Download PDF
J Pediatr Genet 2021; 10(01): 057-062
DOI: 10.1055/s-0040-1705110
Case Report

A Case of Salt-Wasting Congenital Adrenal Hyperplasia with Triple Homozygous Mutation: Review of Literature

Maria Laura Iezzi
1   Department of Pediatrics, Ospedale Civile San Salvatore, L'Aquila, Italy
,
Gaia Varriale
2   Department of Pediatrics, University of L'Aquila, L'Aquila, Italy
,
Luca Zagaroli
2   Department of Pediatrics, University of L'Aquila, L'Aquila, Italy
,
Stefania Lasorella
2   Department of Pediatrics, University of L'Aquila, L'Aquila, Italy
,
Marco Greco
2   Department of Pediatrics, University of L'Aquila, L'Aquila, Italy
,
Giulia Iapadre
2   Department of Pediatrics, University of L'Aquila, L'Aquila, Italy
,
Alberto Verrotti
2   Department of Pediatrics, University of L'Aquila, L'Aquila, Italy
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency represents a group of autosomal recessive disorders characterized by impaired cortisol production due to altered upstream steroid conversions, subclassified as classic and nonclassic forms. The genotype–phenotype correlation is possible in the most frequent case but not in all. Despite in literature many mutations are known, there is the possibility of finding a new genetic pattern in patients with CAH.

Keywords

salt-wasting CAH - homozygous - CYP21A2 mutation - Q318X - R356W - R369Q


Publication History

Received: 08 October 2019

Accepted: 23 January 2020

Article published online:
09 March 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet 2005; 365 (9477): 2125-2136
    CrossrefPubMedGoogle Scholar
  • 2 Pang S, Clark A, Neto EC. et al. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: newborn screening and its relationship to the diagnosis and treatment of the disorder. Screening 1993; 2 (2–3): 105-139
    CrossrefPubMedGoogle Scholar
  • 3 Grumbach MM, Shaw EB. Further studies on the treatment of congenital adrenal hyperplasia with cortisone: IV. Effect of cortisone and compound B in infants with disturbed electrolyte metabolism, by John F. Crigler Jr, MD, Samuel H. Silverman, MD, and Lawson Wilkins, MD, Pediatrics, 1952;10:397-413. Pediatrics 1998; 102 (1 Pt 2): 215-221
    CrossrefPubMedGoogle Scholar
  • 4 Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001; 30 (01) 15-30
    CrossrefPubMedGoogle Scholar
  • 5 Oelkers WK. Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure. Steroids 1996; 61 (04) 166-171
    CrossrefPubMedGoogle Scholar
  • 6 Balsamo A, Baldazzi L, Menabò S, Cicognani A. Impact of molecular genetics on congenital adrenal hyperplasia management. Sex Dev 2010; 4 (4-5): 233-248
    CrossrefPubMedGoogle Scholar
  • 7 Speiser PW, Azziz R, Baskin LS. et al; Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95 (09) 4133-4160
    CrossrefPubMedGoogle Scholar
  • 8 Barbaro M, Lajic S, Baldazzi L. et al. Functional analysis of two recurrent amino acid substitutions in the CYP21 gene from Italian patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2004; 89 (05) 2402-2407
    CrossrefPubMedGoogle Scholar
  • 9 Torres N, Mello MP, Germano CMR, Elias LLK, Moreira AC, Castro M. Phenotype and genotype correlation of the microconversion from the CYP21A1P to the CYP21A2 gene in congenital adrenal hyperplasia. Braz J Med Biol Res 2003; 36 (10) 1311-1318
    CrossrefPubMedGoogle Scholar
  • 10 Concolino P, Mello E, Toscano V, Ameglio F, Zuppi C, Capoluongo E. Multiplex ligation-dependent probe amplification (MLPA) assay for the detection of CYP21A2 gene deletions/duplications in congenital adrenal hyperplasia: first technical report. Clin Chim Acta 2009; 402 (1-2): 164-170
    CrossrefPubMedGoogle Scholar
  • 11 Bruque CD, Delea M, Fernández CS. et al. Structure-based activity prediction of CYP21A2 stability variants: a survey of available gene variations. Sci Rep 2016; 6: 39082
    CrossrefPubMedGoogle Scholar
  • 12 Haider S, Islam B, D'Atri V. et al. Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. Proc Natl Acad Sci U S A 2013; 110 (07) 2605-2610
    CrossrefPubMedGoogle Scholar
  • 13 Lee HH. CYP21 mutations and congenital adrenal hyperplasia. Clin Genet 2001; 59 (05) 293-301
    CrossrefPubMedGoogle Scholar
  • 14 Janner M, Pandey AV, Mullis PE, Flück CE. Clinical and biochemical description of a novel CYP21A2 gene mutation 962_963insA using a new 3D model for the P450c21 protein. Eur J Endocrinol 2006; 155 (01) 143-151
    CrossrefPubMedGoogle Scholar
  • 15 White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21 (03) 245-291
    PubMedGoogle Scholar
  • 16 Hsu LC, Hsu NC, Guzova JA, Guzov VM, Chang SF, Chung BC. The common I172N mutation causes conformational change of cytochrome P450c21 revealed by systematic mutation, kinetic, and structural studies. J Biol Chem 1996; 271 (06) 3306-3310
    CrossrefPubMedGoogle Scholar
  • 17 Balsamo A, Cacciari E, Baldazzi L. et al. CYP21 analysis and phenotype/genotype relationship in the screened population of the Italian Emilia-Romagna region. Clin Endocrinol (Oxf) 2000; 53 (01) 117-125
    CrossrefPubMedGoogle Scholar
  • 18 Delague V, Souraty N, Khallouf E. et al. Mutational analysis in Lebanese patients with congenital adrenal hyperplasia due to a deficit in 21-hydroxylase. Horm Res 2000; 53 (02) 77-82
    PubMedGoogle Scholar
  • 19 Krone N, Braun A, Roscher AA, Knorr D, Schwarz HP. Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany. J Clin Endocrinol Metab 2000; 85 (03) 1059-1065
    CrossrefPubMedGoogle Scholar
  • 20 Dracopoulou-Vabouli M, Maniati-Christidi M, Dacou-Voutetakis C. The spectrum of molecular defects of the CYP21 gene in the Hellenic population: variable concordance between genotype and phenotype in the different forms of congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86 (06) 2845-2848
    CrossrefPubMedGoogle Scholar
  • 21 Loke KY, Lee YS, Lee WW, Poh LK. Molecular analysis of CYP-21 mutations for congenital adrenal hyperplasia in Singapore. Horm Res 2001; 55 (04) 179-184
    CrossrefPubMedGoogle Scholar
  • 22 Pinto G, Tardy V, Trivin C. et al. Follow-up of 68 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: relevance of genotype for management. J Clin Endocrinol Metab 2003; 88 (06) 2624-2633
    CrossrefPubMedGoogle Scholar
  • 23 Stikkelbroeck NM, Hoefsloot LH, de Wijs IJ, Otten BJ, Hermus AR, Sistermans EA. CYP21 gene mutation analysis in 198 patients with 21-hydroxylase deficiency in The Netherlands: six novel mutations and a specific cluster of four mutations. J Clin Endocrinol Metab 2003; 88 (08) 3852-3859
    CrossrefPubMedGoogle Scholar
  • 24 Kharrat M, Tardy V, M'Rad R. et al. Molecular genetic analysis of Tunisian patients with a classic form of 21-hydroxylase deficiency: identification of four novel mutations and high prevalence of Q318X mutation. J Clin Endocrinol Metab 2004; 89 (01) 368-374
    CrossrefPubMedGoogle Scholar
  • 25 Baradaran-Heravi A, Vakili R, Robins T. et al. Three novel CYP21A2 mutations and their protein modelling in patients with classical 21-hydroxylase deficiency from northeastern Iran. Clin Endocrinol (Oxf) 2007; 67 (03) 335-341
    CrossrefPubMedGoogle Scholar
  • 26 Wilson RC, Nimkarn S, Dumic M. et al. Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Mol Genet Metab 2007; 90 (04) 414-421
    CrossrefPubMedGoogle Scholar
  • 27 Abid F, Tardy V, Gaouzi A, El Hessni A, Morel Y, Chabraoui L. CYP21A2 gene mutation analysis in Moroccan patients with classic form of 21-hydroxylase deficiency: high regional prevalence of p.Q318X mutation and identification of a novel p.L353R mutation. Clin Chem Lab Med 2008; 46 (12) 1707-1713
    CrossrefPubMedGoogle Scholar
  • 28 Sadeghi F, Yurur-Kutlay N, Berberoglu M. et al. Identification of frequency and distribution of the nine most frequent mutations among patients with 21-hydroxylase deficiency in Turkey. J Pediatr Endocrinol Metab 2008; 21 (08) 781-787
    CrossrefPubMedGoogle Scholar
  • 29 Tardy V, Menassa R, Sulmont V. et al. Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in 46 patients affected with 21-hydroxylase deficiency and in one carrier. J Clin Endocrinol Metab 2010; 95 (03) 1288-1300
    CrossrefPubMedGoogle Scholar
  • 30 Vrzalová Z, Hrubá Z, St'ahlová Hrabincová E. et al. Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency. Int J Mol Med 2010; 26 (04) 595-603
    PubMedGoogle Scholar
  • 31 Finkielstain GP, Chen W, Mehta SP. et al. Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2011; 96 (01) E161-E172
    CrossrefPubMedGoogle Scholar
  • 32 Rabbani B, Mahdieh N, Ashtiani MT. et al. Mutation analysis of the CYP21A2 gene in the Iranian population. Genet Test Mol Biomarkers 2012; 16 (02) 82-90
    CrossrefPubMedGoogle Scholar
  • 33 Toraman B, Ökten A, Kalay E. et al. Investigation of CYP21A2 mutations in Turkish patients with 21-hydroxylase deficiency and a novel founder mutation. Gene 2013; 513 (01) 202-208
    CrossrefPubMedGoogle Scholar
  • 34 Mendes C, Vaz Matos I, Ribeiro L, Oliveira MJ, Cardoso H, Borges T. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: genotype-phenotype correlation. Acta Med Port 2015; 28 (01) 56-62
    CrossrefPubMedGoogle Scholar
  • 35 Milacic I, Barac M, Milenkovic T. et al. Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations. J Endocrinol Invest 2015; 38 (11) 1199-1210
    CrossrefPubMedGoogle Scholar
  • 36 Mohamed S, El-Kholy S, Al-Juryyan N, Al-Nemri AM, Abu-Amero KK. A CYP21A2 gene mutation in patients with congenital adrenal hyperplasia. Molecular genetics report from Saudi Arabia. Saudi Med J 2015; 36 (01) 113-116
    CrossrefPubMedGoogle Scholar
  • 37 Khajuria R, Walia R, Bhansali A, Prasad R. The spectrum of CYP21A2 mutations in congenital adrenal hyperplasia in an Indian cohort. Clin Chim Acta 2017; 464: 189-194
    CrossrefPubMedGoogle Scholar
  • 38 Liu SY, Lee CT, Tung YC, Chien YH, Hwu WL, Tsai WY. Clinical characteristics of Taiwanese children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency detected by neonatal screening. J Formos Med Assoc 2018; 117 (02) 126-131
    CrossrefPubMedGoogle Scholar
  • 39 Zhang B, Lu L, Lu Z. Molecular diagnosis of Chinese patients with 21-hydroxylase deficiency and analysis of genotype-phenotype correlations. J Int Med Res 2017; 45 (02) 481-492
    CrossrefPubMedGoogle Scholar