Structured Abstract
Objective
Hypospadias is a common congenital abnormality that has been increasing in prevalence
over the last decades. Historically, 46,XY patients with severe hypospadias and descended
scrotal testes at birth have frequently lacked a genetic diagnosis. Platforms for
molecular genetic testing have become more readily available and can offer an insight
into underlying genetic causes of severe hypospadias. The goal of this study was to
define the anatomical characteristics of severe hypospadias that can accurately define
patients with 46,XY severe hypospadias and determine the practical utility of performing
molecular genetic testing in this group of patients.
Methods
Patients who met the criteria for 46,XY severe hypospadias were offered a molecular
genetic work-up in consultation with pediatric genetics. Patients were identified
through chart review. Data extracted included karyotype, hypospadias phenotype including
stretched penile length at diagnosis, age at genetic diagnosis, molecular genetic
testing, pathogenic gene variant(s), gender identity, and clinical course. All patients
underwent clinical genetic testing via 46,XY Disorders of Sexual Development (DSD)
panels offered by Invitae®, GeneDx®, or Blueprint Genetics®.
Results
Of the 14 patients that underwent genetic testing, there were 5 previously published
and 3 novel pathogenic or likely pathogenic variants in genes associated with 46,XY
severe hypospadias Table . Pathogenic variants were identified in AR (3), SRD5A2 (1), NR5A1 (2), WT1 (1), and ARTX (1). Two patients had a variant of unknown significance, one in FREM2 and another in CEP41. Four had negative gene panels. The patient with the WT1 pathogenic variant was subsequently found to have developed a Wilms tumor and the
patients with NR5A1 pathogenic variants are now undergoing adrenal insufficiency surveillance.
Discussion/Conclusion: Patients with 46,XY severe hypospadias and descended testes
in the scrotum at birth can benefit from molecular genetic testing as their underlying
disorders may reveal pathogenic variants that could have potentially life-altering
consequences and change surveillance and monitoring.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Pediatric UrologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- What Is Hypospadias?.Clin Pediatr (Phila). 2017; 56: 409-418
- Diacylglycerol kinase K variants impact hypospadias in a California study population.J Urol. 2013; 189: 305-311
- Hypospadias and urethral development.J Urol. 2000; 163: 951-956
- Hypospadias: anatomy, etiology, and technique.J Pediatr Surg. 2006; 41: 463-472
- Hypospadias and endocrine disruption: is there a connection?.Environmental health perspectives. 2001; 109: 1175-1183
- Hypospadias Trends in Two US Surveillance Systems.Pediatrics. 1997; 100: 831-834
- International trends in rates of hypospadias and cryptorchidism.Environ Health Perspect. 1999; 107: 297-302
- Management of severe hypospadias with a 2-stage repair.J Urol. 1994; 152: 749-751
- Objective use of testosterone reveals androgen insensitivity in patients with proximal hypospadias.J Pediatr Urol. 2014; 10: 118-122
- Glans penis width in patients with hypospadias compared to healthy controls.J Pediatr Urol. 2013; 9: 1188-1191
- The genetic factors contributing to hypospadias and their clinical utility in its diagnosis.J Cell Physiol. 2019; 234: 5519-5523
- Macroscopic whole-mounts of the developing human fetal urogenital-genital tract: Indifferent stage to male and female differentiation.Differentiation. 2018; 103: 5-13
- Development of the human penis and clitoris.Differentiation. 2018; 103: 74-85
- Canalization of the urethral plate precedes fusion of the urethral folds during male penile urethral development: the double zipper hypothesis.J Urol. 2015; 193: 1353-1359
- Canalization of the Vestibular Plate in the Absence of Urethral Fusion Characterizes Development of the Human Clitoris: The Single Zipper Hypothesis.J Urol. 2016; 195: 1275-1283
- Complex epithelial remodeling underlie the fusion event in early fetal development of the human penile urethra.Differentiation. 2016; 92: 169-182
- Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline.J Clin Endocrinol Metab. 2018; 103: 4043-4088
- Molecular and Cellular Mechanisms of Palate Development.J Dent Res. 2017; 96: 1184-1191
- Switching the rate and pattern of cell division for neural tube closure.Neurogenesis (Austin). 2016; 3e1235938
- Androgen and estrogen receptor expression in the developing human penis and clitoris.Differentiation. 2020; 111: 41-59
- The role of 5alpha-reduction in steroid hormone physiology.Reprod Fertil Dev. 2001; 13: 673-678
- Androgen and estrogen receptor expression in the developing human penis and clitoris.Differentiation. 2019; 111: 41-59
- Human glans and preputial development.Differentiation. 2018; 103: 86-99
Domenice S, Arnhold IJP, Costa EMF, Mendonca BB. 46,XY Disorders of Sexual Development. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland J, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA)2000.
- Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life.Endocr Rev. 2019; 40: 1547-1572
In-vitae. AR, ATRX, DHCR7, DHH, MAP3K1, NROB1, NR5A1, SRD5A2, WT1. 2021.
GeneDX. Neonatal 46 XDoSD. ANOS1, AR, ATRX, CHD7, DHCR7, DHH, FGFR1, HESX1, MAPK1, NR0B1, SOX9, SRD5A2, SRY, WT1. 2021.
- Postnatal penile length and growth rate correlate to serum testosterone levels: a longitudinal study of 1962 normal boys.Eur J Endocrinol. 2006; 154: 125-129
- Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals.Birth Defects Res C Embryo Today. 2016; 108: 309-320
- Mutation update for the NR5A1 gene involved in DSD and infertility.Hum Mutat. 2020; 41: 58-68
- The nuclear receptor SF-1 mediates sexually dimorphic expression of Mullerian Inhibiting Substance, in vivo.Development. 1997; 124: 1799-1807
- Description of mutation spectrum and polymorphism of Wilms' tumor 1 (WT1) gene in hypospadias patients in the Indonesian population.J Pediatr Urol. 2018; 14: 237 e231-237 e237
- Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.Cell. 1998; 93: 445-454
- Wilms' tumour 1 (WT1) in development, homeostasis and disease.Development. 2017; 144: 2862-2872
- Male pseudohermaphroditism in sibs with the alpha-thalassemia/mental retardation (ATR-X) syndrome.Am J Med Genet. 1995; 55: 285-287
- Expression of the androgen receptor and 5 alpha-reductase type 2 in the developing human fetal penis and urethra.Cell Tissue Res. 2002; 307: 145-153
- Loss-of-function mutations in FREM2 disrupt eye morphogenesis.Exp Eye Res. 2019; 181: 302-312
- Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes.J Med Genet. 2002; 39: 623-633
- CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium.Nat Genet. 2012; 44: 193-199
- Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies.Am J Hum Genet. 2010; 86: 749-764
- Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature.Genet Med. 2018; 20: 1122-1130
- Clinical whole-exome sequencing for the diagnosis of mendelian disorders.N Engl J Med. 2013; 369: 1502-1511
- Clinical exome sequencing for genetic identification of rare Mendelian disorders.JAMA. 2014; 312: 1880-1887
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-424
- How Far Should We Explore Hypospadias? Next-generation Sequencing Applied to a Large Cohort of Hypospadiac Patients.Eur Urol. 2021;
Article info
Publication history
Accepted:
December 12,
2022
Received:
December 12,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Letter to Editor - Utility of genetic work-up for 46, XY patients with severe hypospadiasJournal of Pediatric Urology
- PreviewIt was really difficult for us to understand the context of this article, which we believe is a combination of clinical observations of hypospadias and scientific data from genetic studies [1]. The authors have included a very small number of hypospadias patients with heterogeneous anatomy, and simply classify them as “standard” and "severe" hypospadias. As per the published literature, the classification of these cases as standard, or cases with a small glans size, etc., lacks a conclusive scientific/anatomical basis.
- Full-Text
- Preview
