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Nonclassic Lipoid Congenital Adrenal Hyperplasia Masquerading as Familial Glucocorticoid Deficiency

Centre for Endocrinology (L.A.M., A.J.L.C.), Queen Mary University of London, and The Orchid Tissue Laboratory, Institute of Cancer (D.M.B.), William Harvey Research Institute, Barts and the London School of Medicine, London EC1M 6BQ, United Kingdom; Institut National de la Santé et de la Recherche Médicale, Unité 855 (D.N., M.B.), Lyon F-69008, France; Department of Endocrinology (G.H.), Saint-Joseph University, Beirut, Lebanon; Children’s Hospital (A.H.), Technical University Dresden, 01187 Dresden, Germany; Cologne Center for Genomics and Institute for Genetics (P.N., G.N.), University of Cologne, D-50674 Cologne, Germany; Discipline of Genetics (J.G.), Faculty of Medicine, Memorial Hospital, St. John’s, NL Germany; Pediatric Endocrinology (M.R.), Helen DeVos Children’s Hospital, Grand Rapids, Michigan 49503; Clinical and Molecular Genetics Unit (L.L., J.C.A.), Developmental Endocrinology Research Group, UCL Institute of Child Health, University College London, London WC1E 6BT, United Kingdom; and Centre for Endocrinology, Diabetes, and Metabolism (J.W.T., N.P.K., W.A.), School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom

Address all correspondence and requests for reprints to: Dr. L. A. Metherell, Centre for Endocrinology, First Floor North, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail: l.a.metherell{at}qmul.ac.uk.

Context: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia and/or overwhelming infection. Mutations of the ACTH receptor (MC2R) and the melanocortin 2 receptor accessory protein (MRAP), FGD types 1 and 2 respectively, account for approximately 45% of cases.

Objective: A locus on chromosome 8 has previously been linked to the disease in three families, but no underlying gene defect has to date been identified.

Design: The study design comprised single-nucleotide polymorphism genotyping and mutation detection.

Setting: The study was conducted at secondary and tertiary referral centers.

Patients: Eighty probands from families referred for investigation of the genetic cause of FGD participated in the study.

Interventions: There were no interventions.

Results: Analysis by single-nucleotide polymorphism array of the genotype of one individual with FGD previously linked to chromosome 8 revealed a large region of homozygosity encompassing the steroidogenic acute regulatory protein gene, STAR. We identified homozygous STAR mutations in this patient and his affected siblings. Screening of our total FGD patient cohort revealed homozygous STAR mutations in a further nine individuals from four other families.

Conclusions: Mutations in STAR usually cause lipoid congenital adrenal hyperplasia, a disorder characterized by both gonadal and adrenal steroid deficiency. Our results demonstrate that certain mutations in STAR (R192C and the previously reported R188C) can present with a phenotype indistinguishable from that seen in FGD.