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

INTRODUCTION

Dyskeratosis congenita (DC) is a clinically and genetically heterogeneous multisystem inherited syndrome caused by mutations in genes that encode the protein components of the telomerase complex and shelterin complex. DC is a rare disease with an estimated annual incidence of 1 in 1,000,000 [1]. Genotype–phenotype correlations are complex due to a variety of gene mutations, disease anticipation, and genetic and environmental modifier effects. The classical clinical form of the disease is characterized by the mucocutaneous triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia [2, 3]. The abnormal skin pigmentation and nail changes usually appear first, often under 10 years of age. Additional features of the clinical presentation include 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. DC patients have an increased risk of developing malignant disease [4, 5]. Bone marrow failure is considered to be an important and major complication of DC, and is a leading cause of death that develops in around 85% of cases. DC is caused by mutations in genes that encode protein components of the telomerase complex and shelterin complex. Since 1998 at least 14 DC genes involved in the telomere’s shortening have been identified, accounting for approximately 70–80% of DC cases [6-8]. These genes encode proteins for the maintenance of telomeres, which are located at the ends of chromosomes. DC can be inherited in an X-linked, autosomal dominant (AD), or autosomal recessive (AR) pattern. Mutations in TINF2 have been reported in 11–20% of all patients with DC and have been associated with bone marrow failure [9]. In addition, mutations of TINF2 were also identified in patients with other diseases associated with bone marrow failure (e.g. ataxia-pancytopenia and aplastic anemia) [10, 11]. In this paper we report on a 19-month old boy with de novo heterozygous mutation in the TINF2 gene and a very early presentation of bone marrow failure as a first clinical manifestation of DC.

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