IMPE Abstracts

Background: Allgrove syndrome (AS) (OMIM MIM*231550) is a rare autosomal recessive multi-system disorder caused by a defect in the nucleoporin ALADIN due to mutations in the corresponding AAAS gene. It is characterized by adrenal insufficiency, achalasia, alacrima, and neurologic impairments. Here, we are presenting a large cohort of this syndrome from one country, highlighting the phenotype-genotype correlation in our patients and reflecting our difficulties in diagnosis and management.

Patients and methods: The initial diagnosis was based on the characteristic clinical signs and symptoms. Furthermore, laboratory findings of (low serum cortisol with a high ACTH level and/or low cortisol on ACTH stimulation) were used to confirm adrenal insufficiency. Shimmer test and barium swallow were used to diagnose the degree of Alacrima and Achalasia respectively. This diagnosis was furtherly confirmed by mutation detection in the AAAS gene.

Results: 43 patients from 29 Sudanese families who had a clinical diagnosis of Allgrove syndromes were included. Many patients had a family history of siblings’ death with a similar presentation. We were able to do genetic testing for 21 families including 33 patients. Six different AAAS mutations mainly in a homozygous form including 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) were identified. The 8 bp-deletion mutation in intron 4 in two families is a novel mutation. 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). Genotype/phenotype analyses revealed a highly variable occurrence of the three main symptoms, age of onset, and severity of the disease between patients with the same AAAS mutation and within one family. The rate of 95 % mutations in a homozygous form reflects the high rate of consanguinity in the Sudanese population.

Conclusion: AS seems to be an underdiagnosed condition in Sudan. The phenotypic presentation was found to be highly variable even in patients within the same family. Early genetic diagnosis in unaffected siblings has helped in disease prediction and early intervention and thus prevented an adrenal crisis and death.