Balkan Journal of Medical Genetics

DE NOVO TINF2 C.845G>A: PATHOGENIC VARIANT IN PATIENT WITH DYSKERATOSIS CONGENITA
Kocheva SA, Gjorgjievska M, Martinova K, Antevska-Trajkova Z, Jovanovska A, Plaseska-Karanfilska D
*Corresponding Author: Svetlana Kocheva, MD, PhD, Department of Hematology and Oncology Children’s Diseases, Majka Tereza 17, Skopje, North Macedonia, tel. +38971378184 e-mail: dr.kocheva@gmail.com
page: 89

DISCUSSION

We report the clinical, laboratory and genetic findings of a 19-month-old Albanian boy from North Macedonia with aplastic anemia as a first clinical presentation of DC. A known pathogenic missense variant, c.845G>A, p.(Arg282His), located in exon 6 of the TINF2 gene, was identified as responsible for DC in our patient. Autosomal dominant DC is a clinically and genetically heterogeneous group of the disease. To date, heterozygous variants in 4 genes (TERC, TERT, RTEL1 and TINF2) have been characterized. Patients harboring TINF2 variants are reported to have extremely short telomeres, and a frequent early age of presentation (less than 10 years old), and they often present severe manifestation of the disease [8, 14]. Nearly all patients have de novo TINF2 variants that give rise to a different mechanism that causes the disease. List of the known TINF2 pathogenic variants reported to date is given in Table 2. TINF2 mutations can be associated with a broad spectrum of phenotypes (Table 2, on the next page). The classical clinical form of the disease is characterized by dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck and oral leukoplakia. BMF, myelodysplastic syndrome (MDS), epiphora, blepharitis, premature graining, alopecia, growth retardation, cerebellar hypoplasia and microcephaly, esophageal stenosis, urethral stenosis, liver disease, pulmonary fibrosis, and avascular necrosis of the hips or shoulders can be included in the clinical presentation. Progressive bone marrow failure may appear at any age and may be the only sign until the age of 10. Macrocytosis and elevated hemoglobin F levels may be seen in these patients. Patients have an increased risk of the development of malignant disease. Solid tumors may be the first manifestation of DC in persons who do not have BMF and are younger than 50 years of age [15]. Most DC patients have normal intelligence and development of motor skills. In severe forms of the disease, developmental delay may occur. In Hoyeraal Hreidaarsson syndrome, a severe form of the disease, affected individuals have an unusually small and underdeveloped cerebellum and intrauterine growth retardation. In addition to the other symptoms of dyskeratosis congenita, bilateral exudative retinopathy and intracranial calcifications are characteristic for the other severe variant of DC, called Revesz syndrome [16]. Pulmonary fibrosis was found in DC patients with the c.844C>T p.(Arg282Cys), c.851C>G p.(Thr284Arg) and c.872_875del p.(Arg291IlefsTer25) TINF2 pathogenic variants [14, 17, 18]. The TINF2 pathogenic variant c.845G>A, p.Arg282His that was identified in our patient has been previously reported in patients with severe clinical presentations, such as Hoyeraal Hreidarsson syndrome and Revesz syndrome (8, 11).

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