DISEASE CARD

Definition

Dowling-Degos disease (DDD) belongs to the genetically heterogeneous group of reticulate pigment disorders of the skin. This group of disorders shows similar clinical features (see table 1) and includes Galli-Galli disease (GGD), Kitamura's disease (RPK), Haber's syndrome (HS), and reticulate acropigmentation of Dohi (RAD).^{1, 2}
DDD was differentiated from acanthosis nigricans by Dowling and Freudenthal in 19383 and described as a reticulate pigmentation dermatosis by Degos and Ossipowski in 1954 4. Mutations in KRT5 gene (12q13.13) have been identified as pathogenic. ^{5, 6}

Clinical Description

Onset of the disease is during (early) adolescence. Patients present with reticulated hyperpigmented macules, mainly located in the flexures and large body folds. The lesions appear as round to oval hyperpigmented lentigo‐like macules of various sizes that may coalesce. Hyperkeratosis is occasionally present. Pitted perioral acne-like scars are additional features, as well as comedo-like hyperkeratotic follicular papules on the neck and axillae^.1 Pruritus in flexural areas has been reported. Genital and perianal reticulated pigmented lesions have also been described.⁷ Generally, the disease is progressive with age. 

Pathogenesis

Various mutations in the KRT5 gene region have been identified to cause this condition. The pathomechanism is not entirely clear. Mutations in the KRT5 gene are also responsible for other skin disorders that include pigmentation abnormalities, e.g., epidermolysis bullosa simplex with mottled pigmentation. These similarities suggest a role of KRT5, and probably its dimerization partner KRT14, in melanin transfer from melanocytes to keratinocytes.⁶ Recently, mutations in POGLUT1, POFUT1 and PSENEN have been associated with DDD. POGLUT1 and POFUT1 play a critical role in Notch signaling, essential for regulating melanocyte and keratinocyte proliferation and differentiation and result phenotypically in a more diffuse distribution of pigmentary changes.^{8, 9} PSENEN gene mutations affect the Notch signaling pathway by modification of an enhancer gene that encodes a component of γ‐secretase protein complex. Patients harboring this mutation present with hidradenitis suppurativa and DDD like lesions, localized to the scrotum.¹⁰ 

Diagnosis

The various reticulate pigment disorders share many clinical features, which makes them hard to distinguish, based solely on clinical and histopathological findings. This is especially the case for DDD and GGD, which share most of their clinical characteristics, and it was suggested that GGD, caused by a KRT5 mutation allelic to those seen in DDD, is a variant of DDD.^{5, 11}

Histologically, GGD shows a moderate to severe acantholysis of the suprabasal epidermis, an important feature to distinguish it from DDD. Histopathologic criteria of DDD include hyperkeratosis, thinning of the suprapapillary epithelium, elongated rete ridges with basal hyperpigmentation, dermal melanosis and fibrosis along rete ridges. There is no increase in melanocyte number.¹ If genetic testing is performed, sequencing of KRT5, POFUT1, POGLUT1 and PSENEN genes is recommended. In a patient presenting with generalized DDD, mutations in POFUT1 genes are most likely.²

Table 1. Differentialdiagnosis of Dowling-Degos disease (DDD)

Treatment

Treatment is limited to symptomatic measures (e.g. use of skin lightening cosmetics). Patients must be advised to avoid friction (e.g. through clothing). Sun protective measures are recommended to avoid aggravation of the hyperpigmentation. Topical steroids may be helpful in case of pruritus. Case reports indicate improvement of hyperpigmentation after treatment with Er:YAG laser. Systemic retinoids are ineffective, however, topical retinoid (adapalene) resulted in an improvement of hyperpigmentation in a patient.^{2, 12, 13}

References

^{1.    Müller CS, Tremezaygues L, Pföhler C, Vogt T. The spectrum of reticulate pigment disorders of the skin revisited. Eur J Dermatol. 2012;22(5):596-604.
2.    Stephan C, Kurban M, Abbas O. Dowling-Degos disease: a review. Int J Dermatol. 2020.
3.    Dowling GB, Freudenthal W. Acanthosis Nigricans. Proc R Soc Med. 1938;31(9):1147-1150.
4.    Degos R, Ossipowski B. [Reticulated pigmentary dermatosis of the folds: relation to acanthosis nigricans]. Ann Dermatol Syphiligr (Paris). 1954;81(2):147-151.
5.    Hanneken S, Rütten A, Pasternack SM, Eigelshoven S, El Shabrawi-Caelen L, Wenzel J, et al. Systematic mutation screening of KRT5 supports the hypothesis that Galli-Galli disease is a variant of Dowling-Degos disease. Br J Dermatol. 2010;163(1):197-200.
6.    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. 2006;78(3):510-519.
7.    Kim YC, Davis MD, Schanbacher CF, Su WP. Dowling-Degos disease (reticulate pigmented anomaly of the flexures): a clinical and histopathologic study of 6 cases. J Am Acad Dermatol. 1999;40(3):462-467.
8.    Li M, Cheng R, Liang J, Yan H, Zhang H, Yang L, et al. Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease. Am J Hum Genet. 2013;92(6):895-903.
9.    Basmanav FB, Oprisoreanu AM, Pasternack SM, Thiele H, Fritz G, Wenzel J, et al. Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease. Am J Hum Genet. 2014;94(1):135-143.
10.    Ren J, Zeng LY. Scrotal Dowling-Degos disease caused by a novel frameshift variant in gamma-secretase subunit presenile enhancer gene. Australas J Dermatol. 2020;61(4):e399-e402.
11.    Sprecher E, Indelman M, Khamaysi Z, Lugassy J, Petronius D, Bergman R. Galli-Galli disease is an acantholytic variant of Dowling-Degos disease. Br J Dermatol. 2007;156(3):572-574.
12.    Altomare G, Capella GL, Fracchiolla C, Frigerio E. Effectiveness of topical adapalene in Dowling-Degos disease. Dermatology. 1999;198(2):176-177.
13.    Yun JH, Kim JH, Choi JS, Roh JY, Lee JR. Treatment of Dowling-Degos disease with fractional Er:YAG laser. J Cosmet Laser Ther. 2013;15(6):336-339.}