Israel Medical Association Journal

Background: Bone marrow failure syndromes (BMFs) comprise a heterogeneous group of genetic disorders characterized by impaired hematopoiesis and multisystem involvement. Dyskeratosis congenita (DC) is a telomere biology disorder caused by defects in telomerase or telomere maintenance, leading to progressive BMF and variable extra-hematopoietic manifestations.

Objectives: To describe the clinical, immunologic, genetic, and telomere biology findings in a patient with DC caused by a novel biallelic telomerase reverse transcriptase (TERT) mutation, and to highlight diagnostic and therapeutic considerations in telomere-associated BMFs.

Methods: We assessed cellular and humoral immune functions. Genetic analysis was conducted using whole-exome sequencing (WES) with segregation analysis. Telomere length was assessed by flow-FISH. Functional and radiologic evaluations were performed to define disease extent.

Results: A 2-year old male born to consanguineous parents presented with multisystemic clinical features, and hypocellular bone marrow. WES identified a novel homozygous TERT missense variant (c.3052G>A; p.Ala109Thr) supported by markedly shortened telomeres. Neuroimaging revealed cerebellar hypoplasia consistent with Hoyeraal-Hreidarsson syndrome. Immunologic evaluation demonstrated skewed CD4:CD8 ratios. An incidental heterozygous MEN1 variant was also detected.

Conclusions: We expand the clinical and genetic spectrum of TERT-associated DC and illustrate the critical role of genomic diagnostics and telomere assessment in BMFs. Early molecular diagnosis enables targeted evaluation, informs prognosis, and guides personalized management in telomere biology disorders. In addition, the identification of actionable secondary variants further highlights both the power and complexity of comprehensive genomic testing.

Type 1 diabetes mellitus is caused by an autoimmune destruction of pancreatic islet beta cells, leading to insulin deficiency. Beta-cell replacement is considered the optimal treatment for type 1 diabetes, however it is severely limited by the shortage of human organ donors. An effective cell replacement strategy depends on the development of an abundant supply of beta cells and their protection from recurring immune destruction. Stem/progenitor cells, which can be expanded in tissue culture and induced to differentiate into multiple cell types, represent an attractive source for generation of cells with beta-cell properties: insulin biosynthesis, storage, and regulated secretion in response to physiologic signals. Embryonic stem cells have been shown to spontaneously differentiate into insulin-producing cells at a low frequency, and this capacity could be further enhanced by tissue culture conditions, soluble agents, and expression of dominant transcription factor genes. Progenitor cells from fetal and adult tissues, such as liver and bone marrow, have also been shown capable of differentiation towards the beta-cell phenotype in vivo, or following expression of dominant transcription factors in vitro. These approaches offer novel ways for generation of cells for transplantation into patients with type 1 diabetes.