Superior discriminating value of ACTH-stimulated serum 21-deoxycortisol in identifying heterozygote carriers for 21-hydroxylase deficiency.
BACKGROUND
Congenital adrenal hyperplasia caused by classic 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder with a high prevalence of asymptomatic heterozygote carriers (HTZ) in the general population, making case detection desirable by routine methodology. HTZ for classic and nonclassic (NC) forms have basal and ACTH-stimulated values of 17-hydroxyprogesterone (17OHP) that fail to discriminate them from the general population. 21-Deoxycortisol (21DF), an 11-hydroxylated derivative of 17OHP, is an alternative approach to identify 21OHD HTZ.


OBJECTIVE
To determine the discriminating value of basal and ACTH-stimulated serum levels of 21DF in comparison with 17OHP in a population of HTZ for 21OHD (n = 60), as well as in NC patients (n = 16) and in genotypically normal control subjects (CS, n = 30), using fourth generation tandem mass spectrometry after HPLC separation (LC-MS/MS).


RESULTS
Basal 21DF levels were not different between HTZ and CS, but stimulated values were increased in the former and virtually nonresponsive in CS. Only 17·7% of the ACTH-stimulated 21DF levels overlapped with CS, when compared to 46·8% for 17OHP. For 100% specificity, the sensitivities achieved for ACTH-stimulated 21DF, 17OHP and the quotient [(21DF + 17OHP)/F] were 82·3%, 53·2% and 87%, using cut-offs of 40, 300 ng/dl and 46 (unitless), respectively. Similar to 17OHP, ACTH-stimulated 21DF levels did not overlap between HTZ and NC patients. A positive and highly significant correlation (r = 0·846; P < 0·001) was observed between 21DF and 17OHP pairs of values from NC and HTZ.


CONCLUSIONS
This study confirms the superiority of ACTH-stimulated 21DF, when compared to 17OHP, both measured by LC-MS/MS, in identifying carriers for 21OHD. Serum 21DF is a useful tool in genetic counselling to screen carriers among relatives in families with affected subjects, giving support to molecular results.
Costa-Barbosa
Flávia A
FA
Steroids Laboratory, Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil.
Tonetto-Fernandes
Vânia F
VF
Carvalho
Valdemir M
VM
Nakamura
Odete H
OH
Moura
Vivian
V
Bachega
Tânia A S S
TA
Vieira
José G H
JG
Kater
Claudio E
CE
D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics; D000324:Adrenocorticotropic Hormone / Q000737:chemistry*; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D003350:Cortodoxone / Q000097:blood*; D005260:Female; D006580:Genetic Carrier Screening / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
C003556:21-deoxycortisol; D000324:Adrenocorticotropic Hormone; D013255:Steroid 21-Hydroxylase; D003350:Cortodoxone