Importance of genetic diagnosis of DAX-1 deficiency: example from a large, multigenerational family.
BACKGROUND
Inactivating mutations of DAX-1 give rise to the X-linked form of adrenal hypoplasia congenita (AHC). Affected fetuses are at risk of early postnatal Addisonian crisis, but the variable phenotypic expression of DAX-1 insufficiency renders this diagnosis challenging.


METHODS
We describe the familial transmission of AHC over several generations. The proband was diagnosed with adrenal insufficiency at age 3.5 years: molecular analysis revealed a novel, 373-bp deletion including the second exon of DAX-1. Given the familial history of several unexplained deaths in male infants related to the proband via his maternal great-grandmother, we hypothesized that all these boys had been affected with AHC. Another female member of the family being pregnant with a male fetus at the time, we performed DAX-1 analysis on the mother and the newborn. The mother was heterozygous for the deletion, and the newborn hemizygous: he presented an adrenal crisis at 10 days of life, and is now doing well on hormone replacement therapy.


CONCLUSIONS
The unfortunate deaths of male infants at each generation of this family underlie the importance of early and precise diagnosis of this rare condition, stressing the value of genetic diagnosis in six potential female carriers of this family entering their reproductive years.
Ostermann
Sandrine
S
Service of Endocrinology, University Hospital, Lausanne, Switzerland.
Salvi
Roberto
R
Lang-Muritano
Mariarosaria
M
Voirol
Marie-Jeanne
MJ
Puttinger
Rudolf
R
Gaillard
Rolf C
RC
Schoenle
Eugen
E
Pralong
François P
FP
D000309:Adrenal Insufficiency / Q000151:congenital* / Q000175:diagnosis* / Q000209:etiology; D001483:Base Sequence; D002648:Child; D057137:DAX-1 Orphan Nuclear Receptor; D004247:DNA / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D003677:Deficiency Diseases / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D005091:Exons / Q000235:genetics; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis; D020249:Hormone Replacement Therapy; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011296:Prenatal Diagnosis; D018168:Receptors, Retinoic Acid / Q000172:deficiency* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D004247:DNA