Israel Medical Association Journal

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.

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.

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: Exertional heat stroke (EHS) is common among individuals engaged in high-intensity physical activity. It can lead to long-term organ damage and be a life-threatening condition when diagnosed and treated incorrectly.

Objectives: To track the changes in biomarkers among EHS patients, to suggest a standardized protocol of clinically relevant biomarkers to be followed during hospitalization

Methods: We conducted a retrospective analysis on biomarker changes in seven EHS patients (aged 18–25 years) who were hospitalized for a minimum of 84 hours. Diagnosis of heat stroke was based on extreme body temperature and neurological deficits. Biomarkers indicative of kidney function, liver function, coagulation, muscle breakdown, and systemic inflammation during their hospitalization were analyzed.

Results: The initial average rectal temperature (T_re) was 41.1°C. Patients were cooled to approximately 38.5°C before being transferred to the emergency department (ED). Within the first 24–36 hours of hospitalization, biomarker levels reach peak levels depending on EHS severity. Renal biomarkers rose to 1.5–3 times normal values, while transaminases increased 7–15 times. Creatine phosphokinase, indicating muscle injury, reached an average of 100 times its reference range. Within 24–72 hours. all biomarker levels were normalized.

Conclusions: There is often a gap between the initial temperature of an EHS patient and the temperature recorded at ED admission after cooling. Accurate assessment is context-specific and requires precise biomarker follow-up. Clinical evaluation should continue for at least 48 hours to track organ damage and guide prognosis.

The Holocaust represents an extreme failure of medical ethics, with physicians actively involved in crimes against humanity. Rheumatology is directly affected through eponyms that honor Nazi perpetrators and through persistent musculoskeletal consequences observed in Holocaust survivors. In this article, we critically analyzed symbolic (nomenclature) and biological (trauma-related disability) legacies of Nazism in rheumatology. Narrative reviews of PubMed/MEDLINE, Scopus, and Israel Medical Association Journal (IMAJ) as well as key historiographic analyses and clinical studies of musculoskeletal outcomes among Holocaust survivors were included. Ethical codes emerging post-Holocaust (Nuremberg Code and Declaration of Helsinki) were integrated. Renaming Reiter’s syndrome as reactive arthritis and Wegener’s granulomatosis as granulomatosis with polyangiitis represents ethical correction. Clinical evidence shows Holocaust survivors experience such as reduced functional recovery after hip fracture, lower perceived health despite similar objective measures, and greater cardiovascular burden impairing rehabilitation tolerance. Rheumatology must align nomenclature with ethical responsibility and recognize trauma-associated musculoskeletal vulnerability. Historical memory should guide clinical decisions, language, and education

It is 3:00 in the morning at an Israeli medical center. The rhythmic beeping of monitors pierces the silence as an on-call team gathers around a patient's bed. The team includes a Jewish doctor, a Muslim nurse, and a Christian physician. In these critical moments, the only language spoken is the language of medicine–a seamless blend of physiology, pharmacology, and an ancient medical oath.

For us in Israel, this reality is natural and common. Yet, viewed through a historical lens, particularly against the backdrop of World War II when medicine itself was weaponized and conscripted into an extermination machine, this collaboration was nothing short of a monumental triumph of the human spirit. In this editorial, I invite you on a historical journey to revisit two profound narratives where physicians from diverse backgrounds transformed their clinical knowledge and authority into instruments of life and resistance.

Background: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and internal organs. Its expression can vary across ethnic groups.

Objectives: To compare clinical and serological manifestations of SSc between Jewish and Arab patients in Israel.

Methods: We conducted a retrospective single-center study included 100 patients with SSc selected from our rheumatology clinic at Meir Medical Center, comprising 50 Jewish and 50 Arab patients with available complete clinical and laboratory data. Demographic characteristics, disease features, autoantibody profiles, organ involvement, and treatment patterns were collected.

Results: Most clinical, laboratory, and treatment variables did not differ significantly between Jewish and Arab patients. Significant difference was the higher prevalence of skin telangiectasia in Jewish patients (86%) compared to Arab patients (38%) (P < 0.001) as well as Raynaud phenomenon and pulmonary hypertension. Other manifestations, including organ involvement and autoantibody prevalence, were similar across the groups.

Conclusions: This study reveals significant similarities in the clinical and serological expression of SSc between Jewish and Arab patients in Israel. The higher prevalence of telangiectasia in Jewish patients suggests a possible ethnic or environmental influence on vascular manifestations. Further research is needed to explore the potential genetic or environmental factors contributing to this difference and to assess if this impacts disease progression or treatment outcomes.

Background: Acute myocarditis (AM) is an inflammatory cardiac condition with heterogeneous clinical manifestations that often overlap with other acute cardiac syndromes, making diagnosis challenging.

Objectives: To characterize the prevalence, clinical profile, and outcomes of AM patients with respiratory viral pathogen detection on nasopharyngeal swabs at admission.

Methods: We retrospectively analyzed all patients admitted to the Sheba Medical Center with confirmed AM between January 2005 and December 2020. Diagnosis was based on compatible presentation, elevated cardiac biomarkers, and supportive imaging findings. Nasopharyngeal swab results, when performed, were reviewed for respiratory viral detection.

Results: Among 425 identified AM cases, 146 (34%) underwent swab testing; 11 (8%) tested positive for respiratory viral pathogens, most commonly influenza A (n=5) and adenovirus (n=3). With one exception, all positive cases occurred during winter or early spring (10/77, 13%). Compared with swab-negative patients, swab-positive individuals were older (47 ± 22 vs. 35 ± 14 years, P = 0.03), more frequently female (45% vs. 14%, P = 0.007), and more often presented with dyspnea (55% vs. 25%, P = 0.036) but less commonly with ST-segment elevation (27% vs. 70%, P = 0.003). No differences were observed in inflammatory markers, imaging findings, or hospital stay.

Conclusions: Respiratory viral detection in AM is uncommon and predominantly seasonal. Nasopharyngeal swabbing is a simple, non-invasive tool that may help identify treatable viral pathogens and guide patient management. These data provide a pre-COVID-19 reference for future studies investigating the impact of viral infection on myocardial injury.

Background: Nasal obstruction is one of the most common symptoms encountered in the otorhinolaryngology clinic, with diverse etiology including deviated nasal septum (DNS) and sinusitis. When surgical intervention is considered, the referring surgeon must decide whether preoperative imaging is indicated.

Objective: To identify clinical and physical examination predictors associated with significant sinus findings on computed tomography (CT) imaging in patients with nasal obstruction. To define specific factors in the medical history and physical examination of patients with nasal obstruction, which are associated with positive CT findings.

Methods: We conducted a retrospective review of patients presenting with nasal obstruction. We collected demographic data, clinical and physical examination findings, CT imaging results, and surgical outcomes.

Results: A total of 242 patients were included (mean age 38.5 ± 16.8 years, 65.7% male), all of whom underwent CT imaging prior to surgery. On univariate analysis, nasal edema, ostiomeatal complex (OMC) blockage, or edema, were all associated with positive findings from the CT (defined as Lund–Mackay > 3). On multivariate analysis, OMC obstruction or edema were associated with positive CT findings.

Conclusion: A thorough patient history and detailed physical examination are essential for evaluating nasal obstruction and identifying patients who may benefit from preoperative CT imaging. Specific clinical symptoms can indicate chronic sinusitis, thus guiding surgeons to perform preoperative imaging for accurate diagnosis and targeted treatment beyond deviated nasal septum management.

Background: Apparent treatment-resistant hypertension (aTRH) is a high-risk phenotype associated with increased cardiovascular and renal morbidity. Renal denervation (RDN) has emerged as a promising intervention for patients with refractory blood pressure (BP) despite maximal medical therapy.

Objectives: To present the first Israeli prospective cohort evaluating RDN outcomes in aTRH patients.

Methods: The Tel Aviv Renal Denervation registry is a single-center, prospective cohort of 19 patients with aTRH who underwent RDN between 2021 and 2024. Baseline data included demographics, co-morbidities, medication burden, ambulatory BP monitoring (ABPM), and renal function. Outcomes were assessed at 3 and 12 months post-procedure, with repeated measures analyses used to evaluate longitudinal trends.

Results: The cohort (median age 62 years, 42% female) exhibited a high burden of co-morbidities including ischemic heart disease (37%), diabetes (26%), and chronic kidney disease (21%). Baseline ABPM showed a median 24-hour systolic BP of 152 mmHg. Following RDN, mean systolic BP decreased to 143 mmHg at 3 months and 138 mmHg at 12 months (P = 0.097), with a significant reduction in nighttime systolic BP (P = 0.033). Pill burden decreased from a median of 7 to 4 pills daily (P = 0.037). The number of antihypertensive drug classes declined from 6 to 4 (P = 0.052). Renal function remained stable throughout follow-up.

Conclusions: In this Israeli RDN cohort, patients with aTRH experienced clinically meaningful reductions in BP and medication burden, with preserved renal function and minimal complications. These findings support further expansion of national RDN registries to better guide patient selection and optimize long-term outcomes.

Pulmonary medicine, a major subspecialty of internal medicine, has advanced dramatically over the past decade and continues to grow at an impressive pace. The subspeciality is a uniquely multifaceted field, requiring thoughtful integration of the patient’s history, physical findings, laboratory data, and imaging to reach an accurate diagnosis and suggest proper treatment. This clinical depth is complemented by a rapidly expanding therapeutic arsenal for complex lung diseases. At the same time, technological progress has transformed our practice. Innovations in imaging and in both diagnostic and therapeutic bronchoscopy–central components of interventional pulmonology–have evolved so rapidly that tools used only a decade or two ago now seem outdated [1]. All these advancements offer meaningful opportunities to enhance the health outcomes of our patients. What a fascinating specialty and what an exciting time to be a pulmonologist.

Background: The incidence of autologous breast reconstruction has been steadily increasing in recent years. Deep inferior epigastric perforator (DIEP) flap reconstruction is considered the gold standard for breast reconstruction despite its demanding technical expertise, time intensiveness, and rigorous postoperative monitoring.

Methods: We retrospectively collected data from 102 DIEP flaps utilized for breast reconstruction in 70 patients treated at private clinics between 2013 and 2024. All surgeries were performed by a single, experienced surgeon.

Results: The mean age at surgery was 42.2 ± 8 years. Immediate reconstructions were conducted in 34 patients (48%); 46% of patients had prior radiation therapy. Only one patient received adjuvant radiation therapy. Free DIEP flaps vascularized by one (53%), two (32%), or three (10%) perforators were preferentially anastomosed to the internal mammary vessels. One patient underwent a muscle-sparing procedure due to the absence of available perforators. Total flap failure occurred in four cases (3.9%), three occurred as a unilateral loss in patients who underwent bilateral reconstruction. Postoperative revisions of the microvascular anastomosis were performed in three patients, with successful flap salvage in two (67%). Fat necrosis was diagnosed in 26 breasts (25%), only a minority of cases required follow-up surgery. All patients were managed completely in a private clinic, with none requiring hospitalization in the public system.

Conclusions: Free DIEP flap breast reconstruction necessitates meticulous surgical planning, a well-coordinated surgical team, and close postoperative monitoring. Nevertheless, this surgery can be safely and effectively performed in a private clinic setting, with complication rates comparable to that of the public setting.

In the 1950s, ionizing radiation to the scalp was commonly used in Israel as a treatment for tinea capitis. Decades later, epidemiological studies identified an increased incidence of head and neck malignancies, particularly basal cell carcinoma, as well as intracranial tumors such as meningiomas among individuals who underwent this therapy in childhood. In addition to the oncologic risk, irradiated scalp skin presents significant reconstructive challenges due to chronic skin atrophy, hypovascularity, fibrosis, and impaired wound healing. In this study, we present our clinical experience with a modified, skin-sparing surgical protocol for managing reconstruction post excision of non-melanoma skin cancer of the scalp in patients previously irradiated for tinea capitis. The surgical strategy is tailored according to lesion size, depth, periosteal involvement, and scalp tissue quality. It incorporates components of the reconstructive ladder as appropriate. We present three representative cases highlighting key surgical challenges and considerations in this complex population.

Background: Identifying drug–drug interactions (DDIs) in dermatology can be cumbersome and time-consuming using traditional methods.

Objectives: To explore the potential of ChatGPT-4o, an artificial intelligence (AI)-based chatbot, to streamline the identification process.

Methods: ChatGPT-4o was tasked with assessing DDIs among commonly prescribed dermatological medications. The accuracy and reliability of the chatbot's outputs were compared against established references for 43 interactions.

Results: ChatGPT-4o successfully identified all evaluated interactions. It accurately described the interaction effects in 42 cases, with only one example of misdescription.

Conclusions: The findings highlight the potential of ChatGPT to serve as an effective and efficient alternative for identifying and understanding DDIs in dermatology, despite one noted error that emphasizes the need for ongoing verification against trusted references. Further research is needed to validate its use across a broader range of medications and clinical scenarios.