Phenotype and molecular characteristics in 45 Chinese children with 5α‐reductase type 2 deficiency from South China

Cheng, Jing; Lin, Ruizhu; Zhang, Wen; Liu, Guochang; Sheng, Huiying; Li, Xiuzhen; Zhou, Zhihong; Mao, Xiaojian; Liu, Li

doi:10.1111/cen.12799

Cited by 37 publications

(41 citation statements)

References 40 publications

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“…The exclusion of the diagnosis of 5α-reductase deficiency was based on the normal testosterone to dihydrotestosterone ratio, except in 3 cases where a mutation was excluded. There have been instances reported in the littérature of affected individuals who did not meet this hormonal criteria [34]. …”

Section: Discussionmentioning

confidence: 99%

Familial forms of disorders of sex development may be common if infertility is considered a comorbidity

et al. 2016

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BackgroundFamilies with 46,XY Disorders of Sex Development (DSD) have been reported, but they are considered to be exceptionally rare, with the exception of the familial forms of disorders affecting androgen synthesis or action. The families of some patients with anorchia may include individuals with 46,XY gonadal dysgenesis. We therefore analysed a large series of patients with 46,XY DSD or anorchia for the occurrence in their family of one of these phenotypes and/or ovarian insufficiency and/or infertility and/or cryptorchidism.MethodsA retrospective study chart review was performed for 114 patients with 46,XY DSD and 26 patients with 46,XY bilateral anorchia examined at a single institution over a 33 year period.ResultsOf the 140 patients, 25 probands with DSD belonged to 21 families and 7 with anorchia belonged to 7 families. Familial forms represent 22% (25/114) of the 46,XY DSD and 27% (7/26) of the anorchia cases. No case had disorders affecting androgen synthesis or action or 5 α-reductase deficiency. The presenting symptom was genital ambiguity (n = 12), hypospadias (n = 11) or discordance between 46,XY karyotyping performed in utero to exclude trisomy and female external genitalia (n = 2) or anorchia (n = 7). Other familial affected individuals presented with DSD and/or premature menopause (4 families) or male infertility (4 families) and/or cryptorchidism. In four families mutations were identified in the genes SRY, NR5A1, GATA4 and FOG2/ZFPM2. Surgery discovered dysgerminoma or gonadoblastoma in two cases with gonadal dysgenesis.ConclusionsThis study reveals a surprisingly high frequency of familial forms of 46,XY DSD and anorchia when premature menopause or male factor infertility are included. It also demonstrates the variability of the expression of the phenotype within the families. It highlights the need to the physician to take a full family history including fertility status. This could be important to identify familial cases, understand modes of transmission of the phenotype and eventually understand the genetic factors that are involved.

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Section: Discussionmentioning

confidence: 99%

Familial forms of disorders of sex development may be common if infertility is considered a comorbidity

et al. 2016

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“…We identified 434 cases of 5α-reductase type 2 deficiency in the literature from 44 different countries (Table 1), which means that this condition has a worldwide distribution. It is noteworthy that many cases have recently been reported in China and Turkey, [32][33][34] besides reports in countries without no previous cases, as Bulgaria. 8 Neonatal diagnosis was carried out in 29.7%.…”

Section: The 5α-reductases Enzymes and 5α-reductases Genesmentioning

confidence: 92%

<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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“…This mutation yields impaired 5 α‐reductase activity as a consequence of reduced NADPH binding capacity (Mendonca et al, ). The p.Asn193Ser mutation was first reported in an Iranian 5‐alpha‐reductase deficiency type 2 patient and has also been previously reported in Spanish (Fernández‐Cancio et al, ), Polish (Boudon et al, ; Fénichel et al, ), Chinese (Chan et al, ; Cheng et al, ; Fernández‐Cancio et al, ), African, Brazilian (Maimoun et al, ) and Mexican‐Mestizo (Vilchis et al, ) families. To date, around 130 different mutations have been described in the SRD5A2 gene causing 5‐alpha‐reductase type 2 deficiency.…”

Section: Discussionmentioning

confidence: 68%

Molecular investigation of mutations in androgen receptor and 5‐alpha‐reductase‐2 genes in 46,XY Disorders of Sex Development with normal testicular development

et al. 2019

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In this study, we aimed to determine androgen receptor (AR) and SRD5A2 gene mutations in 45 patients characterised by 46,XY Disorders of Sex Differentiation (DSD) signs with normal testicular development referred to the Children's Medical Center from February 2015 to September 2017. Karyotype and sex hormone analyses were performed. Cytogenetic investigation showed that seven patients were 46,XX DSD, six patients were chromosomal DSD and 32 patients were 46,XY DSD. Eight exons of the AR gene and five exons of the SRD5A2 gene were amplified. Two cases were affected with androgen insensitivity syndrome (AIS) (missense mutation on exon 7, position c.3637 G>A: p.R841H and position c.3610 G>A: p.R832Q), one case was affected with 5‐alpha‐reductase deficiency type 2 (missense mutation at c.578A>G: p.N193S on exon 4), and 22 cases (88%) did not demonstrate AIS or 5α‐RD2 gene abnormality. Due to the great impact of these disorders on human lifestyle, evaluation of genes involved can improve genetic counselling and therapeutic management. We focused on the AR and SRD5A2 genes in patients with 46,XY DSDs with normal testicular development referred to the Children's Medical Center from all over the country to eventually culminate in a reliable prenatal diagnosis protocol at this major referral centre giving service to a great number of families with consanguineous marriages.

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Phenotype and molecular characteristics in 45 Chinese children with 5α‐reductase type 2 deficiency from South China

Cited by 37 publications

References 40 publications

Familial forms of disorders of sex development may be common if infertility is considered a comorbidity

Familial forms of disorders of sex development may be common if infertility is considered a comorbidity

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

Molecular investigation of mutations in androgen receptor and 5‐alpha‐reductase‐2 genes in 46,XY Disorders of Sex Development with normal testicular development

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