Israel Medical Association Journal

Inborn errors of immunity represent a heterogeneous group of disorders with variable clinical manifestations. Within this group of disorders, severe combined immunodeficiency (SCID) is the most profound disorder, where affected infants present clinically early in life, and have almost uniformly fatal outcome unless hematopoietic stem cell transplantation (HSCT) is performed. Gene therapy or enzyme replacement therapy are options in some specific SCID forms [1]. The estimated incidence of SCID in the United States is 1 in 58,000 live births, while in Israel the incidence is as high as 1 in 29,000 live births. This higher rate is due to a high rate of consanguineous marriages in certain communities [2].

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: Several studies have identified associations between low vitamin D concentrations and risk of upper respiratory infections (URI). T lymphocytes have a major anti-viral role, are affected by vitamin D metabolism, and may mediate the link between vitamin D and URIs. Competitive swimmers have a relatively high rate of URIs, alongside a high prevalence of low vitamin D concentration. 

Objectives: To examine the associations linking T cell receptor excision circles (TREC, markers of thymus activity), circulating 25(OH)D concentrations and the effect of vitamin D supplementation, and URI symptoms in young competitive swimmers.

Methods: We tested 82 adolescent swimmers for serum 25(OH)D and TREC concentrations and found that 55 had vitamin D insufficiency. Randomized supplementation of either vitamin D3 or placebo was given for 12 winter weeks. URI symptoms were recorded weekly. The associations between TREC copy numbers, vitamin D and URI burden were examined.

Results: TREC concentrations decreased with the participants’ age (r = -0.346, P = 0.003), with no significant between-gender difference. TREC concentrations did not materially differ among subjects with normal, insufficient or deficient vitamin D status, and were not affected by vitamin D supplementation. No significant correlations were found between TREC levels or their changes during the study period, and mean URI severity or duration. 

Conclusions: Thymus activity, represented by higher TREC levels, was not related to vitamin D concentrations or status, and was not affected by vitamin D supplementation in adolescent swimmers. TREC concentrations were not associated with URI severity or duration in this population.

 

Objective: To assess the ability of TREC and KREC counts to identify patients with combined T and B cell immunodeficiency in a pilot study in Israel.

Methods: We studied seven children born in Israel during the years 2010–2011 and later diagnosed with SCID, and an additional patient with pure B cell immunodeficiency. TREC and KREC in peripheral blood upon diagnosis and in their neonatal Guthrie cards were analyzed using real-time quantitative polymerase chain reaction, as were Guthrie cards with dried blood spots from healthy newborns and from normal and SCID-like controls.

Results: The first features suggestive of SCID presented at age 3.1 ± 2.4 months in all patients. Yet, the diagnosis was made 4.1 ± 2.9 months later. Their TREC were undetectable or significantly low at their clinical diagnosis and in their originally stored Guthrie cards, irrespective of the amount of their circulating T cells. KREC were undetectable in six SCID patients who displayed B cell lymphopenia in addition to T cell lymphopenia. KREC were also undetectable in one patient with pure B cell immunodeficiency.

Conclusions: TREC and KREC quantification are useful screening tests for severe T and B cell immunodeficiency. Implementation of these tests is highly important especially in countries such as Israel where a high frequency of consanguinity is known to exist.