Tricho-Hepato-Enteric Syndromic Immunodeficiency: Clinical Spectrum, Pathobiology, and Emerging Therapies

Area of Science:

• Genetics
• Immunology
• Pediatrics

Background:

• Syndromic inborn errors of immunity (IEIs) present with immune dysfunction, congenital anomalies, and multisystem involvement.
• Tricho-hepato-enteric syndrome (THES) is an ultra-rare autosomal recessive IEI caused by variants in TTC37 or SKIV2L, often diagnosed late due to its diverse clinical spectrum.

Purpose of the Study:

• To detail the clinical, immunological, genetic, and histopathological features of two pediatric THES cases.
• To propose a structured diagnostic pathway for syndromic immunodeficiencies.

Main Methods:

• Retrospective review of clinical data, laboratory results, immune phenotyping, and histopathology in two THES patients.
• Whole-exome sequencing for molecular confirmation of THES diagnosis.

Main Results:

• Both patients exhibited intractable diarrhea, failure to thrive, dysmorphic features, and brittle hair, indicative of THES.
• Immunological findings included inverted CD4/CD8 ratios, humoral immune abnormalities, and poor vaccine responses.
• Histopathology showed chronic active colitis resembling very-early-onset inflammatory bowel disease; genetic analysis revealed pathogenic variants in SKIV2L and TTC37.

Conclusions:

• Prompt diagnosis of THES is facilitated by recognizing syndromic features, comprehensive immune assessment, and early genomic testing.
• Multidisciplinary management, genetic counseling, and exploration of novel therapies are essential for THES patients.