Genome analyses and androgen quantification for an infant with 5α-reductase type 2 deficiency

Abstract Objectives 5α-reductase type 2 deficiency due to biallelic SRD5A2 variants is a common form of 46,XY disorders of sex development. Case presentation A Chinese neonate presented with ambiguous genitalia. He carried a homozygous likely_pathogenic SRD5A2 variant (c.650C>A, p.A217E). His apparently nonconsanguineous parents were heterozygotes for the variant. The variant has previously been identified in two Chinese patients. Our patient carried 14.2 Mb loss-of-heterogeneity regions distributed in the genome. The SRD5A2 variant in this family was invariably coupled with two polymorphisms in exon 1 and intron 1. In the patient, blood testosterone (T)/5α-dihydrotestosterone (5αDHT) ratios were elevated before and during mini puberty, and were higher when measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) than measured by conventional immune assays. Conclusions This study provides evidence for the founder effect of an SRD5A2 variant. Furthermore, our data indicate that there is a need to establish a new reference value for T/5αDHT ratios using LC-MS/MS.

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New insights into 5α-reductase type 2 deficiency based on a multi-centre study: regional distribution and genotype–phenotype profiling of SRD5A2 in 190 Chinese patients

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105915 ◽

2019 ◽

Vol 56 (10) ◽

pp. 685-692 ◽

Cited By ~ 2

Author(s):

Baoheng Gui ◽

Yanning Song ◽

Zhe Su ◽

Fei-Hong Luo ◽

Linqi Chen ◽

...

Keyword(s):

Regional Distribution ◽

Clinical Manifestations ◽

Disorders Of Sex Development ◽

Chinese Patients ◽

Compound Heterozygous ◽

Multi Centre Study ◽

Proximal Hypospadias ◽

Sex Development ◽

Distal Hypospadias

BackgroundThe 5α-reductase type 2 (5α-RD2) deficiency caused by mutations in the steroid 5α-reductase 2 (SRD5A2) gene results in variable degrees of undervirilisation in patients with 46,XY disorders of sex development. This study aims to profile the regional distribution and phenotype–genotype characteristics of SRD5A2 in a large Chinese 5α-RD2 deficiency cohort through multi-centre analysis.Methods190 subjects diagnosed with 5α-RD2 deficiency were consecutively enrolled from eight medical centres in China. Their clinical manifestations and genetic variants were analysed.ResultsHypospadias (isolated or combined with microphallus and/or cryptorchidism) was fairly common in the enrolled subjects (66.32%). 42 variants, including 13 novel variants, were identified in SRD5A2. Homozygous and compound heterozygous mutations presented in 38.42% and 61.58% of subjects, respectively, and predominated in exons 1, 4 and 5. The most prevalent variant was c.680G > A (52.37%), followed by c.16C > T, (10.79%), c.607G > A, (9.21%) and c.737G > A, (8.95%). However, their distributions were different: c.680G > A was more common in South China than in North China (62.62% vs 39.16%, p < 0.001), whereas the regional prevalence of c.16C > T was reversed (6.07% vs 16.87%, p = 0.001). Furthermore, c.680G > A prevailed in cases with normal meatus (68.75%) or distal hypospadias (66.28%), compared with those with proximal hypospadias (35.54%, p < 0.001). However, cases with proximal hypospadias showed a higher frequency of c.16C > T (20.48%) than those with normal meatus (3.13%) or distal hypospadias (3.49%, p < 0.001).ConclusionsThis study profiled variable phenotypic presentation and wide mutational spectrum of SRD5A2, revealing its distinctive regional distribution in Chinese patients and further shaping the founder effect and genotype–phenotype correlation of SRD5A2.

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Characterising SRD5A2 Gene Variants in 37 Indonesian Patients with 5-Alpha-Reductase Type 2 Deficiency

International Journal of Endocrinology ◽

10.1155/2019/7676341 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Nanis S. Marzuki ◽

Firman P. Idris ◽

Hannie D. Kartapradja ◽

Alida R. Harahap ◽

Jose R. L. Batubara

Keyword(s):

Autosomal Recessive ◽

Disorders Of Sex Development ◽

External Genitalia ◽

Compound Heterozygous ◽

Phenotypic Characteristics ◽

Sex Development ◽

Srd5a2 Gene ◽

Diagnostic Approaches ◽

Autosomal Recessive Condition

The 5-alpha-reductase type 2 deficiency (5ARD2) is an autosomal recessive condition associated with impairment in the conversion of testosterone to dihydrotestosterone. This condition leads to undervirilisation in 46,XY individuals. To date, there have been more than 100 variations identified in the gene responsible for 5ARD2 development (steroid 5-alpha-reductase 2, SRD5A2). However, few studies have examined the molecular characterisation of Indonesian 5ARD2 cases. In the current study, we analysed 37 subjects diagnosed with 46,XY DSD (disorders of sex development) with confirmed variations in the SRD5A2 gene. We examined results from testosterone/dihydrotestosterone (T/DHT) and urinary etiocholanolone/androsterone (Et/An) ratios, as well as from molecular and clinical analyses. Twelve variants in the SRD5A2 gene were identified, and 6 of which were novel, namely, c.34–38delGinsCCAGC, p.Arg50His, p.Tyr136∗, p.Gly191Arg, p.Phe194Ile, and p.Ile253Val variants. Moreover, we determined that 20 individuals contained harmful mutations, while the remaining 17 variants were benign. Those containing harmful mutations exhibited more severe phenotypes with median external genitalia masculinisation scores (EMS) of 3 (1.5–9) and were more likely to be diagnosed at a later age, reared as female, and virilised at pubertal age. In addition, the respective sensitivities for detecting severe 5ARD2 cases using T/DHT (cutoff: 10) and urinary Et/An ratios (cutoff: 0.95) were 85% and 90%, whereas mild cases were only identified with 64.7% and 47.1% sensitivity, respectively. Although we were unable to identify clear correlations between genotypic and phenotypic characteristics in this study, we clearly showed that individuals who were homozygous or compound heterozygous for any of the harmful mutations were more likely to exhibit classic 5ARD2 phenotypes, lower EMS, female assignment at birth, and virilisation during puberty. These results serve to inform the development of improved clinical and molecular 5ARD2 diagnostic approaches, specifically in Indonesian patients.

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What Term to Choose: Ambiguous Genitalia or Disorders of Sex Development (DSD)?

Frontiers in Pediatrics ◽

10.3389/fped.2019.00316 ◽

2019 ◽

Vol 7 ◽

Cited By ~ 3

Author(s):

Smail Acimi

Keyword(s):

Disorders Of Sex Development ◽

Ambiguous Genitalia ◽

Sex Development

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Disorders of sex development

10.1093/med/9780199659579.003.0124 ◽

2017 ◽

Author(s):

David F.M. Thomas

Keyword(s):

Disorders Of Sex Development ◽

Ambiguous Genitalia ◽

Surgical Reconstruction ◽

Adrenal Hyperplasia ◽

Specialist Care ◽

Gender Assignment ◽

Developmental Abnormalities ◽

Sex Development

The aetiology of disorders of sex development (DSD) is multifactorial and includes chromosomal defects, developmental abnormalities of the gonads, and defects of hormonal synthesis and expression. Infants born with ambiguous genitalia require urgent investigation because of the risk of hyponatraemia associated with congenital adrenal hyperplasia (CAH) and to permit an informed decision on gender assignment. CAH is the commonest form of DSD, accounting for around 80% of all infants born with ambiguous genitalia. Despite controversy regarding timing and consent, feminizing genitoplasty in early childhood remains the accepted management for girls with significant clitoromegaly. Surgical reconstruction for 46XY DSD is guided by several factors, notably the size of the phallus and gonadal phenotype. The majority of individuals with disorders of sex development will require ongoing specialist care and long-term multidisciplinary follow-up and support.

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Genetic Analysis of 25 Patients with 5α-Reductase Deficiency in Chinese Population

BioMed Research International ◽

10.1155/2020/1789514 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Bing Han ◽

Tong Cheng ◽

Hui Zhu ◽

Jie Yu ◽

Wen-jiao Zhu ◽

...

Keyword(s):

Chinese Population ◽

Autosomal Recessive Disorder ◽

Ambiguous Genitalia ◽

Chinese Patients ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Reductase Deficiency ◽

Significant Difference ◽

Hotspot Mutations

Background. A deficiency in steroid 5α-reductase type 2 is an autosomal recessive disorder. Affected individuals manifested ambiguous genitalia, which is caused by decreased dihydrotestosterone (DHT) synthesis in the fetus. Methods. We analyzed 25 patients with 5α-reductase deficiency in China. Seventeen of the 25 patients (68%) were initially raised as females. Sixteen patients changed their social gender from female to male after puberty. Results. Eighteen mutations were identified in these patients. p.Gly203Ser and p.Gln6∗ were found to be the most prevalent mutations. On the basis of the genotype of these patients, we divided them into different groups. There was no significant difference in hormone levels and external masculinization score (EMS) in patients with or without these prevalent mutations. Twelve common single-nucleotide polymorphisms (SNPs) near the p.Gln6∗ mutation were chosen for haplotype analysis. Three haplotypes were observed in 6 patients who had the p.Gln6∗ mutation (12 alleles). Conclusion. We analyzed mutations of the SRD5A2 gene in Chinese patients with 5α-reductase deficiency. Although hotspot mutations exist, no founder effect of prevalent mutations in the SRD5A2 gene was detected in the Chinese population.

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Etiology and Clinical Presentation of Disorders of Sex Development in Kenyan Children and Adolescents

International Journal of Endocrinology ◽

10.1155/2019/2985347 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9

Author(s):

Prisca Amolo ◽

Paul Laigong ◽

Anjumanara Omar ◽

Stenvert Drop

Keyword(s):

Children And Adolescents ◽

Sex Chromosome ◽

Clinical Laboratory ◽

Molecular Genetic ◽

Management Strategies ◽

Disorders Of Sex Development ◽

Ambiguous Genitalia ◽

Molecular Genetic Analysis ◽

High Rate ◽

Sex Development

Objective. The purpose of this study was to describe baseline data on etiological, clinical, laboratory, and management strategies in Kenyan children and adolescents with Disorders of Sex Development (DSD). Methods. This retrospective study included patients diagnosed with DSD who presented at ages 0–19 years from January 2008 to December 2015 at the Kenyatta National (KNH) and Gertrude’s Children’s (GCH) Hospitals. After conducting a search in the data registry, a structured data collection sheet was used for collection of demographic and clinical data. Data analysis involved description of the frequency of occurrence of various variables, such as etiologic diagnoses and patient characteristics. Results. Data from the records of 71 children and adolescents were reviewed at KNH (n = 57, 80.3%) and GCH (n = 14, 19.7%). The mean age at the time of diagnosis was 2.7 years with a median of 3 months. Thirty-nine (54.9%) children had karyotype testing done. The median age (IQR) of children with reported karyotypes and those without was 3.3 years (1.3–8.9) and 8.3 years (3.6–12.1), respectively (p=0.021). Based on karyotype analysis, 19 (48.7%) of karyotyped children had 46,XY DSD and 18 (46.2%) had 46,XX DSD. There were two (5.1%) children with sex chromosome DSD. Among the 71 patients, the most common presumed causes of DSD were ovotesticular DSD (14.1%) and CAH (11.3%). Majority (95.7%) of the patients presented with symptoms of DSD at birth. The most common presenting symptom was ambiguous genitalia, which was present in 66 (93.0%) patients either in isolation or in association with other symptoms. An ambiguous genitalia was initially observed by the patient’s mother in 51.6% of 62 cases despite the high rate (84.7%) of delivery in hospital. Seventeen (23.9%) of the cases had a gender reassignment at final diagnosis. A psychologist/psychiatrist or counselor was involved in the management of 23.9% of the patients. Conclusion. The commonest presumed cause of DSD was ovotesticular DSD in contrast to western studies, which found CAH to be more common. Investigation of DSD cases is expensive and needs to be supported. We would have liked to do molecular genetic analysis outside the country but financial challenges made it impossible. A network for detailed diagnostics in resource-limited countries would be highly desirable. There is a need to train health care workers and medical students for early diagnosis. Psychological evaluation should be carried out for all patients at diagnosis and support given for families.

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Genetic approach to ambiguous genitalia and disorders of sex development: What clinicians need to know

Seminars in Perinatology ◽

10.1053/j.semperi.2017.03.016 ◽

2017 ◽

Vol 41 (4) ◽

pp. 232-243 ◽

Cited By ~ 12

Author(s):

Svetlana A. Yatsenko ◽

Selma Feldman Witchel

Keyword(s):

Disorders Of Sex Development ◽

Ambiguous Genitalia ◽

Genetic Approach ◽

Sex Development

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Spectrum of external genital anomalies in disorders of Sex Development at Children Hospital & Institute of Child Health, Lahore, Pakistan

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.37.1.2991 ◽

2020 ◽

Vol 37 (1) ◽

Author(s):

Sarah Khan ◽

Raafea Tafweez ◽

Areiba Haider ◽

Muhammad Yaqoob

Keyword(s):

Child Health ◽

Wide Spectrum ◽

Disorders Of Sex Development ◽

Ambiguous Genitalia ◽

Delayed Puberty ◽

Female Sex ◽

Sex Development ◽

Mode Of Presentation ◽

Genital Ambiguity ◽

Male Sex

Objective: To describe the mode of presentation and frequency of external genital anomalies in disorder of sex development (DSD) Methods: This cross-sectional study was conducted at Children Hospital & Institute of Child Health, Lahore from January to December, 2016 on Children with DSD above 10 years of age. A detailed history and physical examination were done. Positive findings were recorded on a predesigned proforma and analyzed by SPSS 21. Karyotyping on blood samples was done to determine their genetic sex. Results: Out of 83 DSD children, 67% (n=56) were assigned a female sex at birth of which 9% (n=5) had ambiguous genitalia. Male sex at birth was given to 33% (n=27) of which 96% (n=26) had genital ambiguity. Mode of presentation other than ambiguous genitalia were delayed puberty, amenorrhea, hirsuitism, gynaecomastia, cyclic hematuria etc. Clitoromegaly was the main finding in 62.5% (n=5) and micropenis in 45% (n=9). Karyotypic sex of 56 female sex of rearing was 46XX 80% (n=45), 45X0 13% (n=7), XXX 2% (n=1) and 46 XY in 5% (n=3). Karyotypic sex of 27 male sex of rearing was 46XY in 78% (n=21), 46XX in 15% (n=4) and 47XXY in 7% (n=2). Conclusion: Disorders of sex development presented with a wide spectrum of external genital anomalies ranging from clitoromegaly in females to micropenis and hypospadias in males. There was also an extreme diversity in mode of presentation of these cases including pubertal delay, amenorrhea in females and gender confusion disorders. doi: https://doi.org/10.12669/pjms.37.1.2991 How to cite this:Khan S, Tafweez R, Haider A, Yaqoob M. Spectrum of external genital anomalies in disorders of Sex Development at Children Hospital & Institute of Child Health, Lahore, Pakistan. Pak J Med Sci. 2021;37(1):244-249. doi: https://doi.org/10.12669/pjms.37.1.2991 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Ovotesticular Disorder of Sex Development: An Unusual Presentation

Journal of Clinical Imaging Science ◽

10.25259/jcis_45_2019 ◽

2019 ◽

Vol 9 ◽

pp. 34 ◽

Cited By ~ 2

Author(s):

Meltem Özdemir ◽

Rasime Pelin Kavak ◽

Ihsan Yalcinkaya ◽

Kursat Guresci

Keyword(s):

Unusual Case ◽

Disorders Of Sex Development ◽

Ambiguous Genitalia ◽

Normal Male ◽

Genital Organ ◽

Rare Form ◽

Disorder Of Sex Development ◽

Breast Enlargement ◽

Sex Development ◽

Bilateral Breast Enlargement

Disorder of sex development is an inclusive term that refers to any problem where the genital organ is atypical in relation to chromosomes or gonads. Ovotesticular disorder of sex development, which is formerly known as “true hermaphroditism,” is the most rare form among all disorders of sex development in humans. It is characterized by the simultaneous presence of both ovarian and testicular tissues in the same individual and characteristically presents with ambiguous genitalia in neonates or infants. Herein, we present an unusual case of a 19-year-old individual with phenotypically nearly normal male genitalia who presented with the complaint of bilateral breast enlargement.

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