Wolcott-Rallison Syndrome With Different Clinical Presentations and Genetic Patterns in 2 Infants

Area of Science:

• Genetics
• Pediatrics
• Endocrinology

Background:

• Wolcott-Rallison syndrome is a rare genetic disorder characterized by early-onset insulin-dependent diabetes mellitus (DM) before six months of age.
• Key features include skeletal dysplasia appearing after six months and potential liver failure, alongside other serious complications like renal failure and neurological issues.
• The syndrome is primarily linked to mutations in the EIF2AK3 gene, which plays a crucial role in cellular stress responses.

Observation:

• Two pediatric patients from Iran presented with insulin-dependent DM before six months of age.
• The first patient, an infant, showed an autosomal recessive inheritance pattern with a novel deletion in the EIF2AK3 gene; her sister previously died from complications related to the syndrome.
• The second patient experienced diabetic ketoacidosis (DKA) at 45 days old, with transient renal and coagulation abnormalities, and was diagnosed with an EIF2AK3 nonsense homozygous mutation.

Findings:

• Genetic analysis revealed distinct EIF2AK3 mutations (a novel deletion and a nonsense homozygous mutation) in the two unrelated patients.
• These findings confirm the critical role of EIF2AK3 in the pathogenesis of Wolcott-Rallison syndrome.
• The study underscores the genetic heterogeneity and phenotypic variability within the syndrome, even with mutations in the same gene.

Implications:

• Early genetic screening for EIF2AK3 mutations is crucial for diagnosing patients with severe, early-onset diabetes.
• Comprehensive clinical evaluation, including screening for skeletal dysplasia and monitoring of renal, liver, and thyroid function, is recommended for affected individuals.
• Understanding the genetic basis of Wolcott-Rallison syndrome aids in genetic counseling and potential development of targeted therapies.