ESPE Abstracts

Background: AAAS is an autosomal recessive disorder characterized by adrenal insufficiency, alacrimia, achalasia and neurological symptoms. The disease-causing AAAS gene encodes for the ALADIN nuclear pore protein.

Case presentation: Case 1: A girl (born to unrelated parents) presented at age 3.9 years with fatigue and hyperpigmented skin. Clinical examination was normal, clumsy gait was noted. Endocrine studies confirmed adrenal insufficiency (F=9 mg/ml, ACTH=563 pg/ml), and glucocorticoid therapy was started. Diagnosis of AAAS was made later at age 15, when she developed muscle weakness, hypereflexia and ataxia. Electromyoneurography demonstrated motor-sensitive polyneuropathy. Alacrimia was diagnosed by Schirmer test. During follow-up (at age 18), she developed feeding difficulties that led to diagnosis of achalasia. Molecular analysis showed a compound heterozygosity for previously known AAAS mutations 43C→A(GlnLyS)/IVS14+IG>A. Case2: a boy born to unrelated parents presented at age 14 years because of important weight loss (BMI=14 kg/m²) and fatigue. He had been diagnosed with achalasia one year earlier. Past history revealed congenital twisted feet and dysphagia since 4–6 months of age. On clinical examination, cutaneous-mucosal hyperpigmentation, muscle weakness and nasal speech were noted. Endocrine studies confirmed adrenal insufficiency (F=12–mcg/L, ACTH>1250–pg/ml); elettromyoneurography demonstrated axonal polyneuropathy and Schirmer test was indicative for alacrimia. Glucocorticoid therapy was immediately started. Molecular analysis revealed a novel homozygous intronic variant (IVS11-2), inherited from the heterozygous parents (both from Sardinia). The molecular characterization of this novel variant, based on mRNA analysis, showed that this variant affects the splicing site of the exon 11 into the ALADIN gene, causing the production of an aberrant protein with a premature stop codon.

Conclusion: Our finding of a novel causative IVS in AAAS gene supports the notion of genetic heterogeneity for this disorder, although other genetic mechanisms cannot be excluded. The variable presentation/progression of disease manifestations observed in our two patients with AAAS could support this hypothesis.