Bo Yang Baker1, Lin Lin1, Chan Jong Kim1, Jamal Raza1, Claire P Smith1, Walter L Miller1, John C Achermann1. 1. Department of Pediatrics (B.Y.B., C.J.K., W.L.M.), University of California, San Francisco, CA 94143; UCL Institute of Child Health & Department of Medicine (L.L., J.C.A.), University College London, London WC1N 1EH, UK; Endocrinology (J.R.), National Institute of Child Health, Karachi 75520, Pakistan; Department of Paediatrics (C.P.S.), East Lancashire Hospitals NHS Trust, Blackburn BB2 3HH, UK.
Abstract
CONTEXT: Lipoid congenital adrenal hyperplasia is a severe disorder of adrenal and gonadal steroidogenesis caused by mutations in the steroidogenic acute regulatory protein (StAR). Affected children typically present with life-threatening adrenal insufficiency in early infancy due to a failure of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) biosynthesis, and 46,XY genetic males have complete lack of androgenization and appear phenotypically female due to impaired testicular androgen secretion in utero. OBJECTIVE: The objective of this study was to investigate whether nonclassic forms of this condition exist. PATIENTS AND METHODS: Sequence analysis of the gene encoding StAR was undertaken in three children from two families who presented with primary adrenal insufficiency at 2-4 yr of age; the males had normal genital development. Identified mutants were tested in a series of biochemical assays. RESULTS: DNA sequencing identified homozygous StAR mutations Val187Met and Arg188Cys in these two families. Functional studies of StAR activity in cells and in vitro and cholesterol-binding assays showed these mutants retained approximately 20% of wild-type activity. CONCLUSIONS: These patients define a new disorder, nonclassic lipoid congenital adrenal hyperplasia, and represent a new cause of nonautoimmune Addison disease (primary adrenal failure).
CONTEXT: Lipoid congenital adrenal hyperplasia is a severe disorder of adrenal and gonadal steroidogenesis caused by mutations in the steroidogenic acute regulatory protein (StAR). Affected children typically present with life-threatening adrenal insufficiency in early infancy due to a failure of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) biosynthesis, and 46,XY genetic males have complete lack of androgenization and appear phenotypically female due to impaired testicular androgen secretion in utero. OBJECTIVE: The objective of this study was to investigate whether nonclassic forms of this condition exist. PATIENTS AND METHODS: Sequence analysis of the gene encoding StAR was undertaken in three children from two families who presented with primary adrenal insufficiency at 2-4 yr of age; the males had normal genital development. Identified mutants were tested in a series of biochemical assays. RESULTS: DNA sequencing identified homozygous StAR mutations Val187Met and Arg188Cys in these two families. Functional studies of StAR activity in cells and in vitro and cholesterol-binding assays showed these mutants retained approximately 20% of wild-type activity. CONCLUSIONS: These patients define a new disorder, nonclassic lipoid congenital adrenal hyperplasia, and represent a new cause of nonautoimmune Addison disease (primary adrenal failure).
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