title: Importance of genetic diagnosis of DAX-1 deficiency: example from a large, multigenerational family.
abstract: 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.
authors.affiliation: Service of Endocrinology, University Hospital, Lausanne, Switzerland.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ostermann
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvi
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Lang-Muritano
authors.forename: Marie-Jeanne
authors.initials: MJ
authors.lastname: Voirol
authors.forename: Rudolf
authors.initials: R
authors.lastname: Puttinger
authors.forename: Rolf C
authors.initials: RC
authors.lastname: Gaillard
authors.forename: Eugen
authors.initials: E
authors.lastname: Schoenle
authors.forename: François P
authors.initials: FP
authors.lastname: Pralong
mesh_terms: 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
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D004247:DNA