The Open Pediatric Medicine Journal




ISSN: 1874-3099 ― Volume 10, 2020
CASE REPORT

Simple Virilizing Congenital Adrenal Hyperplasia: A case Report of Sudanese 46, XY DSD male with G293D variant in CYP21A2



Mona Ellaithi1, *, Idoia Martinez de LaPiscina2, Ana Belen de La Hoz2, Gustavo Perez de Nanclares2, Marwah Abdelrahman Alasha3, Maisa Aldai Hemaida3, Luis Castano2
1 Faculty of Medical laboratory Science, Al-Neelain University, Khartoum, Sudan
2 Biocruces Bizkaia Health Research Institute, Cruces University Hospital, UPV/EHU, CIBERER, CIBERDEM. Barakaldo, Spain
3 Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, Sudan

Abstract

Congenital Adrenal Hyperplasia (CAH) is a family of inherited disorders that constitute the largest group of Disorders of Sexual Development (DSDs). The classical CAH has two types; the salt-wasting (SW-CAH) and the simple virilizing (SV-CAH). This study is a report of an SV-CAH regarding 46, XY DSD Sudanese male with early signs of puberty at the age of six years.

We designed a customized panel that included 48 genes associated with Disorders of Sexual Development (DSDs) and using Next Generation Sequencing (NGS) technology, detected the pathogenic G293D alteration in the CYP21A2 gene. This variant has been reported in the salt-wasting (SW) form of 46, XX CAH.

Keywords: Congenital adrenal hyperplasia, CAH, Simple virilizing (SV) salt wasting (SW), Next Generation Sequencing (NGS), Early puberty, Disorders of sexual development (DSDs).


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 9
First Page: 7
Last Page: 11
Publisher Id: TOPEDJ-9-7
DOI: 10.2174/1874309901909010007

Article History:

Received Date: 21/09/2019
Revision Received Date: 04/12/2019
Acceptance Date: 10/12/2019
Electronic publication date: 31/12/2019
Collection year: 2019

© 2019 Ellaithi et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Faculty of Medical Laboratory Sciences, Al-Neelain University, Khartoum, Sudan; E-mail: mona.ellaithi@gmail.com





1. BACKGROUND

Congenital Adrenal Hyperplasia (CAH) is the largest classified group in Disorders of Sexual Developments (DSDs). CAH has two forms; the severe classical /salt wasting (SW-CAH) and the milder non-classical/ simple virilizing (SV-CAH). Both forms are caused by deficient or decreased cortisol biosynthesis [1Partsch CJ, Sippell WG, MacKenzie IZ, Aynsley-Green A. The steroid hormonal milieu of the undisturbed human fetus and mother at 16-20 weeks gestation. J Clin Endocrinol Metab 1991; 73(5): 969-74.
[http://dx.doi.org/10.1210/jcem-73-5-969] [PMID: 1939534]
-4Nermoen I, Husebye ES, Myhre AG, Løvås K. Classic congenital adrenal hyperplasia. Tidsskr Nor Laegeforen 2017; 137(7): 540-3.
[http://dx.doi.org/10.4045/tidsskr.16.0376] [PMID: 28383228]
]. Inefficient cortisol biosynthesis leads to increased production of corticotrophin-releasing hormone, adrenocorticotropic hormone and hyperplasia of the adrenal glands. Thus this leads the adrenals to produce excessive amounts of androgens as early as 6–7 weeks of gestation [5Antoniou-Tsigkos A, Zapanti E, Ghizzoni L, George Mastorakos G. Adrenal Androgens. 2019 Jan 5. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. Available from. https://www.ncbi.nlm. nih.gov/books/NBK278929/-7New M, Yau M, Lekarev O, et al. Congenital Adrenal Hyperplasia. [Updated 2017 Mar 15]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: . https://www.ncbi.nlm.nih.gov/books/ NBK278953/]. Therefore, most of the CAH patients are unable to synthesize sufficient amounts of aldosterone and are prone to the life-threatening SW crises. So in SV-CAH, the aldosterone is normal and is usually ignored in boys because excess of androgen during childhood results in overgrowth and early signs of puberty [8Pescovitz OH, Comite F, Cassorla F, et al. True precocious puberty complicating congenital adrenal hyperplasia: Treatment with a luteinizing hormone-releasing hormone analog. J Clin Endocrinol Metab 1984; 58(5): 857-61.
[http://dx.doi.org/10.1210/jcem-58-5-857] [PMID: 6368580]
-10Atta I, Laghari TM, Khan YN, Lone SW, Ibrahim M, Raza J. Precocious puberty in children. J Coll Physicians Surg Pak 2015; 25(2): 124-8.
[PMID: 25703757]
].

Individuals with CAH have a deficiency in 21-hydroxylase enzyme (21-OHD) [11White PC, New MI, Dupont B. Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci USA 1986; 83(14): 5111-5.
[http://dx.doi.org/10.1073/pnas.83.14.5111] [PMID: 3487786]
]. This enzyme, encoded by the CYP21A2 gene [12Cantürk C, Baade U, Salazar R, Storm N, Pörtner R, Höppner W. Sequence analysis of CYP21A1P in a German population to aid in the molecular biological diagnosis of congenital adrenal hyperplasia. Clin Chem 2011; 57(3): 511-7.
[http://dx.doi.org/10.1373/clinchem.2010.156893] [PMID: 21148302]
-20Su L, Yin X, Cheng J, et al. Clinical presentation and mutational spectrum in a series of 166 patients with classical 21-hydroxylase deficiency from South China. Clin Chim Acta 2018; 486: 142-50.
[http://dx.doi.org/10.1016/j.cca.2018.07.039] [PMID: 30048636]
] is mutated in 95% of CAH cases [21New MI, Wilson RC. Steroid disorders in children: congenital adrenal hyperplasia and apparent mineralocorticoid excess. Proc Natl Acad Sci USA 1999; 96(22): 12790-7.
[http://dx.doi.org/10.1073/pnas.96.22.12790] [PMID: 10536001]
-23Greene CN, Cordovado SK, Turner DP, Keong LM, Shulman D, Mueller PW. Novel method to characterize CYP21A2 in Florida patients with congenital adrenal hyperplasia and commercially available cell lines. Mol Genet Metab Rep 2014; 1: 312-23.
[http://dx.doi.org/10.1016/j.ymgmr.2014.07.002] [PMID: 27896104]
, 15Bruque 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.
[http://dx.doi.org/10.1038/srep39082] [PMID: 27966633]
] and is located within the HLA region of the short arm of chromosome 6 (6p21.3), next to its inactive pseudogene (CYP21A1P) [11White PC, New MI, Dupont B. Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci USA 1986; 83(14): 5111-5.
[http://dx.doi.org/10.1073/pnas.83.14.5111] [PMID: 3487786]
, 24Vrzalová 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(4): 595-603.
[PMID: 20818501]
, 25Xu Z, Chen W, Merke DP, McDonnell NB. Comprehensive mutation analysis of the CYP21A2 gene: an efficient multistep approach to the molecular diagnosis of congenital adrenal hyperplasia. J Mol Diagn 2013; 15(6): 745-53.
[http://dx.doi.org/10.1016/j.jmoldx.2013.06.001] [PMID: 24071710]
]. The CYP21A2 and CYP21A1P have 98% homology in exons and 96% in introns [21New MI, Wilson RC. Steroid disorders in children: congenital adrenal hyperplasia and apparent mineralocorticoid excess. Proc Natl Acad Sci USA 1999; 96(22): 12790-7.
[http://dx.doi.org/10.1073/pnas.96.22.12790] [PMID: 10536001]
, 25Xu Z, Chen W, Merke DP, McDonnell NB. Comprehensive mutation analysis of the CYP21A2 gene: an efficient multistep approach to the molecular diagnosis of congenital adrenal hyperplasia. J Mol Diagn 2013; 15(6): 745-53.
[http://dx.doi.org/10.1016/j.jmoldx.2013.06.001] [PMID: 24071710]
, 26Kolahdouz M, Hashemipour M, Khanahmad H, et al. Mutation detection of CYP21A2 gene in nonclassical congenital adrenal hyperplasia patients with premature pubarche. Adv Biomed Res 2016; 5: 33.
[http://dx.doi.org/10.4103/2277-9175.178794] [PMID: 27099846]
]. Both gene and pseudogene contain 10 exons with 3.1 kb in length [27Concolino P, Mello E, Minucci A, et al. A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form. BMC Med Genet 2009; 10: 72.
[http://dx.doi.org/10.1186/1471-2350-10-72] [PMID: 19624807]
].

The molecular genetics of CAH has identified different mutations which have been classified based on 21-hydroxylase activity [28Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 1995; 80(8): 2322-9.
[PMID: 7629224]
]. Over 100 mutations in CYP21A2 have been discovered to cause 21-hydroxylase deficiency. Approximately, 65–70% of these occur due to micro-conversions derived from its pseudogene [25Xu Z, Chen W, Merke DP, McDonnell NB. Comprehensive mutation analysis of the CYP21A2 gene: an efficient multistep approach to the molecular diagnosis of congenital adrenal hyperplasia. J Mol Diagn 2013; 15(6): 745-53.
[http://dx.doi.org/10.1016/j.jmoldx.2013.06.001] [PMID: 24071710]
] such as the most common c.293-13A/C>G in intron 2 or p.I172L gene changes [29Sharaf S, Hafez M, ElAbd D, Ismail A, Thabet G, Elsharkawy M. High frequency of splice site mutation in 21-hydroxylase deficiency children. J Endocrinol Invest 2015; 38(5): 505-11.
[http://dx.doi.org/10.1007/s40618-014-0207-1] [PMID: 25501839]
]. The rest are caused by copy number variants (CNV) (25-30%) or point mutations [25Xu Z, Chen W, Merke DP, McDonnell NB. Comprehensive mutation analysis of the CYP21A2 gene: an efficient multistep approach to the molecular diagnosis of congenital adrenal hyperplasia. J Mol Diagn 2013; 15(6): 745-53.
[http://dx.doi.org/10.1016/j.jmoldx.2013.06.001] [PMID: 24071710]
]. Compound heterozygous mutations have been also identified in the SW form, even though a single mutation could have a mild effect [30Haider S, Islam B, D’Atri V, et al. Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. Proc Natl Acad Sci USA 2013; 110(7): 2605-10.
[http://dx.doi.org/10.1073/pnas.1221133110] [PMID: 23359706]
]. Moreover, previous studies have shown that p.Q318Y and p.R356W had 0% enzyme activity, while c. 293-13A/C>G and p.I172L presented minimal residual activity and were associated with the classic form of the syndrome [31Krone 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(3): 1059-65.
[http://dx.doi.org/10.1210/jcem.85.3.6441] [PMID: 10720040]
].

2. CASE REPORT

Here we present a 12 years old boy, with 46, XY karyotype who developed early signs of puberty at age 6, including pubic hair, Tanner stage II without axillary hair, acne, and dark facial skin. His voice also changed to be more like an adult male voice. Penile length and testicular volume were 7.5 cm and 2 ml, respectively. His testes were not diagnosed with pathological condition. Testosterone level was 2.8 ng/ml and normal level of electrolytes. Accordingly; the boy was diagnosed with SV-CAH and administered hydrocortisone 17 mg (10 mg in the morning and 7 in the evening). At age 8 years old, his bone age was equal to that of 12-13 years old male. Testicular volume was 4 ml, FSH was 7.67mU/ml and LH 1.21 mU/ml. His weight was 37 Kg and was 137 cm tall. Furthermore, there wasn’t a family history of this particular condition; however, the patient had a sister who presented with ambiguous genitalia at an early age but died right after that. Their biological parents were not relatives and there was no information of a similar conditions in their extended family.

Genomic DNA was isolated from peripheral blood leukocytes using the automated MagPurix 12S system from Zinexts (Zinexts Life Science Corp., Taiwan) and the MagPurix Blood DNA Extraction Kit 200 (Zinexts Life Science Corp). Genetic alteration causing Disorders of Sexual Development (DSD) was analyzed using a customized gene panel designed with the Ion AmpliSeq Designer software (https://www.ampliseq.com) that included all exons and exon-intron boundaries of the selected 48 genes (Table 1). Libraries were prepared according to the manufacturer’s instructions and samples were sequenced using the Ion Torrent PGM platform (Thermo Fisher Scientific). Amplicons (9.3%) not appropriately covered (<20x fold) were assessed by Sanger sequencing (Sequences of the primers are available under request).

The sequencing data were analyzed using the Ion Reporter software (Thermo Fisher Scientific). Variants were filtered to include those with a p-value <0.001 and a Minor Allele Frequency (MAF) ≤0.001 in the annotation settings of the Ion Reporter software (dbSNP, ClinVar and 5000 exomes databases). Moreover, the allele frequency was further checked for each ethnic group in 1000 genomes browser (http://browser.1000genomes.org/) and others. Variants were discounted if they were common. Accordingly, there were 12 variants in different genes (Table 2). The impact of protein functionality of missense alterations was evaluated using in silico prediction programs (Table 2), including SIFT (http://sift.jcvi.org/), PolyPhen2 (http://genetics.bwh.harvard .edu/pph2/), PROVEAN (http://provean.jcvi.org/index.php), Mutation Taster (http://www.mutationtaster.org/), SNPs & GO (https://snps-and-go.biocomp.unibo.it/snps-and-go/), and Panther (http://www.pantherdb.org). We identified the pathogenic homozygous missense mutation c.878G>A (p.G293D) in exon 7 of the CYP21A2 gene (NM_000500.7) (Table 2). Sanger sequencing was then used for confirmation of the mutation.

3. DISCUSSION

Diagnosis of congenital adrenal hyperplasia (CAH) is challenging especially within clinical settings of the developing countries. Here, the patient was diagnosed with SV-CAH, based on his clinical presentation and available laboratory investigations. Genotyping analysis showed that the patient had the G293D variant in homozygosis in CYP21A2. The patient’s sister might have been another carrier of this point mutation as she was born with ambiguous genitalia. To the best of our knowledge, a single study has detected the G293D protein change in a female with CAH. Tardy et al. described a newborn girl with Prader stage 4 and severe virilization of genitalia [32Tardy 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(3): 1288-300.
[http://dx.doi.org/10.1210/jc.2009-1202] [PMID: 20080860]
]. Although biochemical values were not determined, the patient was diagnosed with SW-CAH form.

Table 1
Included genes in the DSD panel.


Table 2
Identified variants in the patient and predicted function according to different software


It is well-known that the severity of the disease correlates well with the level of enzymatic deficiency and the location of the residue [33Zhao B, Lei L, Kagawa N, et al. Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants. J Biol Chem 2012; 287(13): 10613-22.
[http://dx.doi.org/10.1074/jbc.M111.323501] [PMID: 22262854]
]. For example, point mutations that disrupt the binding of heme cofactor cause an SW phenotype, while alterations in hydrophobic residues lead to SV-CAH [34Haider SM, Patel JS, Poojari CS, Neidle S. Molecular modeling on inhibitor complexes and active-site dynamics of cytochrome P450 C17, a target for prostate cancer therapy. J Mol Biol 2010; 400(5): 1078-98.
[http://dx.doi.org/10.1016/j.jmb.2010.05.069] [PMID: 20595043]
]. The highly conserved G293 residue, covering the proximal substrate-binding site is responsible for the flexibility of the I-helix. Therefore, the G293D mutation makes the bending and swiveling of the pocket difficult [30Haider S, Islam B, D’Atri V, et al. Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. Proc Natl Acad Sci USA 2013; 110(7): 2605-10.
[http://dx.doi.org/10.1073/pnas.1221133110] [PMID: 23359706]
, 33Zhao B, Lei L, Kagawa N, et al. Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants. J Biol Chem 2012; 287(13): 10613-22.
[http://dx.doi.org/10.1074/jbc.M111.323501] [PMID: 22262854]
]. Certainly, in vitro studies revealed that the mutation decreases the residual activity to <1% [32Tardy 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(3): 1288-300.
[http://dx.doi.org/10.1210/jc.2009-1202] [PMID: 20080860]
].

The main difference between the SW and SV-CAH forms is the insufficient aldosterone secretion that leads to a fatal drop of electrolytes in the first [35Bryan GT, Kliman B, Bartter FC. Impaired Aldosterone Production in “Salt-losing” Congenital Adrenal Hyperplasia. J Clin Invest 1965; 44(6): 957-65.
[http://dx.doi.org/10.1172/JCI105213] [PMID: 14322030]
-39Song JH, Lee KH, Kim SD, Cho BS. Long-term Follow up of Congenital Adrenal Hyperplasia Patients with Hyponatremia. Electrolyte Blood Press 2007; 5(2): 140-6.
[http://dx.doi.org/10.5049/EBP.2007.5.2.140] [PMID: 24459514]
]. The normal electrolyte levels observed in SV-CAH might be explained by the role of testosterone as a down-regulator of aldosterone secretion [40Kau MM, Lo MJ, Wang SW, et al. Inhibition of aldosterone production by testosterone in male rats. Metabolism 1999; 48(9): 1108-14.
[http://dx.doi.org/10.1016/S0026-0495(99)90123-3] [PMID: 10484049]
]. Unfortunately, we were not able to measure the aldosterone level because the test is not available in Sudan. Functional studies by Toot et al in 2008, concluded that testosterone influences the excretion of Na (sodium) and K (potassium) through an androgen receptor dependent mechanism [41Toot J, Jenkins C, Dunphy G, et al. Testosterone influences renal electrolyte excretion in SHR/y and WKY males. BMC Physiol 2008; 8: 5.
[http://dx.doi.org/10.1186/1472-6793-8-5] [PMID: 18366771]
]. Similar findings were later published [42Liu B, Ely D. Testosterone increases: sodium reabsorption, blood pressure, and renal pathology in female spontaneously hypertensive rats on a high sodium diet. Adv Pharmacol Sci 2011; 2011817835
[http://dx.doi.org/10.1155/2011/817835] [PMID: 21603136]
, 43Loh SY, Salleh N. Influence of testosterone on mean arterial pressure: A physiological study in male and female normotensive WKY and hypertensive SHR rats. Physiol Int 2017; 104(1): 25-34.
[http://dx.doi.org/10.1556/2060.104.2017.1.3] [PMID: 28361574]
]. However, CAH, either SW or SV, displays variable degrees of sodium depletion which is not always significant [44Cabrera MS, Vogiatzi MG, New MI. Long term outcome in adult males with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86(7): 3070-8.
[http://dx.doi.org/10.1210/jc.86.7.3070] [PMID: 11443169]
-49Van der Kamp HJ, Otten BJ, Buitenweg N, et al. Longitudinal analysis of growth and puberty in 21-hydroxylase deficiency patients. Arch Dis Child 2002; 87(2): 139-44.
[http://dx.doi.org/10.1136/adc.87.2.139] [PMID: 12138066]
]. This might depend on the function of the testes. Cabrera et al found that patients with SW-CAH had a higher frequency of developing testicular nodules compared to SV-CAH [44Cabrera MS, Vogiatzi MG, New MI. Long term outcome in adult males with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86(7): 3070-8.
[http://dx.doi.org/10.1210/jc.86.7.3070] [PMID: 11443169]
]. Our patient was referred to early puberty signs but no nodules or testicular abnormalities affecting his function were observed. Thus, we can speculate that although the G293D mutation was found first in SW-CAH, his elevated testosterone levels could have played a role in electrolyte balance since gonads were normal.

CONCLUSION

In this study, the c.878G>A (p.G293D) variant in CYP21A2, previously related to CAH-SW, was identified in homozygous state in a patient diagnosed with SV-CAH. We believe that testosterone had balanced electrolytes through one of the androgen biological pathways. Thus, the level of electrolytes is not only affected by the severity of the enzymatic activity, but also by androgen levels in individuals diagnosed with CAH.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

This patient is part of DSD-Sudan project approved by the National Research Ethics Committee, National Ministry of Health, Sudan with Ethical Number (No. 93-5-09).

HUMAN AND ANIMAL RIGHTS

Not applicable.

CONSENT FOR PUBLICATION

A written informed consent was obtained from the parents when they were enrolled.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Authors would like to thank Dr. Ishraga Al-Hassan from Sudan International University who is an English language professor for revising the language and grammar of the manuscript.

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