Hypospadias is one of the most common congenital malformations, and its main clinical manifestation is the abnormal opening of the urethra. Etiologically, it can be attributed to many factors, mainly including genetic, hormonal, and environmental factors. Recently studies about its genetic etiologies have found a variety of hypospadias-associated genes from the aspects of epidemiology and polymorphism, mainly those involving the formation of the penis, the development of the testis, the anabolism of androgens, and so on. This review focuses on the progress in the studies on the genetic etiology of hypospadias.
Androgens ; metabolism ; Humans ; Hypospadias ; genetics ; Male ; Penis ; embryology ; Polymorphism, Genetic ; Testis ; embryology ; Urethra

OBJECTIVETo investigate the role of single nucleotide polymorphisms of the gene of diacylglycerol kinase κ (DGKK) in hypospadias in Chinese children.

METHODSWe performed direct sequencing on 2 hypospadias-related candidate single nucleotide polymorphisms of the DGKK gene (rs1934179 and rs7063116, never previously reported in the Chinese population) from 300 children with sporadic hypospadias and 200 healthy controls, and compared the results between the two groups.

RESULTSThe mutation frequencies of rs1934179 and rs7063116 were 5.0% (15/300) and 5.67% (17/300) respectively in the hypospadias patients, significantly higher than 1.5% (3/200) and 2.0% (4/200) in the normal controls (P <0.05). The mutation frequencies of rs1934179 and rs7063116 in the cases of distal and middle hypospadias were also remarkably higher (6.5%, [13/200] and 7.5% [15/200], P <0.05), but those in the proximal cases (both 2.0% [2/100]) showed no statistically significant difference from the control (P >0.05).

CONCLUSIONThe polymorphisms of the DGKK gene may be associated with hypospadias, particularly distal and middle hypospadias, in Chinese children.

Asian Continental Ancestry Group ; Case-Control Studies ; Child ; China ; Diacylglycerol Kinase ; genetics ; Humans ; Hypospadias ; enzymology ; genetics ; Male ; Polymorphism, Single Nucleotide

OBJECTIVETo study genic mutation of androgen receptor in hypospadias in Chinese.

METHODSNinety-two patients with hypospadias were selected for the AR gene study (penile 33, scrotal 49, perineal 10; cryptorchidism 15, micropenis 34, indirect hernia 3, augmentation of breast 2, other deformities 8; posses family history 23) while 93 health men as the control. The DNA was collected from 5 ml venous blood by using the method of phenol/chloroform, and quantified with the agarose gel electrophoresis. The 2-8 exons of AR genes were directly sequenced with a PCR technique. The locus of mutation,the change of amino acid caused by genic mutation and the functional influence of target organ were also analyzed.

RESULTSThere were 4 mutations found from the ligand binding domain of AR: exon 4[1 locus:664(ATT-->ACT] and exon 7[3 locuses: 840(CGT-->CAT),855(CGC-->CAC),859(CTC-->CTA)] in experimental group. The amino acid change of Iso664Thr may te the first findings in the world. The mutation of 859(CTC-->CTA) didn't cause the change of the code amino acid. The main clinical symptoms of exon 4[664(ATT-->ACT) were micropenis, slight hypospadias and augmentation of breasts. The exon 7[840(CGT-->CAT), 855(CGC-->CAC)]was showing micropenis and severe hypospadias. The last mutation [859(CTC-->CTA)] of exon 7 showed mild hypospadias.

CONCLUSIONSThe rate of exon 2-7 mutations of the androgen receptor was 4.3%. The mutations were concentrated on ligand binding domain(exon 4-7), and the main phenotypes were hypospadias accompanying with micropenis found in our experimental group.

Adolescent ; Adult ; Base Sequence ; Case-Control Studies ; Child ; Exons ; Humans ; Hypospadias ; genetics ; Male ; Mutation ; Receptors, Androgen ; genetics ; Young Adult

This article reported the clinical characteristics and SRD5A2 gene mutation pattern of a child with steroid 5-α reductase type 2 deficiency. The 2-month-old boy showed hypospadias and short penis shortly after birth. DNA was extracted from the peripheral blood of the child and his parents. The endocrine disease-related genes were captured and sequenced by high-throughput sequencing technology, and the family DNA samples were verified by Sanger sequencing. The results showed that c.680G>A(p.R227Q) and c.608G>A(p.G203D) compound heterozygous mutations existed in the SRD5A2 gene of the child. The c.680G>A mutation inherited from his father, which was a known pathogenic mutation. The c.608G>A mutation originated from his mother, which was a novel mutation discovered in this study. These results provide molecular evidence for the etiological diagnosis of the child and genetic counseling for the family, as well as extend the mutation spectrum of SRD5A2 gene.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase ; genetics ; Base Sequence ; Child ; Female ; Humans ; Hypospadias ; Infant ; Male ; Membrane Proteins ; genetics ; Mutation

OBJECTIVEEstrogen is closely associated with hypospadias. The present study was to explore the molecular mechanism of hypospadias caused by estradiol.

METHODSFibroblasts obtained from the prepuce of hypospadiac and normal children were cultured in vitro and treated with 17-beta ethinyl estradiol (17-EE) at the concentrations of 1 micromol/L to 0.1 nmol/L for 2 hours, or at 0.1 micromol/L for 0.5, 1, 2, 4, 8, 16 and 24 hours. MTT assay was used to evaluate the effect of 17-EE on the proliferation of the cells, and RT-PCR was employed to detect the expressions of the activating transcription factor-3 (ATF3) and connective tissue growth factor (CTGF) in the hypospadiac tissue. The results were compared with those obtained from the nonhypospadiac tissue.

RESULTSThe expressions of ATF3 and CTGF were significantly upregulated in the hypospadiac tissue as compared with the nonhypospadiac group. At the concentration of 1 micromol/L, 17-EE significantly inhibited the proliferation of the cells. ATF3 mRNA was elevated at 1-2 hours, while CTGF mRNA showed no significant changes in 24 hours.

CONCLUSIONATF3 and CTGF are two candidate genes involved in the etiology of hypospadias. And estradiol may induce hypospadias by upregulating the expressions of ATF3 and CTGF.

Activating Transcription Factor 3 ; genetics ; metabolism ; Cells, Cultured ; Child ; Connective Tissue Growth Factor ; genetics ; metabolism ; Estradiol ; pharmacology ; Estrogens ; pharmacology ; Fibroblasts ; metabolism ; Foreskin ; metabolism ; Humans ; Hypospadias ; genetics ; metabolism ; Male

OBJECTIVETo investigate the role of the HoxA13 gene from the HOX family in the development of hypospadias by detecting the transcription and expression of HoxA13 in the prepuce and urethral plate of hypospadias patients.

METHODSWe collected the tissues from the prepuce and urethral plate of 30 hypospadias patients aged 3.3 - 11.6 years, the prepuce of 10 phimosis children aged 3.1 - 10.4 years and the urethra of 10 penile carcinoma patients aged 48.1 - 75.6 years with no urethral involvement, the latter 20 taken as controls. We divided the tissue samples into a distal, an intermedial, a proximal and a control group, and detected the expressions of HoxA13 mRNA and protein in different groups by RT-PCR and immunohistochemistry.

RESULTSRT-PCR showed that the HoxA13 mRNA expressions in the prepuce and urethral plate were significantly higher in the control group (1.409 +/- 0.441 and 1.270 +/- 0.209) than in the intermedial (0.848 +/- 0.338 and 0.684 +/- 0.228) and proximal group (0.497 +/- 0.218 and 0.464 +/- 0.164) (P < 0.05 or P < 0.01), and so were they in the distal (1.071 +/- 0.342 and 1.054 +/- 0.189) than in the proximal group (P < 0.05). Immunohistochemistry revealed that the HoxA13 protein expressions in the prepuce and urethral plate were remarkably higher in the control group (12 050 +/- 4 112 and 13 420 +/- 2 636) than in the intermedial (5 217 +/- 1 993 and 5 238 +/- 3 065) and proximal group (2 095 +/- 1 591 and 2 238 +/- 2 217) (P < 0.05 or P < 0.01), and so were they in the distal (8 223 +/- 3 212 and 10 450 +/- 2 123) than in the proximal group (P < 0.05).

CONCLUSIONThe transcription and expression of HoxA13 in the prepuce and urethral plate of hypospadias patients are closely related with the abnormal position of the urethral meatus, and their abnormal expressions may affect the development and formation of the urethra.

Aged ; Case-Control Studies ; Child ; Child, Preschool ; Foreskin ; metabolism ; Homeodomain Proteins ; genetics ; metabolism ; Humans ; Hypospadias ; genetics ; metabolism ; Male ; Middle Aged ; Urethra ; metabolism

Objective: To investigate the association of the polymorphisms of the gene of estrogen receptor α 1 (ESR1) with the risk of hypospadias in children of Northeast China. METHODS: This study included 95 hypospadias patients aged 3.2±0.6 years and 105 children aged 3.1±0.7 years as normal controls. Using PCR and gene sequencing, we determined the genotypes of the polymorphisms of ESR1 rs2077647 and rs6932902 in the two groups of subjects. RESULTS: The results of PCR and gene sequencing showed statistically significant differences in the genotype and allele frequency distribution of the polymorphisms rs2077647 (χ2 = 8.552) and rs6932902 (χ2 = 16.251) (P<0.05) in the hypospadias and control groups. The hypospadias patients, in comparison with the normal controls, exhibited a markedly higher frequency of the SNP C allele in rs2077647 (OR = 1.410 ［1.130－1.759］, P<0.05), but a remarkably lower frequency of the SNP G allele in rs6932902 (OR = 2.263 ［1.503－3.408］, P<0.01). CONCLUSIONS The rs2077647 and rs6932902 polymorphisms of the ESR1 gene are associated with the risk of hypospadias, and so is its haplotype in children in Northeast China.
Alleles ; Case-Control Studies ; Child, Preschool ; China ; Estrogen Receptor alpha ; genetics ; Genotype ; Haplotypes ; Humans ; Hypospadias ; genetics ; Male ; Polymorphism, Single Nucleotide ; Risk

OBJECTIVE: To retrospectively analyze sex chromosomal abnormalities and clinical manifestations of children with disorders of sex development (DSD). METHODS: A total of 14 857 children with clinical features of DSD including short stature, cryptorchidism, hypospadia, buried penis and developmental delay were recruited from Zhengzhou Children's Hospital from January 2013 to March 2022. Fluorescence in situ hybridization (FISH) and chromosomal karyotyping were carried out for such children. RESULTS: In total 423 children were found to harbor sex chromosome abnormalities, which has yielded a detection rate of 2.85%. There were 327 cases (77.30%) with Turner syndrome and a 45,X karyotype or its mosaicism. Among these, 325 were females with short stature as the main clinical manifestation, 2 were males with short stature, cryptorchidism and hypospadia as the main manifestations. Sixty-two children (14.66%) had a 47,XXY karyotype or its mosaicism, and showed characteristics of Klinefelter syndrome (KS) including cryptorchidism, buried penis and hypospadia. Nineteen cases (4.49%) had sex chromosome mosaicisms (XO/XY), which included 11 females with short stature, 8 males with hypospadia, and 6 cases with cryptorchidism, buried penis, testicular torsion and hypospadia. The remainder 15 cases (3.55%) included 9 children with a XYY karyotype or mosaicisms, with main clinical manifestations including cryptorchidisms and hypospadia, 4 children with a 47,XXX karyotype and clinical manifestations including short stature and labial adhesion, 1 child with a 46,XX/46,XY karyotype and clinical manifestations including micropenis, hypospadia, syndactyly and polydactyly, and 1 case with XXXX syndrome and clinical manifestations including growth retardation. CONCLUSION Among children with DSD due to sex chromosomal abnormalities, sex chromosome characteristics consistent with Turner syndrome was most common, among which mosaicism (XO/XX) was the commonest. In terms of clinical manifestations, the females mainly featured short stature, while males mainly featured external genital abnormalities. Early diagnosis and treatment are particularly important for improving the quality of life in such children.
Humans ; Male ; Female ; Turner Syndrome/genetics* ; In Situ Hybridization, Fluorescence ; Cryptorchidism ; Hypospadias ; Retrospective Studies ; Quality of Life ; Sex Chromosome Aberrations ; Karyotyping ; Mosaicism ; Disorders of Sex Development/genetics*

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Child ; China/epidemiology* ; Cryptorchidism/genetics* ; Disorders of Sex Development/genetics* ; Female ; Genital Diseases, Male ; Genotype ; Humans ; Hypospadias/genetics* ; Male ; Membrane Proteins/genetics* ; Penis/abnormalities* ; Phenotype ; Retrospective Studies ; Steroid 21-Hydroxylase/genetics*

OBJECTIVETo investigate the role of the MAMLD1 gene mutation in the pathogenesis of hypospadias in the Chinese population.

METHODSWe collected peripheral venous blood from 150 Chinese children with hypospadias (the case group) and another 120 normal healthy ones (the control group), aged 0.5 to 6 years. We obtained their DNA samples and performed DNA sequencing on the single-nucleotide polymorphisms of MAMLD1, followed by comparative analysis.

RESULTSA known missense mutation polymorphism p. N589S was identified in 12 (8.0%) of the hypospadias patients and 4 (3.0%) of the normal controls, and a novel missense mutation polymorphism p. N567S was identified in 4 (2.7%) of the patients and 3 (2.5%) of the controls, neither with statistically significant differences between the two groups (P > 0.05).

CONCLUSIONThe results re-emphasized the importance of replication in genetic association approaches, and might reveal a real difference in susceptibility genes among different populations. The single-nucleotide polymorphisms of MAMLD1 bear no obvious correlation with hypospadias, and MAMLD1 is not a candidate gene in its pathogenesis in the Chinese population.

Asian Continental Ancestry Group ; genetics ; Case-Control Studies ; Child ; Child, Preschool ; DNA-Binding Proteins ; genetics ; Gene Frequency ; Haplotypes ; Humans ; Hypospadias ; genetics ; Infant ; Male ; Nuclear Proteins ; genetics ; Polymorphism, Single Nucleotide ; Transcription Factors ; genetics