Exp Clin Endocrinol Diabetes 2003; 111(1): 27-32
DOI: 10.1055/s-2003-37497
Article

J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York

Limited Value of Serum Steroid Measurements in Identification of Mild Form of 21-Hydroxylase Deficiency

D. Török 1 , Z. Halász 1 , M. Garami 1 , J. Homoki 2 , G. Fekete 1 , J. Sólyom 1
  • 12nd Department of Paediatrics, Faculty of Medicine, Semmelweis University, Budapest, Hungary
  • 2Department of Paediatrics, University of Ulm, Ulm, Germany
Weitere Informationen

Publikationsverlauf

Received: June 7, 2001 First decision: August 21, 2001

Accepted: May 30, 2002

Publikationsdatum:
26. Februar 2003 (online)

Abstract

Background

ACTH stimulation test is widely used as a basic diagnostic method for non-classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). However, the interpretation of this test has not been definitely established. To determine the cut-off values of basal and post-ACTH serum 17-OHP concentrations, data of patients with suspected 21-OHD has been analysed.

Patients and Methods

Two hundred and eighty-seven patients with postnatal/peripubertal virilization were investigated. Serum steroid concentrations were measured by RIA, urinary steroid profile was determined by capillary gas chromatography and mutation analysis of CYP21 gene was performed by allele specific PCR. 21-OHD was diagnosed by elevated serum 17-OHP concentrations, high level of the urinary 17-OHP metabolites and/or homozygosity for CYP21 mutations.

Results

Twenty-one patients of the total of 287 subjects (7.3 %) were identified as having 21-OHD. The numbers of 21-OHD patients compared to total numbers of patients with different ranges of serum 17-OHP were as follows: basal values below 3.5 ng/ml (mean + 1 SD) 0/225; between 3.5 - 6.6 ng/ml 3/41; above 6.6 ng/ml (mean + 2 SD) 18/21. Post-ACTH values below 6.4 ng/ml (mean + 1 SD) 0/226, between 6.4 - 10.3 ng/ml 0/35, above 10.3 ng/ml (mean + 2 SD) 21/26.

Conclusion

There are patients with inappropriate peripubertal virilization who have slightly elevated 17-OHP concentrations. In this subgroup of patients more sensitive and specific methods are needed to establish the diagnosis of 21-OHD. Therefore we suggest performing an ACTH stimulation test in patients with a morning 17-OHP level above 3.5 ng/ml. Furthermore, urinary steroid profile and/or CYP21 gene analysis are needed in patients with a stimulated 17-OHP value between 10 and 30 ng/ml. These tests will distinguish between patients with non-classical 21-OHD and patients with other disorders.

References

  • 1 Azziz R, Zacur H A. 21-hydroxylase deficiency in female hyperandrogenism: screening and diagnosis.  J Clin Endocrinol Metab. 1989;  69 577-584
  • 2 Azziz R, Dewailly D, Owerbach D. Nonclassic adrenal hyperplasia: current concepts.  J Clin Endocrinol Metab. 1994;  78 810-815
  • 3 Cisternino M, Doudi E, Martinetti M, Lorini R, Salvaneschi L, Cuccia M, Severi F. Exaggerated 17-hydroxyprogesterone response to short-term adrenal stimulation and evidence for CYP21 B gene point mutations in true precocious puberty.  Clin Endocrinol. 1998;  84 555-560
  • 4 Dacou-Voutetakis C, Dracopoulou M. High incidence of molecular defects of the CYP21 gene in patients with premature adrenarche.  J Clin Endocrinol Metab. 1999;  84 1570-1574
  • 5 Dewailly D, Vantyghem-Haudiquet M-C, Sainsard C, Buvat J, Cappoen J P, Ardaens K, Racadot A, Lefebvre J, Fossati P. Clinical and biological phenotypes in late-onset 21-hydroxylase deficiency.  J Clin Endocrinol Metab. 1986;  63 418-423
  • 6 Ehrmann D A, Rosenfield R L, Barnes R B, Brigell D F, Sheikh Z. Detection of functional ovarian hyperandrogenism in women with androgen excess.  N Engl J Med. 1992;  327 157-162
  • 7 Emans S J, Grace E, Fleischnick E, Mansfield M J, Crigler J F. Detection of late-onset 21-hydroxylase deficiency congenital adrenal hyperplasia in adolescents.  Paediatrics. 1983;  72 690-695
  • 8 Erel C T, Senturk L M, Oral E, Mutlu H, Colgar U, Seyisoglu H, Ertungealp E. Results of the ACTH stimulation test in hirsute women.  J Reprod Med. 1999;  44 247-252
  • 9 Ezquieta B, Oliver A, Gracia R, Gancedo P G. Analysis of steroid 21-hydroxylase gene mutations in the Spanish population.  Hum Genet. 1995;  96 198-204
  • 10 Ferenczi A, Garami M, Kiss E, Pék M, Sasvári-Székely M, Barta C S, Staub M, Sólyom J, Fekete G. Screening for mutations of 21-hydroxylase gene in Hungarian patients with congenital adrenal hyperplasia.  J Clin Endocrinol Metab. 1999;  84 2369-2372
  • 11 Homoki J, Sólyom J, Teller W M. Detection of late onset steroid 21-hydroxylase deficiency (LO-CAH) by capillary gas chromatography profiling of urinary steroids in children and adolescents.  Eur J Pediatr. 1988;  147 257-262
  • 12 Hughes I A. Congenital adrenal hyperplasia - a continuum of disorders.  Lancet. 1998;  352 752-754
  • 13 Knochenhauer E S, Cortet-Rudelli C, Cunnigham R D, Conway-Myers B A, Dewailly D, Azziz R. Carriers of 21-hydroxylase deficiency are not at increased risk for hyperandrogenism.  J Clin Endocrinol Metab. 1997;  82 479-485
  • 14 Krone N, Braun A, Roscher A A, Knorr D, Schwarz H P. Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from Southern Germany.  J Clin Endocrinol Metab. 2000;  85 1059-1065
  • 15 Krone N, Roscher A A, Schwarz H P, Braun A. Comprehensive analytical strategy for mutation screening in 21-hydroxylase deficiency.  Clin Chem. 1998;  44 2075-2082
  • 16 Kutten F, Couillin P, Girard F, Billand L, Vingens M, Boucekkine C, Thalabard J-C, Maudelonde T, Spritzer P, Mowszowicz I, Boue A, Mauvais-Jarvis P. Late-onset adrenal hyperplasia in hirsutism.  New Engl J Med. 1985;  313 224-231
  • 17 Lobo R A, Goebelsmann U. Adult manifestation of congenital adrenal hyperplasia due to incomplete 21-hydroxylase deficiency mimicking polycystic ovarian disease.  Am J Obstet Gynecol. 1980;  138 720-726
  • 18 McKenna T J, Cunningham S K. The pathogenesis of adrenal and extra adrenal hyperandrogenism.  J Steroid Biochem Molec Biol. 1993;  45 117-121
  • 19 New M I, Lorenzen F, Lerner A J, Kohn B, Oberfield S E, Pollack M S, Dupont B, Stoner E, Levy D J, Pang S, Levine L S. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data.  J Clin Endocrinol Metab. 1983;  57 320-326
  • 20 New M I. Basic and clinical aspects of congenital adrenal hyperplasia.  J Steroid Biochem. 1987;  27 1-7
  • 21 Pang S. Congenital adrenal hyperplasia.  Endocrin Metab Clin. 1997;  26 853-891
  • 22 Peter M, Sippell W G, Lorenzen F, Willig R P, Westphal E, Grosse-Wilde H. Improved test to identify heterozygotes for congenital adrenal hyperplasia without index case examination.  Lancet. 1990;  335 1296-1299
  • 23 Rittmaster R S. Medical treatment of androgen-dependent hirsutism.  J Clin Endocrinol Metab. 1995;  80 2559-2563
  • 24 Rumsby G, Avey C J, Conway G S, Honour J W. Genotype-phenotype analysis in late onset 21-hydroxylase deficiency in comparison to the classical forms.  Clin Endocrinol. 1998;  48 707-711
  • 25 Sólyom J, Gács G, Keszei K, Láng K, Örley J, Petheő I, Ságodi L. Detection of late-onset adrenal hyperplasia in girls with peripubertal virilization.  Acta Endocrinol (Kbh). 1987;  115 413-418
  • 26 Sólyom J, Rácz K, Péter F, Homoki J, Sippell W G, Peter M. Clinical, hormonal and molecular genetic characterisation of Hungarian patients with 11β-hydroxylase deficiency. J.  Endocr Genetics. 2001;  2 37-44
  • 27 Speiser P W, Dupont J, Zhu D, Serrat J, Buegeleisen M, Tusie-Luna M T, Lesser M, New M I, White P C. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  J Clin Invest. 1992;  90 584-595
  • 28 Speiser P W, White P C. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency.  Clin Endocrinol. 1998;  49 411-417
  • 29 Temeck J W, Pang S, Nelson C, New M I. Genetic defects of steroidogenesis in premature pubarche.  J Clin Endocrinol Metab. 1987;  64 609-617
  • 30 Tóth M, Rácz K, Gláz E. Increased plasma 17-hydroxyprogesterone response to ACTH in patients with nonhyperfunctioning adrenal adenomas is not due to a deficiency in 21-hydroxylase activity.  J Clin Endocrinol Metab. 1998;  83 3756-3757
  • 31 Vasconcelos Leite M, Mendonca B B, Arnhold I JP, Estefan V, Nunes C. Identification of nonclassical 21-hydroxylase deficiency in girls with precocious pubarche.  J Endocrinol Invest. 1991;  14 11-15
  • 32 Wedell A, Thilén A, Ritzén F E, Stengler B, Luthman H. Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implication for genetic diagnosis and association with disease manifestation.  J Clin Endocrinol Metab. 1994;  78 1145-1152
  • 33 Wedell A. Molecular genetics of congenital adrenal hyperplasia (21-hydroxyalse deficiency): implications for diagnosis, prognosis and treatment.  Acta Paediatr. 1998;  87 159-164
  • 34 Weil J, Bidlingmaier F, Sippell W G, Butenandt O, Knorr D. Comparison of two tests for heterozigosity in congenital adrenal hyperplasia (CAH).  Acta Endocrinol (Copenh). 1979;  91 109-121
  • 35 White P C, Speiser P W. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  Endocr Rev. 2000;  21 245-291

J. Sólyom

2nd Department of Paediatrics · Faculty of Medicine · Semmelweis University

Tűzoltó u. 7 - 9

Budapest H-1094

Hungary

Fax: +36/(1)2175770

eMail: soljan@gyer2.sote.hu