5-α-Reductase type 2 deficiency: is there a genotype-phenotype correlation? A review

Avendaño, Andrea; Paradisi, Irene; Cammarata‐Scalisi, Francisco; Callea, Michele

doi:10.1007/s42000-018-0013-9

Cited by 43 publications

(71 citation statements)

References 64 publications

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“…This rate is in agreement with a previous study which includes 55 individuals with 5α-R2 deficiency and also with other 5α-RD2 deficiency review. 7,43 The positions 196, 227, 235 and 246 are hotspots of the SRD5A2 gene. Collectively, they make up 25% of all AV reported as causative of 5α-reductase type 2 deficiency.…”

Section: Genotypementioning

confidence: 99%

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

Batista¹,

Mendonca²

2020

TACG

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The conversion of testosterone into dihydrotestosterone is catalyzed by the 5αreductase type 2 enzyme which plays a crucial role in the external genitalia virilization. It is encoded by the SRD5A2 gene. Allelic variants in this gene cause a 46,XY DSD with no genotype-phenotype relationship. It was firstly reported in the early 70s from isolated clusters. Since then, several cases have been reported. Putting together, it will expand the knowledge on the molecular bases of androgen milieu. Methods: We searched for SRD5A2 allelic variants (AV) in the literature (PubMed, Embase, MEDLINE) and websites (ensembl, HGMD, ClinVar). Only cases with AV in both alleles, either in homozygous or compound heterozygous were included. The included cases were analyzed according to ethnicity, exon, domain, aminoacid (aa) conservation, age at diagnosis, sex assignment, gender reassignment, external genitalia virilization and functional studies. External genitalia virilization was scored using Sinnecker scale. Conservation analysis was carried out using the CONSURF platform. For categorical variables, we used X2 test and Cramer's V. Continuous variables were analyzed by t test or ANOVA. Concordance was estimated by Kappa. Results: We identified 434 cases of 5ARD2 deficiencies from 44 countries. Most came from Turkey (23%), China (17%), Italy (9%), and Brazil (7%). Sixty-nine percent were assigned as female. There were 70% of homozygous allelic variants and 30% compound heterozygous. Most were missense variants (76%). However, small indels (11%), splicing (5%) and large deletions (4%) were all reported. They were distributed along with all exons with exon 1 (33%) and exon 4 (25%) predominance. Allelic variants in the exon 4 (NADPH-binding domain) resulted in lower virilization (p<0.0001). The codons 55, 65, 196, 235 and 246 are hotspots making up 25% of all allelic variants. Most of them (76%) were located at conserved aa. However, allelic variants at non-conserved aa were more frequently indels (28% vs 6%; p<0.01). The overall rate of gender change from female to male ranged from 16% to 70%. The lowest rate of gender change from female to male occurred in Turkey and the highest in Brazil. External genitalia virilization was similar between those who changed and those who kept their assigned gender. The gender change rate was significantly different across the countries (V=0.44; p<0.001) even with similar virilization scores. Conclusion: 5ARD2 deficiency has a worldwide distribution. Allelic variants at the NADPHligand region cause lower virilization. Genitalia virilization influenced sex assignment but not gender change which was influenced by cultural aspects across the countries. Molecular diagnosis influenced on sex assignment, favoring male sex assignment in newborns with 5α-reductase type 2 deficiency.

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Section: Genotypementioning

confidence: 99%

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

Batista¹,

Mendonca²

2020

TACG

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“…Although some SRD5A2 mutations cause no enzyme activity and others just influence the proportion of inactivation, no genotype/phenotype correlation has been reported, even in patients carrying the same mutations [3,13]. However, the clinical variability in our patients was probably due to the timing of the therapeutic procedures.…”

Section: A B Discussionmentioning

confidence: 69%

“…Delayed diagnosis of 5-ARD is still common [12][13][14]. The XY karyotype in an individual with female or undermasculinized external genitalia should raise suspicion of 5-ARD.…”

Section: A B Discussionmentioning

confidence: 99%

“…Urinary steroid profiling using tandem mass spectrometry is proposed when available [6]. If clinical criteria for 5-ARD are met, mutational analysis is preferable for the final diagnosis and it has become increasingly available [13,16,17]. In Patient 1 the diagnosis was made clinically and on the basis of testosterone/DHT ratio, and in Patient 2, based on the family history and virilization during puberty.…”

Section: A B Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Novel genotype in two siblings with 5-α-reductase 2 deficiency: Different clinical course due to the time of diagnosis

Kočova

Plaseska-Karanfilska

Noveski

et al. 2019

Balkan Journal of Medical Genetics

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Steroid 5-α-reductase-2 (5-ARD) deficiency is a result of mutations of the SRD5A2 gene. It causes the disorder of sexual differentiation (DSD) in 46,XY individuals with a variable genital phenotype. We present two siblings with female external genitalia at birth and bilateral inguinal testes, raised as females. These are the first molecularly characterized patients from the Republic of North Macedonia (RN Macedonia) with a different clinical course due to the time of the diagnosis. Diagnosis of Patient 1 was based upon the detection of bilateral inguinal testes and testosterone/dihidrotestosterone ratio. Sex reversal was initiated by testes removal at the age of 20 months. Breast implantation and vaginoplasty were performed in adolescence and the girl is comfortable with the female sex. Her sibling, Patient 2, raised as a girl, was clinically assessed at 11.5 years due to the growth of phalus, deep voice and Adam’s apple enlargement. No change of gender was accepted. Complex molecular analysis including multiplex quantitative fluorescent polymerase chain reaction (PCR) screening for sex chromosome aneuploidies and SRY presence, Sanger sequencing combined with multiplex ligation-dependent probe amplification (MLPA), microarray-based comparative genomic hybridization (aCGH), and real-time PCR analysis for detection of exon copy number changes confirmed a novel c.146C>A (p.Ala49Asp) point mutation in the first exon inherited from the mother, and complete deletion of the first exon and adjacent regions inherited from the father. Novel genotype causing 5-ARD is presented. Genetic analysis is useful for the diagnosis and timely gender assignment in patients with 5-ARD. However, final gender assignment is difficult and requires combined medical interventions.

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“…4 Patients with the SRD5A2 mutations may have variable clinical features from complete female genitalia, genital ambiguity to undervirilized male genitalia. 5,6 Signs such as bifid scrotum, clitoral-like phallus, cryptorchidism, and pseudovaginal perineoscrotal hypospadias may be observed in patients. 3,7 More than one hundred SRD5A2 mutations have been reported at Human Gene Mutation Database (http://www.…”

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confidence: 99%

A novel pathogenic variant of SRD5A2 in an Iranian psuedohermaphrodite male

Dalili

Rabbani

Rad

et al. 2020

Clinical Case Reports

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SRD5A2 mutations have been reported to cause an autosomal recessive form of male pseudohermaphroditism (disorders of sex development: SDS). Here, a novel mutation in SRD5A2 gene is reported in an Iranian patient with pseudohermaphroditism. A 5-month-old infant with female genitalia referred to endocrinology clinic at Pediatric Center of Excellence. Existence of testes was confirmed by ultrasonography. Karyotype showed a 46,XY DSD. Molecular analysis including PCR and sequencing of SRD5A2 showed a novel variant in this gene. In silico analyses were also performed to determine the potential pathogenecity of this mutation. Sequencing of SRD5A2 gene showed a novel variant, c.476T > G (p.Ile159Arg). The variant was heterozygous in the patient's parents. Prediction analysis using available software tools such as PROVEAN and Phyre2 was consistent with pathogenicity of the variant. Considering that the

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5-α-Reductase type 2 deficiency: is there a genotype-phenotype correlation? A review

Cited by 43 publications

References 64 publications

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

Novel genotype in two siblings with 5-α-reductase 2 deficiency: Different clinical course due to the time of diagnosis

A novel pathogenic variant of SRD5A2 in an Iranian psuedohermaphrodite male

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