Clinical heterogeneity and molecular profile of triple A syndrome: a study of seven cases

Abstract

Abstract Background Triple A syndrome is characterized by achalasia, alacrima and adrenal insufficiency with neurological manifestations occurring later in the course of the disease. It occurs due to biallelic mutations in the AAAS gene which codes for the nuclear pore protein ALADIN. A number of other features have been reported over time in this heterogeneous and multisystemic disorder. Unlike other autosomal recessive disorders, triple A syndrome patients show a wide phenotypic variability both among different patients and family members harboring the same mutation(s). A gene-environment interaction has been thought to be a plausible cause. Methods A retrospective analysis of six families and seven patients presenting with triple A syndrome was carried out. The clinical, biochemical and molecular testing data were collected and correlated. The results of treatment and follow-up and genetic counseling of the families were obtained wherever feasible. Results Our cohort consisted mostly of children and displayed a wide phenotypic variability in the presenting symptoms ranging from hypoglycemic seizures at the severe end of the spectrum to insidious hyperpigmentation and delayed development. Neurological and autonomic features were present in a few patients, suggesting requirement of prolonged follow-up for these patients. A significant gap between the onset of symptoms and confirmatory diagnosis was noted, suggesting that a high index of suspicion is required for diagnosing this disorder. Sudden unexplained death was observed in siblings, and early diagnosis and treatment could help in preventing early mortality and improving the quality of life for these patients. Conclusion High index of suspicion for a potentially treatable disorder allows early appropriate intervention.