Allgrove et al. (1978) reported 2 pairs of sibs (3 boys and 1 girl) with glucocorticoid deficiency and achalasia of the stomach cardia. Three had defective tear formation (alacrima) and 1 showed other signs of autonomic dysfunction. Postmortem ... Allgrove et al. (1978) reported 2 pairs of sibs (3 boys and 1 girl) with glucocorticoid deficiency and achalasia of the stomach cardia. Three had defective tear formation (alacrima) and 1 showed other signs of autonomic dysfunction. Postmortem studies of 1 patient showed absence of the zona fasciculata and zona reticularis with almost normal zona glomerulosa. The authors knew of 2 other families with the association. Allgrove et al. (1978) stated that 2 sisters reported by Kelch et al. (1972) had developed achalasia, 1 of whom also had ACTH-resistant adrenal insufficiency. Vaughan and Williams (1973) reported 2 brothers with achalasia, 1 of whom was found to have skin pigmentation and adrenal insufficiency. Lanes et al. (1984) reported the case of an 8-year-old Saudi Arabian girl with alacrima, achalasia and adrenal insufficiency which included partial mineralocorticoid deficiency as well as glucocorticoid deficiency. Lanes et al. (1984) suggested that a degenerative process of progressive nature may be responsible for the 3 features of this syndrome of alacrima-achalasia-addisonianism, and suggested that the 'triple-A syndrome' may be a useful designation. Ehrich et al. (1987) reported 2 brothers with achalasia, adrenal insufficiency (both glucocorticoid and mineralocorticoid), and alacrima, as well as short stature, microcephaly, ataxia, optic atrophy, and severe developmental delay. Ehrich et al. (1987) commented on the significant impairment of the central nervous system in the 2 brothers, and noted that some previous reports had described delay in motor and speech developments, ataxia, and anisocoria. Grant et al. (1992) provided follow-up on the patients originally described by Allgrove et al. (1978) and documented that they had developed neurologic manifestations, including polyneuropathy with sensory, motor, and autonomic components, long-tract degeneration, parkinsonism, and mild dementia. Tsao et al. (1994) reported the cases of 2 first cousins, a 17-year-old girl and a 9-year-old boy, with adrenal insufficiency and microcephaly who also developed peripheral neuropathy, achalasia, and alacrima. In this kindred, 2 brothers had married 2 sisters. A sister of the 9-year-old boy had died at the age of 18 months of the same disorder. Because of the similarities to adrenoleukodystrophy and adrenomyeloneuropathy, Tsao et al. (1994) excluded these possibilities by demonstrating normal levels of plasma very long chain fatty acids, pipecolic acid and phytanic acid, and normal cranial CT scan. Muscle mitochondrial respiratory chain enzymes were also normal. In a review of ACTH resistance syndromes, Clark and Weber (1994) reported that no mutations in the ACTH receptor (607397), which cause familial glucocorticoid deficiency (202200), had been demonstrated in triple-A syndrome. They pointed out that the triple-A syndrome has some features of a contiguous gene syndrome. There are patients in whom only 2 of the 3 features are present, and the occurrence and nature of the neurologic defects seem to vary considerably from one family to another. Glucocorticoid replacement therapy seems to have no influence on the development and progression of neurologic features. Gazarian et al. (1995) described 4 children, of whom 2 were sibs, with what they referred to as the 4A syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurologic abnormalities. The children were between 3 and 6 years of age at the time of diagnosis. All of them had clinical neurologic abnormalities when examined between 6 and 8 years of age. Cardiovascular autonomic testing in 3 of the subjects showed abnormal heart rate variation during deep breathing in all 3, abnormal Valsalva ratio in 2, and abnormal postural systolic blood pressure response in 1. Pupillary reflexes were abnormal in the only subject in which they could be measured. Gazarian et al. (1995) proposed that autonomic neuropathy be considered an integral feature of this disorder, making it the 4A syndrome rather than the triple-A syndrome. Chu et al. (1996) reported orthostatic hypotension with compensatory tachycardia in 2 unrelated Hispanic teenagers with Allgrove syndrome. They suggested that Allgrove syndrome could be explained by a 'progressive loss of cholinergic function.' Caksen et al. (2002) described a 7-year-old boy with classic features of Allgrove syndrome associated with a small ectopic left kidney in the pelvis. The authors suggested that the ectopic kidney was coincidental because the incidence of renal ectopia was placed as high as 1 in 900 in the population (Elder, 2000). Goizet et al. (2002) reported a Portuguese woman who presented at age 33 years with progressive bulbospinal amyotrophy and autonomic dysfunction associated with typical features of the triple-A syndrome that had been present since birth. She was found to have a homozygous nonsense mutation (605378.0002) in the AAAS gene. The authors noted that marked bulbospinal amyotrophy can be part of the phenotypic neurologic spectrum in triple-A syndrome and suggested that autonomic dysfunction and amyotrophy be added to the eponym. De Carvalho and Houlden (2002) reported that they had seen patients with the triple-A syndrome with severe neurologic involvement, including spastic tetraparesis, bulbospinal amyotrophy, and motor peripheral neuropathy. Prpic et al. (2003) demonstrated the marked phenotypic variability in 3 patients with genetically confirmed triple-A syndrome. Two patients had achalasia, alacrima, and adrenocortical deficiency as well as neurologic and autonomic dysfunction. The third patient had only achalasia and neurologic dysfunction. All patients were homozygous for mutations in the AAAS gene. In the patient with isolated achalasia, the diagnosis of triple-A syndrome could only be made on the basis of the molecular genetic analysis of the AAAS gene, which identified a mutation (605378.0007). Prpic et al. (2003) remarked on the variable pattern of neurologic and autonomic dysfunction demonstrated by patients with triple-A syndrome, including mental retardation, hyperreflexia, impaired visual evoked potentials, muscle weakness, abnormal sweating, anisocoria (106240), and postural hypotension. The authors proposed that the diagnosis of triple-A syndrome should be made on the basis of molecular analysis of the AAAS gene and may therefore include patients with 1 or 2 of the 3 main symptoms. - Achalasia-Alacrima Syndrome Efrati and Mares (1985) described a 5-year-old Arabian girl with infantile achalasia in association with alacrima. Nussinson et al. (1988) observed a family in which 3 of 5 sibs with achalasia and absent tear production were born to consanguineous parents. None of the sibs described by Nussinson et al. (1988) showed any clinical evidence of adrenal insufficiency, which was excluded on specific testing in 1 of the sibs. Haverkamp et al. (1989) described another Arabian family in which a boy and 2 girls had achalasia and alacrima without adrenal insufficiency. They suggested that this may represent a disorder distinct from the triple-A syndrome by reason of lack of adrenal insufficiency. Koehler et al. (2008) reported a 14-year-old girl who presented with a slowly progressive axonal motor neuropathy with conspicuous muscle wasting of the hypothenar and calf muscles since the first years of life. She also had pes cavus. Nerve conduction studies clearly indicated a motor axonal neuropathy, but EMG, muscle ultrasound, muscle MRI and muscle biopsy showed nonspecific myopathic features. Other features included alacrima since infancy, difficulty swallowing, hyperreflexia, and hyperkeratosis of the soles. There was no evidence of adrenal insufficiency. Genetic analysis identified compound heterozygosity for 2 mutations in the AAAS gene (605378.0009 and 605378.0010).
In 14 families in which at least 1 member was affected with triple-A syndrome, Tullio-Pelet et al. (2000) found 5 homozygous truncating mutations (605378.0001-605378.0005) in the AAAS gene. Most of the families were consanguineous. Nine of 10 families ... In 14 families in which at least 1 member was affected with triple-A syndrome, Tullio-Pelet et al. (2000) found 5 homozygous truncating mutations (605378.0001-605378.0005) in the AAAS gene. Most of the families were consanguineous. Nine of 10 families from North Africa had the same splice site mutation (605378.0005), and the authors calculated that this founder mutation first occurred more than 2,400 years ago. Two unrelated patients from 2 of the families with the founder mutation had achalasia and alacrima without adrenal insufficiency, while each of their sibs had all 3 disease features. The authors suggested that other unlinked genes or environmental factors may modify the expression of the mutant genotype. In 9 patients with triple-A syndrome, Handschug et al. (2001) found 8 different homozygous and compound heterozygous mutations (see, e.g., 605378.0006) in the AAAS gene, most of which predicted truncation of the protein. Northern blot analysis revealed marked expression in neuroendocrine and gastrointestinal structures, which are predominantly affected in triple-A syndrome.