A Novel Variant in Triple A Syndrome

Area of Science:

• Genetics and Molecular Biology
• Endocrinology
• Rare Diseases

Background:

• Triple A syndrome, also known as Allgrove syndrome, is an autosomal recessive disorder characterized by adrenal insufficiency, alacrima, and achalasia.
• The syndrome exhibits significant genotypic and phenotypic heterogeneity, with mutations in the AAAS gene on chromosome 12q13 being the primary cause.
• Accurate diagnosis is crucial for managing the multisystemic complications associated with Triple A syndrome.

Observation:

• A 14-year-old male presented with progressive weakness and skin hyperpigmentation.
• Clinical examination revealed skin and mucosal hyperpigmentation, absent tears (alacrima), and esophageal stenosis.
• Biochemical tests showed low morning cortisol and significantly elevated ACTH levels, indicative of adrenal insufficiency.

Findings:

• Molecular genetic analysis identified a homozygous c.1368_1372delGCTCA (p.Gln456HisfsTer38) mutation in the AAAS gene.
• This specific mutation results in a frameshift, altering the protein structure and leading to a pathogenic variant.
• Parental genetic analysis confirmed heterozygous carrier status for the identified mutation, consistent with autosomal recessive inheritance.

Implications:

• This case represents the first reported instance of the homozygous c.1368_1372delGCTCA mutation in Triple A syndrome.
• The findings contribute to the understanding of genotype-phenotype correlations within Triple A syndrome.
• Early molecular diagnosis is essential for timely intervention and improved management of patients with Triple A syndrome.