Clinical Manifestations and Immunologic Features of Chediak–Higashi Syndrome: A 12-Year National Registry Study from Iran

Technical Summary: Clinical Manifestations and Immunologic Features of Chediak–Higashi Syndrome: A 12-Year National Registry Study from Iran

Problem Statement
Chediak–Higashi syndrome (CHS) is a rare autosomal recessive inborn error of immunity caused by biallelic mutations in the LYST gene. While the pathophysiology involving defective intracellular vesicle dynamics and giant cytoplasmic granules is established, population-based data regarding its clinical and immunological spectrum remain scarce, particularly within Middle Eastern populations. Existing literature is largely limited to isolated case reports and small series, often resulting in delayed diagnosis due to the nonspecific nature of early symptoms and the lack of accessible molecular or functional testing in many regions. There is a critical need for registry-based cohort studies to characterize the disease burden, diagnostic delays, and outcomes in specific geographic contexts to inform clinical practice.

Methodology
This study employed a retrospective cohort design utilizing data from the Iranian Primary Immunodeficiency Registry (IPIDR). The study population comprised 23 patients with a confirmed diagnosis of CHS registered between April 2011 and March 2023. Inclusion criteria required a diagnosis established via ESID criteria, specifically the presence of characteristic cytological findings (giant intracytoplasmic granules in peripheral blood leukocytes) and/or the identification of pathogenic LYST gene variants.

Data were extracted from standardized registry records covering three domains:

1. Demographics: Age, sex, parental consanguinity, family history, and survival status.
2. Clinical: Age at symptom onset and diagnosis, diagnostic delay, presenting symptoms, recurrent infections, dermatological/neurological features, organomegaly, and occurrence of the accelerated phase.
3. Laboratory/Immunological: Complete blood counts, hepatic enzymes, immunoglobulin levels, lymphocyte subsets, and functional immune assay results where available.

Statistical analysis was performed using IBM SPSS Statistics (v22.0), presenting continuous variables as medians with interquartile ranges (IQR) and categorical variables as frequencies and percentages.

Key Results

• Demographics and Survival: The cohort included 23 patients (14 male, 9 female). Parental consanguinity was high, present in 18 patients (78.3%). The median age at data extraction was 216 months. At final follow-up, 21 patients (91.3%) were alive; one patient died from sepsis, and the status of one was unknown.
• Diagnostic Timeline: Symptoms typically began at a median age of 12 months (IQR: 6.5–18), but the median age at diagnosis was 24 months (IQR: 12–48), resulting in a median diagnostic delay of 5.8 months.
• Clinical Manifestations: The most common clinical features included recurrent respiratory and skin infections, partial oculocutaneous albinism, silvery hair, nystagmus, hepatosplenomegaly, and pancytopenia. Enteropathy was the most frequent specific manifestation (43.5%), followed by pneumonia and chronic diarrhea (39.1% each). Fever was the predominant initial presenting symptom (60.9%).
• Hematological and Biochemical Findings: Pancytopenia was prevalent, with median hemoglobin at 9.2 g/dL and platelets at 125,000/µL. Hepatic enzymes were frequently elevated (median AST: 45 U/L; ALT: 36 U/L; ALP: 377 U/L).
• Immunological Profile: Despite the immunodeficiency, lymphocyte counts and immunoglobulin levels were largely preserved. Median IgG was 1,350 mg/dL, and CD3+ T-cell percentages were near normal (61.5%). However, the study notes that cytotoxic function is qualitatively impaired despite normal cell numbers, consistent with the known pathophysiology of defective degranulation.

Key Contributions

• Regional Characterization: This study provides the first comprehensive registry-based characterization of CHS in Iran, filling a gap in data regarding Middle Eastern populations.
• Diagnostic Delay Quantification: It quantifies a significant diagnostic delay (median ~6 months), highlighting the challenge of recognizing CHS in early childhood due to overlapping symptoms with common pediatric infections.
• Clinical Spectrum Definition: The paper details the specific frequency of manifestations in this cohort, identifying enteropathy and chronic diarrhea as highly prevalent features alongside the classic triad of albinism, infections, and bleeding tendencies.
• Registry Utility: It demonstrates the value of national registries (IPIDR) in capturing real-world data for ultra-rare disorders that are difficult to study through conventional trial designs.

Significance and Claims
The authors claim that CHS in Iran presents as an early-onset, multisystemic disorder with a substantial infectious and hematologic burden. The study underscores that while survival rates in this cohort appear favorable compared to historical data (likely due to improved infection management), the risk of progression to the accelerated phase (a hyperinflammatory state resembling HLH) remains a critical threat.

The paper emphasizes that early genetic screening in high-risk families (given the high rate of consanguinity) and timely referral for hematopoietic stem cell transplantation (HSCT) before the onset of the accelerated phase are essential for curative outcomes. It concludes that registry-based data are indispensable for characterizing such rare disorders and guiding clinical decision-making, genetic counseling, and future prospective studies. The authors modestly note limitations, including the retrospective nature of the data, potential incompleteness of functional assays, and the small sample size inherent to the rarity of the disease.