Updated Review of Genetic Reticulate Pigmentary Disorders

J. Zhang; M. Li; Z. Yao

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

Dyskeratosis Congenita

Dyskeratosis congenita (DC), is usually characterized by a triad of dysplastic nails, reticular pigmentation of the upper chest or neck and oral leucoplakia (Figure 9). The age at onset of these features varies among affected individuals. Moreover, DC is a heterogeneous disease, and a variety of complications such as marrow failure, pulmonary fibrosis, neurodevelopmental impairment and cancer predisposition can be observed in patients with DC. Histologically, atrophic epidermis with areas of increased pigment in the basal layer, melanophages, telangiectasia, and a mild inflammatory infiltrate in the upper dermis can be observed in the reticular pigmented lesions.^[66]

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Figure 9.

Clinical features of dyskeratosis congenita: a triad of reticular pigmentation of the upper chest or neck (a), dysplastic nails (b) and oral leucoplakia (c). (Picture kindly provided by Dr Jianwen Han.)

Eight pathogenic genes: DKC1 (X-linked); TERC and TINF2 (autosomal dominant); TERT (autosomal dominant/autosomal recessive); CTC1, WRAP53, NHP2 and NOP10 (autosomal recessive) are the pathogenic genes known to be responsible for approximately half of DC cases.^[67] Hoyeraal–Hreidarsson syndrome (OMIM 300240; corresponding genes RTEL1 and DKC1) refers to a severe variant of DC characterized by cerebellar hypoplasia, failure of bone marrow, intrauterine growth restriction and immunodeficiency, which usually lead to death in early childhood.^[68] Révész syndrome (OMIM 268130; corresponding gene TINF2) is another rare variant of DC. In addition to the classic DC features, this syndrome mainly manifests as bilateral exudative retinopathy, intrauterine growth retardation, intracranial calcifications and neurocognitive defects.^[69]

Before using molecular genetic tests in individuals with suspected DC, leucocyte telomere-length testing can first be applied to analyse telomere length, which is found to be associated with disease severity and to decline with age in DC.^[70]

Differential Diagnosis

NFJS is distinguished from DC by lack of leucoplakia, bone marrow failure and an increased risk of malignancies. Fanconi anaemia usually presents with diffuse pigmentary abnormalities and early-onset pancytopenia compared with DC.

Clinical Management

The long-term prognosis of most patients with DC is poor. Associated complications such as failure of bone marrow, cutaneous, haematological or gastrointestinal malignancies and severe infection by opportunistic agents were the major causes of mortality, mainly in the second or third decade. Genetic counselling and prenatal diagnosis are important for the affected family.

Multidisciplinary care and monitoring for development of malignancies is required. Low-dose use of systemic retinoids was reported to result in certain clinical improvement of the skin and nails,^[71] but long-term benefit and side-effects are uncertain. A positive response in haematopoietic abnormalities was reported in patients with DC treated with androgen or androgen derivative (e.g. oxymetholone, danazol) by modulation of telomerase.^[72] Allogeneic haematopoietic stem cell transplantation is the only curative therapy for the haematopoietic abnormalities associated with DC, but it was also associated with a high rate of complications and risk of poor long-term survival.^[67]

Notably, several exogenous targeted therapeutics that can correct the telomerase defect and improve cell growth were investigated,^[73,74] suggesting a new therapeutic method. Moreover, sirtuin modulators, involved in telomere maintenance, are already being evaluated in clinical trials for DC.^[75]

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Table 1. Clinical and molecular characteristics of reticulate pigment dermatoses. Note that classic Dowling-Degos disease (DDD), a variant of DDD called Galli-Galli disease (GGD), generalized DDD and generalized GGD all belong to the phenotype spectrum of DDD
Phenotype	Gene	Inherited mode	Features of pigment anomaly	Other major clinical features
Generalized phenotypes
Phenotypes with lentigines and/or dyschromatosis	SASH1	AD/AR	Generalized lentigines predominantly present on the face and upper trunk (sun-exposed areas), and can exhibit hyper- and hypopigmentation on the trunk and extremitiesOnset age: infancy or early childhood	Palmoplantar keratoderma and skin carcinoma (homozygous SASH1 mutation)
DUH	ABCB6	AD	Hyper- and hypopigmented macules in a generalized distribution including the facePathology: increased or decreased melanin pigmentation in the basal cells of hyperpigmented lesions or hypopigmented maculesOnset age: infancy or early childhood	Ocular abnormalities (in some cases)
Generalized DDD	POFUT1 KRT5	AD	Reticular hyperpigmentation and/or hypopigmentation on the neck, chest, abdomen, flexural areas and the acral regionsPathology: thin branch-like patterns of epidermal down growthOnset age: young adulthood	Involvement of the acral regions with hyperpigmentation, palmar pits and interrupted dermatoglyphics (in some cases)
Generalized DDD/GGD	POGLUT1	AD	Reticulate hyperpigmentation and hyperkeratotic brown papules on non-flexural areas such as extremities, trunk/back and neckPathology: a digitiform rete acanthosis with pronounced hyperpigmentation at the tips of the rete ridges, minor acantholysisOnset age: between 18 and 53 years	None
XLRPD	POLA1	XLR	Affected males: diffuse reticulate hyper- and hypopigmentationPathology: deposition of amyloid-like material in the papillary dermisFemale carriers: only patchy pigmentary skin lesions along the lines of BlaschkoOnset age: infancy	In affected males, characteristic upswept hair and flared eyebrows, recurrent infection, corneal opacification, gastrointestinal inflammation, urethral stricture and failure to thrive
Localized phenotypes
DSH	ADAR1	AD	Hyper- and hypopigmented macules on extremities, and sometimes on the facePathology: focal increase or decrease in melanin content or in the number of melanocytes of the basal layerOnset age: young adulthood	AGS phenotypes: neurological symptoms and brain calcification (homozygous or compound heterozygous ADAR1 mutations)
Classic DDD	KRT5	AD	Reticular pigmentation, usually in a flexural distributionPathology: thin branch-like patterns of epidermal down growthOnset age: young adulthood	Comedone-like lesions (hyperkeratotic red-brown papules or plaques) of the flexures
GGD	KRT5	AD	A variant of DDDExhibits acantholysis on histopathology	Comedone-like lesions (hyperkeratotic red-brown papules or plaques) of the flexures
RAK	ADAM10	AD	Reticular pigmentation on the dorsa of the hands and feetPathology: hyperkeratosis without parakeratosis, slightly elongated rete ridgesOnset age: ranges from 5 to 12 years	Palmoplantar pits
EBS-MP	KRT5 KRT14	AD	Mottled pigmentation of the trunk and limbs	Nonscarring acral blisters, punctate hyperkeratosis of the palms and soles and dystrophic nails
DPR	KRT5 KRT14	AD	Localized mottled pigmentation	Noncicatricial alopecia, onychodystrophy and loss of dermatoglyphicsCan present with features of ectodermal dysplasia (Naegeli-Franceschetti-Jadassohn syndrome)
DC	CTC1 DKC1 TERC TERT TINF2 NHP2 NOP10 WRAP53	AD/AR/XL	Reticular pigmentation of the upper chest or neck	Dysplastic nails, and oral leucoplakiaMarrow failure, pulmonary fibrosis, neurodevelopmental impairment, cancer predisposition, etc.

AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive; XLRPD, X-linked reticulate pigmentary disorder; DUH, dyschromatosis universalis hereditaria; DSH, dyschromatosis symmetrica hereditaria; RAK, reticulate acropigmentation of Kitamura; EBS-MP, epidermolysis bullosa simplex with mottled pigmentation; DPR, dermatopathia pigmentosa reticularis; DC, dyskeratosis congenita.