Dyskeratosis congenita with a novel genetic variant in the DKC1 gene: a case report

Abstract

Background: Dyskeratosis congenita (DC) is a rare genetic disorder of bone marrow failure inherited in an X-linked, autosomal dominant or autosomal recessive pattern. It has a wide array of clinical features and patients may be cared for by many medical sub specialties. The typical clinical features consist of lacy reticular skin pigmentation, nail dystrophy and oral leukoplakia. As the disease advances, patients may develop progressive bone marrow failure, pulmonary fibrosis, oesophageal stenosis, urethral stenosis, liver cirrhosis as well as haematological and solid malignancies. Several genes have been implicated in the pathogenesis of dyskeratosis congenita, with the dyskerin pseudouridine synthase 1 (DKC1) gene mutations being the X-linked recessive gene.

Case presentation: Herein, we report a 31-year-old male with history of recurrent febrile episodes who was found to have reticulate skin pigmentation interspersed with hypopigmented macules involving the face, neck and extremities, hyperkeratosis of palms and soles, nail dystrophy, leukoplakia of the tongue, premature graying of hair, watery eyes and dental caries. Several of his male relatives, including two maternal uncles and three maternal cousins were affected with a similar type of disease condition. Pedigree analysis suggested a possible X-linked pattern of inheritance. Genetic testing in the proband showed a novel hemizygous, non-synonymous likely pathogenic variant [NM_001363.4: c.1054A > G: p.Thr352Ala] in the PUA domain of the DKC1 gene. Quantitative polymerase chain reaction for relative telomere length measurements performed in the proband showed that he had very short telomeres [0.38, compared to a control median of 0.71 (range 0.44-1.19)], which is consistent with the DC diagnosis. Co-segregation analysis of the novel mutation and telomere length measurements in the extended family members could not be performed as they were unwilling to provide consent for testing.

Conclusions: The novel variant detected in the DKC1 gene adds further to the existing scientific literature on the genotype-phenotype correlation of DC, and has important implications for the clinical and molecular characterization of the disease.

Keywords: DKC1; Dyskeratosis congenita; Nail dystrophy; Oral leukoplakia; Pancytopenia; Skin pigmentation.

Fig. 1

Clinical features of the proband with dyskeratosis congenita showing: a oral leukoplakia, reticular hyperpigmentation of the neck and upper chest, b hypopigmented patches on the leg, c dysplastic finger nails, d adermatoglyphia, e lacy reticular hyperpigmentation of the lower limb

Fig. 2

Pedigree constructed from the details provided by the proband’s mother: i) proband’s maternal uncle died due to a febrile illness at the age of 26 years, ii) proband’s maternal uncle died at the age of 50 years due to tuberculosis, iii) proband’s sister is a probable carrier with history of similar localised skin pigmentation and nail changes but no history of significant illnesses or recurrent infections

Fig. 3

Proband has short telomeres relative to age matched controls. qPCR telomere length assay was performed using genomic DNA as a template on the proband and 66 controls of variable ages. Telomere length is plotted versus age in years. ● = controls ▲ = proband, marked with an arrow