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.

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Infantile hypertrophic pyloric stenosis (IHPS), characterized by enlarged pyloric musculature and gastric-outlet obstruction, is associated with altered expression of neuronal nitric oxide synthase (nNOS). Here we have studied molecular mechanisms by which nNOS gene expression is altered in pyloric tissues of 16 infants with IHPS and 9 controls. A significant decreased expression of total nNOS mRNA was found by quantitative RT-PCR in IHPS after normalization against GAPDH, which predominantly affected exon 1c with a reduction of 88% compared with controls (P < 0.001). After normalization against the neuronal-specific gene PGP9.5, expression of exon 1c was still decreased (P < 0.001), whereas expression of exon 1f was increased significantly (P ‫؍‬ I nfantile hypertrophic pyloric stenosis (IHPS), with an incidence of 1-5 per 1,000 live births in whites and a marked preponderance of males to females (4:1), is the most frequent disorder requiring surgery in the first year of life (1). A genetic contribution toward the etiology of IHPS is well established with familiar aggregation, a concordance rate of 25-40% in monogenetic twins, a recurrence risk of 10% for males and 2% for females born after an affected child, and a ratio of risk of 18 for first-degree relatives compared with the general population (2).IHPS is characterized by hypertrophy and hyperplasia of the circular muscle layer of the pylorus, leading to persistent vomiting 2-12 weeks after birth (3, 4). Defective pyloric relaxation and increased pyloric smooth muscle mass have been suggested to be responsible for gastric-outlet obstruction. In most cases, surgical pyloromyotomy is the treatment of choice, but conservative management has sometimes been used successfully (5, 6). Within a few months, hypertrophy resolves and no permanent functional or morphological abnormalities have been detected after healing (5,7,8).Recent evidence suggested a reduced expression of neuronal nitric oxide synthase (nNOS) in IHPS, because the pyloric circular muscle layer shows decreased staining of nNOS-positive neurons (9) and decreased expression of nNOS mRNA normalized against GAPDH (10). Additionally, genetic-linkage analysis suggests the nNOS gene as a susceptibility locus for hereditary IHPS (11). In addition to decreased nNOS expression, other abnormalities have been described, such as a reduced amount of interstitial cells of Cajal (12) NO, generated by nNOS, is a major inhibitory transmitter in the gut. It is involved in the intrinsic and extrinsic inhibitory innervation of the pyloric muscle (14), and genetic deletion of nNOS␣ in mice causes a phenotype closely resembling IHPS with delayed gastric emptying, enlargement of the stomach, and hypertrophy of the muscle layer of the antrum (15, 16). Furthermore, deletion of cGMP-dependent kinase I, the downstream target of the NO͞cGMP signaling pathway, leads to a similar phenotype with pyloric stenosis, delayed gastric emptying, and thickened pyloric muscle (17). Additional evidence for an important role of the NO͞cGMP...