Triple A syndrome with a new mutation pattern, first documented case in Austria: a case report with literature review.

Abstract

Purpose: Triple A syndrome, also known as Allgrove syndrome, is a rare autosomal recessive disorder, characterised by achalasia, alacrima, and adrenal insufficiency. The syndrome is caused by various mutations in the AAAS gene, encoding the protein ALADIN, leading to many heterogeneous clinical manifestations.

Methods: We conducted a case-based literature review. The patient gave his informed consent prior to his inclusion in this study. All personal data was anonymised. This study was approved by the Ethics committee of the Medical University of Vienna and performed in accordance with the Declaration of Helsinki.

Results: We report a case of a 51-year-old male patient with recurring symptoms of dysphagia due to achalasia, who was previously treated by Heller myotomy and repeated endoscopic dilations. He was diagnosed with primary adrenal insufficiency in childhood and substituted with fludrocortisone and hydrocortisone. The Schirmer test confirmed total alacrima, and neurological testing showed mild peripheral and central neuropathy. Genetic analysis was performed using PCR-amplification of the AAAS coding exons followed by sequencing. Long-read sequencing confirmed compound heterozygosity for two point mutations in the AAAS gene: a missense mutation, ENST00000209873.9:c.938T>A (p.Val313Asp) in exon 10, and a novel nonsense mutation, ENST00000209873.9:c.1264C>T (p.Gln422Ter) in exon 14.

Conclusion: This is the first documented case of Triple A syndrome in Austria. Notably, some of the patient's characteristic symptoms presented unusually late in life. By utilising long-read sequencing, we experimentally confirmed the in trans orientation of a new mutation located at a previously described position and a novel nonsense variant. We strongly recommend genetic testing for patients presenting with at least two symptoms of the Triple A triad (achalasia, adrenal insufficiency, alacrima) or associated neurological symptoms, as clinical manifestations can be delayed.