Identification of a novel mutation in DAX1/NR0B1A gene in two siblings with severe clinical presentation of adrenal hypoplasia congenita

Abstract

Objective: To search for mutations in DAX1/NR0B1A gene in siblings to establish the molecular etiology of the adrenal hypoplasia congenita (AHC), a rare potentially life-threatening disorder. Case report: We describe two siblings who presented with salt-wasting syndrome in the newborn period and received hormonal replacement for primary adrenal insufficiency. A diagnostic hypothesis of AHC was suspected because the children maintained, during hormonal treatment, low plasma 17-OH progesterone (17-OHP) and androgens, despite high ACTH levels. Results: DAX1 gene was studied by molecular analysis, which showed a mutation, confirming the diagnosis in the siblings and a heterozygous state in the mother. Direct sequencing of DAX1 revealed an insertion of an adenine base (c1382-1383 A ins), which lead to a pMet461Asp substitution. Conclusion: A novel frameshift mutation of DAX1 gene, which established the molecular etiology of the AHC in the siblings, was identified. Obtaining a precise genetic diagnosis of this adrenal disorder, which, sometimes, cannot be confirmed only by clinical aspects, may have important implications for the long-term management of the disease. Arq Bras Endocrinol Metab. 2009;53(6):771-6 Keywords Congenital, hereditary, and neonatal diseases and abnormalities; adrenal insufficiency; frameshift mutation; genetic counseling resumo Objetivo: Pesquisar mutações no gene DAX1/NR0B1A em dois irmãos com suspeita de hipoplasia adrenal congênita (HAC), rara doença potencialmente fatal, para estabelecer sua etiologia molecular. Relato dos casos: São apresentados os relatos de dois irmãos com síndrome perdedora de sal no período neonatal que receberam terapia de reposição hormonal para insuficiência adrenal primária. O diagnóstico de HAC foi suspeitado porque as crianças mantiveram, durante o tratamento hormonal, níveis plasmáticos reduzidos de 17-OH-progesterona e andrógenos ao lado de níveis elevados de ACTH. Resultados: A análise molecular do gene DAX1 mostrou a mutação, confirmando o diagnóstico nos irmãos e o estado heterozigoto da mãe. No sequenciamento direto do DAX1 foi encontrada inserção de uma adenina (c1382-1383 A ins), levando à substituição pMet461Asp. Conclusão: Uma nova mutação da fase de leitura no gene DAX1 foi identificada, estabelecendo a etiologia molecular da HAC nos dois irmãos. Um diagnóstico genético preciso deste distúrbio adrenal, frequentemente não confirmado apenas pelos aspectos clínicos, pode ter importantes implicações para o manuseio em longo prazo da doença. Arq Bras Endocrinol Metab. 2009;53(6):771-6 Descritores Doenças congênitas, hereditárias e neonatais e anormalidades; insuficiência adrenal; mutação da fase de leitura; aconselhamento genético

A novel mutation in the DAX1 gene in a newborn with adrenal hypoplasia congenita in Korea

“…The DAX1 gene has significance in adrenal development and function. Mutations in this gene may cause AHC, a rare cause of primary adrenal insufficiency in childhood [8]. AHC is caused by mutations in DAX1 gene on the X chromosome (Xp21).…”

“…In this report, by the time he became 7 years old, he remained stable on follow-up and had no adrenal crisis at all. Another patient who was diagnosed as AHC in the neonatal period, presented with an episode of adrenal insufficiency at 7 months [8]. However, no other unexpected events had happened by the time he was 4-years-old.…”

A novel DAX1/NR0B1 mutation in a patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism

“…DAX1 is expressed in the adrenal gland, gonads, hypothalamus, and pituitary gonadotropes (3,8,15,17), and plays a significant role at several levels of the function and development of the reproductive axis (15). HH in patients with DAX1 mutations involves deficiencies at both hypothalamic and pituitary levels.…”

“…Up to mid-2006, approximately 80 to 100 DAX1 mutations had been described (8,20). Currently, approximately 200 DAX1 mutations are known, including deletions involving the NR0B1 gene alone or along adjacent genes, such as the gene associated with Duchenne muscular dystrophy or glycerol kinase, in a kind of "contiguous gene syndrome" and nonsense, frameshift, or missense mutations (22).…”

“…DAX1 is located on the short arm of X chromosome (Xp21), and is composed by two exons containing, respectively, 1,168 and 254 bp, separated by a 3,385-bp intron. It encodes a 470-amino-acid protein (4,6,8).…”