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46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency. C...

2026-05-10
Asta MONDO:0009923 Model: Asta Scientific Corpus Retrieval 18 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency. C...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide

  • Authors: R. Batista, B. Mendonca
  • Year: 2020
  • Venue: The Application of Clinical Genetics
  • URL: https://www.semanticscholar.org/paper/50bc30f4f3d8e973c42376743fc015f8bb9a238e
  • DOI: 10.2147/TACG.S198178
  • PMID: 32346305
  • PMCID: 7167369
  • Citations: 39
  • Influential citations: 3
  • Summary: 5ARD2 deficiency has a worldwide distribution and influenced on sex assignment, favoring male sex assignment in newborns with 5α-reductase type 2 deficiency, and gender change was significantly different across the countries.
  • Evidence snippets:
  • Snippet 1 (score: 0.651) > 5α-reductase type 2 deficiency is a rare condition with a worldwide distribution which needs to be considered as a diagnosis in front of all 46,XY newborn with atypical genitalia. It results from allelic variants in the SRD5A2 gene, leading to a broad spectrum of external genitalia phenotypes with no strong genotype-phenotype relationship. However, allelic variants at exon 4 and indels consistently caused more severe phenotypes. The genotypephenotype incongruence occurs even in individuals carrying the same variant and also in individuals from the same family, suggesting that other factors beyond the 5αreductase type 2 enzyme play a role in phenotype. These factors are still unclear and constitute a relevant field for future research. Although many allelic variants in the SRD5A2 gene have been reported, other genetic mechanisms that may influence gene expression have not yet been investigated. The role of SRD5A2 polymorphisms in human diseases is debatable. Most cases of 5α-reductase type 2 deficiency were assigned as female at birth due to severe undervirilization of external genitalia. Later, many changed from female to male gender. It clearly favors to base the sex assignment on molecular diagnosis instead on external genitalia appearance. There has been an improvement in the number of 5α-reductase type 2 deficiencies individuals raised as boys. However, the impact of this change on long-term health outcomes requires further research.

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

  • Authors: N. S. Marzuki, F. P. Idris, Hannie Kartapradja, A. Harahap, Jose R. L. Batubara
  • Year: 2019
  • Venue: International Journal of Endocrinology
  • URL: https://www.semanticscholar.org/paper/0ac3adfd455409d77d75d0839caa412f75ca352a
  • DOI: 10.1155/2019/7676341
  • PMID: 31885560
  • PMCID: 6914983
  • Citations: 13
  • Influential citations: 2
  • Summary: It was 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.
  • Evidence snippets:
  • Snippet 1 (score: 0.633) > Steroid 5-alpha-reductase type 2 deficiency (5ARD2) is a rare autosomal recessive disorder, caused by failure of testosterone to convert to dihydrotestosterone (DHT), which is an androgen that is 10 times more biologically active than testosterone [1,2]. During foetal development, DHT induces the development of male external genitalia. us, reduced expression of DHT results in undervirilisation in affected 46,XY infants and clinical presentation that includes the presence of a micropenis, hypospadia, ambiguous genitalia, or external genitalia that resembles that of a female. Hence, individuals presenting with the classic form of 5ARD2 are often raised as females, who then undergo masculinisation during puberty, resulting in female to male gender reassignment procedures being performed in 56-63% of these cases [3]. e T/DHT ratio is widely used in diagnostics for 46,XY disorder of sex development (DSD) cases suspected of 5ARD2. However, there is increasing evidence that this ratio may yield conflicting results [4][5][6][7]. A consensus has not been reached regarding the appropriate cutoff values required for diagnosis of 5ARD2 cases, and thus the T/DHT ratio is commonly reported to generate false negative results, most notably in prepubertal children. Alternatively, urinary steroid profiling (USP) for 5β/5α metabolites and confirmatory molecular analysis of SRD5A2 gene is employed in the diagnosis of 5ARD2. e 5-alpha-reductase type 2 enzyme is encoded by the SRD5A2 gene, which is located on chromosome 2p23. More than 100 mutations throughout the coding and flanking intronic regions of SRD5A2 have been identified as associated with 5ARD2 development ( e Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php, accessed on February 2019). Since the DHT test is unavailable routinely in Indonesia, due to low demand, and is routinely sent abroad for analysis, the alternative tests are important to be set up in the diagnosis of 5ARD2.
  • Snippet 2 (score: 0.633) > 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 ph

[3] Clinical and molecular characterization of 5α-reductase type 2 deficiency due to mutations (p.Q6X, p.R246Q) in SRD5A2 gene.

  • Authors: Wenyu Jia, Dongmei Zheng, Liya Zhang, Changzhong Li, Xu Zhang et al.
  • Year: 2018
  • Venue: Endocrine journal
  • URL: https://www.semanticscholar.org/paper/2eba17ec65cfe4bec8187a604c8908692dbd759a
  • DOI: 10.1507/endocrj.EJ17-0542
  • PMID: 29643321
  • Citations: 5
  • Summary: The homology modeling and molecular docking of 5α-reductase for the first time was conducted, which provided a homology model for further investigations and suggested gonadectomy or testis descent should be performed early for 5 α-RD2 patient, as delayed treatment would have maintained the testes in a tumorigenic condition.
  • Evidence snippets:
  • Snippet 1 (score: 0.625) > ously, it is most important to diagnose DSDs correctly as soon as possible which will allow the patient to live as normal a life as possible. However, confirming a cause for DSD and devising a management plan is one of the most challenging clinical conditions for the clinicians. > One of the more unusual DSDs is 5α-reductase type 2 deficiency (5α-RD2). In this condition, although the affected individuals have male (46, XY) chromosomes, they usually present with ambiguous external genitalia at birth and are assigned female gender and raised up as girls [1,2]. As is shown in Fig. 1, it is caused by a deficiency of 5α-reductase isoenzymes, an enzyme that convert testosterone (T) into more biologically active dihydrotestosterone (DHT). > 5α-RD2 is clinically and genetically heterogeneous. The clinical spectrum ranges from a total female appearance to a nearly complete male phenotype with mild symptoms of under-masculinization. Detailed genotypephenotype analysis may provide information necessary to improve diagnosis and treatment of 5α-RD2. 5α-RD2 is related to mutations in the 5α-reductase type 2 (SRD5A2, NM_000348.3) gene, which is located in chromosome 2p23 and contains five exons. So far, more than 100 different mutations have been reported in the SRD5A2 gene. However, it is difficult to investigate how the structure changes affect the enzyme activity as no homological model of the enzyme is available. Moreover, due to the low morbidity and different awareness of the disease, the histological and pathological changes of the genital system of 5α-RD2 patient are largely unknown. And it remains to be discussed which sex is suitable for a certain patient as most of the patients will be faced with a choice to be a male or female. > In the present study, we identified a DSD patient and made a detailed analysis of his clinical features, laboratory data, and management. Mutation analysis of the SRD5A2 gene was performed to make a molecular diagnosis. For the first time, homology modeling and molecular docking of 5α-reductase

[4] Clinical, hormonal, and molecular-genetic characteristics of three cases of 46XY disorder of sex development caused by type II 5-alpha reductase deficiency

  • Authors: A. Kolodkina, M. Karmanov, N. Kalinchenko, A. Nizhnik, M. A. Nokel et al.
  • Year: 2010
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/45092e5a270156ec451af3230cf46676faf4d204
  • DOI: 10.14341/PROBL201056334-40
  • Citations: 2
  • Summary: Low diagnostic value of the T/DHT ratio is demonstrated (at least as determined by the immunoenzyme assay) and the necessity of analysis of the SRD5A2 gene in all patients with suspected deficiency of type II 5-alpha reductase is emphasized.
  • Evidence snippets:
  • Snippet 1 (score: 0.613) > Clinical, hormonal, and molecular-genetic characteristics of three cases of 46XY disorder of sex development caused by type II 5-alpha reductase deficiency

[5] Genomic technologies and the diagnosis of 46, XY differences of sex development

  • Authors: Firman P. Idris, Andrew H Sinclair, K. Ayers
  • Year: 2024
  • Venue: Andrology
  • URL: https://www.semanticscholar.org/paper/515cc06a603661191269701fa387e11a5f16bff1
  • DOI: 10.1111/andr.13708
  • PMID: 39081229
  • PMCID: 12183017
  • Citations: 5
  • Summary: This review will discuss 46, XY differences/disorders of sex development, its molecular causes, and the genomic technologies currently utilized for diagnosis with focus on reports from the last 5 years.
  • Evidence snippets:
  • Snippet 1 (score: 0.573) > Differences/disorders of sex development can be caused by disruptions to the molecular and cellular mechanisms that control development and sex determination of the reproductive organs with 1:100 live births affected. Multiple genes are associated with 46, XY differences/disorders of sex development that can cause varying clinical phenotypes. An accurate genetic diagnosis is essential to guide clinical care for individuals with 46, XY differences/disorders of sex development and can contribute to family planning. The use of genomics in differences/disorders of sex development has grown, with several advances employed in genetic diagnosis; however, diagnostic rates have stagnated at less than 50% for these conditions. This review will discuss 46, XY differences/disorders of sex development, its molecular causes, and the genomic technologies currently utilized for diagnosis with focus on reports from the last 5 years. We also touch on the challenges in diagnosing 46, XY differences/disorders of sex development and discuss new and future technologies that promise to improved diagnostic rates for these difficult conditions.

[6] 5‐Alpha reductase deficiency; an important cause of 46, XY DSD: Report of three cases within a family

  • Authors: Samaneh Noroozi Asl, R. Ibrahimi, S. Bagheri, Mojtaba Lotfi
  • Year: 2023
  • Venue: Clinical Case Reports
  • URL: https://www.semanticscholar.org/paper/ba4faec3982974e37c28dd8b05da71122ce2c26f
  • DOI: 10.1002/ccr3.7269
  • PMID: 37180321
  • PMCID: 10172458
  • Citations: 1
  • Summary: Sex assignment should be deferred until puberty because spontaneous virilization occurs and the patient can engage in the decision‐making process.
  • Evidence snippets:
  • Snippet 1 (score: 0.564) > In this report we presented three patients with 5-Alpha reductase deficiency who were relatives. Their clinical characteristics were reported and were those typically presented in the literature. > Infants whose external genitalia are not typically male or female or their genital appearance is not compatible with their chromosomal sex are considered to have disorder of sex development or DSD. 1 XY DSD occurs due to insufficient androgen action. 5-Alpha reductase deficiency is one of the causes of XY DSD. This is a condition with autosomal recessive inheritance. 2 5-Alpha reductase is the enzyme responsible for the conversion of testosterone to dehydrotestosterone (DHT). > Typical clinical feature of this disorder is a 46, XY male with female appearance of the external genitalia at birth. However, it may present as varying degrees of undervirilization in a male infant.. 5,6 The internal genital structures are male and mullerian structures are absent because anti mullerian hormones do act normally. 7 Most children with this condition are diagnosed at birth due to the atypical appearance of their external genitalia but in cases that go underdiagnosed because of the typical female appearance of their genitalia, the diagnosis is always made at puberty while the secondary male sexual characteristics like increased muscle mass and voice changes ensue. 8 This was true for our second and third case. Our first reported case was also with typical female genitalia but was diagnosed sooner due to the presence of inguinal hernia and palpation of the testes. > Biochemical findings that support the diagnosis of 5-Alpha reductase deficiency are that of a normal serum testosterone value and increased ratio of serum testosterone to DHT. 9 Definitive diagnosis is made via DNA mutation analysis. 10,11 This was performed in our first patient and mutation of SRD5A2 gene was detected and final diagnosis confirmed. > Treatment of children with 5-Alpha reductase deficiency depends on many factors. The most important factor is the patient's phenotype and gender assignment at the time of diagnosis. 12 ultidisciplinary team with good expertise in disorders of sex development is needed for the best management of these patients. 13
  • Snippet 2 (score: 0.505) > 5‐Alpha reductase deficiency is an important cause of 46, XY disorder of sex development. Timely diagnosis and proper management by a multidisciplinary team can lead to a favorable outcome. Sex assignment should be deferred until puberty because spontaneous virilization occurs and the patient can engage in the decision‐making process.

[7] Clinical characteristics and genetic expansion of 46,XY disorders of sex development children in a Chinese prospective study

  • Authors: Yijun Tang, Yao Chen, Jiayi Wang, Qianwen Zhang, Yirou Wang et al.
  • Year: 2023
  • Venue: Endocrine Connections
  • URL: https://www.semanticscholar.org/paper/b9817472bc1bde063df6cff0b2fab8180f738f1f
  • DOI: 10.1530/EC-23-0029
  • PMID: 37493574
  • PMCID: 10503230
  • Citations: 9
  • Summary: Overall, this was a large cohort of 46,XY DSD patients with a common clinical classification and phenotype spectrum of Chinese patients, and novel candidate genes related to DSD (GHR (growth hormone receptor) and PHIP (pleckstrin homology domain-interacting protein)) were identified.
  • Evidence snippets:
  • Snippet 1 (score: 0.533) > Diagnosis and management strategy of disorders of sex development (DSD) are difficult and various due to heterogeneous phenotype and genotype. Under widespread use of genomic sequencing technologies, multiple genes and mechanisms have been identified and proposed as genetic causes of 46,XY DSD. In this study, 178 46,XY DSD patients were enrolled and underwent gene sequencing (either whole-exome sequencing or targeted panel gene sequencing). Detailed clinical phenotype and genotype information were summarized which showed that the most common clinical manifestations were micropenis (56.74%, 101/178), cryptorchidism (34.27%, 61/178), and hypospadias (17.42%, 31/178). Androgen synthesis/action disorders and idiopathic hypogonadotropic hypogonadism were the most frequent clinical diagnoses, accounting, respectively, for 40.90 and 21.59%. From all next-generation sequencing results, 103 candidate variants distributed across 32 genes were identified in 88 patients. The overall molecular detection rate was 49.44% (88/178), including 35.96% (64/178) pathogenic/likely pathogenic variants and 13.48% (24/178) variants of uncertain significance. Of all, 19.42% (20/103) variants were first reported in 46,XY DSD patients. Mutation c.680G>A (p.R227Q) on SRD5A2 (steroid 5-alpha-reductase 2) (36.67%, 11/30) was a hotspot mutation in the Chinese population. Novel candidate genes related to DSD (GHR (growth hormone receptor) and PHIP (pleckstrin homology domain-interacting protein)) were identified. Overall, this was a large cohort of 46,XY DSD patients with a common clinical classification and phenotype spectrum of Chinese patients. Targeted gene panel sequencing covered most of the genes contributing to DSD, whereas whole-exome sequencing detected more candidate genes.

[8] Clinical presentations and molecular characterization of Indonesian children with 5 alpha-reductase deficiency

  • Authors: N. S. Marzuki, L. P. Suciati, F. P. Idris, B. Tridjaja
  • Year: 2013
  • Venue: International Journal of Pediatric Endocrinology
  • URL: https://www.semanticscholar.org/paper/3ca18d48f1fdca7992d9208379b431496761e374
  • DOI: 10.1186/1687-9856-2013-S1-P191
  • PMCID: 3850067
  • Citations: 1
  • Summary: Clinical, hormonal, and molecular profiles of 14 children with 46,XY DSD and undervirilization due to 5-alpha reductase deficiency are described, who all presented with genitalia ambiguity and mostly raised as girls.
  • Evidence snippets:
  • Snippet 1 (score: 0.510) > Inactivating mutations in 5 alpha-reductase (SRD5A2) gene lead to steroid 5 alpha-reductase deficiency, a rare autosomal recessive condition affecting 46,XY individuals, who generally present with clinical spectrum ranging from a male phenotype with hypospadia to a female phenotype with normal wolffian structures. More than 50 different mutations responsible for this disorder have been documented. This study is to extend our previous report, which described two siblings with 2 novel mutations of SRD5A2 gene, on Indonesian children with 5 alpha-reductase deficiency. > We describe clinical, hormonal, and molecular profiles of 14 children with 46,XY DSD and undervirilization due to 5-alpha reductase deficiency. DNAs extracted from peripheral blood lymphocytes, and the 5 exons of SRD5A2 gene were amplified using specific primers and sequenced. > All of the patients (aged 2 months-18 years old) presented with genitalia ambiguity, including variable degree of hypospadia, phallic enlargement, palpable testis in ‘girls’, micropenis, cryptorchidism, virilization during puberty in ‘girls’ (8 out of 12 patients), and dismorphic appearances in 1 case. Twelve of them raised as girls, while eight patients who had entered pubertal age changed their identity to male. The T/DHT ratio were more than 20 in 8 patients with documented hormonal results. Three mutations including p.Gly34Fs, c.699-1 G>T, and p.Glu135Lys, which have not been reported in other populations were detected. The p.Arg227Gln was the most frequent mutations found (in 13/14 patients or 13/28 alleles). The combination of p.Val89Leu and p.Arg227Gln, which rarely reported in other populations, were detected in 6 patients. > In our series, who all presented with genitalia ambiguity and mostly raised as girls, three mutations, including p.Gly34Fs, c.699-1 G>T, and p.Glu135Lys, which never

[9] Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development

  • Authors: Huifang Peng, Wenyuan Peng, Jiali Chen, Keyan Hu, Yingyu Zhang et al.
  • Year: 2025
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/ff11ed0f8a3776fc0ef16b1d0673cc0735fc84a2
  • DOI: 10.3389/fendo.2025.1507749
  • PMID: 40026690
  • PMCID: 11867910
  • Citations: 1
  • Summary: Although the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear, ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways may be affected.
  • Evidence snippets:
  • Snippet 1 (score: 0.504) > The RNA helicase DHX37 gene is involved in ribosomal biological processes, and linked to human genetic diseases associated with 46,XY disorders of sex development (46,XY DSD) or neurodevelopment. Recently, relevant reports have primarily focused on 46,XY DSD. However, there is still a lack of overall understanding of the genetic characteristics, phenotype, etc. of the DHX37 gene in human genetic diseases, and its molecular mechanism is not fully understood. We searched literature databases and summarized and analyzed all the literature related to DHX37 to date, including case reports, cohort studies, and molecular mechanism studies, to comprehensively demonstrate the role of DHX37 in human genetic diseases. Sixty patients were reported to have DHX37-related 46,XY DSD, with p.R308Q, p.R674W variants being the two most common mutation hotspots, accounting for 36.67% and 11.67% of cases respectively. In DSD cohorts, DHX37 gene mutations have different detection frequencies (0.77%–45.45%), whereas in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts, they have a high detection rate. The gonadal development and fertility of female (46,XX) carriers with DHX37 gene mutations are not affected; however, incomplete penetrance may be observed in males (46,XY). The treatments are primarily surgical intervention and hormone replacement therapy administered at appropriate times; however, the long-term prognosis remains unknown. Although the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear, ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways may be affected. This review summarizes the profile of DHX37 defects in human genetic diseases.

[10] Digenic Origin of Difference of Sex Development in a Patient Harbouring DHX37 and MAMLD1 Variants

  • Authors: K. Margiotti, F. Libotte, M. Fabiani, A. Mesoraca, Claudio Giorlandino
  • Year: 2024
  • Venue: Case Reports in Pediatrics
  • URL: https://www.semanticscholar.org/paper/ea0e8d225cbbc11e81f0843a349fc5b38f85ac0c
  • DOI: 10.1155/2024/4896940
  • PMID: 38962685
  • PMCID: 11221946
  • Citations: 4
  • Summary: This is the first case with the combined presence of pathogenic mutations in the MAMLD1 gene and DHX37 gene in a patient with gonadal dysgenesis, and a digenic inheritance due to two known pathogenic mutations in the DHX37 gene and the MAMLD1 gene is investigated.
  • Evidence snippets:
  • Snippet 1 (score: 0.499) > In the year 2006, a novel terminology, namely, "disorders of sex development" (DSDs), was introduced.Tis term encompasses a group of congenital conditions characterized by atypical development of chromosomes, gonads, or anatomical sex [1].Te genetic cause of DSD still cannot be determined in about half of the cases.DSD is characterized by a wide clinical severity spectrum, ranging from genital ambiguity to moderate hypospadias or unilateral cryptorchidism to phenotypes that are so attenuated that they can go unnoticed.Complex genetic networks and hormonal signalling govern the development of the gonads.Comprehensive genetic testing is widely acknowledged as an essential element in the assessment of individuals with DSDs, owing to the intricate nature of gonad production and diferentiation.Disorders of sex development comprise a wide range of clinical presentations that can be identifed at various stages of life, spanning from the newborn period to late adulthood.However, a main common clinical characteristic observed in nearly all cases is infertility.Te estimated incidence of severe 46, XY and 46, XX DSD with uncertain sex is 2.2 per 10,000 births [2,3].Te observed syndrome exhibits a spectrum of manifestations, including variations in genital development such as ambiguous genitalia, moderate hypospadias, or unilateral cryptorchidism.Consequently, categorizing patients with similar or nearly identical phenotypes becomes challenging due to the presence of diverse etiologies and genetic mechanisms underlying this condition [4].Numerous fundamental factors have been identifed as possible causes, including mutations in genes encoding proteins involved in sex determination and development as well as genital development [5].Nevertheless, the assessment of genotype-phenotype relationships remains challenging because of the considerable variability in both phenotypic and genotypic characteristics observed among people.Next-generation sequencing (NGS) technology has led to the identifcation of several novel DSD-causing genes and an improved understanding of the genetic basis and therapeutic management of the disease [6,7].Much is still unclear about the transmission of this pathology; mono-and oligogenic models are hypothesized [8].

[11] Late Diagnosis of 5-α-Reductase Type 2 Deficiency in an Adolescent Girl with Primary Amenorrhoea.

  • Authors: Abdul-Rahman A Hummadi, Ayel Yahya, A. Al-Qahtani
  • Year: 2017
  • Venue: Sultan Qaboos University medical journal
  • URL: https://www.semanticscholar.org/paper/8ef261454e53cb6adea1fef73b1fa306a890260b
  • DOI: 10.18295/squmj.2016.17.02.014
  • PMID: 28690896
  • Citations: 2
  • Summary: An 18-year-old patient who was referred to an endocrinology clinic in Jizan, Saudi Arabia, in April 2014 with primary amenorrhoea, virilisation and a lack of secondary sex characteristics is reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.490) > Deficiency of the 5-α-reductase enzyme has been found to affect male sexual development. We report an 18-year-old patient who was referred to an endocrinology clinic in Jizan, Saudi Arabia, in April 2014 with primary amenorrhoea, virilisation and a lack of secondary sex characteristics. As female external genitalia were present at birth, she had been raised as a female. Magnetic resonance imaging revealed no uterine or ovarian tissue in the pelvis and the presence of a scrotal sac. She was diagnosed with 5-α-reductase type 2 deficiency, a 46,XY disorder of sexual development. Typically, affected males have pseudovaginal perineoscrotal hypospadias and ambiguous genitalia at birth. Individuals who have been raised as female manifest characteristics of virilisation at puberty, including deepening of the vocal tone, phallus enlargement, scrotal hyperpigmentation and increased muscle mass.

[12] A novel SRD5A2 mutation in an Iranian family with sex development disorder

  • Authors: Farzad Hashemi-Gorji, S. Salehpour, M. Miryounesi, R. Mirfakhraie, V. Yassaee
  • Year: 2020
  • Venue: Andrologia
  • URL: https://www.semanticscholar.org/paper/aaba878488bf4ec9ee8d4a8cedfa5549d50dc2c1
  • DOI: 10.1111/and.13847
  • PMID: 33099786
  • Citations: 1
  • Influential citations: 1
  • Summary: The present study confirms the diagnostic value of whole exome sequencing in the detection of DSD aetiology, especially when several differential diagnoses are possible.
  • Evidence snippets:
  • Snippet 1 (score: 0.483) > Disorders of sex development (DSD) are different types of conditions that their accurate diagnosis by using conventional phenotypic and biochemical approaches is a challenging issue. Precise determination of DSD is critical due to the detection of possible life-threatening associated disorders. It may also assist parents in choosing the most suitable management for their affected child. In this study, two affected kids born from consanguineous families who were clinically diagnosed for sex development disorder were investigated for the main cause of the disease. > Biochemical analysis failed to make an accurate diagnosis. Karyotype analysis showed an abnormal sex chromosome pattern. Whole exome sequencing was sequentially applied to precisely ascertain the genetic cause of the disease. A novel deletion, g.40936_53878del12943insTG (NG_008365.1), and one known mutation, c.586G>A (p.Gly196Ser), were detected in SRD5A2 gene in case I and case II respectively. Further analysis was performed using polymerase chain reaction, primer walking and Sanger sequencing to detect the nucleotides changes accurately. Segregation analysis in the families confirmed 13kb novel homozygous deletion of SRD5A2 in case I and c.586G>A in case II. The present study confirms the diagnostic value of whole exome sequencing in the detection of DSD aetiology, especially when several differential diagnoses are possible. Disorders of sex development can arise from a range of different genome alteration such as chromosome aberration, copy number and single gene variants. The rapid detection of DSD molecular reason can be beneficial in making a therapeutic decision (Ahmed et al., 2000). Normal expression of numerous genes is required for the complex process of human gonadal development. Also, DSD genes are classified into three main categories as follows: (a) genes involved in 46, XY DSD, (b) genes involved in 46, XX DSD, and (c) genes involved in steroid hormone biosynthesis (Baetens et al., 2019;Kim et al., 2017).

[13] Molecular genetic diagnosis and surgical management in a cohort of children with 46,XY disorders/differences of sex development

  • Authors: Y. S. Wong, H. Luk, H. Yau, L. Wong, S. W. Poon et al.
  • Year: 2025
  • Venue: Frontiers in Pediatrics
  • URL: https://www.semanticscholar.org/paper/0f189d71bb4129ec6656df5733df393c73cd517c
  • DOI: 10.3389/fped.2025.1456227
  • PMID: 39936125
  • PMCID: 11810906
  • Citations: 3
  • Summary: Molecular genetic diagnosis enhances the understanding of etiology, improves diagnostic accuracy, and provides precise guidance in the counseling and surgical management of children with 46,XY DSD.
  • Evidence snippets:
  • Snippet 1 (score: 0.481) > In total, 21 patients were identified and included in the study. All had the karyotype 46,XY. Of these, 11 and 10 were reared as male and female, respectively. Among those who presented at birth, the sex of rearing was determined through a shareddecision process between the MDT and the parents. Factors taken into consideration included definitive diagnosis, prediction of future gender development, anatomical features of external genitalia, fertility potential, and the need for subsequent medical and surgical treatment. Fourteen patients presented at birth with atypical genitalia, prompting investigations. Two presented with female-typical phenotype at birth with a discordant prenatal karyotype of 46,XY. The remaining five patients, all with female-typical phenotypes, presented with incidental findings of 46,XY karyotype during genetic workup for other comorbidities (n = 2), finding of testis during hernia repair (n = 1), primary amenorrhea (n = 1), and virilization at onset of puberty (n = 1). > Of the whole group, a molecular genetic diagnosis was reached in patients with disorders of androgen action (n = 4), disorders of androgen synthesis (n = 7), and disorders of gonad development (n = 10). All but one patient had pathogenic or likely pathogenic variants in DSD-related genes. The only VUS reported in this study occurred in a patient with GD. Clinical and genetic data of 21 patients are summarized in Table 1. > Four patients had androgen receptor (AR) gene variants, resulting in CAIS (n = 3) and PAIS (n = 1). All three CAIS patients had female-typical phenotypes with palpable testes (n = 1) and impalpable intraabdominal testes (n = 2). The PAIS patient presented with a deepening of voice and clitoromegaly at the onset of puberty. > Of the seven patients who had genetic variants impairing androgen synthesis, five had SRD5A2 variants resulting in 5-alpha reductase type II deficiency (5α-R2D).

[14] Genotype–Phenotype Correlation Analysis and Identification of a Novel SRD5A2 Mutation in Four Unrelated Chinese Patients with 5α-Reductase Deficiency

  • Authors: Ting Gui, F. Yao, Xinzhuang Yang, Xi Wang, M. Nie et al.
  • Year: 2022
  • Venue: International Journal of General Medicine
  • URL: https://www.semanticscholar.org/paper/c9fc2d5af6fc6fdd15ab7dcd1b949cbb836dba5c
  • DOI: 10.2147/IJGM.S377675
  • PMID: 36016984
  • PMCID: 9395993
  • Citations: 1
  • Summary: Mutation analysis of SRD5A2 gene is crucial for differential diagnosis in patients with 5α-reductase type 2 deficiency, and the novel variant p.P251A enlarges the spectrum of SRDs, predicted to affect protein function and be “probably damaging”.
  • Evidence snippets:
  • Snippet 1 (score: 0.481) > The 5α-reductase type 2 deficiency, first described in the 1970s, is characterized by genital ambiguity attributable to undervirilization in genetic males. 1,2 The affected individuals usually have normal internal male genitalia but ambiguous external genitalia ranging from a male phenotype with hypospadias or micropenis to a nearly female structure with clitoromegaly. 3 This disease has been reported to account for about 7-25% of 46, XY disorders of sex development cases. 4 In a previous review published in 2020, 434 cases of 5α-reductase type 2 deficiency were identified in the literature from 44 different countries, indicating that this disease has a worldwide distribution. 5 The gene SRD5A2 mutation is considered to be a crucial pathogenic factor for 5α-reductase type 2 deficiency. It is located on chromosome 2p23 containing 5 exons and 4 introns, and encodes a 254 amino acid protein named the steroid 5α-reductase type 2 enzyme which is expressed in external genital tissues and prostate early in gestation. 6 This enzyme catalyzes the conversion of testosterone (T) to the more active dihydrotestosterone (DHT). T and DHT interact with the same androgen receptor, but produce distinct biological responses. T plays an important role in transforming the Wolffian ducts into male internal genitalia, 3 while DHT is crucial for differentiation and development of the external genitalia into male type. 7,8 A defect of the SRD5A2 gene could impair the activity of 5α-reductase type 2 enzyme, which in turn reduces the DHT level and affects the differentiation of external genitalia into male type. Up to now, a total of 185 SRD5A2 gene mutations have been identified (Human Gene Mutation Database, www.hgmd.cf.ac.uk), including 133 (71.89%) missense or nonsense mutations, 12 (6.49%) splicing site changes, 1 (0.54%) regulatory sequence, 19 (0.27%) small deletions, 9 (4.86%) small insertions, 5 (2.7%) small indels, and

[15] Identification of a Rare Variant in the SRD5A2 Gene in Siblings With 46,XY Disorders of Sexual Development

  • Authors: Leena Rawal, Deepak Panwar, Ravinder Kumar, Gaurav Sharma, Sumit Jangra et al.
  • Year: 2025
  • Venue: Case Reports in Genetics
  • URL: https://www.semanticscholar.org/paper/e77a9efff0fc80959ac78e8716cb9d5d805bd874
  • DOI: 10.1155/crig/5546459
  • PMID: 41210722
  • PMCID: 12591823
  • Summary: This case highlights phenotypic variability in siblings with the same homozygous SRD5A2 variant from a nonconsanguineous Indian family, underscoring the need for early genetic workup and multidisciplinary evaluation in 46,XY DSD.
  • Evidence snippets:
  • Snippet 1 (score: 0.476) > The SRD5A2 gene encodes the steroid 5α-reductase-2 isozyme, which converts testosterone to dihydrotestosterone and plays a key role in sexual development and androgen physiology. Deficiency of this enzyme leads to an autosomal recessive sex-linked disorder associated with ambiguous genitalia and hypovirilization/complete feminization of external genitalia in individuals with a 46,XY karyotype. The present study emphasizes the indispensable role of molecular genetic testing in siblings (Probands 1 and 2) presented with disorders of sexual development (DSD). The biochemical, cytogenetics, and molecular testing, encompassing hormonal testing, chromosomal analysis, fluorescence in situ hybridization (FISH), and whole exome sequencing (WES), were carried out at our National Reference Laboratory. In addition, Sanger sequencing confirmed the identified variant, and bioinformatics tools were used to assess its impact on protein structure and stability, thereby assessing its pathogenic potential. The biochemical profile revealed highly elevated testosterone/dihydrotestosterone in Probands 1 and 2 as 45.4 and 43.2, respectively (biological reference range < 10). The cytogenetic analysis confirmed a 46,XY karyotype, and FISH validated the presence of the SRY gene. WES identified a pathogenic homozygous variant, c.737G > A(p.Arg246Gln) in the SRD5A2 gene. Protein structure predictions and stability analyses indicated the variant's damaging effects. This study supports diagnosis through comprehensive molecular testing and highlights the significance of genetic insights in managing 46,XY DSD. This case highlights phenotypic variability in siblings with the same homozygous SRD5A2 variant from a nonconsanguineous Indian family, underscoring the need for early genetic workup and multidisciplinary evaluation in 46,XY DSD.

[16] Male pseudohermaphroditism due to 5-alpha reductase type-2 deficiency in a 20-month old boy

  • Authors: Ida Bagus Andhita, Wayan Bikin Suryawan
  • Year: 2016
  • Venue: Paediatrica Indonesiana
  • URL: https://www.semanticscholar.org/paper/60d97400e5e72839a064d6f71dbc36b83930ea1d
  • DOI: 10.14238/pi46.5.2006.236-40
  • Citations: 1
  • Summary: A 20-month old patient with male pseudohermaphroditism due to 5-alpha reductase type-2 deficiency is reported, and the baseline testosterone-to-DHT ratio is 1:2.
  • Evidence snippets:
  • Snippet 1 (score: 0.476) > 5-alpha-reductase (5-ARD) type 2 deficiency is an autosomal sex-linked disorder, resulting in the inability to convert testosterone to the more physiological active dihydrotestosterone (DHT). DHT is the most potent androgen, bound selec- tively to the androgen receptors in genital skin and fibroblasts, making its action necessary for the de- velopment of normal male genital anatomy. Since DHT is required for normal masculinizaton of the external genitalia in utero, genetic males with 5- ARD are usually born with ambiguous genitalia (male pseudohermaphroditism). The hallmark of 5-ARD is elevated ratio of serum testosterone to DHT. In healthy prepubertal children, the baseline testosterone-to-DHT ratio is 1:2. This paper reports a 20-month old patient with male pseudohermaphroditism due to 5-alpha reductase type-2 deficiency.

[17] Disorders of sex development (DSD) 46.XY due to type 2 5-α reductase deficiency in three siblings: Case report from a low-resource setting

  • Authors: Artha Falentin Putri Susilo, K. Tjandraprawira, P. Bayu, Hartanto Bayuaji
  • Year: 2022
  • Venue: Annals of Medicine and Surgery
  • URL: https://www.semanticscholar.org/paper/a5c92d3368d74747b06588696f2c8c148fa2e9bc
  • DOI: 10.1016/j.amsu.2022.104577
  • PMID: 36268297
  • PMCID: 9577524
  • Citations: 2
  • Summary: DSD 46, XY due to type 2 5-α reductase deficiency is a rare autosomal recessive genetic disorder requiring comprehensive diagnostics and holistic management to improve patient quality of life.
  • Evidence snippets:
  • Snippet 1 (score: 0.471) > Disorders of sex development (DSD) 46.XY due to type 2 5-α reductase deficiency in three siblings: Case report from a low-resource setting

[18] RF02 | PMON189 Temporal and Social trends towards sex assignment and gender change in the 5α-reductase type 2 deficiency

  • Authors: R. Batista, S. Domenice, B. Mendonca
  • Year: 2022
  • Venue: Journal of the Endocrine Society
  • URL: https://www.semanticscholar.org/paper/8407d5062cffc23d2b9f92750817c9ac188d1681
  • DOI: 10.1210/jendso/bvac150.1320
  • PMCID: 9625474
  • Summary: An apparent temporal trend indicates an increased likelihood of affected 5αR2 deficiency individuals being raised as boys, providing a gender change drop and there is no correlation between either both sex assignment and gender development with 5 αR2 genetics.
  • Evidence snippets:
  • Snippet 1 (score: 0.471) > Abstract   5α-reductase type 2 (5αR2) deficiency is an autosomal recessive inherited condition affecting 46,XY individuals resulting from the inability to convert testosterone into dihydrotestosterone. Affected individuals present a range of external genitalia undervirilization at birth and pronounced masculinization at puberty. Unlike most other 46,XY DSD, the frequency of gender change among 5αR2 deficiency is high. Objective to analyze the 451 individuals carrying pathogenic 5αR2 variants in the SRD5A2 gene in both alleles (in homozygous or compound heterozygous state) in the literature (Pubmed, EMBASE, Medline) and websites (ensemble, HGMD, ClinVar) regarding sex assignment, external genitalia virilization (1-5 Sinnecker score), and gender change accordingly country income Methods A total of 357 cases out of 451 had clinical information. All patients included were divided between those born before or after 2006 (the DSD consensus year). Country income was based on the 2018 World Bank classification, classifying income into four categories: low, lower-middle, upper-middle, and high (www.worldbank.org). Categorical variables were analyzed using the Chi-square test followed by the Cramer's V. Continuous variables were analyzed either by Student t-test or ANOVA one way. A binary logistic regression was built using sex assignment and gender change as categorical dependent variables. A p<.05 was considered significant. Results When we divided the individuals into those diagnosed after and before 2006, the percentage of female sex assignments dropped from 72% to 56% (p<.0001), followed by an odds ratio reduction (from 2.52 to 1.65) for female sex assignment. Country income did not impact sex assignment (p=.21). However, most cases (86%) were reported from countries with high and upper-middle economies. The absence of reports from low-income countries may be due to several reasons, such as barriers to molecular diagnosis, scientific access, and specialized medical assistance. Most cases were assigned as female (69%). The overall rate of gender change was 25% (89 out 357). All but one changed their

Notes

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