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      Clinical and Novel Molecular Findings in a 6.8-Year-Old Turkish Boy with Triple A Syndrome

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          Background: The triple A syndrome is characterized by the main features adrenal insufficiency, achalasia and alacrima. Other organ systems can be involved in a variable manner. Patient: We report clinical and novel molecular findings in a 6.8-year-old Kurdish boy, who presented with relapsing vomiting and failure to thrive. He was diagnosed as having achalasia and primary adrenocortical hypofunction. History and clinical examination showed that the boy was unable to produce tears. In addition, a large number of associated neurological and dermatological features was present in this patient. Thus, the clinical diagnosis of triple A syndrome was made. Results: Initial molecular marker analysis supported linkage to the triple A critical region on chromosome 12q13. Further, a homozygous G → A transition in exon 9 of the newly identified AAAS gene, resulting in a stop codon (W295X) and predicting a truncated protein with loss of function, confirmed the diagnosis. This new mutation was also detected in another family of Kurdish origin. In turned out that both families were related.

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          Mutant WD-repeat protein in triple-A syndrome.

          Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals. We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago. The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.

            Author and article information

            Horm Res Paediatr
            Hormone Research in Paediatrics
            S. Karger AG
            31 January 2002
            : 56
            : 1-2
            : 67-72
            aDepartment of Hematology/Oncology and Endocrinology, University Children’s Hospital, Essen, and bChildren’s Hospital, Technical University Dresden, Germany
            48093 Horm Res 2001;56:67–72
            © 2002 S. Karger AG, Basel

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            Page count
            Figures: 2, Tables: 2, References: 13, Pages: 6
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