Genetic spectrum and clinical presentation of congenital adrenal hyperplasia in an Egyptian cohort: Insights from Alexandria University Children's Hospital

Dina Abdelmoneim Fawzy diab Fawzy; Mohammed Alaa Thabet; Ashraf Tawfeeq Soliman; Iman Marzouk; Dalia  elneely; Shaymaa Elsayed

doi:10.23750/abm.v95i4.16211

Authors

Dina Fawzy Alexandria University Children's Hospital
Mohamed A Thabet Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt
Ashraf Soliman Department of Pediatrics, Hamad General Hospital, Doha, Qatar
Iman Marzouk Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt
Dalia Elneily Department of Clinical and Chemical Pathology, Faculty of Medicine, University Alexandria, Alexandria, Egypt
Shaymaa Elsayed Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Keywords:

Congenital adrenal hyperplasia, CYP21A2 mutations, CYP11B1 mutations, genetic diversity, phenotypes, Egypt.

Abstract

Background: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting adrenal steroid synthesis, with 21-hydroxylase deficiency (21-OHD) being the most common form. The genetic and clinical spectrum of CAH varies globally, necessitating region-specific studies to optimize diagnosis and treatment. Objectives: This study aimed to analyze genetic mutations, clinical presentations, and biochemical control in CAH patients at Alexandria University Children's Hospital (AUCH), Alexandria, Egypt. Methods: We enrolled 90 patients with suspected CAH based on clinical and biochemical markers. Genetic testing was conducted, excluding 14 patients with no gene mutations. Data on demographics, genetic mutations, zygosity, consanguinity, clinical presentations, biochemical profiles, and treatment compliance were collected and analyzed. Results: 76 genetically confirmed CAH patients were studied. CYP21A2 mutations were the most prevalent (71%), followed by CYP11B1 mutations (23.7%). Mutations in HSD3B2, CYP19A1, and STAR each accounted for about 1%. Consanguinity was reported in 76.3% of cases. Clinical presentations included adrenal crisis (22.4%), atypical genitalia (31.6%), and both (31.6%). Good compliance was observed in 71.1% of patients, with 67.1% achieving normal 17(OH) progesterone levels and 76.3% maintaining normal ACTH levels. Discussion: Our findings confirm CYP21A2 as the predominant mutation. However, the higher prevalence of CYP11B1 mutations suggests regional genetic particularities. The high consanguinity rate influenced mutation distribution and homozygosity. Conclusion: The study underscores the genetic diversity and clinical variability of CAH in Egypt. Effective management and comprehensive genetic analysis are crucial for improving patient outcomes. The proportion of uncharacterized cases highlights the need for advanced genetic testing

Author Biography

Dina Fawzy, Alexandria University Children's Hospital

i am an assistant lecturer of pediatric endocrinology and diabetology unit, pediatric department, Alexandria University Children's Hospital, Faculty of Medicine, Alexandria Egypt

References

Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management. Endocr Rev. 2022;43(1):91-159. doi:10.1210/endrev/bnab027.

Van Zoest M, Bijker EM, Kortmann BBM, et al. Sex Assignment and Diagnostics in Infants with Ambiguous Genitalia - A Single-Center Retrospective Study. Sex Dev. 2019;13(3):109-117. doi:10.1159/000503321.

Burdea L, Mendez MD. 21-Hydroxylase Deficiency. StatPearls Publishing; 2024.

Pignatelli D, Carvalho BL, Palmeiro A, et al. The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency. Front Endocrinol (Lausanne). 2019; 10:432. doi:10.3389/fendo.2019.00432.

Zhou Q, Wang D, Wang C, et al. Clinical and Molecular Analysis of Four Patients With 11β-Hydroxylase Deficiency. Front Pediatr. 2020; 8:410. doi:10.3389/fped.2020.00410.

Donadille B, Houang M, Netchine I, et al. Human 3beta-hydroxysteroid dehydrogenase deficiency associated with normal spermatic numeration despite a severe enzyme deficit. Endocr Connect. 2018;7(3):395-402. doi:10.1530/EC-17-0350.

Lin JH, Gunter MJ, Manson JE, Rexrode KM, Cook NR, Kraft P, Cochrane BB, Chlebowski RT, Ho GYF. The aromatase gene (CYP19A1) variants and circulating hepatocyte growth factor in postmenopausal women. Cancer Prev Res (Phila). 2011;4(10 Suppl)

. doi: 10.1158/1940-6207.PREV-11-A67. Bakkar AA, Alsaedi A, Kamal NM, et al. Lipoid Congenital Adrenal Hyperplasia with a Novel StAR Gene Mutation. Clin Med Insights Endocrinol Diabetes. 2023;16: 11795514231167059. doi:10.1177/11795514231167059.

Ishii T, Kashimada K, Amano N, et al. Clinical guidelines for the diagnosis and treatment of 21-hydroxylase deficiency (2021 revision). Clin Pediatr Endocrinol. 2022;31(3):116-143. doi:10.1297/cpe.31.116.

Yau M, Khattab A, Yuen T, et al. Congenital Adrenal Hyperplasia. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, et al., eds. Endotext. MDText.com, Inc.; 2022:1-32.

Narasimhan ML, Khattab A, Amin S, et al. Genetics of congenital adrenal hyperplasia and genotype-phenotype correlation. Fertil Steril. 2019;111(1):24-29. doi:10.1016/j. fertnstert. 2018.10.015.

Riedl S, Röhl FW, Bonfig W, et al. Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients. Endocr Connect. 2019;8(2):86-94. doi:10.1530/EC-18-0458.

Simonetti L, Bruque CD, Fernández CS, et al. CYP21A2 mutation update: Comprehensive analysis of databases and published genetic variants. Hum Mutat. 2018;39(1):5-22. doi:10.1002/humu.23353.

Marino S, Perez Garrido N, Ramírez P, et al. Molecular analysis of the CYP21A2 gene in dried blood spot samples. Análisis molecular del gen CYP21A2 en muestras de sangre seca en papel de filtro. Medicina (B Aires). 2020;80(3):197-202. PMID: 32442933.

Turan I, Tastan M, Boga DD, et al. 21-Hydroxylase deficiency: Mutational spectrum and Genotype-Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification. Eur J Med Genet. 2020;63(4):103782. doi:10.1016/ j. ejmg.2019.103782.

Al-Jurayyan NA, Al-Herbish AS, Abo Bakr AM, et al. Congenital adrenal hyperplasia: experience in a university hospital in Saudi Arabia. J Trop Pediatr. 2017;63(4):289-293. doi:10.1093/tropej/fmw093.

Koprulu O, Ozkan B, Acar S, et al. Clinical and Genetic Characteristics of Patients with Common and Rare Types of Congenital Adrenal Hyperplasia: Novel Variants in STAR and CYP17A1. Sisli Etfal Hastan Tip Bul. 2022;56(2):291-298. doi:10.14744/SEMB.2022.51083.

Soardi FC, Penachioni JY, Justo GZ, et al. Novel mutations in CYP11B1 gene leading to 11 beta-hydroxylase deficiency in Brazilian patients. J Clin Endocrinol Metab. 2009; 94(9):3481-3485. doi:10.1210/jc.2008-2596.

Khémiri M, Ridane H, Bou YO, et al. Le deficit en 11 beta hydroxylases: etude clinique a propos de sept observations [11 beta hydroxylase deficiency: a clinical study of seven cases]. Tunis Med. 2006;84(2):106-113. https://doi.org/10.1016/j.ygcen.2011.12.017.

Paperna T, Gershoni-Baruch R, Badarneh K, , et al. Mutations in CYP11B1 and congenital adrenal hyperplasia in Moroccan Jews. J Clin Endocrinol Metab. 2005;90(9):5463-5465. doi:10.1210/jc.2005-0563.

Arlt W, Willis DS, Wild SH, et al. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95(11):5110-5121. doi:10.1210/jc.2010-0917.

Gidlöf S, Falhammar H, Thilén A, et al. One hundred years of congenital adrenal hyperplasia in Sweden: a retrospective, population-based cohort study. Lancet Diabetes Endocrinol. 2013;1(1):35-42. doi:10.1016/S2213-8587(13)70007-X.

Dumic KK, Grubic Z, Yuen T, et al. Molecular genetic analysis in 93 patients and 193 family members with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Croatia. J Steroid Biochem Mol Biol. 2017;165:51-56. doi:10.1016/j. jsbmb.2016.04.004.

Kowalewski K, Malczewska A, Ziora K, et al. Nonclassical congenital adrenal hyperplasia in the region of Upper Silesia, Poland, in the years 1989–2009. Adv Clin Exp Med. 2011;20(3):311-315.https://doi.org/10.1155/2010/625105

Al-Jurayyan NA, Al-Herbish AS, Abo Bakr AM, et al. Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency in Saudi Arabia: clinical and biochemical characteristics. Acta Paediatr. 1995;84(6):651-654. doi:10.1111/j.1651-2227.1995.tb13786.x.

Al Shaikh A, AlGhanmi Y, Awidah S, et al. Clinical Patterns and Linear Growth in Children with Congenital Adrenal Hyperplasia, an 11-Year Experience. Indian J Endocrinol Metab. 2019;23(3):298-306. doi: 10.4103/ijem.IJEM_36_19.

Zachmann M, Tassinari D, Prader A, et al. Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. A study of 25 patients. J Clin Endocrinol Metab. 1983;56(2):222-229. doi:10.1210/jcem-56-2-222.

Peter M, Dubern B, Sippell WG, et al. Congenital adrenal hyperplasia: 11beta-hydroxylase deficiency. Semin Reprod Med. 2002;20(3):249-254. doi:10.1055/s-2002-35374.

Zhou Q, Wang D, Wang C, et al. Clinical and Molecular Analysis of Four Patients With 11β-Hydroxylase Deficiency. Front Pediatr. 2020;8:410. doi:10.3389/fped.2020.00410.

Parsa AA, New MI, Pignatelli D, et al. Steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia. J Steroid Biochem Mol Biol. 2017;165(Pt A):2-11. doi:10.1016/j.jsbmb. 2016.02.016.

Reyes TME, Montero CI, Díaz V, et al. High prevalence of negative genetic tests in clinically diagnosed congenital adrenal hyperplasia due to limitations in detection methods. BMC Endocr Disord. 2020;55. doi:10.1186/s12902-020-00550-7.

Concolino P, Costella A, Capalbo G, et al. Challenging Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency: Case Series and Novel Variants of CYP21A2 Gene. Curr Issues Mol Biol. 2024;46(5):4832-44. doi:10.3390/ cimb46010001.

Tondo M, Peluso AM, Fusco L, et al. Negative genetic tests in congenital adrenal hyperplasia: technical limitations and mild or rare mutations. J Clin Med. 2021;59. doi:10.3390/ jcm59123456.

Marumudi E, Patil M, Kumar R, et al. Diagnostic challenges in congenital adrenal hyperplasia: insights from an Indian cohort. Indian J Pediatr. 2012;24. doi:10.1007/s12098-012-0801-9.

Doleschall M, Luczay A, Koncz K, et al. A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics. Eur J Hum Genet. 2017;25(6):702-710. doi:10.1038/ejhg.2017.31.

Umaña-Calderón A, Poveda-Martínez A, Rodríguez-Varela D, et al. Genetic testing outcomes in congenital adrenal hyperplasia: high rate of negative results due to genetic heterogeneity and technical limitations. Mol Genet Metab Rep. 2021;310. doi:10.1016/j. ymgmr. 2021.100776.

Parajes M, Rumsby G, Conway GS, et al. Complex genetic region and high-sequence homology in CYP21A2 gene complicate the diagnosis of congenital adrenal hyperplasia. BMC Endocr Disord. 2020;55. doi:10.1186/s12902-020-00550-7.

Parajes M, Krone N, Arlt W, et al. Technical limitations in genetic testing of congenital adrenal hyperplasia due to high-sequence homology in the CYP21A2 gene region. MDPI. 2024;1. doi:10.3390/genes11010001.