Updated Review of Genetic Reticulate Pigmentary Disorders

J. Zhang; M. Li; Z. Yao


The British Journal of Dermatology. 2017;177(4):945-959. 

In This Article

The Spectrum of Dowling-degos Disease

DDD is an autosomal-dominant genetic skin disorder characterized by a reticular pigmented anomaly, and reddish-brown or dark-brown hyperkeratotic papules (which occur in most patients). DDD usually presents with a flexural distribution, (such as the neck, axilla, antecubital fossa, submammary area and groin) in adulthood, with the main age of onset between 20 and 50 years (Figure 1). Burning or itching can occur in some patients. Histologically, the characteristic finding is a thin branch-like pattern of epidermal down growth. In some cases, a moderate superficial lymphocytic perivascular infiltrate can be observed in hyperkeratotic erythematous papules. There is also a generalized form with hyper- and hypopigmented lesions, called generalized DDD[1] (Figure 2), and an acantholytic variant termed Galli-Galli disease (GGD).[2]

Figure 1.

Clinical features of classic Dowling-Degos disease in a patient with a KRT5 mutation: (a, b) spotted and reticulate pigmentation, hyperkeratotic reddish-brown papules of the flexures. (c, d) Histological findings show thin branch-like patterns of epidermal downgrowth and no obvious phenomenon of acantholysis. (Picture kindly provided by Dr Jianbo Wang and Dr Jianguo Li.)

Figure 2.

Clinical features of generalized Dowling-Degos disease in a patient with a POFUT1 mutation: generalized spotted pigmentation with hypopigmentation.

Loss-of-function mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1) and protein O-glucosyltransferase 1 (POGLUT1), genes that play a crucial role in melanin transport, have been identified as being responsible for a wide spectrum of DDD[3–6] with distinct phenotypes (i.e. mainly in the flexures or in a generalized distribution; hyper- and/or hypopigmented macules; early or late onset; histologically either acantholytic or not) that exhibit genetic and phenotypic heterogeneity (Table S1; see Supporting Information).[2,4] Specifically, the flexural form occurs only in patients with mutations in KRT5; patients with mutations in POFUT1 show not only flexural distribution, but also involvement of the trunk and acral region, while patients with mutations in POGLUT1 show involvement of the trunk and extremities (Table S1).

KRT5-related Dowling-degos Disease Phenotypes

Mutations in the KRT5 gene were reported to cause a wide range of different and overlapping phenotypes: classic DDD, generalized DDD and GGD. Until now, five heterozygous frameshift/nonsense mutations (p.Gln4*, p.Ser5*, p.Ser14Glnfs*3, p.Ile140Asnfs*39 and p.Ser148fs*30) and two initiation codon mutations c.2T>C (p.Met1?) and c.2T>G (p.Met1?) have been reported to cause DDD.[2,5,7,8] These mutations were specifically located in the head domain of KRT5 and resulted in haploinsufficiency of keratin 5.[8] By contrast, most of the missense mutations of KRT5 and a small number of frameshift/nonsense/splice site mutations in other regions cause a blistering phenotype, epidermolysis bullosa simplex (EBS).[9,10] This finding supports the opinion that frameshift/nonsense mutations in the head domain of KRT5 play a crucial role in melanin distribution.[11] Among these mutations, three (p.Ser5*, p.Ile140Asnfs*39 and p.Ser148fs*30) cause classic DDD, whereas cases with p.Gln4* and c.2T>G (p.Met1?) show generalized DDD phenotypes (generalized pigmentation plus hypopigmented macules and papules mainly in the trunk and flexures).[2,8] Phenotypic variations in the distribution of lesions may depend predominantly on environmental factors and potential modifier genes.

Galli-Galli disease is similarly characterized by reticulate hyperpigmented macules, comedo-like hyperkeratotic papules mainly of the flexures, and histopathological findings of prominent acantholysis.[12]

The mutations p.Gln4*, p.Ser14fs, p.Ile140Asnfs*39 and c.2T>C (p.Met1?) in KRT5 were reported to cause classic GGD or generalized GGD.[8,13,14] In particular, a mosaic missense mutation (p.Pro159Leu) located in the head domain of KRT5 was revealed in the acantholytic epidermal area of a segmental GGD phenotype,[15] which should serve as a reminder for dermatologists to be aware of mosaic GGD.

Clinically, GGD highly resembles DDD; histopathological findings of acantholysis have also been observed in a large number of patients who had previously been diagnosed with DDD.[16] In addition, at a molecular level, a given KRT5 mutation (e.g. p.Gln4* and p.Ile140Asnfs*39) can lead to both DDD and GGD,[5,16,17] which provides further evidence that it is reasonable to consider DDD and GGD as being on a spectrum of DDD with a certain degree of phenotype variability.

POFUT1- and POGLUT1-related Dowling-degos Disease Phenotypes

Notch signalling controls many cellular functions of melanocytes and plays an important role in melanocyte homeostasis.[18] The enzymes POGLUT1 and POFUT1 (encoded by POGLUT1 and POFUT1, respectively) are both essential components of the Notch signalling pathway and are involved in the post-translational modification of Notch proteins.[4]

Through genome-wide linkage analysis and exome sequencing, Li et al. first identified two pathogenic mutations, p.Glu144*and c.482delA in POFUT1 in two families with generalized DDD phenotypes. These phenotypes manifested as reticular hyper- and hypopigmentation of the flexures, with numerous hyperpigmented, hypopigmented or erythematous macules and papules on the neck, chest, abdomen, and acral region (Figure 2).[3] Li et al. then performed a functional study (Morpholino knockdown of pofut1 in zebrafish and knockdown of POFUT1 in HaCat cells) and showed that POFUT1 played a significant and conserved role in melanin synthesis and transport. Soon afterwards, many mutations in POFUT1 were identified in patients with similarly generalized DDD phenotypes.[19–21] Some patients did not show hypopigmented skin lesions,[19,20] whereas others presented with palmar pits, interrupted dermatoglyphics and hyperpigmentation on the acral regions, suggesting the phenotypic complexity of POFUT1-mutant DDD.

A report by Basmanav et al. identified heterozygous mutations in POGLUT1 in individuals with generalized GGD phenotypes (a disseminated pattern of brownish macular and lentiginous lesions on the extremities, trunk and neck, and minor acantholysis on histology).[4]

Screening Strategy for Dowling-degos Disease Spectrum

Betz and colleagues found that loss-of-function mutations in KRT5 were responsible for fewer than half of patients with DDD,[5] and POGLUT1 mutations were identified in one-third of their DDD cases.[4,5,19] Considering that 11 distinct POFUT1 mutations have been reported, and taking all of these results into account, all three genes (KRT5, POFUT1, and POGLUT1) should be sequenced in patients with conditions on the DDD spectrum. Among these genes, the KRT5 test should have priority, especially for those who manifest reticular pigmentation and erythematous erosive papules mainly in the flexures; POFUT1 sequencing should be considered first for generalized DDD phenotypes with hypopigmentation that is additionally on the neck, chest, abdomen and limbs; and the genetic analysis of POGLUT1 is relatively effective in those with generalized GGD phenotypes.

Overall, few reports of cases with POFUT1 and POGLUT1 mutations are available, so it is impossible to summarize the specific features with 100% accuracy. Moreover, the phenotype of the patient is sometimes atypical. Therefore, on some occasions, all three genes should be tested.

Differential Diagnosis

Acanthosis nigricans, which should be differentiated from DDD cases presenting with red-brown hyperkeratotic papules, is distinguished clinically by velvety plaques. Darier disease is distinguished clinically by brown, warty papules in seborrhoeic areas (forehead, central chest, back, flexures and scalp margins). As for patients with DDD presenting with only pigmentary abnormalities, there can be overlap with DUH and RAK (details of these two disorders are described below). Histological and molecular findings help to differentiate these disorders.

Clinical Management

Patients with DDD have adult-onset skin lesions that predominantly affect the appearance of the skin. An erbium-doped yttrium aluminium garnet (Er:YAG) ablative laser was reported to treat abnormal epidermal tissue (red to brown papules) successfully in a white patient with DDD, and no lesions relapsed after an observation period of 2·5 years.[22,23] However, the potential risks of postlaser hyperpigmentation in Asians (who have relatively darker skin) and patients with facial lesions are still a concern. Another study reported that using a fractional Er:YAG laser led to improvement of pigmentation in facial lesions of an Asian patient with DDD and was effective in reducing postoperative inflammation but could not produce the therapeutic results of an ablative approach.[24] Recently, one case report showed that the pigmentation of lentigines in patients with DDD could be treated successfully using intense pulsed light, suggesting an alternative option for pigmented lesions in DDD.[25]