Markouli et al. report the results of a systematic review of the literature where they identified 9 individuals with a detected mutation in the 5α-reductase type 2 enzyme gene that subsequently were able to conceive in their adult life [
]. This manuscript highlights the importance of early genotyping to confirm diagnosis. Diagnostic workup of patients with differences in sexual development is guided based on phenotype assessment and the tendency is to genotype (gene panel, exome, genome and more recently long-read sequencing) cases with what the clinician interprets as “severe/classic phenotype” or those with possible syndromic features [
- Markouli M.
- Michala L.
Fertility potential in 5α-reductase type 2 deficient males.
J Pediatr Urol [Internet]. 2022 Sep 9; (Available from:) (S1477-5131(22)00365-5. Epub ahead of print. PMID: 36153242)https://doi.org/10.1016/j.jpurol.2022.09.002
]. Milder phenotype anomalies are generally not studied and rarely end up undergoing genetic sequencing. Variable expressivity and incomplete penetrance generates low genotype/phenotype correlation. Subtle phenotype nuances may not be evaluated in depth and accurate genetic diagnosis can be missed. Clinical impact of a lack or delayed diagnosis affects patient's and families at multiple levels. Recent reports have shown rising positive detection of mutations for milder phenotypes [
- Byers H.M.
- Fossum M.
- Wu H.Y.
How geneticists think about differences/disorders of sexual development (DSD): a conversation.
J Pediatr Urol. 2020; 16: 760-767
]. Growing understanding of variants of uncertain significance may improve genetic detection in this group of patients. Genotyping milder phenotypes (isolated distal hypospadias) and ideally all cases with suspicion for a difference in sexual development, regardless of severity of the phenotype, will offer the ability to use the genotype as a predictive variable to guide management such as preoperative testosterone for specific reconstructive cases as well as a predictor for surgical outcomes beyond the current indications to guide diagnosis, counseling oncological risk, future fertility potential and future generation recurrence.
- Ea V.
- Bergougnoux A.
- Philibert P.
- Servant-Fauconnet N.
- Faure A.
- Breaud J.
- et al.
How far should we explore hypospadias? Next-generation sequencing applied to a large cohort of hypospadiac patients [formula presented].
Eur Urol. 2021 Apr 1; 79: 507-515
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- Fertility potential in 5α-reductase type 2 deficient males.J Pediatr Urol [Internet]. 2022 Sep 9; (Available from:) (S1477-5131(22)00365-5. Epub ahead of print. PMID: 36153242)https://doi.org/10.1016/j.jpurol.2022.09.002
- How geneticists think about differences/disorders of sexual development (DSD): a conversation.J Pediatr Urol. 2020; 16: 760-767
- How far should we explore hypospadias? Next-generation sequencing applied to a large cohort of hypospadiac patients [formula presented].Eur Urol. 2021 Apr 1; 79: 507-515
Published online: October 14, 2022
Accepted: September 20, 2022
Received: September 14, 2022
© 2022 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
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- Fertility potential in 5α-reductase type 2 deficient malesJournal of Pediatric UrologyVol. 19Issue 1
- Author's response to commentary to ‘Fertility potential in 5α-reductase type 2 deficient males’Journal of Pediatric UrologyVol. 19Issue 1
- PreviewWe highly appreciate the authors' commentary on our recent article ‘Fertility potential in 5α-reductase type 2 deficient males’ published in ‘Journal of Pediatric Urology’. We would like to elaborate on the importance of genetically assessing not only severe, but also phenotypically milder cases of disorders of sexual development (DSD), in order to achieve an early diagnosis and create a future management plan, but also identify the likelihood of an inheritance pattern and predict potential future tumor risk in patients and their families .