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01-12-2020 | Congenital Adrenal Hyperplasia | Research

Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Authors: Helmuth-Günther Dörr, Nadja Schulze, Markus Bettendorf, Gerhard Binder, Walter Bonfig, Christian Denzer, Desiree Dunstheimer, Kirsten Salzgeber, Heinrich Schmidt, Karl Otfried Schwab, Egbert Voss, Martin Wabitsch, Joachim Wölfle

Published in: Molecular and Cellular Pediatrics | Issue 1/2020

Abstract

Background

Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by mutations in the active 21-hydroxylase gene (CYP21A2). The clinical symptoms can vary greatly. To date, no systematic studies have been undertaken in Germany.

Aims

Description of the phenotype, evaluation of the diagnostics and genotype-phenotype correlation

Patients and methodology

Retrospective analysis of the data of 134 patients (age range 0.1–18.6 years) in a multicentre study covering 10 paediatric endocrinology centres in Bavaria and Baden-Württemberg. The data was gathered on site from the medical records. Two hundred and thirty-three alleles with a mutation of the CYP21A2 gene were identified in 126 patients. A genotype-phenotype correlation of the mutation findings was undertaken (C1, severe/mild; C2, mild/mild). Individuals with a heterozygous mutation of the CYP21A2 were also included (C3). The data was collected with the approval of the ethics committee of the University Hospital of Erlangen during the period of 2014 and 2015.

Results (MW ± SD)

One hundred and seventeen out of 134 patients (115 f, 29 m) were symptomatic. The chronological age (CA) at diagnosis was 7.1 ± 4.4 years. The most frequent symptom (73.5%) was premature pubarche. The height-SDS on diagnosis was 0.8 ± 1.3 and the BMI-SDS was 0.8 ± 1.2. Bone age (BA) was ascertained in 82.9% of the symptomatic patients. The difference between BA and CA was 1.9 ± 1.4 years. Basal 17OHP concentrations were 14.5 ± 19.1 ng/ml (18 patients < 2 ng/ml). In total, 58.1% mild and 34.7% severe mutations were found. The most common mutation was p.Val281Leu (39.1%); 65.8% of the patients could be allocated to group C1. No phenotypical differences were found between the 3 mutation groups. The 17OHP levels (basal and after ACTH) in the standard ACTH stimulation test were highest in group C1 and also significantly higher in group C2 as in C3, the ACTH-stimulated cortisol levels (ng/ml) were significantly lower in groups C1 (192.1 ± 62.5) and C2 (218 ± 50) than in C3 (297.3 ± 98.7).

Conclusion

Most of the patients have symptoms of mild androgenisation. Male patients are underdiagnosed. Diagnostics are not standardised. Differences between the types of mutations are found in the hormone concentrations but not in phenotype. We speculate that further, as yet not clearly defined, factors are responsible for the development of the respective phenotypes.

Hannah-Shmouni F, Morissette R, Sinaii N et al (2017) Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genet Med 19:1267–1279

White PC, Speiser PW (2000) Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 21:245–291PubMed

Krone N, Braun A, Roscher AA et al (2000) Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany. J Clin Endocrinol Metab 85:1059–1065PubMed

Speiser PW, Dupont J, Zhu D et al (1992) Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Invest 90:584–595PubMedPubMedCentral

Wedell A, Thilen A, Ritzen EM et al (1994) Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J Clin Endocrinol Metab 78:1145–1152PubMed

Bachega TA, Billerbeck AE, Marcondes JA et al (2000) Influence of different genotypes on 17-hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endocrinol 52:601–607

Tusie-Luna MT, Traktman P, White PC (1990) Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. J Biol Chem 265:20916–20922PubMed

Riedl S, Rohl FW, Bonfig W et al (2019) Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients. Endocrine connections 8:86–94PubMedPubMedCentral

Kromeyer-Hauschild K, Wabitsch M, Kunze D, Geller F, Geiß HC, Hesse V, Von Hippel U, Jaeger D, Johnsen W, Korte K, Menner G, Müller J, Müller M, Niemann-Pilatus A, Remer T, Schaefer F, Wittchen HU, Zabransky S, Zellner K, Ziegler A, Hebebrand J (2001) Perzentile für den Body-mass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Monatsschr Kinderheilkd 149:11

10.

Greulich WW, Pyle SI (1959) Radiographic atlas of skeletal development of the hand and wrist. Stanford University Press, Stanford

11.

Merke DP, Bornstein SR (2005) Congenital adrenal hyperplasia. Lancet 365:2125–2136PubMed

12.

New MI (2004) An update of congenital adrenal hyperplasia. Ann N Y Acad Sci 1038:14–43PubMed

13.

Speiser PW, Arlt W, Auchus RJ et al (2018) Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 103:1–46

14.

Falhammar H, Nordenstrom A (2015) Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome. Endocrine 50:32–50PubMed

15.

Witchel SF (2012) Nonclassic congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes 19:151–158PubMed

16.

New MI (2006) Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 91:4205–4214PubMed

17.

Bizzarri C, Crea F, Marini R et al (2012) Clinical features suggestive of non-classical 21-hydroxylase deficiency in children presenting with precocious pubarche. J Pediatr Endocrinol Metab 25:1059–1064PubMed

18.

Livadas S, Dracopoulou M, Dastamani A et al (2015) The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. Clin Endocrinol 82:543–549

19.

Savas-Erdeve S, Cetinkaya S, Abali ZY et al (2017) Clinical, biochemical and genetic features with nonclassical 21-hydroxylase deficiency and final height. J Pediatr Endocrinol Metab 30:759–766PubMed

20.

Moran C, Azziz R, Carmina E et al (2000) 21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: a multicenter study. Am J Obstet Gynecol 183:1468–1474PubMed

21.

Bidet M, Bellanne-Chantelot C, Galand-Portier MB et al (2009) Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. J Clin Endocrinol Metab 94:1570–1578PubMed

22.

Einaudi S, Napolitano E, Restivo F et al (2011) Genotype, phenotype and hormonal levels correlation in non-classical congenital adrenal hyperplasia. J Endocrinol Investig 34:660–664

23.

Eyal O, Tenenbaum-Rakover Y, Shalitin S et al (2013) Adult height of subjects with nonclassical 21-hydroxylase deficiency. Acta Paediatr 102:419–423PubMed

24.

Pijnenburg-Kleizen KJ, Borm GF, Otten BJ et al (2012) Absence of clinically relevant growth acceleration in untreated children with non-classical congenital adrenal hyperplasia. Horm Res Paediatr 77:164–169PubMed

25.

Ezquieta B, Cueva E, Varela J et al (2002) Non-classical 21-hydroxylase deficiency in children: association of adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone with the risk of compound heterozygosity with severe mutations. Acta Paediatr 91:892–898PubMed

26.

Skordis N, Shammas C, Efstathiou E et al (2011) Endocrine profile and phenotype-genotype correlation in unrelated patients with non-classical congenital adrenal hyperplasia. Clin Biochem 44:959–963PubMed

27.

Armengaud JB, Charkaluk ML, Trivin C et al (2009) Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrinol Metab 94:2835–2840PubMed

28.

Azziz R, Zacur HA (1989) 21-Hydroxylase deficiency in female hyperandrogenism: screening and diagnosis. J Clin Endocrinol Metab 69:577–584PubMed

29.

Bello R, Lebenthal Y, Lazar L et al (2017) Basal 17-hydroxyprogesterone cannot accurately predict nonclassical congenital adrenal hyperplasia in children and adolescents. Acta Paediatr 106:155–160PubMed

30.

Dewailly D, Vantyghem-Haudiquet MC, Sainsard C et al (1986) Clinical and biological phenotypes in late-onset 21-hydroxylase deficiency. J Clin Endocrinol Metab 63:418–423PubMed

31.

New MI, Lorenzen F, Lerner AJ et al (1983) Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 57:320–326PubMed

32.

Ambroziak U, Kepczynska-Nyk A, Kurylowicz A et al (2016) The diagnosis of nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, based on serum basal or post-ACTH stimulation 17-hydroxyprogesterone, can lead to false-positive diagnosis. Clin Endocrinol 84:23–29

33.

Witchel SF, Lee PA (1998) Identification of heterozygotic carriers of 21-hydroxylase deficiency: sensitivity of ACTH stimulation tests. Am J Med Genet 76:337–342PubMed

34.

Wilson RC, Mercado AB, Cheng KC et al (1995) Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 80:2322–2329PubMed

35.

Feuillan P, Pang S, Schurmeyer T et al (1988) The hypothalamic-pituitary-adrenal axis in partial (late-onset) 21-hydroxylase deficiency. J Clin Endocrinol Metab 67:154–160PubMed

36.

Huerta R, Dewailly D, Decanter C et al (2000) Adrenocortical hyperresponsivity to adrenocorticotropic hormone: a mechanism favoring the normal production of cortisol in 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Fertil Steril 74:329–334PubMed

37.

Trakakis E, Chryssikopoulos A, Sarandakou A et al (2001) Hypothalamic-pituitary-thyroidal axis dysfunction and cortisol secretion in patients with nonclassical congenital adrenal hyperplasia. Int J Fertil Womens Med 46:37–41PubMed

38.

Stoupa A, Gonzalez-Briceno L, Pinto G et al (2015) Inadequate cortisol response to the tetracosactide (Synacthen(R)) test in non-classic congenital adrenal hyperplasia: an exception to the rule? Horm Res Paediatr 83:262–267PubMed

39.

Karachaliou FH, Kafetzi M, Dracopoulou M et al (2016) Cortisol response to adrenocorticotropin testing in non-classical congenital adrenal hyperplasia (NCCAH). J Pediatr Endocrinol Metab 29:1365–1371PubMed

40.

Mccann-Crosby B, Chen MJ, Lyons SK et al (2014) Nonclassical congenital adrenal hyperplasia: targets of treatment and transition. Pediatr Endocrinol Rev 12:224–238PubMed

41.

Lajic S, Clauin S, Robins T et al (2002) Novel mutations in CYP21 detected in individuals with hyperandrogenism. J Clin Endocrinol Metab 87:2824–2829PubMed

42.

Blanche H, Vexiau P, Clauin S et al (1997) Exhaustive screening of the 21-hydroxylase gene in a population of hyperandrogenic women. Hum Genet 101:56–60PubMed

43.

Witchel SF, Lee PA, Suda-Hartman M et al (1997) Hyperandrogenism and manifesting heterozygotes for 21-hydroxylase deficiency. Biochem Mol Med 62:151–158PubMed

44.

Pignatelli D, Carvalho BL, Palmeiro A et al (2019) The complexities in genotyping of congenital adrenal hyperplasia: 21-hydroxylase deficiency. Front Endocrinol 10:432

Title: Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Authors: Helmuth-Günther Dörr
Nadja Schulze
Markus Bettendorf
Gerhard Binder
Walter Bonfig
Christian Denzer
Desiree Dunstheimer
Kirsten Salzgeber
Heinrich Schmidt
Karl Otfried Schwab
Egbert Voss
Martin Wabitsch
Joachim Wölfle
Publication date: 01-12-2020
Publisher: Springer Berlin Heidelberg
Keywords: Congenital Adrenal Hyperplasia
Congenital Adrenal Hyperplasia
Published in: Molecular and Cellular Pediatrics / Issue 1/2020
Electronic ISSN: 2194-7791
DOI: https://doi.org/10.1186/s40348-020-00100-w

At a glance: The STEP trials

Springer Medicine

Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Abstract

Background

Aims

Patients and methodology

Results (MW ± SD)

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Aims

Patients and methodology

Results (MW ± SD)

Conclusion

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