New frontiers on the molecular underpinnings of hypospadias according to severity

Abstract

Hypospadias, which is characterised by the displacement of the urethral meatus from its typical anatomical location in males, shows various degrees of severity. In this systematic review, we surveyed our current understanding of the genetics of isolated hypospadias in humans according to the severity of the condition. We found that sequencing and genotyping approaches were the preferred methods of study and that single nucleotide polymorphisms were the most common finding associated with hypospadias. Most genes fell into four gene-pathway categories related to androgens, oestrogens, growth factors, or transcription factors. Few hypospadias studies classify their findings by severity. Taken together, we argue that it is advantageous to take into consideration the severity of the condition in search of novel candidates in the aetiology of hypospadias. Abbreviations: AR: androgen receptor; ATF3: activating transcription factor 3; BMP4: bone morphogenetic protein 4; BMP7: bone morphogenetic protein 7; CYP17: steroid 17-alpha-hydroxylase/17,20 lyase; CYP1A1: cytochrome P450 1A1; CYP3A4: cytochrome P450 3A4; CNVs: copy number variants; DGKK: diacylglycerol kinase kappa; ESR1: oestrogen receptor 1; ESR2: oestrogen receptor 2; FGF8: fibroblast growth factor 8; FGF10: fibroblast growth factor 10; FGFR2: fibroblast growth factor receptor 2; HOXA4: homeobox protein Hox-A4; HOXB6: homeobox protein Hox-B6; HSD17B3: hydroxysteroid 17-beta dehydrogenase 3; MAMLD1: mastermind-like domain-containing protein 1; SF-1: splicing factor 1; SHH: sonic hedgehog; SNPs: single nucleotide polymorphisms; SOX9: SRY-box 9; SRD5A2: steroid 5 alpha-reductase 2; SRY: sex-determining region Y protein; STAR: steroidogenic acute regulatory protein; STARD3: StAR-related lipid transfer protein 3; STS: steryl-sulfatase; WT1: Wilms tumour protein; ZEB1: zinc finger oestrogen-box binding homeobox 1.

Keywords: Hypospadias; aetiology; human genetics; molecular biology; urogenital.

Figure 1.

Algorithm for the systematic review. (a) A total of 340 studies evaluated isolated hypospadias in humans employing molecular biology as the main experimental approach. After inclusion and exclusion criteria, 82 studies underwent full review to assess methodological approach and from these, 68 studies took advantage of sequencing and genotyping approaches. (b) Trend line in the frequency of studies that employed molecular biology approaches in the search for hypospadias’ aetiology (1979–2018)

Figure 2.

Anatomical features of hypospadias. (A) The anatomical position of the urethral meatus in males is used as the criterion to classify the severity of hypospadias. Several classification systems of hypospadias' severities are depicted. Illustration modified after Piñeyro-Ruiz C, Chorna NE, Pérez-Brayfield MR, Jorge JC. Severity-Dependent Profile of the metabolome in hypospadias. Front Pediatr. 2020 [Epub ahead of print]. 9 pages. http://doi.org/10.3389/fped.2020.00202. Copyright © 2020 Piñeyro-Ruiz, Chorna, Pérez-Brayfield and Jorge. [This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.] Modifications from original: grey tones and elimination of sample size numbers for some anatomical locations of the urethral meatus. (B) Hypospadias can be accompanied by penile curvature of varying degrees, ventral deficiency, and dorsal excess of foreskin

Figure 3.

Genetics and molecular biology of hypospadias. (a) Sequencing and genotyping have been the most common methodological approach and (b) single nucleotide polymorphisms (SNPs) have been the most commonly reported finding in the search of hypospadias’ aetiology (n = 68 studies)