The prevalence of hypospadias varied internationally. However, epidemiological data on hypospadias in contemporary China remain limited. We aim to examine the epidemiological characteristics of hypospadias in Chinese population. We performed a prevalence analysis using data from the Chinese Birth Defects Monitoring Network from 2010 to 2020. We analyzed the prevalence of overall, isolated, and associated hypospadias by birth year, maternal age, maternal residence, and geographic region. We used Poisson regression with adjusted prevalence rate ratios for assessing the impact of demographic characteristics and Joinpoint regression for analyzing temporal trends. A total of 11,782 hypospadias cases were identified among 11,575,036 male births with a prevalence of 10.18 per 10,000 male births. Of these, 9700 (82.3%) were isolated and 2082 (17.7%) were associated hypospadias. Of these cases, 639 (5.4%) were classified as anterior hypospadias, 1052 (8.9%) as middle hypospadias, 413 (3.5%) as proximal hypospadias, and 9678 (82.1%) as unspecified hypospadias, based on their severity. The prevalence of overall, isolated, and associated hypospadias increased significantly over the study period. Prevalence also varied significantly by maternal residence, maternal age, and geographical region. Infants with associated hypospadias experienced a significant higher risk of perinatal death. The most frequent associated anomalies involved the cardiovascular, genitourinary, and musculoskeletal systems. This study provides contemporary national data on the epidemiology of hypospadias in China. The observed increasing prevalence and variations by severity underscore the need for further etiological, epidemiological, and clinical research.

To present the prenatal sonographic features and genomic spectrum of pregnancies with fetal Rubinstein-Taybi syndrome (RSTS). This was a retrospective study of 12 cases with RSTS with fetal features identified by prenatal ultrasound and confirmed by genetic testing. Chromosomal microarray analysis utilizing an Affymetrix CytoScan 750k SNP array was employed to detect pathogenic copy number variations (CNVs). Trio exome sequencing was used to detect monogenic conditions. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, molecular testing sequencing results, and pregnancy outcomes. All cases had unremarkable first-trimester ultrasound scans without reporting limb malformations. Seven cases presented with abnormal second-trimester ultrasounds: three instances of cardiac defects, two instances of limb abnormalities (one with short long bones and one with duplication of big toes), one case of intracranial malformation (dysgenesis of the corpus callosum), and one instance of restricted fetal growth. Five pregnancies exhibited abnormal sonographic signs in the third trimester: two cases of restricted fetal growth, one with clubfeet and polyhydramnios, one with hypospadias, and one with isolated polyhydramnios. CNVs involving CREBBP deletions were detected in two cases. Variants were identified in two genes: CREBBP in six instances and EP300 in four instances; all CNVs or variants were de novo. Our results underscore the challenges faced in the prenatal detection of RSTS due to the lack of specific clinical presentations. Our study highlights that even nonspecific findings on prenatal ultrasound may justify exome sequencing, enabling timely potential genetic diagnoses and improving clinical management.

Sex differentiation is a complex process controlled by several genes. GATA4 and NR5A1 interact at all stages of this process, starting from bipotential gonad development to testicular differentiation. Mutations in these two genes, which are in close relationship to each other in both Leydig and Sertoli cell development and function, may cause similar phenotypes. There have been reports in the literature of patients with the NR5A1 mutation becoming virilized at puberty, but no reports of GATA4 virilizing at puberty. We evaluated the characteristics of 46, XY gonadal dysgenesis patients with NR5A1 and GATA4 mutations, which we follow in our clinic to determine diagnostic clues. We had ten 46, XY cases with NR5A1 and/or GATA4 mutations (10 from 8 different families). Clinical and hormonal features of all cases were compatible with gonadal dysgenesis. The phenotype was variable, such as ambiguous genitalia, amenorrhea, or pubertal virilization. Six out of 10 cases were raised as girls. A broad range of 46, XY DSD phenotypes, including isolated hypospadias, ambiguous external genitalia with a bifid scrotum, and/or micropenis up to fully female external genitalia, have been linked to GATA4 and NR5A1 variations. In our study, we have one case with a GATA4 mutation and two cases with NR5A1 mutation that became virilized at puberty. In cases of DSD, abnormal expression of the GATA4 gene should be considered even if there is no congenital heart disease (CHD). The NR5A1 and GATA4 gene mutations should be included in the differential diagnosis of DSD patients when virilization during puberty has been identified.

Sex chromosome abnormalities in cattle are rare, and manifestations of genital anomalies due to such abnormalities are even less frequently reported. Among these, XXX/XY chimerism is particularly uncommon. This report presents a Japanese black calf with complex urogenital malformations linked to XXX/XY chimerism, contributing valuable insights into bovine sex determination and reproductive development. A Japanese black calf of phenotypic indeterminate sex, born co-twin to a phenotypically normal male, presented with hypospadias-like features and ambiguous genitalia. Clinical examination revealed a scrotum-like structure without palpable testes or vulva. An hCG stimulation test indicated a lack of functional testicular tissue. Chromosomal analysis of leukocytes revealed the presence of two distinct cells with 60, XY and 61, XXX, revealing XXX/XY chimerism. The ratio of male to trisomic cells was 63:37 (95% confidence intervals; XY: 54-72%, XXX: 28-46%) in the affected calf. Necropsy revealed both male (testis, epididymis, ductus deferens) and female (uterus-like) reproductive structures, with uterus-like organs embedded within the perineal tissue. Histological and immunohistochemical analyses confirmed the presence of the uterine remnant and revealed Sertoli cell-only testicular tissue, indicating spermatogenic failure. PCR-based sex determination performed on multiple tissues revealed three distinct genotypic patterns, with evidence of tissue-specific variation in the distribution of the X and Y chromosomes. Some tissues lacked detectable Y-linked AMEL-Y, despite the presence of SRY, suggesting a complex chimeric constitution with potential deletion of the AMEL-Y region in some XY cell populations. This case highlights a rare instance of systemic XXX/XY chimerism associated with ambiguous genitalia and mixed internal reproductive structures, which is distinct from typical freemartinism or isolated X-trisomy syndromes. The differential chromosomal mosaicism across tissues likely influences the phenotypic outcome. These findings emphasize the complexity and plasticity of bovine sex differentiation, particularly in twin pregnancies, and underscore the importance of integrating clinical, cytogenetic, and molecular diagnostics to accurately identify and manage congenital reproductive anomalies in livestock. MYRF-related cardiac urogenital syndrome (MYRF-CUGS) is primarily characterized by anomalies of the internal and external genitalia, congenital heart defects, and eye anomalies. 46,XY individuals can have a range of anomalies of the genitalia, from isolated unilateral cryptorchidism to ambiguous genitalia to typical-appearing female genitalia. Although the data is extremely limited, there may be an increased risk of gonadoblastoma in affected 46,XY individuals. 46,XX individuals can have atypical internal genitalia including absent uterus, absent fallopian tubes, small or absent ovaries, absent vagina, or blind-ending vagina. A number of congenital heart defects have been described, with scimitar syndrome being the most common. Eye issues, present in a vast majority of affected individuals, include high hyperopia and nanophthalmos (an ocular malformation featuring short axial length due to small anterior and posterior segments with thickened choroid and sclera and normal lens volume). Because of the common nature of the eye anomalies, it has been suggested that this condition may be more accurately referred to as "MYRF-related ocular cardiac urogenital syndrome." Other features of the condition include a broad range of developmental delay /intellectual disability (DD/ID), from typical development and cognition to severe DD/ID; pulmonary abnormalities and diaphragmatic issues (congenital diaphragmatic hernia / diaphragmatic eventration); intestinal malrotation; and mild growth and feeding problems. The diagnosis of MYRF-CUGS is established in a proband with suggestive findings and a heterozygous pathogenic variant in MYRF identified by molecular genetic testing. Treatment of manifestations: Standard treatment for differences of sex development (DSD) conditions, including hormone therapy, psychosocial support, gender identity assessment, and surgical intervention (e.g., orchidopexy and/or hypospadias repair); thyroid replacement therapy for hypothyroidism; standard treatment of refractive error, nanophthalmos, DD/ID, congenital heart defects, diaphragmatic defects, pulmonary hypoplasia, intestinal malrotation, splenic anomalies, and renal anomalies. Surveillance: Measurement of growth parameters, assessment of developmental progress and educational needs, and monitoring for respiratory insufficiency at each visit; at least annual ophthalmic evaluations; monitoring for onset and progression of puberty at each visit from around age seven years until puberty is complete; assessment of mood, libido, energy, erectile function, acne, breast tenderness, and presence or progression of gynecomastia at each visit in undervirilized 46,XY adolescents and adults; monitoring for gonadoblastoma in 46,XY individuals with remaining gonads, particularly in those with a history of cryptorchidism; DXA scan in individuals with DSD every three to five years after puberty, or annually if osteopenia is identified. For those on testosterone replacement therapy, measurement of serum testosterone levels at three-month intervals to help establish an optimal dose with subsequent annual measurements; measurement of hematocrit, prostate-specific antigen level, and digital rectal exam three, six, and 12 months after initiation of testosterone therapy and then annually; lipid profile and liver function tests annually. Agents/circumstances to avoid: Hormone replacement therapy in those with hormone-responsive cancers; oral androgens (e.g., methyltestosterone or fluoxymesterone) for long-term therapy due to liver toxicity. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of screening and treatment measures. MYRF-CUGS is inherited in an autosomal dominant manner. Many affected individuals reported to date have the disorder as the result of a de novo MYRF pathogenic variant. Each child of an individual with MYRF-CUGS has a 50% chance of inheriting the MYRF pathogenic variant. Manifestations within a family are highly variable, and offspring may have significantly more or fewer manifestations than the proband. Once the MYRF pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

To describe the outcomes of pregnancies exposed to IL-1 targeted therapies (anti-IL-1): anakinra and/or canakinumab. We performed a descriptive observational study based on data from CRAT, the French Teratology Information Service. We included prospective and retrospective pregnancies exposed to anakinra and/or canakinumab with known outcomes. Pregnancy, foetal and neonatal outcomes were analysed. Between 2007 and 2023, 57 pregnant women exposed to anti-IL-1 were referred, including 27 (47.3%) treated for Still's disease. Among prospective cases, 52 foetuses (one twin pregnancy) were exposed to anakinra (n = 43), canakinumab (n = 5) or both medications (n = 4). For anakinra: (i) 40/47 cases (85.1%) were exposed during the first trimester (T1), and 21/47 (44.7%) during all pregnancy, (ii) 40/47 (85.1%) resulted in livebirths, 5/47 (10.6%) early miscarriages, one medical abortion (mother-transmitted syndrome) and one elective abortion, (iii) one isolated hypospadias was reported (anakinra between 0 and 4 weeks of gestation), for a prevalence of major congenital malformation of 3.03% IC 95% [0.1-15.1] among T1-exposed pregnancies. For canakinumab, all cases (9/9) were exposed during T1 and 2/9 during all pregnancy: all resulted in livebirths with no malformation. Concerning retrospective pregnancies (anakinra = 6/6), all resulted in live births. Cardiopathy with hypospadias was identified in a child with a rare genetic anomaly. No significant effects were reported while breastfeeding (n = 9). In this study, the largest series to date, our results do not suggest occurrence of specific negative outcomes in pregnancies exposed to anti-IL-1. The imputability of anakinra in the malformations observed is unlikely. If needed, their use during pregnancy should be considered.