Endocrine Abstracts

JOINT1737

Background: Triple A syndrome (TAS), is a rare autosomal recessive multisystem disorder due to mutations in the AAAS gene, which encodes the ALADIN protein. Alacrima, adrenal insufficiency, achalasia, autonomic dysfunction, and variable neurological features are the most common symptoms to be reported. Limited data exists on TAS from Sub-Saharan Africa and Arab countries with only a small series or case reports. A comprehensive clinical and genetic analysis was performed in patients diagnosed with TAS from Sudan, highlighting the genotype-phenotype correlation of this syndrome from a limited resource setting. This is considered the largest reported cohort of TAS from Sub-Saharan African countries.

Patients and Methods: 48 patients from 32 families with a clinical diagnosis of TAS were investigated. The initial diagnosis was based on the characteristic clinical and biochemical findings followed by genetic testing performed on 31 patients from 20 families who were included in this study.

Results: Alacrima was detected in all patients (100%), hyperpigmentation indicating the presence of ACTH-resistant adrenal insufficiency in 90 %, difficulty of swallowing in 35%, and the complete triad was detected in 35 % at presentation. Other features include autonomic and neurological features in 39%, facial dysmorphism in 45%, and short stature in 39%. Rare features include hypertensive encephalopathy in two patients and excessive thick nasal discharge in four patients which has not been previously reported. Eight families (40 %) reported deaths of one or more siblings who had shown similar symptoms. Genetic analysis confirmed six different AAAS mutations mainly in a homozygous form. This included three nonsense mutations, one frameshift mutation leading to a truncated protein, and 2 splice defects among them the Arabic founder mutation c.1331+1G>A (intron 14) in 32 % (6 families). The 8 bp-deletion mutation in intron 4 in two families is novel. As a further novel AAAS mutation, we identified a 1 bp-deletion in exon 9 in three families. The most abundant mutation was a previously described mutation in exon 9 (c.934C>T, p.Arg312*) present in 37 % (7 families).

Conclusion: TAS seems to be underdiagnosed in Sudan, and the presence of 95 % mutations in a homozygous form reflects the high rate of consanguinity in this population. Genotype/phenotype analyses revealed a high variability in disease severity even between patients from the same family or with identical AAAS mutation. Early genetic diagnosis in unaffected siblings has helped in disease prediction and early intervention and thus prevented an adrenal crisis and death.