Late-Onset Triple A Syndrome: A Risk of Overlooked or Delayed Diagnosis and Management

Abstract

Background/Aims: A 33-year-old man was referred for the first time to the Division of Neurology because of the presence and progression of neurological symptoms. Dysphagia, weakness, reduced tear production, and nasal speech were present. In order to point the attention of late-onset triple A syndrome we describe this case and review the literature. Methods: Hormonal and biochemical evaluation, Schirmer test, tilt test and genetic testing for AAAS gene mutations. Results: Late-onset triple A syndrome caused by a novel homozygous missense mutation in the AAAS gene (A167V in exon 6) was diagnosed at least 17 years after symptom onset. Conclusions: The association between typical signs and symptoms of triple A syndrome should suggest the diagnosis even if they manifest in adulthood. The diagnosis should be confirmed by Schirmer test, endocrine testing (both basal and dynamic), genetic analysis, and detailed gastroenterological and neurological evaluations. Awareness of the possible late onset of the disease and of diagnosis in adulthood is still poor among clinicians, the acquaintance with the disease is more common among pediatricians. The importance of an adequate multidisciplinary clinical approach, dynamic testing for early diagnosis of adrenal insufficiency and periodical reassessment of adrenal function are emphasized.

Neurological features in adult Triple-A (Allgrove) syndrome

“…In pediatric series, they usually are the initial symptoms of the disease [1,7] but can be partially missing in late-onset cases [6,9,10].…”

“…This discrepancy appears to be characteristic of this condition. However, other reports relate sensorimotor demyelination [25], motor myelin alterations [7], mixed axonal-demyelinating sensorimotor polyneuropathy [10] or anterior horn syndrome [14,18]. Questions about a possible additional myopathic process have been raised [23].…”

“…Diagnosis is especially difficult [10] if endocrine or gastrointestinal signs are minor. In case of unexplained neurological symptoms on examination, these signs should be carefully looked for in order to suspect this disease.…”

“…However, endocrine and gastroenterological symptoms are usually prominent, and they are the first symptoms to occur in most patients [7,8]. The presentation of lateonset patients seems to be predominantly neurological, and can thus be misleading [6,9,10].…”

Achalasia: will genetic studies provide insights?

“…Achalasia occurs in around 75% of patients with Allgrove syndrome and is its main presenting feature. The achalasia is usually diagnosed in infancy even when the remaining symptoms of triple A syndrome become clinically manifest at puberty or in adulthood (Gazarian et al 1995;Grant et al 1993;Houlden et al 2002;Prpic et al 2003;Salmaggi et al 2008;Toromanovic et al 2009). Although frameshift, stop codon, and other functionally significant mutations appear to be associated with a more severe phenotype (including an earlier age of onset), the type of mutation does not fully explain the observed variability, which must involve additional (possibly genetic) factors (Huebner et al 2002).…”