Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia.
BACKGROUND
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.


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).
Baker
Bo Yang
BY
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.
Lin
Lin
L
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.
Kim
Chan Jong
CJ
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.
Raza
Jamal
J
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.
Smith
Claire P
CP
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.
Miller
Walter L
WL
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.
Achermann
John C
JC
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.
D000224:Addison Disease / Q000175:diagnosis / Q000209:etiology; D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D005260:Female; D005837:Genitalia, Male / Q000033:anatomy & histology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017433:Protein Structure, Secondary; D014162:Transfection; D000098682:Steroidogenic Acute Regulatory Protein
D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein