title: A novel missense mutation in DAX-1 with an unusual presentation of X-linked adrenal hypoplasia congenita.
abstract: A male presented at age 2.2 years with a 6-week history of intermittent vomiting and hyperpigmentation. Investigations showed salt wasting with hyperkalaemia, a grossly impaired cortisol response to ACTH stimulation, elevated renin and ACTH. Family history revealed that two maternal uncles had died soon after birth. A third uncle failed to thrive during infancy but improved with a course of cortisone, then being untreated until further investigation revealed adrenal insufficiency. A fourth uncle died aged 10 days, with urinary salt loss and hypoplastic adrenal glands at postmortem. Molecular studies on the proband, his mother, maternal grandmother, and surviving uncle showed a novel C to G substitution at nucleotide position 794 (missense mutation T265R) in the DAX1 (NR0B1) gene. The proband has responded well to steroid replacement but has proved sensitive to 9alpha-fludrocortisone treatment, developing hypertension on a dose of 133 microg/m(2)/day. At 8.8 years he was noted to have testicular volumes of 4 ml, despite no other evidence of secondary sexual development and prepubertal gonadotrophin levels. Novel features of this family include a novel DAX1 mutation, marked variability in age of presentation, hypertension on 'standard' doses of 9alpha-fludrocortisone and mild testicular enlargement.
authors.affiliation: Department of Child Health, Royal Hospital for Sick Children, Yorkhill, Glasgow, UK.
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
authors.forename: Wendy F
authors.initials: WF
authors.lastname: Paterson
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Peter
authors.initials: P
authors.lastname: Adlard
authors.forename: Philippa
authors.initials: P
authors.lastname: Duncan
authors.forename: John
authors.initials: J
authors.lastname: Tolmie
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
authors.forename: Malcolm D C
authors.initials: MD
authors.lastname: Donaldson
mesh_terms: D000311:Adrenal Glands / Q000002:abnormalities* / Q000503:physiopathology; D000309:Adrenal Insufficiency / Q000151:congenital* / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002675:Child, Preschool; D003348:Cortisone / Q000009:adverse effects / Q000031:analogs & derivatives; D057137:DAX-1 Orphan Nuclear Receptor; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D040181:Genetic Diseases, X-Linked / Q000188:drug therapy / Q000503:physiopathology*; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D013737:Testis / Q000503:physiopathology*
chemical_list: D000893:Anti-Inflammatory Agents; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; C033001:9-fluorocortisone; D003348:Cortisone; D006854:Hydrocortisone