Updated Review of Genetic Reticulate Pigmentary Disorders

J. Zhang; M. Li; Z. Yao

Disclosures

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

In This Article

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]

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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