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.

Background: Cardiac amyloidosis (CA) is characterized by the extracellular deposition of misfolded protein in the heart. Precise identification of the amyloid type is often challenging, but critical, since the treatment and prognosis depend on the disease form and the type of deposited amyloid. Coexistence of clinical conditions such as old age, monoclonal gammopathy, chronic inflammation, or peripheral neuropathy in a patient with cardiomyopathy creates a differential diagnosis between the major types of CA: amyloidosis light chains (AL), amyloidosis transthyretin (ATTR) and amyloidosis A (AA).

Objectives: To demonstrate the utility of the Western blotting (WB)-based amyloid typing method in patients diagnosed with cardiac amyloidosis where the type of amyloid was not obvious based on the clinical context.

Methods: Congo red positive endomyocardial biopsy specimens were studied in patients where the type of amyloid was uncertain. Amyloid proteins were extracted and identified by WB. Mass spectrometry (MS) of the electrophoretically resolved protein-in-gel bands was used for confirmation of WB data.

Results: WB analysis allowed differentiation between AL, AA, and ATTR in cardiac biopsies based on specific immunoreactivity of the electrophoretically separated proteins and their characteristic molecular weight. The obtained results were confirmed by MS.

Conclusions: WB-based amyloid typing method is cheaper and more readily available than the complex and expensive gold standard techniques such as MS analysis or immunoelectron microscopy. Notably, it is more sensitive and specific than the commonly used immunohistochemical techniques and may provide an accessible diagnostic service to patients with amyloidosis in Israel.