Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000–2005

Brooks, BP; Kleta, Robert; Stuart, Caroline; Tuchman, Mendel; Jeong, Andrew; Stergiopoulos, SG; Bei, Thalia; Björnson, Bruce; Russell, Liane B.; Chanoine, Jean‐Pierre; Tsagarakis, Stylianos; Kalsner, LR; Stratakis, C. A.

doi:10.1111/j.1399-0004.2005.00482.x

Cited by 83 publications

(86 citation statements)

References 34 publications

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“…In all our patients, except one, decreased tear production was either present from birth or was noted in the first year of life. Similar results were presented in other case reports [4,19]. In two of our patients (nos.…”

Section: Discussionsupporting

confidence: 93%

“…In a proteomic approach, ALADIN was identified as a protein of the nuclear pore complex [6], which is most probably engaged in structural scaffolding [20]. Homozygous and compound heterozygous mutations in the AAAS gene have been identified in a number of families affected by triple A syndrome [4]. Studies conducted so far have not established significant genotype-phenotype relationship [2].…”

Section: Introductionmentioning

confidence: 98%

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Triple A syndrome: 32 years experience of a single centre (1977–2008)

et al. 2010

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Triple A syndrome is an autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and neurodegeneration. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Over the period 1977-2008 we evaluated ten subjects with the clinical diagnosis of triple A syndrome. Molecular analysis was performed in seven patients and revealed that all except one are compound heterozygotes for two mutations in the AAAS gene. Two novel mutations were detected: c.123+2T>C resulted in splice defect while c.1261_1262insG mutation resulted in a truncated protein (p.V421fs), which most probably is not functional. Genotype-phenotype correlation could not be established. In all our patients, except one sibling of previously diagnosed brother and sister, genetic analysis was performed when at least two symptoms were present, usually alacrima and achalasia. Based on our experience, we recommend that in case of the presence of alacrima and at least one more symptom of triple A syndrome, adrenal function testing and molecular analysis should be performed. In all children with mutation in AAAS gene, regular follow up of adrenal function is necessary to avoid adrenal crisis and start substitution therapy as soon as adrenal insufficiency is noted.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 98%

Triple A syndrome: 32 years experience of a single centre (1977–2008)

et al. 2010

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“…In the present case, history revealed a lack of tears since birth, but the parents never discussed this problem with a paediatrician, because the child had not shown any signs of eye discomfort. Symptoms of achalasia may be present for years before the diagnosis is made [2]. Despite recurrent vomiting from the age of 10 months, the diagnosis of achalasia was made in our patient at the age of 6 years.…”

Section: Discussionmentioning

confidence: 91%

Clinical and molecular genetic findings in a 6-year-old Bosnian boy with triple A syndrome

et al. 2008

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The triple A syndrome is a rare autosomal recessive disease that is characterised by the triad of adrenocorticotropin (ACTH)-resistant adrenal insufficiency, achalasia and alacrima. In most patients, neurological and dermatological abnormalities are associated features. We report on the first Bosnian patient with triple A syndrome. Endocrine investigation confirmed primary adrenal insufficiency at the age of 5.8 years. Two months later, achalasia was diagnosed, and in the presence of alacrima, the patient satisfies the diagnostic criteria of triple A syndrome. In addition, a large number of associated neurological and dermatological features were present in this patient. Moreover, he has dysmorphic facial features, which have not been previously described in triple A syndrome. Triple A syndrome was confirmed by molecular analysis, revealing a nonsense mutation p.W84X in the AAAS gene. The parents are both heterozygous carriers of the mutation. The affected twin brother unfortunately died from hypoglycaemic shock, despite a normal cortisol rise in an ACTH stimulation test. Further, triple A syndrome patients carrying the identical homozygous p.W84X mutation have to be studied to assess a genotype-phenotype relationship for this mutation.

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“…Homozygous and compound heterozygous AAAS gene mutations have been described in 95% of the patients with triple A syndrome from different ethnic backgrounds (1,18). The majority of mutations in AAAS gene are nonsense, frameshift, or splice site with some missense mutations (23,41). Though the function of ALADIN is not yet well established, this protein localizes in the nuclear pore and is involved in the nucleocytoplasmic transport (17,18,42).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in the molecular basis of ACTH resistance syndrome.

Collares

Antunes‐Rodrigues²,

Moreira³

et al. 2008

European Journal of Endocrinology

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Objective: ACTH resistance syndromes are rare, autosomal, and genetically heterogeneous diseases that include familial glucocorticoid deficiency (FGD) and triple A syndrome. FGD has been shown to segregate with mutations in the gene coding for ACTH receptor (MC2R) or melanocortin 2 receptor accessory protein (MRAP), whereas mutations in the triple A syndrome (AAAS, Allgrove syndrome) gene have been found in segregation with triple A syndrome. We describe the clinical findings and molecular analysis of MC2R, MRAP, and AAAS genes in five Brazilian patients with ACTH resistance syndrome. Design and methods: Genomic DNA from patients and their unaffected relatives was extracted from peripheral blood leucocytes and amplified by PCR, followed by automated sequencing. Functional analysis was carried out using Y6 cells expressing wild-type and mutant MC2R. Results: All five patients showed low cortisol and elevated plasma ACTH levels. One patient had achalasia and alacrima, besides the symptoms of adrenal insufficiency. The molecular analysis of FGD patients revealed a novel p.Gly116Val mutation in the MC2R gene in one patient and p.Met1Ile mutation in the MRAP gene in another patient. Expression of p.Gly116Val MC2R mutant in Y6 cells revealed that this variant failed to stimulate cAMP production. The analysis of the AAAS gene in the patient with triple A syndrome showed a novel g.782_783delTG deletion. The molecular analysis of DNA from other two patients showed no mutation in MC2R, MRAP, or AAAS gene. Conclusions: In conclusion, the molecular basis of ACTH resistance syndrome is heterogeneous, segregating with genes coding for proteins involved with ACTH receptor signaling/expression or adrenal gland development and other unknown genes.European Journal of Endocrinology 159 61-68

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Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000–2005

Cited by 83 publications

References 34 publications

Triple A syndrome: 32 years experience of a single centre (1977–2008)

Triple A syndrome: 32 years experience of a single centre (1977–2008)

Clinical and molecular genetic findings in a 6-year-old Bosnian boy with triple A syndrome

Heterogeneity in the molecular basis of ACTH resistance syndrome.

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