scars.
  • In addition, speckled macules involving the dorsum of the hands, the proximal nail folds, or the scrotum3 may be seen. Fingernail dystrophy may be present.11 The finding of speckled macules on the scrotum is isolated and limited to the scrotal and penile skin.3 This pigmented eruption on the male external genitalia is possibly a cutaneous marker of underlying testicular carcinoma. In female patients, speckled macules may be found on the vulva.15, 16

Causes

  • See Pathophysiology.
  • DDD may coexist with hidradenitis suppurativa. The follicular occlusion inherent in DDD may predispose to the development of hidradenitis suppurativa.17


DIFFERENTIALS

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Carney Syndrome
Keratosis Follicularis (Darier Disease)
Transient Acantholytic Dermatosis

Other Problems to be Considered

  • Kitamura reticulate acropigmentation
  • Haber syndrome
  • Galli-Galli disease18 - Best considered a subtype of DDD with clinical and histologic features similar to transient acantholytic dermatosis19
  • Epidermolysis bullosa with mottled pigmentation
  • Scleroderma - May rarely be associated reticulate hyperpigmentation of the trunk, upper limbs, and lower limbs20


WORKUP

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Other Tests

The dermoscopic findings of DDD are not specific, but they may be useful in selected patients to rule out melanoma of the vulva.16

Histologic Findings

Histopathologically, pigmented rete ridge elongation with thinning of the suprapapillary epithelium, dermal melanosis, and perivascular lymphohistiocytic infiltration is present. The downward elongations are composed of regular pigmented basaloid cells.

A small study showed all pigmented cells in the basal layer were recognized by Anti-PEP-1, anti-PEP-2, HMB-45, and NKI/beteb antibodies.21 Supranuclear "caps" of brown granules were observed within most basal keratinocytes in the hyperpigmentation area. The melanocytes contained regular melanosomes in all stages of maturation in their cytoplasms. Melanosomes, mainly of stages III and IV, were evident within keratinocytes, distributed either as scattered patterns or forming caps over the nucleus.


TREATMENT

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Medical Care

No treatment is effective.11 Topical retinoic acids, topical steroids, hydroquinone, tretinoin, and systemic retinoids have been used without success.


FOLLOW-UP

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Prognosis

DDD is slowly progressive but not life threatening.

Patient Education

The patient and his or her family should be educated about the common autosomal dominant nature of this disorder.


MULTIMEDIA

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Media file 1:  Speckled macules on the male external genitalia.
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Media type:  Photo

Media file 2:  Histologic view showing elongated thin rete ridges with melanin concentrated at the tips (hematoxylin and eosin).
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REFERENCES

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  1. Dowling GD, Freudenthal W. Acanthosis nigricans. Proc Roy Soc Med. 1938;31:1147-50.
  2. Degos R, Ossipowski B. [Reticulated pigmentary dermatosis of the folds: relation to acanthosis nigricans.]. Ann Dermatol Syphiligr (Paris). Mar-Apr 1954;81(2):147-51. [Medline].
  3. Schwartz RA, Birnkrant AP, Burgess GH, Stoll HL Jr, Yaqub M, Fox MD. Reticulate pigmented anomaly. Cutis. Oct 1980;26(4):380-1. [Medline].
  4. Drut R, Pollono D, Drut RM. Bilateral nephroblastoma in familial Hay-Wells syndrome associated with familial reticulate pigmentation of the skin. Am J Med Genet. Jun 15 2002;110(2):164-9. [Medline].
  5. El Shabrawi-Caelen L, Rutten A, Kerl H. The expanding spectrum of Galli-Galli disease. J Am Acad Dermatol. May 2007;56(5 Suppl):S86-91. [Medline].
  6. Brown WG. Reticulate pigmented anomaly of the flexures. Case reports and genetic investigation. Arch Dermatol. Jul 1982;118(7):490-3. [Medline].
  7. Li CR, Xing QH, Li M, Qin W, Yue XZ, Zhang XJ, et al. A gene locus responsible for reticulate pigmented anomaly of the flexures maps to chromosome 17p13.3. J Invest Dermatol. Jun 2006;126(6):1297-301. [Medline].
  8. Betz RC, Planko L, Eigelshoven S, Hanneken S, Pasternack SM, Bussow H, et al. Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet. Mar 2006;78(3):510-9. [Medline].
  9. Liao H, Zhao Y, Baty DU, McGrath JA, Mellerio JE, McLean WH. A heterozygous frameshift mutation in the V1 domain of keratin 5 in a family with Dowling-Degos disease. J Invest Dermatol. Feb 2007;127(2):298-300. [Medline].
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  14. Loo WJ, Rytina E, Todd PM. Hidradenitis suppurativa, Dowling-Degos and multiple epidermal cysts: a new follicular occlusion triad. Clin Exp Dermatol. Nov 2004;29(6):622-4. [Medline].
  15. O'Goshi K, Terui T, Tagami H. Dowling-Degos disease affecting the vulva. Acta Derm Venereol. May 2001;81(2):148. [Medline].
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Reticulate Pigmented Anomaly excerpt

Article Last Updated: May 1, 2008