Childhood-onset alpha-gal syndrome in the central black sea region: real-world data on diagnostic delays, age-specific clinical patterns, environmental risk factors, and anaphylaxis predictors.
Alpha-gal syndrome (AGS) remains underdiagnosed in the pediatric population despite increasing awareness. This study comprehensively evaluates diagnostic delays, age-specific clinical presentations, environmental risk factors, and novel biomarkers for anaphylaxis prediction in childhood-onset AGS. This study examined 39 childhood-onset AGS cases diagnosed at the Ondokuz Mayıs University Pediatric Allergy and Immunology Clinic, with symptom onset at 18 years of age or younger. Patients underwent comprehensive clinical evaluation including alpha-gal specific IgE testing (≥ 0.35 kU/L), skin prick tests, and oral food challenge tests when deemed necessary. Diagnostic delay was defined as the time interval between symptom onset and definitive diagnosis. Clinical phenotypes, environmental exposures, laboratory parameters, and vitamin D levels were systematically evaluated. Among 39 patients (69.2% male), the median age of symptom onset was 7 years (range: 1-18), with a median diagnostic delay of 2 years (range: 0-35). Diagnostic delay exceeded 2 years in 43.6% of patients, with 12.8% experiencing extreme delay (> 10 years). Anaphylaxis occurred in 76.9% of patients and was predominantly early-onset (≤ 6 h: 61.5%). Tick bite history was present in 84.6% of patients, hazelnut orchard exposure in 69.2%, and family history of meat allergy in 53.8%. Alpha-gal IgE levels were significantly higher in males (10.10 ± 8.39 vs. 5.31 ± 2.70 ng/mL, p < 0.05) and patients with anaphylaxis (9.42 ± 8.04 vs. 5.99 ± 2.96 ng/mL, p = 0.048). Our novel findings revealed significantly lower vitamin D levels in anaphylactic patients (15.58 vs. 20.31 ng/mL, p = 0.049). Fresh meat prick tests demonstrated superior sensitivity (100%) compared to commercial extracts (51.3%). Patients without concurrent allergic disease showed significantly higher rates of diagnostic delay (52.9% vs. 13.6%, p = 0.008).  Childhood-onset AGS presents with age-dependent clinical variability and diagnosis is frequently delayed until adulthood. The high sensitivity of fresh meat extracts in diagnosis and the association between vitamin D deficiency and anaphylaxis are clinically noteworthy. Familial clustering suggests genetic predisposition, emphasizing the importance of family screening and early diagnostic approaches in endemic regions. • Alpha-gal syndrome is an IgE-mediated delayed hypersensitivity reaction to mammalian meat following tick exposure, characterized by symptoms occurring 2-6 hours after consumption, making diagnosis particularly challenging in children. • Pediatric-onset alpha-gal syndrome cases are rarely reported in the literature, and many patients experience significant diagnostic delays with symptoms often remaining undiagnosed until adulthood. • This study identifies vitamin D deficiency as a novel biomarker associated with anaphylaxis risk in childhood-onset alpha-gal syndrome, and demonstrates that fresh red meat prick-to-prick testing has superior diagnostic sensitivity (100%) compared to commercial extracts (51.3%). • Children without comorbid allergic diseases experience significantly longer diagnostic delays, and the high rate of familial clustering (53.8%) suggests genetic predisposition, emphasizing the importance of family screening in endemic regions. Key Messages • Alpha-gal syndrome is an IgE-mediated allergy characterized by delayed anaphylaxis following red meat consumption, typically triggered by prior tick exposure. Pediatric-onset cases are rarely reported and often remain undiagnosed until adulthood. • This is the first study to systematically evaluate childhood-onset alpha-gal syndrome in the Central Black Sea Region. It highlights novel predictors such as the association between low vitamin D levels and anaphylaxis, demonstrates the high diagnostic sensitivity of fresh red meat prick testing, and explores how the presence or absence of comorbid allergic diseases influences diagnostic delay. • The findings support incorporating fresh meat prick-to-prick testing into routine diagnostic algorithms and suggest that alpha-gal specific IgE levels and vitamin D deficiency may serve as predictive markers for severe reactions. These insights may aid in risk stratification and early diagnosis in pediatric patients living in endemic areas.