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UCL Institute of Child Health and Department of Medicine (L.L., W.S.T., J.C.A.), University College London, London WC1N 1EH, United Kingdom; Department of Medicine (W.-X.G., J.L.J.), Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois 60611; Division of Endocrinology and Metabolism (G.O.), Gulhane Askeri Tip Akademisi Medical School, Haydarpasa Hospital, Istanbul 34670, Turkey; and Institute of Human Genetics (C.J.O.), School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne NE1 3BZ, United Kingdom
Address all correspondence and requests for reprints to: Dr. John C. Achermann, Biochemistry, Endocrinology & Metabolism, University College London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. E-mail: j.achermann{at}ich.ucl.ac.uk.
Context: Primary adrenal failure is a life-threatening condition that can be caused by a range of etiologies, including autoimmune, metabolic, and developmental disorders. The nuclear receptors DAX1 (NR0B1) and steroidogenic factor-1 (SF1/Ad4BP, NR5A1) play an important role in adrenal development and function, and mutations in these transcription factors have been found in patients with adrenal hypoplasia.
Objective: Our objective was to investigate the prevalence of DAX1 and SF1 mutations in children and adults with primary adrenal failure of unknown etiology (i.e. not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease).
Patients: One hundred seventeen patients were included. Eighty-eight individuals presented in infancy or childhood with adrenal hypoplasia or primary adrenal failure of unknown etiology (n = 64 46,XY phenotypic males; n = 17 46,XY gonadal dysgenesis/impaired androgenization; n = 7 46,XX females). Twenty-nine individuals presented in adulthood with Addison’s disease of unknown etiology.
Methods: Mutational analysis of DAX1 (NR0B1) (including exon 2
/1A) and SF1 (NR5A1) was done by direct sequencing.
Results: DAX1 mutations were found in 58% (37 of 64) of 46,XY phenotypic boys referred with adrenal hypoplasia and in all boys (eight of eight) with hypogonadotropic hypogonadism and a family history suggestive of adrenal failure in males. SF1 mutations causing adrenal failure were found in only two patients with 46,XY gonadal dysgenesis. No DAX1 or SF1 mutations were identified in the adult-onset group.
Conclusions: DAX1 mutations are a relatively frequent cause of adrenal failure in this group of boys. SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals.
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