Israel Medical Association Journal

From the first day of medical school, most physicians are indoctrinated with the concept that open communication with our patients is how medicine should be practiced. Regardless of our specialty, this forthright approach is thought to be the ideal. Whether it is taking a solid history, revealing a diagnosis, discussing therapeutic options and adverse events, discussing disease prognosis, or even conveying distressing information, this approach is the gold standard of management. We are communicating not only with the patient, but also with significant others such as family, partners, and friends; therefore, the physician must often repeat the message to different listeners. In the environment of medicine today in Canada and in many other places, is this situation ideal, and if so what is the cost?

In the setting of shortages, whether it is manpower, access to consultation or testing, therapeutic maneuvers, or blunt cost, what are the issues to consider when properly communicating with the patient? In this focus article, I do not offer new insights, just a perspective.

Background: Healthcare utilization in patients with psoriasis has been described from the perspective of psoriasis healthcare centers. Psoriasis healthcare utilization at the population level, including appointments with family physicians, impacts the overall financial expenditure.

Objectives: To describe the utilization of healthcare services in patients with psoriasis compared to the general non-psoriasis population.

Methods: We conducted a cross-sectional, population-based analysis of data from Clalit Health Services, the largest public health service provider in Israel, comparing the annual healthcare utilization and medication consumption of all Clalit members with psoriasis in 2023 with an age- and sex-matched group at a primary care clinic. We compared up to five non-psoriasis items.

Results: The study included 835,422 people (140,927 individuals with psoriasis and 694,671 without). Patients with psoriasis had more annual physician appointments than controls, and the meetings were longer. Patients with psoriasis took more sick leave and required more hospital admission compared to the control group. Tumor necrosis factor (TNF) inhibitors were prescribed much more often to patients with psoriasis than to the control group (3147 patients vs. 1857 in the matched control). More IL-17 blockers and IL-23 blockers were also prescribed more in the psoriasis group, although at a much lower level than the TNF inhibitors.

Conclusions: Patients with psoriasis used more healthcare services than the control group. Healthcare providers should allocate more resources to psoriasis care, both for primary care and at specialized psoriasis centers.

Background: Although the epidemiology of Creutzfeldt-Jakob disease (CJD) in Israel has been studied extensively, it is unknown whether its incidence is mainly a result of vertical transmission due to the high penetrance of the E200K mutation in patients with familial CJD (f-CJD) compared to sporadic CJD (s-CJD), or whether there are other yet undiscovered contributing factors.

Objectives: To conduct an age-period-cohort (APC) analysis of Creutzfeldt-Jakob disease in Israel.

Methods: In this APC analysis, we used a web-based statistical tool to identify whether patient age, period of birth, and cohort had any effect on incidence trends of s-CJD and f-CJD.

Results: APC analysis demonstrated no significant shifts in net drift, indicating the absence of any overall trend of changes over time. Cohort analysis revealed that individuals affected by either s-CJD or f-CJD who were mostly born in Israel in the second half of the 20th century exhibited the same risk as those born mainly in Libya at the beginning of 20th century. There were no changes in risk of s-CJD and f-CJD between 1985 and 2019.

Conclusions: The incidence rates of s-CJD and f-CJD in Israel have remained unchanged, indicating that the probability of a future increase in the incidence is negligible.

Background: Vitamin B6 is an essential cofactor in amino acid metabolism. Its deficiency is linked to neuropathy, anemia, and cardiovascular risk. Deficiency is common among hemodialysis patients due to dialytic losses and restrictive diets; however, data related to high-flux (HF) dialysis membranes and Mediterranean dietary patterns are scarce.

Objectives: To assess the prevalence and determinants of deficiency in unsupplemented Israeli hemodialysis patients.

Methods: This retrospective chart review, utilizing a cross-sectional design, was conducted in August 2024. We included 27 chronic hemodialysis patients not receiving vitamin B6 supplementation, representing the available unsupplemented cohort from a unit of approximately 150 patients. Vitamin B6 status was assessed by measuring plasma pyridoxal-5'-phosphate (PLP); deficiency < 20 ng/ml. Clinical and nutritional parameters were evaluated to identify deficiency.

Results: Vitamin B6 deficiency was noted in 63% of patients (median PLP 18 ng/ml, interquartile range 13–23). The cohort was 67% male, median age 74 years. All patients were treated with HF dialyzers. No significant correlations were found between PLP levels and nutritional indices or laboratory markers. A non-significant trend was observed between older age and lower PLP levels (r = -0.35, P = 0.098).

Conclusions: Vitamin B6 deficiency was common among Israeli hemodialysis patients treated with HF dialyzers, despite a presumed Mediterranean diet. It was not associated with nutritional status, suggesting dialysis-related losses, potentially augmented by high-flux membranes, may outweigh intake. Given the high prevalence of deficiency and low cost, routine low-dose vitamin B6 supplementation may be warranted, particularly in older patients.

Background: Elbow range of motion (ROM) is commonly assessed during initial evaluation and follow-up. While goniometry is considered the current gold standard, previous studies have raised concerns regarding its user dependence and measurement consistency.

Objective: To evaluate whether smartphone application-based elbow ROM measurements are comparable to visual estimation and goniometry in patients following elbow trauma.

Methods: We conducted a prospective cohort study of 18 patients with elbow injuries. Demographic and medical data were collected. Maximal flexion-extension active ROM was measured by goniometry, smartphone application, and visual estimation by orthopedic surgeons. Measurements were compared to determine agreement and accuracy among different modalities.

Results: Eighteen patients with elbow injuries were included. Inter-rater reliability was good to excellent across all rater groups (intraclass correlation coefficient 0.78–0.93). Using paired t-tests with Bonferroni correction, only one attending surgeon showed a significant underestimation of extension compared to goniometry (16.9° vs. 22.5°, P < 0.05). No significant differences were found for residents, other attendings, or smartphone measurements in either extension or flexion (P > 0.05). Bland-Altman analysis revealed modest mean bias within ± 6° for all methods, although limits of agreement were wide (up to ± 20–30°). Smartphone-based measurements demonstrated significantly higher and less variable Pearson correlation coefficients with goniometry compared to surgeon visual estimations (0.91–0.95 vs. 0.81–0.93, P < 0.05).

Conclusions: Smartphone-based elbow ROM measurements were statistically comparable to goniometry and demonstrated superior correlation and accuracy relative to clinical visual assessments. These findings support the integration of smartphone tools in the clinical setting.

Immunoglobulin E-mediated cow's milk allergy (IgE-CMA) is the most common food allergy in infancy. Recent evidence suggests that early infant feeding practices, particularly the pattern of cow's milk formula (CMF) exposure during the first days and months of life, may influence the risk of developing IgE-CMA. Studies indicate that transient CMF supplementation followed by prolonged avoidance is associated with an increased risk of IgE-CMA, whereas continued regular CMF consumption after initial exposure may reduce this risk. This review summarizes the current evidence regarding IgE-CMA prevention, discusses the limitations of the available data, presents the recommendations of the Israeli Association of Allergy and Clinical Immunology, and highlights key unanswered questions requiring further research.

Inborn errors of immunity (IEI) result from pathogenic germline variants. These disorders are clinically characterized by increased susceptibility to infections and immune dysregulation, often leading to reduced survival [1]. By linking specific monogenic defects to immune phenotypes, IEI serve as experiments of nature that provide powerful models for dissecting human immunology [2]. The International Union of Immunological Societies (IUIS) currently classifies IEI into 10 major categories with overlapping phenotypes [3]: combined T- and B-cell immunodeficiencies, combined immunodeficiencies with syndromic features, predominantly antibody deficiencies, diseases of immune dysregulation, congenital defects of phagocytes, defects in intrinsic and innate immunity, autoinflammatory diseases, complement deficiencies, bone marrow failure, and phenocopies of IEIs. The recent 2024 IUIS update was designed to serve clinicians and researchers and to inform the design of targeted sequencing panels that facilitate the genetic diagnosis of IEI. It lists 508 genes underlying 559 conditions [3]. Of note, molecular, cellular, and clinical investigations of IEI have transformed our understanding of disease pathogenesis and enabled effective targeted therapies.

The field of inborn errors of immunity (IEI), previously known as primary immune deficiencies, includes susceptibility to infections, autoimmunity, uncontrolled inflammation and malignancy is rapidly expanding. Novel scientific discoveries together with artificial intelligence and machine learning are transformed into advances in the diagnosis and treatment of affected patients. These changes require adjustments in the knowledge, skills and attitudes of health care providers, and particularly expert clinicians managing patients with IEI. In this perspective, we highlighted some of the educational needs that should be adapted to ensure that the next generation of physicians provide best care for those affected by IEI.

STING-associated vasculopathy with onset in infancy (SAVI) is a rare monogenic type I interferonopathy that may present with heterogeneous clinical manifestations and mimic common inflammatory disorders of childhood. We report the first familial case of SAVI in Israel, affecting a father and daughter carrying an identical pathogenic gain-of-function TMEM173 variant. The daughter initially presented with features fulfilling criteria for rheumatoid factor-positive juvenile idiopathic arthritis (JIA), later developing growth failure and progressive interstitial lung disease. In contrast, the father developed adolescent-onset inflammatory arthritis, subsequently lung disease, and a severe infectious neurological complication during treatment. This case highlights marked intrafamilial phenotypic variability, the diagnostic challenges posed by atypical inflammatory arthritis and the importance of genetic testing in treatment-refractory or systemic disease. Our findings underscore both the benefits and limitations of JAK inhibition in SAVI, particularly with respect to pulmonary disease and growth outcomes.

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].

Inborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders affecting immune function, associated with a broad clinical spectrum including recurrent infections and immune dysregulation consisting of poly-autoimmunity, multiple allergies, and malignancies. To date, more than 550 causative genes have been identified, with inheritance patterns that may be autosomal dominant, autosomal recessive, or X-linked. Pathogenic variants may result in loss-of-function, dominant-negative, or gain-of-function effects, leading to variable phenotypic presentations and, at times, incomplete penetrance. Despite advances in genomic technologies, a definitive molecular diagnosis is reached in only 30–35% of cases. Early and accurate genetic diagnosis is crucial for guiding targeted therapy and providing effective genetic counseling. This review presents an updated overview of IEI from the geneticist's perspective and offers a practical approach to the genetic evaluation and diagnosis of these conditions.

Neutrophils serve as a cornerstone of innate immunity. Beyond their classical antimicrobial repertoire, these cells are versatile and capable of shaping the adaptive immune response through direct interactions with dendritic cells and lymphocytes in addition to cytokine-mediated effects. Additional functional phenotypes have also been described with regard to cancer and chronic inflammation. The clinical importance of neutrophils in host defense is perhaps best illustrated by the spectrum of inborn neutrophil disorders, ranging from congenital neutropenia to defects of adhesion and phagocytosis. We present a patient with clinical and laboratory features of hemophagocytic lymphohistiocytosis with a bacterial infection. The patient was subsequently found to carry a homozygous variant in the NCF2 gene, establishing a diagnosis of autosomal recessive chronic granulomatous disease (CGD). This presentation, combining cytokine storm with ongoing infection-driven inflammation, exemplifies the multifaceted role of neutrophils in health and disease. In this review, we provide clinical and immunological insights into neutrophil disorders, illustrated through a case of CGD as a paradigm of primary neutrophil dysfunction.

Background: Syndromic inborn errors of immunity (IEIs) are a heterogeneous group of disorders characterized by immune dysfunction associated with congenital anomalies and multisystem involvement. Tricho-hepato-enteric syndrome (THES) is an ultra-rare autosomal recessive syndromic IEI caused by biallelic pathogenic variants in TTC37 or SKIV2L. Delayed recognition is common because of its broad clinical spectrum.

Objectives: To describe the clinical, immunologic, genetic, and histopathologic characteristics of two children with THES and to highlight a structured diagnostic approach for syndromic immunodeficiencies.

Methods: We retrospectively reviewed the clinical presentation, laboratory investigations, immune phenotyping, endoscopic and histopathologic findings, and molecular analyses of two unrelated children diagnosed with THES at a tertiary pediatric immunology center. Molecular confirmation was obtained by whole-exome sequencing.

Results: Both patients presented during early infancy with intractable diarrhea, severe failure to thrive, characteristic dysmorphic features, brittle woolly hair, and inflammatory enteropathy requiring prolonged nutritional support. Immunologic evaluation demonstrated immune dysregulation, including inverted CD4/CD8 ratios, abnormalities of humoral immunity, and impaired vaccine-specific antibody responses. Histopathology revealed chronic active colitis with crypt distortion, inflammatory infiltrates, and crypt abscesses, consistent with very-early-onset inflammatory bowel disease-like enteropathy. Whole-exome sequencing identified homozygous pathogenic variants in SKIV2L in one patient and TTC37 in the other, establishing the diagnosis. Management included nutritional support, immunoglobulin replacement, antimicrobial prophylaxis, and immunomodulatory therapy.

Conclusions: Recognition of syndromic phenotype combined with comprehensive immune evaluation and early genomic testing facilitates prompt diagnosis, multidisciplinary management, genetic counseling, and consideration of emerging targeted therapies.

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: Common variable immunodeficiency (CVID) is the most common clinically significant primary immunodeficiency disorder, typically presenting with hypogammaglobulinemia and recurrent infections. Mechanistically, CVID is caused by abnormal B-cell maturation or function. These abnormalities lead to an impaired ability to generate a normal quantity or diversity of antibodies and an impaired response to neo-antigens. In addition to the resulted immunodeficiency, CVID can also involve immune dysregulation affecting different organ systems, with the lungs being one of the more commonly involved organs. Granulomatous lymphocytic interstitial lung disease (GLILD) is a challenging and well known CVID-related complication. It is associated with high morbidity and increased risk of mortality.

Objectives: To describe the clinical and immunological features of five CVID patients with radiologic and/or pathologic features consistent with granulomatous lymphocytic interstitial lung disease.

Methods: We conducted a review of clinical, laboratory, imaging, and pathology data, as well as B-cell and T-cell immunophenotyping of patient PBMCs, focusing on unique characteristics of CVID GLILD patients.

Results: CVID GLILD patients showed several clinical characteristics, including multiorgan involvement with cytopenias and lymphoproliferation but without significant gastrointestinal involvement. B-cell phenotyping showed abnormal B-cell maturation and development with severely impaired class switching. In addition, unique T-cell phenotype with low to near-absent naive CD4⁺ T cells was observed.

Conclusions: Lung involvement in the form of GLILD is associated with significant co-morbidity and typical B-cell and T-cell immunophenotyping. Patients should be actively screened for the possibility of GLILD, especially when regularly performed lymphocyte immunophenotyping suggests similar patterns.