ArticleOrphanet journal of rare diseases2014
Extensive clinical, hormonal and genetic screening in a large consecutive series of 46,XY neonates and infants with atypical sexual development.
Article in Orphanet journal of rare diseases, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 60 citations in OpenAlex.
- Hirschsprung's disease in children with Mowat-Wilson syndrome.Pediatric surgery international · 2015Pooled it
- Spectrum and genotype-phenotype correlation of NR5A1 variants in 46,XY DSD: a systematic review and meta-analysis.Endocrine connections · 2026Article
- The intersection of disorders of sex development and cardiovascular diseases.Biology of sex differences · 2026Review
- <italic>WT1</italic> Deletion in 46,XY DSD: The Importance of Copy Number Variant Analysis.Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation · 2026Article
- 5-Alpha Reductase Deficiency - An Uncommon Disorder of Sexual Development: A Case Study of Four Turkish Patients within a Family.Current gene therapy · 2026Article
- Oligogenic analysis across broad phenotypes of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study.EBioMedicine · 2025Article
- Characterization of 35 Novel NR5A1/SF-1 Variants Identified in Individuals With Atypical Sexual Development: The SF1next Study.The Journal of clinical endocrinology and metabolism · 2025Article
- Molecular genetic diagnosis and surgical management in a cohort of children with 46,XY disorders/differences of sex development.Frontiers in pediatrics · 2025Article
- Mutations inJournal of clinical research in pediatric endocrinology · 2022Article
- The laboratory in the multidisciplinary diagnosis of differences or disorders of sex development (DSD): I) Physiology, classification, approach, and methodologyII) Biochemical and genetic markers in 46,XX DSD.Advances in laboratory medicine · 2021Review
- The laboratory in the multidisciplinary diagnosis of differences or disorders of sex development (DSD): III) Biochemical and genetic markers in the 46,XYIV) Proposals for the differential diagnosis of DSD.Advances in laboratory medicine · 2021Review
- El laboratorio en el diagnóstico multidisciplinar del desarrollo sexual anómalo o diferente (DSD): III) Marcadores bioquímicos y genéticos en los 46,XY IV) Propuestas para el diagnóstico diferencial de los DSD.Advances in laboratory medicine · 2021Review
- The evolving role of whole-exome sequencing in the management of disorders of sex development.Endocrine connections · 2021Article
- Under-reported aspects of diagnosis and treatment addressed in the Dutch-Flemish guideline for comprehensive diagnostics in disorders/differences of sex development.Journal of medical genetics · 2020Review
- Discordant sex between fetal screening and postnatal phenotype requires evaluation.Journal of perinatology : official journal of the California Perinatal Association · 2019Article
- Sex Assignment and Diagnostics in Infants with Ambiguous Genitalia - A Single-Center Retrospective Study.Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation · 2019Article
- Integrating clinical and genetic approaches in the diagnosis of 46,XY disorders of sex development.Endocrine connections · 2018Article
- GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’European journal of endocrinology · 2018Review
- Caring for individuals with a difference of sex development (DSD): a Consensus Statement.Nature reviews. Endocrinology · 2018Review
- Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development.Human mutation · 2018Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundOne in 4500 children is born with ambiguous genitalia, milder phenotypes occur in one in 300 newborns. Conventional time-consuming hormonal and genetic work-up provides a genetic diagnosis in around 20-40% of 46,XY cases with ambiguous genitalia. All others remain without a definitive diagnosis. The investigation of milder cases, as suggested by recent reports remains controversial.
methodsIntegrated clinical, hormonal and genetic screening was performed in a sequential series of 46, XY children, sex-assigned male, who were referred to our pediatric endocrine service for atypical genitalia (2007-2013).
resultsA consecutive cohort of undervirilized 46,XY children with external masculinization score (EMS) 2-12, was extensively investigated. In four patients, a clinical diagnosis of Kallmann syndrome or Mowat-Wilson syndrome was made and genetically supported in 2/3 and 1/1 cases respectively. Hormonal data were suggestive of a (dihydro)testosterone biosynthesis disorder in four cases, however no HSD17B3 or SRD5A2 mutations were found. Array-CGH revealed a causal structural variation in 2/6 syndromic patients. In addition, three novel NR5A1 mutations were found in non-syndromic patients. Interestingly, one mutation was present in a fertile male, underlining the inter- and intrafamilial phenotypic variability of NR5A1-associated phenotypes. No AR, SRY or WT1 mutations were identified.
conclusionOverall, a genetic diagnosis could be established in 19% of non-syndromic and 33% of syndromic cases. There is no difference in diagnostic yield between patients with more or less pronounced phenotypes, as expressed by the external masculinisation score (EMS). The clinical utility of array-CGH is high in syndromic cases. Finally, a sequential gene-by-gene approach is time-consuming, expensive and inefficient. Given the low yield and high expense of Sanger sequencing, we anticipate that massively parallel sequencing of gene panels and whole exome sequencing hold promise for genetic diagnosis of 46,XY DSD boys with an undervirilized phenotype.
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