Dowling-Degos Disease 1

A number sign (#) is used with this entry because of evidence that Dowling-Degos disease-1 (DDD1) is caused by heterozygous mutation in the KRT5 gene (148040) on chromosome 12q13.


Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by reticular pigmentation, usually in a flexural distribution. However, generalized DDD can also occur, with numerous hypopigmented or erythematous macules and papules on the neck, chest, and abdomen. The histopathology of DDD shows characteristic thin branch-like patterns of epidermal downgrowth (summary by Li et al., 2013).

Review of Reticulate Pigment Disorders

Muller et al. (2012) reviewed the spectrum of reticulate pigment disorders of the skin, tabulating all reported cases of patients with Dowling-Degos disease, reticulate acropigmentation of Kitamura (RAK; 615537), reticulate acropigmentation of Dohi (RAD; 127400), Galli-Galli disease (GGD), and Haber syndrome (HS). Of 82 cases, 26 (31.7%) were clinically diagnosed as DDD, 13 (15.9%) as RAD, 11 (13.4%) as GGD, 8 (9.8%) as RAK, and 8 (9.8%) as HS; in addition, 16 (19.5%) of the cases showed overlap between DDD and RAK. Muller et al. (2012) also published photographs of an affected individual exhibiting an overlap of clinical features of DDD, GGD, RAD, and RAK. The authors noted that in reticulate disorders of the skin, the main disease entity is DDD, with a subset of cases exhibiting acantholysis (GGD), facial erythema (HS), or an acral distribution (RAD; RAK). Muller et al. (2012) concluded that all reticulate pigment diseases of the skin are varying manifestations of a single entity.

Genetic Heterogeneity of Reticulate Pigment Disorders

Dowling-Degos disease-2 (DDD2; 615327) is caused by mutation in the POFUT1 gene (607491) on chromosome 20q11. Dowling-Degos disease-3 (DDD3; 615674) has been mapped to chromosome 17p33.3. Dowling-Degos disease-4 (DDD4; 615696) is caused by mutation in the POGLUT1 gene (615618) on chromosome 3q13. Dyschromatosis symmetrica hereditaria (DSH; 127400), also known as reticulate acropigmentation of Dohi (RAD), is caused by mutation in the ADAR gene (146920) on chromosome 1q21. Reticulate acropigmentation of Kitamura (RAK; 615537) is caused by mutation in the ADAM10 gene (602192) on chromosome 15q21.

Clinical Features

Dowling-Degos disease is an autosomal dominant form of reticulate pigmentary disorder. It was first described by Dowling and Freudenthal (1938) and was termed 'dermatose reticulee des plis' (reticulate dermatosis of flexures) by Degos and Ossipowski (1954).

Individuals with Dowling-Degos disease develop a postpubertal reticulate hyperpigmentation that is progressive and disfiguring, and small hyperkeratotic dark brown papules that affect mainly the flexures and great skin folds. Pitted perioral acneiform scars and genital and perianal reticulated pigmented lesions have also been described (Milde et al., 1992; Jafari et al., 2003). Patients usually show no abnormalities of the hair or nails. Histology shows filiform epithelial downgrowth of epidermal rete ridges, with a concentration of melanin at the tips.

Reticulate acropigmentation of Kitamura and Dowling-Degos disease are characterized by reticulate patterns of hyperpigmented macules without hypopigmented macules, affecting acral areas in the former and flexures in the latter (Al Hawsawi et al., 2002). Several groups considered Kitamura reticulate acropigmentation and DDD to be the same disorder with different spectra (e.g., Cox and Long, 1991; Lestringant et al., 1997). Thami et al. (1998) described a large kindred in which reticulate acropigmentation of Kitamura and acropigmentation of Dohi were associated with features of DDD.

Milde et al. (1994) described the disorder in 2 sisters as Dowling-Degos-Kitamura disease.

Shen et al. (2011) described a 55-year-old woman with reticulate hyperpigmentation on the neck, axillae, inframammary region, inguinal areas, extremities, and the dorsa of hands and feet. Scalp hair and nails were normal, but axillary hair was sparse. The eruptions began in childhood and became more extensive throughout adulthood, with pigmentation worsening after sun exposure. Beginning at age 40, a large number of seborrheic keratosis-like lesions gradually developed, predominantly in the flexural pigmented areas, and she also had pitted perioral scars. Some family members had a similar presentation. Histopathology of inguinal skin showed thin branching and elongation of rete ridges with basal hyperpigmentation. Biopsy of a seborrheic papule showed features typical of adenoid or reticulated seborrheic keratoses including epidermal thickening consisting of basaloid cells and multiple keratin-filled cysts. Shen et al. (2011) suggested that this patient might represent an unusual variant of DDD, associated with RAK and scarce axillary hair.


Autosomal dominant inheritance of Dowling-Degos disease was established by Crovato et al. (1983) and Biltz and Kiessling (1988).


Betz et al. (2006) performed a genomewide linkage analysis of the 2 German families described by Biltz and Kiessling (1988) and Milde et al. (1994) and mapped a DDD locus to 12q13.11-q15, with a total lod score of 4.42 (theta = 0.0) for marker D12S368.

Molecular Genetics

The region on 12q to which Betz et al. (2006) mapped a locus for DDD includes the keratin gene cluster. Betz et al. (2006) screened the cluster for mutations and identified heterozygosity for loss-of-function mutations in the keratin-5 gene (418dupA, 148040.0018; S5X, 148040.0019) in all affected members of the families described by Biltz and Kiessling (1988) and Milde et al. (1994) and in 6 unrelated patients with DDD. This was said to be the first identified mutation that led to haploinsufficiency in a keratin gene. The finding, along with the results from additional functional studies, suggested a crucial role for keratins in the organization of cell adhesion, melanosome uptake, organelle transport, and nuclear anchorage.

The findings of Betz et al. (2006) together with those of Uttam et al. (1996) demonstrating a missense mutation in the KRT5 gene (P25L; 148040.0009) as the cause of epidermolysis bullosa simplex with mottled pigmentation (131960) suggested a distinct role for KRT5 in melanosome transport.

In 7 unrelated patients who had been diagnosed with Galli-Galli disease (GGD), in which the clinical presentation is identical to DDD but patients exhibit acantholysis on histopathology, Hanneken et al. (2010) sequenced the KRT5 gene and identified heterozygosity for the 418dupA mutation in 5 of them. The duplication was also present in 4 clinically affected family members of 1 of the probands. In addition, the authors reviewed the histopathologic findings in 3 DDD patients previously found to carry the 418dupA mutation in KRT5 by Betz et al. (2006) and in 3 DDD patients who did not carry a mutation in KRT5, and found characteristic acantholytic changes in biopsy specimens from all 6 patients. Hanneken et al. (2010) concluded that GGD is a variant of DDD rather than a distinct entity.