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

© 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: ( 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:


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).


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 [1-4]. 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 [5-7]. 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 [8-10].

Individuals with CAH have a deficiency in 21-hydroxylase enzyme (21-OHD) [11]. This enzyme, encoded by the CYP21A2 gene [12-20] is mutated in 95% of CAH cases [21-23, 15] and is located within the HLA region of the short arm of chromosome 6 (6p21.3), next to its inactive pseudogene (CYP21A1P) [11, 24, 25]. The CYP21A2 and CYP21A1P have 98% homology in exons and 96% in introns [21, 25, 26]. Both gene and pseudogene contain 10 exons with 3.1 kb in length [27].

The molecular genetics of CAH has identified different mutations which have been classified based on 21-hydroxylase activity [28]. 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 [25] such as the most common c.293-13A/C>G in intron 2 or p.I172L gene changes [29]. The rest are caused by copy number variants (CNV) (25-30%) or point mutations [25]. Compound heterozygous mutations have been also identified in the SW form, even though a single mutation could have a mild effect [30]. 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 [31].


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 ( 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 ( 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 (, PolyPhen2 (http://genetics.bwh.harvard .edu/pph2/), PROVEAN (, Mutation Taster (, SNPs & GO (, and Panther ( 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.


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 [32]. Although biochemical values were not determined, the patient was diagnosed with SW-CAH form.

Table 1. Included genes in the DSD panel.
Gene Name Locus Gene Name Locus
AMH Anti-Mullerian Hormone 19p13.3 INHA Inhibin Alpha Subunit 2q35
AMHR2 Anti-Mullerian Hormone Receptor Type 2 12q13.13 INSL3 Insulin-Like 3 19p13.11
AR Androgen Receptor Xq12 KISS1 KiSS-1 Metastasis-Suppressor 1q32.1
ATRX Mental Retardation, X-Linked Xq21.1 KISS1R KISS1 Receptor 19p13.3
BMP15 Bone Morphogenetic Protein 15 Xp11.22 RXFP2 Relaxin/Insulin Like Family Peptide Receptor 2 13q13.1
CBX2 Chromobox 2 17q25.3 LHCGR Luteinizing Hormone/Choriogonadotropin Receptor 2p16.3
CYP11A1 Cytochrome P450 Family 11 Subfamily A Member 1 15q24.1 MAMLD1 Mastermind Like Domain Containing 1 Xq28
CYP11B1 Cytochrome P450 Family 11 Subfamily B Member 1 8q24.3 MAP3K1 Mitogen-Activated Protein Kinase Kinase Kinase 1 5q11.2
CYP17A1 Cytochrome P450 Family 17 Subfamily A Member 1 10q24.32 NR0B1 Nuclear Receptor Subfamily 0 Group B Member 1 Xp21.2
CYP19A1 Cytochrome P450 Family 19 Subfamily A Member 1 15q21.2 ESR1 Estrogen Receptor 1 6q25.1
CYP21A2 Cytochrome P450 Family 21 Subfamily A Member 2 6p21.33 ESR2 Estrogen Receptor 2 14q23.3
DHH Desert Hedgehog 12q13.12 NR5A1 Nuclear Receptor Subfamily 5 Group A Member 1 9q33.3
DMRT1 Doublesex And Mab-3 Related Transcription Factor 1 9p24.3 POR Cytochrome P450 Oxidoreductase 7q11.23
DMRT2 Doublesex And Mab-3 Related Transcription Factor 2 9p24.3 PSMC3IP Proteasome 26S ATPase Subunit 3-Interacting Protein 17q21.2
FGF9 Fibroblast Growth Factor 9 13q12.11 RSPO1 R-Spondin 1 1p34.3
FOG2 Zinc Finger Protein, FOG Family Member 2 8q22.3 SOX3 SRY-Box 3 Xq27.1
FOXL2 Forkhead Box L2 3q22.3 SOX9 SRY-Box 9 17q24.3
FOXO3 Forkhead Box O3 6q21 SRD5A2 Steroid 5 Alpha-Reductase 2 2p23.1
FSHR Follicle Stimulating Hormone Receptor 2p16.3 SRY Sex Determining Region Y Yp11.2
GATA4 GATA Binding Protein 4 8p23.1 STAR Steroidogenic Acute Regulatory Protein 8p11.23
HARS2 Histidyl-TRNA Synthetase 2, Mitochondrial 5q31.3 TSPYL1 Testis-Specific Y-Encoded-Like Protein 6q22.1
HSD17B3 Hydroxysteroid 17-Beta Dehydrogenase 3 9q22.32 WNT4 Wingless-Type MMTV Integration Site Family, Member 4 1p36.12
HSD17B4 Hydroxysteroid 17-Beta Dehydrogenase 4 5q23.1 WT1 Wilms Tumor 1 11p13
HSD3B2 Hydroxy-Delta-5-Steroid Dehydrogenase, 3 Beta- And Steroid Delta-Isomerase 2 1p12 WWOX WW Domain Containing Oxidoreductase 16q23.1
Table 2. Identified variants in the patient and predicted function according to different software
Genes Exon Transcript Variation dbSNP gnomAD3 PROVEAN SIFT POLYPHEN Mutation Taster SNPs & GO PANTHER
KISS1 2 NM_002256.3 c.58G>A;p.E20K2 rs12998 0.03257 Del Dam Poss dam DC N Poss dam
MAP3K1 3 NM_005921.1 c.743G>A;p.R248Q2 rs201579608 0.0001499 N Dam Poss dam DC N Prob dam
MAP3K1 14 NM_005921.1 c.2845_2847delACA;p.T942del2 rs769777412 0.0004191 ND
HSD17B4 7 NM_000414.3 c.420A>T; p.K140N2 rs28943589 0.007370 Del Tol B P D Poss dam
HSD17B4 24 NM_000414.3 c.2182A>G;p.M728V2 rs28943594 0.01051 N Tol B P N Prob dam
CYP21A2 7 NM_000500.7 c.878G>A;p.G293D1 Del Dam Prob dam DC D Prob dam
TSPYL1 1 NM_003309.3 c.527_528insGGT;p.V176dup2 rs56100880 ND ND
GATA4 6 NM_002052.4 c.1129A>G;p.S377G2 rs3729856 0.09643 N Tol B P D Prob B
GATA4 6 NM_002052.4 c.1138G>A;p.V380M2 rs114868912 0.005689 N Tol B P D Prob B
DMRT2 4 NM_181872.4 c.815A>G;p.N272S2 rs138608089 0.001039 N Tol Poss dam DC Poss dam
CYP19A1 5 NM_000103.3 c.602C>T;p.T201M2 rs28757184 0.02471 N Tol B P N Prob B
SOX3 1 NM_005634.2 c.307C>A;p.P103T2 rs201101913 0.006186 N Dam B DC N Prob B
B, benign; D, disease; Dam, damaging; DC, disease causing; Del, deleterious; N, neutral; ND, not determined; P, polymorphism; Poss, possibly; Prob, probably; Tol, tolerated.
1 Variant found in homozygous state. 2 Variant found in heterozygosis. 3Allelic frequencies correspond to both Exome and Genome analyses.

It is well-known that the severity of the disease correlates well with the level of enzymatic deficiency and the location of the residue [33]. For example, point mutations that disrupt the binding of heme cofactor cause an SW phenotype, while alterations in hydrophobic residues lead to SV-CAH [34]. 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 [30, 33]. Certainly, in vitro studies revealed that the mutation decreases the residual activity to <1% [32].

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 [35-39]. The normal electrolyte levels observed in SV-CAH might be explained by the role of testosterone as a down-regulator of aldosterone secretion [40]. 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 [41]. Similar findings were later published [42, 43]. However, CAH, either SW or SV, displays variable degrees of sodium depletion which is not always significant [44-49]. 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 [44]. 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.


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.


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).


Not applicable.


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




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


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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