Genotype–phenotype correlation, gonadal malignancy risk, gender preference, and testosterone/dihydrotestosterone ratio in steroid 5-alpha-reductase type 2 deficiency: a multicenter study from Turkey

Abacı, Ayhan; Çatlı, Gönül; Kırbıyık, Özgür; Şahı̇n, Niyazi; Abalı, Zehra Yavaş; Ünal, Edip; Şıklar, Zeynep; Mengen, Eda; Özen, Samim; Güran, Tülay; Kara, Cengiz; Yildiz, Melek; Eren, Erdal; Nalbantoğlu, Özlem; Güven, Ayla; Çayır, Atilla; Akbaş, Emine Demet; Kör, Yılmaz; Çürek, Yusuf; Aycan, Zehra; Baş, Firdevs; Darcan, Şükran; Berberoğlu, Merih

doi:10.1007/s40618-018-0940-y

Cited by 20 publications

(50 citation statements)

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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%

“…60 On the other hand, frameshifting indels usually are deleterious, leading to mRNA degradation owing to nonsense-mediated mRNA decay or the production of severely truncated proteins, which could explain the lower external genitalia virilization. 61 Except by the p. Met157del reported in patients from Turkey, 7,33 all the others small indels in the SRD5A2 are frameshifting leading to a premature stop codon (Table 4). As in other inherited disorders, allelic variants in canonical splicing sites use to be deleterious.…”

Section: Functional Studies On Allelic Variants Of the Srd5a2 Genementioning

confidence: 98%

“…As an example, the p. Arg246Gln mutation was reported in India, Austria, Brazil, Italy, Korea, Pakistan, Dominican Republic, Egypt, China, Saudi Arabia and Mexico 6,42,[44][45][46][47][48] as well as the p.Gly196Ser in Turkey, China, Bulgaria, Italy, and the United Kingdom. 8,33,[49][50][51] On the other hand, many SRD5A2 mutations remain from specific ethnicities, such as p.Pro59Arg from Algeria, p.Asn160Asp from Egypt, c.188_189insTA from India, c.453delC from Italy, p.Gly183Ser from Brazil and p.Ala65Pro from Turkey. 7,33,[52][53][54] Therefore, ethnicity does not seem to impact on phenotype-genotype correlation.…”

Section: Genotypementioning

confidence: 99%

“…8,33,[49][50][51] On the other hand, many SRD5A2 mutations remain from specific ethnicities, such as p.Pro59Arg from Algeria, p.Asn160Asp from Egypt, c.188_189insTA from India, c.453delC from Italy, p.Gly183Ser from Brazil and p.Ala65Pro from Turkey. 7,33,[52][53][54] Therefore, ethnicity does not seem to impact on phenotype-genotype correlation.…”

Section: Genotypementioning

confidence: 99%

“…The Sinnecker's scores of the p.Leu55Gly, reported in individuals from Turkey, Lebanon and Iraq, ranged from 2a to 4b. 33,82,[92][93][94] For the p.Ala65Pro variant reported in individuals from Turkey, the Sinnecker's scores ranged from 2a to 5. 33 For the p.pro181Leu variant, which was reported in Saudi Arabia and Turkey, the Sinnecker's scores ranged from 2a to 4a.…”

Section: Genotype-phenotype Relationship In Individuals With 5α-reducmentioning

confidence: 99%

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<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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