Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency
Author(s)
Type
Journal Article
Abstract
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.
Partial loss-of-function mutations in StAR can present with glucocorticoid deficiency alone; genetic diagnosis in familial glucocorticoid deficiency is therefore important for correct replacement therapy and genetic counseling.
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.
Partial loss-of-function mutations in StAR can present with glucocorticoid deficiency alone; genetic diagnosis in familial glucocorticoid deficiency is therefore important for correct replacement therapy and genetic counseling.
Date Issued
2009-10-01
Date Acceptance
2009-07-27
Citation
Journal of Clinical Endocrinology and Metabolism (JCEM), 2009, 94 (10), pp.3865-3871
ISSN
0021-972X
Publisher
Oxford University Press
Start Page
3865
End Page
3871
Journal / Book Title
Journal of Clinical Endocrinology and Metabolism (JCEM)
Volume
94
Issue
10
Copyright Statement
Copyright © 2009 by The Endocrine Society.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/19773404
PII: jc.2009-0467
Subjects
ACUTE-REGULATORY-PROTEIN
ADRENOCORTICOTROPIN RECEPTOR
DISORDERS
Endocrinology & Metabolism
FEMALE-PATIENT
Life Sciences & Biomedicine
MUTATIONS
NR5A1
Science & Technology
STAR GENE
STEROIDOGENESIS
TYPE-2
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2009-09-22