X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism: report on new mutation of the DAX-1 gene in two siblings.
OBJECTIVE
Adrenal hypoplasia congenita (AHC) is a hereditary disorder that leads to adrenal insufficiency and hypogonadotropic hypogonadism (HHG) in childhood. The gene responsible for the X-linked form, DAX-1 (dosage-sensitive sex-reversal, AHC, on the X-chromosome, gene 1)/NR0B1, encodes for an unusual member of the nuclear receptor superfamily. Deletions and point mutations in the DAX-1 gene have been described in more than 70 AHC families. Inter- and intra-familial variability in the clinical presentation of AHC has been observed. Here we present the clinical and genetic data of two brothers affected by AHC.


METHODS
Clinical heterogeneity was observed in the two brothers: the first presented with adrenal insufficiency in early infancy, while the second required no substitution therapy until 4 yr of age. Interestingly, mineralcorticoid hormone deficiency preceded cortisol deficiency in both brothers. HHG was observed at pubertal age in both patients and required substitution therapy with gonadal steroids.


RESULTS
Sequence analysis revealed a novel mutation in the DAX-1 gene in the two brothers and in their carrier mother. The mutation, a three nucleotide deletion, results in the loss of leucine 278 (del278L). A missense mutation affecting the same leucine (L278P) was previously shown to cause marked reduction of repressor function with respect to the wild type protein in transcription assays.


CONCLUSIONS
Missense mutations or amino acid loss in the DAX-1 gene are very rare. Their identification and genotype-phenotype correlation are important for the characterization of protein function and for patient management.
Department of Pediatrics, University of Genoa, "G. Gaslini" Institute, Genoa, Italy.
V
V
Calvari
M G
MG
Alpigiani
E
E
Poggi
B
B
Podesta
G
G
Camerino
R
R
Lorini
D000293:Adolescent; D000309:Adrenal Insufficiency / Q000151:congenital* / Q000235:genetics; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002675:Child, Preschool; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins