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Table of Contents
Year : 2021  |  Volume : 32  |  Issue : 1  |  Page : 40-43

Early diagnosis of CYP17A1 compound heterozygous mutations in a 46, XY child with disorders of sexual development

1 Department of Biomedical Science, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
2 Department of Pediatrics, Division of Pediatric Endocrinology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
3 Central Research Laboratory, Translational Research Center, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
4 Department of Surgery, Division of Pediatric Surgery, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand

Date of Submission17-Apr-2020
Date of Decision18-Sep-2020
Date of Acceptance08-Oct-2020
Date of Web Publication27-Mar-2021

Correspondence Address:
Surasak Sangkhathat
Department of Surgery, Division of Pediatric Surgery, Faculty of Medicine, Prince of Songkla University, Hat Yai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/UROS.UROS_43_20

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17-Hydroxylase/17,20-lyase deficiency is a rare congenital disorder accounting for 1% of congenital adrenal hyperplasia. This disease is recessively expressed as autosomal inheritance through mutations in the CYP17A1 gene, leading to defective levels of glucocorticoids and sex hormones. Individuals with loss-of-function mutations usually present with phenotypic female genitalia, primary amenorrhea, or hypertension in puberty caused by excessive production of mineralocorticoids. In this report, we describe a girl with CYP17A1 mutations diagnosed even though the pathognomonic symptoms had not developed. Herein, we report a case of a 3-year-old girl who prenatally diagnosed as a 46, XY female. After birth, the baby had normal female-type external genitalia without symptoms. She underwent a gonadectomy at the age of 3 years. To explore the pathogenesis of her condition, her genomic data were reviewed for genes involved in disorders of sexual differentiation (DSDs) using high-throughput sequence data from a whole-exome study. Pathogenic variants causing frameshift mutation involving codon 329 of CYP17A1 and a concomitant missense mutation involving codon 358 of the same gene were detected, mutations which are likely to result in loss of function of the enzyme. Each mutation was inherited from each of the parents, both holding carrier status. In addition, her younger sister (46, XX) acquired those identical variants without any abnormal phenotypical traits. Loss-of-function mutations of CYP17A1 which may cause secondary hypertension are not commonly identified in early life because of the wide spectrum of clinical manifestations and various pathophysiologies, which manifest in different sexes. Affected cases usually present later in life with hypertension or primary amenorrhea. High-throughput sequencing is suggested in DSD cases as it may give a precise diagnosis, enabling a proactive treatment plan and prevention of sequelae that potentially occur in puberty.

Keywords: 17-Hydroxylase/17,20-lyase deficiency, CYP17A1 gene, disorders of sexual development, whole-exome sequencing

How to cite this article:
Laochareonsuk W, Jaruratanasirikul S, Maneechay W, Sangkhathat S. Early diagnosis of CYP17A1 compound heterozygous mutations in a 46, XY child with disorders of sexual development. Urol Sci 2021;32:40-3

How to cite this URL:
Laochareonsuk W, Jaruratanasirikul S, Maneechay W, Sangkhathat S. Early diagnosis of CYP17A1 compound heterozygous mutations in a 46, XY child with disorders of sexual development. Urol Sci [serial online] 2021 [cited 2021 Jun 19];32:40-3. Available from: https://www.e-urol-sci.com/text.asp?2021/32/1/40/312433

  Introduction Top

Cytochrome P450c17, a key enzyme in the steroidogenic pathway, plays an important role in the 17-hydroxylase and 17,20-lyase enzymes which are necessary for the production of glucocorticoids and sex hormones. Those reactions require electron donation from redox partner proteins including P450-oxidoreductase (POR) and cytochrome b5. Cytochrome P450c17, encoded by the CYP17A1 gene, is predominately expressed in the endoplasmic reticulum and mitochondria of the adrenal cortex and gonads. Biallelic inactivation of CYP17A1 causes 17α-hydroxylase/17,20-lyase deficiency in 1:100,000 livebirths.[1] Loss of sex hormone synthesis leads to disorders of sexual differentiation (DSDs) which are rare congenital conditions manifested as various chromosomal, genetic, and hormonal defects.[2] Affected individuals are generally characterized by atypical differentiation of sex organs, leading to ambiguous external genitalia.[3]

17α-hydroxylase/17,20-lyase deficiency not only causes a spectrum of external genital ambiguities but is also involved in a glucocorticoid synthesis disorder known as congenital adrenal hyperplasia. This disorder occurs in 30%–50% of all DSDs and both 46, XX and 46, XY DSDs.[4] Development of the reproductive organs requires sequential processes, including sex determination by the sex-determining region Y gene, gonadal and duct differentiation and testosterone synthesis, and peripheral conversion of testosterone to dihydrotestosterone, which ultimately leads to external morphological manifestations.[5] As there are multiple genotype possibilities, high-throughput sequencing enables powerful and precise detection of the causative mutation. In particular, whole-exome sequencing, which can rapidly provide massive genomic data with high coverage, is very suitable for diagnosing such rare congenital disorders.

In this report, we describe the case of a 46, XY DSD girl with biallelic mutations of CYP17A1 leading to a 17α-hydroxylase/17,20-lyase deficiency which could be detected before the manifestation of endocrine consequences. Based on bioinformatic information, the pathogenic mutations were prioritized by various computational criteria and revalidated in the family.

  Case Report Top

This report was reviewed by the Human Research Ethics Committee of the Faculty of Medicine, Prince of Songkla University (REC.63-113-10-1). The patient and her family provided informed consent for reviewing their clinical data from the hospital's electronic medical records and providing peripheral blood for molecular genetics and steroid hormone panel studies.

The index case was a 3-year-old girl who was found to have 46, XY DSD during prenatal screening, and during her 3rd year, she was brought for medical consultation about discordance. During gestation, the mother had consulted an obstetrician due to a prenatal quad test which indicated a high suspicion of trisomy 18. Amniocentesis was performed at the gestational age of 21 weeks, and the chromosomal study showed 46, XY. However, a prenatal ultrasonography screening indicated a healthy female fetus. After delivery, the infant was found to have normal female-type external genitalia with a shallow vaginal cleft and a urogenital meatus in the normal female position without phallumegaly. There were no palpable testes. She had neither dysmorphic features nor symptoms of adrenal crisis at birth. Postnatal karyotyping from peripheral blood confirmed 46, XY. When she was 5 months old, she was taken to a pediatric endocrinologist for hormonal testing. Her testosterone was lower than 0.025 ng/mL [her other steroid hormone levels are shown in [Table 1]]. At the same time, she received a test that detected no testosterone after stimulation with 1500 IU of human chorionic gonadotropin for 3 days. Sex assignment was carried out by a multidisciplinary team, consisting of pediatric endocrinologists, child psychiatrists, and surgeons. Together with parental counseling, the patient was assigned to be a female and gonad-removal surgery was scheduled, followed by hormonal replacement at the beginning of puberty. At the age of 2 years, a laparoscopic gonadectomy was performed. Intraoperatively, both gonads were found at the ipsilateral internal inguinal rings, and neither a uterus nor Fallopian tubes were present. Histopathological study showed that the removed gonads were benign testes with epididymis-like tissue [Figure 1]. Postoperatively, she was scheduled for annual follow-ups for growth and development monitoring.
Figure 1: Histopathology of the removed gonads, showing testicular tissue with epididymis-like structures (H and E)

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Table 1: Electrolyte and hormonal profiles in the patient and her sister with identical mutations

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Molecular and bioinformatic analysis

The patient and her family consented to genetic studies. For the studies, genomic DNA was extracted from peripheral blood. Exon enrichment and adapter ligation were prepared using Agilent SureSelectXT (Agilent Technologies, California, USA). Paired-end sequences were read during the synthesis process in an Illumina HiSeq 2000 (Illumina, California, USA). A computational biology analytic pipeline was executed following the Board Institute's best practice guidelines. Raw reads were aligned with the latest version of the human reference genome GRCh38.p13 using a Burrows-Wheeler Aligner[6] and then preprocessed with SAMTools and Picard. Variants were identified using a genome analysis toolkit. The variants were functionally annotated by a variant effect predictor. Finally, possible pathogenic variants for the index case were prioritized using known disease-causing genes, alleles calling of more than 25% of the total reads, reading depth of more than ×40, and minor allele frequencies of less than 0.01 in East Asian populations. Clinicofunctional annotations of the most significant pathogenic variants were correlated with the selected variants. Using the Human Gene Mutation Database (ClinVar) and the Online Mendelian Inheritance in Man compendium.

Following this prioritization, we found possible causative mutations located in exon 6 of the CYP17A1 gene at positions 102832662 (g.102832662delG) and 102832577 (g.102832577C>T) in chromosome 10, resulting in a frameshift mutation at codon 329 (p.Tyr329fs) and a missense mutation at codon 358 (p.Arg358Gln), respectively. The confirmed variants were rechecked using a conventional sequencing technique, confirming that the autosomal recessive inheritance of CYP17A1 in this patient was derived from the variant at position 102832662 acquired from her mother and the other from her father. Surprisingly, her younger sister (46, XX) also carried both pathogenic mutations [Figure 2]. The pediatric endocrinologist planned annual examinations and hormonal replacement at puberty for both siblings.
Figure 2: The pedigree showing the inheritance pattern of compound heterozygous mutations found in the family. The frameshift mutation at codon 329 located in position 102832662 of chromosome 10 (g.102832662delG, p.Tyr329fs) and the missense mutation at codon 358 located in position 102832662 of chromosome 10 (g.102832577C>T, p.Arg358Gln)

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  Discussion Top

17 alpha-hydroxylase deficiency/17,20-lyase deficiency is a very rare congenital condition with an estimated incidence of 1:100,000 livebirths.[1] Loss-of-function mutations in the CYP17A1 gene are responsible for the defects.[7] These enzymes provide catalytic functions to a redox reaction between heme and the steroid precursors,[8] and then missense mutations of the essential domains, the heme-binding domain, and the steroid-binding domain, result in defects in both redox activities.[9] However, a defect in the redox partner interaction domain can be caused only by an isolated mutation in 17,20-lyase.[10] At the embryonic period, testosterone is essential for male reproductive organ differentiation. Without testosterone activity, 46, XY DSD patients with complete 17 alpha-hydroxylase deficiency/17,20-lyase deficiency exhibit female external genitalia without a uterus and Fallopian tubes. Although 46, XX patients with complete enzymatic deficiency are born as normal females, they usually fail to develop secondary sexual characteristics. Affected individuals not only present with disruption of sexual differentiation but also have high blood pressure and low serum potassium from loss of negative feedback from cortisol and higher production of aldosterone.

Our index case was diagnosed as a 46, XY female after birth without any symptoms of adrenal insufficiency nor an adrenal crisis. Hormonal and molecular studies confirmed that she had null testosterone production. In our culture, sex is assigned early to reduce parental anxiety. When genotypic studies were done on the patient's sister and parents, we found compound heterozygous mutations in both children which were inherited from the parents. These mutations normally cause biallelic loss-of-function mutations of CYP17A1 and loss of enzymatic activity of 17 alpha-hydroxylase/17,20-lyase decreased production of sex hormones from both adrenals and testes, resulting in external genital ambiguity in the affected chromosomally male, but show no phenotypic abnormalities in affected females whose external genitalia was an embryological default. A codon shift mutation of CYP17A1 at codon 329 (p.Tyr329fs) results in an aberrant protein potentially linked to a lack of enzymatic activities. The other point mutation at codon 358 (p.Arg358Gln) detected in this family has been reported as a molecular pathology of isolated 17,20-lyase deficiency. This mutation alters the redox partner interaction domain between P450c17 and POR, leading to loss of electron transfer for the 17,20-lyase reaction.

  Conclusion Top

Although 46, XY with isolated 17,20-lyase deficiency and female phenotype can be diagnosed when a patient develops symptoms of hypertension or primary amenorrhea, earlier diagnosis can be achieved by using clinical genome sequencing in a child with DSD. High-throughput exome sequencing helps in the precise annotation of pathogenic genes involved in DSD. In addition, precise molecular studies may suggest genetic susceptibility in family members, allowing family planning and prevention of further sequelae for asymptomatic individuals who carry mutant enzymes.


Dave Patterson edited English language in the manuscript. The Department of Pathology, Faculty of Medicine, Prince of Songkla University, performed the histopathological study of the removed gonads.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 2009;23:181-92.  Back to cited text no. 1
Lee PA, Houk CP, Ahmed SF, Hughes IA, International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus statement on management of intersex disorders. International consensus conference on intersex. Pediatrics 2006;118:e488-500.  Back to cited text no. 2
Hanauer DA, Gardner M, Sandberg DE. Unbiased identification of patients with disorders of sex development. PLoS One 2014;9:e108702.  Back to cited text no. 3
Ahmed SF, Bashamboo A, Lucas-Herald A, McElreavey K. Understanding the genetic aetiology in patients with XY DSD. Br Med Bull 2013;106:67-89.  Back to cited text no. 4
Délot EC, Papp JC, DSD-TRN Genetics Workgroup, Sandberg DE, Vilain E. Genetics of disorders of sex development: The DSD-TRN experience. Endocrinol Metab Clin North Am 2017;46:519-37.  Back to cited text no. 5
Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26(5):589-95.  Back to cited text no. 6
Sparkes RS, Klisak I, Miller WL. Regional mapping of genes encoding human steroidogenic enzymes: P450scc to 15q23-q24, adrenodoxin to 11q22; adrenodoxin reductase to 17q24-q25; and P450c17 to 10q24-q25. DNA Cell Biol 1991;10:359-65.  Back to cited text no. 7
Petrunak EM, DeVore NM, Porubsky PR, Scott EE. Structures of human steroidogenic cytochrome P450 17A1 with substrates. J Biol Chem 2014;289:32952-64.  Back to cited text no. 8
Yanase T. 17 alpha-Hydroxylase/17,20-lyase defects. J Steroid Biochem Mol Biol 1995;53:153-7.  Back to cited text no. 9
Biason-Lauber A, Leiberman E, Zachmann M. A single amino acid substitution in the putative redox partner-binding site of P450c17 as cause of isolated 17,20-lyase deficiency. J Clin Endocrinol Metab 1997;82:3807-12.  Back to cited text no. 10


  [Figure 1], [Figure 2]

  [Table 1]


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