Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency.
BACKGROUND
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.


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


METHODS
The study was conducted at secondary and tertiary referral centers.


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


METHODS
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.
Metherell
Louise A
LA
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, London EC1M 6BQ, United Kingdom. l.a.metherell@qmul.ac.uk
Naville
Danielle
D
Halaby
George
G
Begeot
Martine
M
Huebner
Angela
A
Nürnberg
Gudrun
G
Nürnberg
Peter
P
Green
Jane
J
Tomlinson
Jeremy W
JW
Krone
Nils P
NP
Lin
Lin
L
Racine
Michael
M
Berney
Dan M
DM
Achermann
John C
JC
Arlt
Wiebke
W
Clark
Adrian J L
AJ
D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis* / Q000235:genetics; D000309:Adrenal Insufficiency / Q000175:diagnosis* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide