Humans ; Esophageal Achalasia/genetics* ; Cardia ; Nerve Tissue Proteins ; Nuclear Pore Complex Proteins

Allgrove syndrome is a rare autosomal recessive disorder. It is also known as the 3A syndrome and characterised by the triad of achalasia, alacrima and adrenal insufficiency. The AAAS gene is encoded on chromosome 12q13. We report the case of a 23-year-old woman who presented at the hospital with adrenal crisis that was triggered by infection of the urinary system and gastrointestinal bleeding. She had a known diagnosis of achalasia for eight years, and ophthalmologic examination revealed alacrima. Based on our findings, the patient was diagnosed with Allgrove syndrome.
Adrenal Insufficiency ; blood ; diagnosis ; genetics ; Adrenocorticotropic Hormone ; blood ; Diagnosis, Differential ; Diagnostic Techniques, Ophthalmological ; Endoscopy, Gastrointestinal ; Esophageal Achalasia ; blood ; diagnosis ; genetics ; Female ; Humans ; Mutation ; Nerve Tissue Proteins ; blood ; genetics ; Nuclear Pore Complex Proteins ; blood ; genetics ; Young Adult

Calcium Channels, L-Type ; genetics ; metabolism ; Esophageal Achalasia ; genetics ; metabolism ; Esophagus ; metabolism ; Humans ; Nitric Oxide Synthase ; metabolism ; Nitric Oxide Synthase Type I ; genetics ; metabolism ; RNA, Messenger ; metabolism ; Real-Time Polymerase Chain Reaction ; Receptors, Calcium-Sensing ; genetics ; metabolism

OBJECTIVEAllgrove syndrome is a rare autosomal recessive disorder characterized by the triad of adrenal insufficiency, achalasia and alacrima and many cases have multi-systems disorder: endocrine, gastrointestinal tract, eyes and nervous system. This syndrome is also known as achalasia-addisonianism-alacrima syndrome or triple A syndrome. Allgrove syndrome is now known to be caused by mutations of AAAS gene encoding the aladin protein. In the present paper, we report a Chinese mainland girl with Allgrove syndrome with mutations in the AAAS gene.

METHODThe patient was a 7-year-old girl complained of coma and dark skin; she was treated as Addison disease for 2 years and had vomiting for 9 months before the second admission. Gene analysis was performed after extracting genomic DNA by amplification and sequencing of the specific fragments of AAA gene.

RESULTSThe patient was confirmed to have adrenal insufficiency at the age of 5 years and 6 months. During the second hospitalization, she was found to have a remarkable brisk reflexion, bilateral optic nerve atrophy, alacrima and achalasia besides ACTH resistance. The girl was born to consanguineous parents. Based on these findings, she was diagnosed as having Allgrove syndrome. Mutation analysis revealed a novel homozygous deletion of a single G, c.771delG, in exon 8 of the AAAS gene. This frame shift mutation was predicted to create a premature stop codon at locus 290, p.R258GfsX33, leading to a truncated and non-functioning aladin protein. Both the parents were heterozygous for the mutation.

CONCLUSIONThe clinical manifestations and AAAS gene mutations analysis confirmed the diagnosis of Allgrove syndrome. Gene analysis indicated that this syndrome is an autosomal recessive inherent disorder. ALADIN is significant for the normal cell function. When compared with reported cases, it seems that there are no remarkable relation between gene mutation loci and clinical manifestations in Allgrove syndrome.

Adrenal Insufficiency ; genetics ; Adrenocorticotropic Hormone ; blood ; China ; Consanguinity ; DNA ; analysis ; DNA Mutational Analysis ; Esophageal Achalasia ; genetics ; Exons ; Female ; Genetic Diseases, Inborn ; genetics ; Humans ; Lacrimal Apparatus Diseases ; genetics ; Mutation ; Nerve Tissue Proteins ; genetics ; Nuclear Pore Complex Proteins ; genetics ; Optic Atrophy ; genetics ; physiopathology

Triple A syndrome is a rare genetic disorder caused by mutations in the achalasia-addisonianism-alacrima syndrome (AAAS) gene which encodes a tryptophan aspartic acid (WD) repeat-containing protein named alacrima-achalasia-adrenal insufficiency neurologic disorder (ALADIN). Northern blot analysis shows that the 2.1 kb AAAS mRNA is expressed in various tissues with stronger expression in testis and pancreas. We show that human ALADIN is a protein with an apparent molecular weight of 60 kDa, and expressed in the adrenal gland, pituitary gland and pancreas. Furthermore, biochemical analysis using anti-ALADIN antibody supports the previous finding of the localization of ALADIN in the nuclear membrane. The mutations S544G and S544X show that alteration of S544 residue affects correct targeting of ALADIN to the nuclear membrane.
Adrenal Insufficiency/*genetics ; Antibodies/immunology ; Cloning, Molecular ; DNA, Complementary/genetics ; Esophageal Achalasia/*genetics ; Gene Expression Profiling ; Hela Cells ; Humans ; Lacrimal Apparatus Diseases/*genetics ; Mutagenesis, Site-Directed ; Nerve Tissue Proteins/*analysis/*genetics/immunology ; Nuclear Pore/chemistry ; Nuclear Pore Complex Proteins/*analysis/*genetics/immunology ; RNA, Messenger/analysis/genetics ; Syndrome ; Tissue Distribution