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


METHODS
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.


CONCLUSIONS
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.
Mantovani
Rafael Machado
RM
Divisão de Endocrinologia Pediátrica, Departamento de Pediatria, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.
Pezzuti
Isabela Leite
IL
Dias
Vera Maria Alves
VM
Silva
Ivani Novato
IN
D000224:Addison Disease / Q000235:genetics*; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D002648:Child; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics*; D016368:Frameshift Mutation / Q000235:genetics*; D005817:Genetic Counseling; D006801:Humans; D008297:Male; D012720:Severity of Illness Index; D035781:Siblings
D057137:DAX-1 Orphan Nuclear Receptor; C539965:NR0B1 protein, human