BACKGROUND:The anuran testis is a heterogeneous organ composed of germline and somatic cells mainly derived from the coelomic epithelium (Sertoli cells) and mesonephros (Leydig cells), which together regulate spermatogenesis and testicular architecture. SUMMARY:We provide an integrative overview of the developmental origin, structure, and function of somatic cells in evolutionary primitive and advanced anurans, with comparisons to other vertebrates. Initially bipotential gonad differentiates into testes by forming seminiferous cords and tubules composed of gonocytes and Sertoli cells, and a peritubular compartment containing Leydig cells. A distinctive feature of anurans is the continued proliferative capacity of Sertoli cells and their ability to form cysts in which spermatogenesis occurs within adult seminiferous tubules. Although key genes involved in testis differentiation are broadly conserved across vertebrates, their timing and functional roles often differ in anurans, where gonadal development is strongly influenced by steroid hormones, a feature typical of anamniotes. KEY MESSAGES:Vertebrate testes are homologous and share a basic organizational plan, differing mainly in cystic spermatogenesis in anamniotes versus tubular spermatogenesis in amniotes. While somatic cell lineages are largely conserved, anurans exhibit increased complexity in molecular regulatory pathways and remain understudied with respect to the developmental origins of specific cell populations.
INTRODUCTION:Delayed puberty in males requires differentiation between self-limited delay and congenital hypogonadotropic hypogonadism (CHH), including Kallmann syndrome (KS). CASE PRESENTATION:We report an adolescent male presenting with delayed puberty and anosmia, consistent with KS. Hormonal evaluation confirmed CHH, and MRI demonstrated olfactory bulb agenesis. Targeted next-generation sequencing identified two heterozygous variants in functionally related genes: a pathogenic nonsense variant in PROK2 and a missense variant in PROKR2 classified as a variant of uncertain significance. Given their ligand-receptor relationship, oligogenic analysis was performed. The variant combination was prioritized as highly likely disease-causing by ORVAL/VarCoPP and further supported by OLIDA-based interpretation, providing objective evidence for digenic inheritance. Parental segregation confirmed trans inheritance. CONCLUSION:To our knowledge, this is the first report with objective support for the high likelihood of the existence of a digenic etiology in a patient with CHH, based on the use of OLIDA, which provides a standardized framework for the interpretation of oligogenic combinations. These findings highlight the contribution of multilocus variation to CHH and underscore the need for standardized approaches to interpret oligogenic mechanisms in clinical practice.
Background: Disorders/differences of sex development (DSDs) comprise a group of congenital conditions characterized by atypical gonadal and/or anatomical development of the reproductive system. Among them, XX DSD (SRY-negative) represents a rare but clinically relevant condition, defined by the presence of testicular or ovotesticular tissue in chromosomal females lacking the SRY gene. This phenotype has been described in humans and several domestic species, including dogs, cats, and goats. Summary: Over the past decades, studies in dogs with 78,XX DSD (SRY-negative) have primarily focused on identifying causative mutations in candidate genes, particularly in SOX9. However, only a limited number of cases have been associated with SOX9 copy number variations, suggesting that additional genetic factors remain to be identified. In contrast, FOXL2, a key regulator of ovarian development and maintenance, has been relatively underexplored in canine studies. Functional evidence from mouse models highlights the importance of FOXL2 in ovarian differentiation and maintenance, as well as in craniofacial and skeletal development. 78,XX DSD has been increasingly reported in French Bulldogs, a breed predisposed to craniofacial and ocular abnormalities. Key Messages: Current evidence indicates that FOXL2 is a biologically plausible candidate gene for 78,XX DSD in dogs, although no causative variants have yet been identified. The observed cryptic relatedness among affected French Bulldogs suggests a shared genetic background. Future studies should include comprehensive sequencing of FOXL2, particularly its GC-rich coding regions, together with detailed clinical phenotyping. Integrating molecular and clinical data may improve understanding of the genetic basis of XX DSD and support more informed breeding strategies.
Introduction: Hybridization and polyploidy are increasingly recognized as major drivers of evolutionary innovation. By merging and multiplying genomes, they induce profound regulatory and structural perturbations that can alter phenotypes, yet the mechanisms by which they influence development remain debated. In particular, while theory predicts that polyploidy increases cause the increase in cell size, resulting in slower development, empirical findings are mixed. Moreover, the independent effects of polyploidization and hybrid genome admixture on early ontogeny are rarely disentangled. Here, we used the Cobitis taenia-C. elongatoides hybrid complex, a natural system comprising two sexual diploids and both diploid and triploid asexual hybrids to investigate how hybridization and polyploidy affect early development. Methods: We examined two key developmental processes: (1) the timing of embryonic progression from the first cleavage to somitogenesis and (2) migration of primordial germ cells (PGCs), which are crucial for reproductive competence. By comparing both hybrid types to each of their sexual progenitors, we were able to isolate the effects of genome merging versus genome multiplication. Results: We found distinct developmental delays linked to effects of the parental genome, hybridization, and ploidy. Initial cleavage dynamics was mostly attributable to differences between the two parental species, while later delays were more pronounced in hybrids, regardless of ploidy, highlighting hybridization-driven developmental shifts. Only at subsequent stages did ploidy-specific effects emerge, prolonging development in triploids against all diploid forms. In contrast, PGC number and migration were primarily influenced by ploidy, with triploids showing higher PGC counts than diploids. Conclusion: Our findings reveal that hybridization and polyploidy exert both independent and interactive effects on early ontogeny. The Cobitis complex thus offers a powerful model for exploring developmental consequences of genome restructuring.
Introduction: Disorders of sex development (DSDs) are rare in free-ranging cervids and remain poorly documented. Case Presentation: We describe a hunted red deer (Cervus elaphus) with well-developed antlers and male-typical morphology but female-like external genitalia, characterized by a hypertrophic clitoris/penile-like protrusion and absence of a scrotum. External genital tissues were available for histopathology, which revealed penile-type structures, including cavernous tissue and urethral-like epithelium. Genetic sex was assessed using PCR amplification of SRY and ZFX/ZFY markers from formalin-fixed, paraffin-embedded (FFPE) material. Due to the degraded DNA, we redesigned ZFY primers to yield a short amplicon suitable for compromised templates. PCR positivity for SRY and ZFY indicated the presence of Y-linked sequences. However, in the absence of internal reproductive organs, karyotyping and hormonal analyses, the etiology and DSD category cannot be determined, and chromosomal mosaicism or other Y-chromosome anomalies cannot be excluded. Conclusion: This report documents an unusual phenotype in a free-ranging red deer and provides a practical short amplicon ZFY assay for sex marker detection in degraded samples. Both genetic and environmental causes of DSD were considered; however, no definitive etiology could be established.
INTRODUCTION:Diagnostic copy number variants (CNVs) have been detected in up to 30% of individuals with DSD. Tools have been developed to detect CNVs from exome/genome sequencing. METHODS:Sequencing data from a cohort of individuals with DSD were re-analysed through a CNV-caller (Ximmer) after no diagnostic single nucleotide variants were identified through traditional sequencing analysis. RESULTS:A deletion was identified for an individual with gonadal dysgenesis that encompassed all exons of the gene WT1. CONCLUSION:This case reinforces the role of CNV analysis as part of genomic analysis, which holds exciting potential for improving diagnostic rates in the future.
Introduction: Tortoiseshell coat color in cats typically occurs in females due to random X-chromosome inactivation, which affects the expression of the orange coat color gene. The presence of a tortoiseshell phenotype in male cats usually indicates an unusual sex chromosome constitution. Case Presentation: A young Maine Coon tomcat with a normally developed penis was referred for genetic examination because of its tortoiseshell coat. At the age of 11 months, he successfully mated with a queen, which subsequently gave birth to five healthy kittens. Results: Cytogenetic analysis of chromosome preparations obtained from leukocyte cultures revealed the presence of 2 cell lines - XX and XY. Molecular studies were performed on DNA extracted from blood, hair follicles, and saliva using a ddPCR approach to estimate the ratio of Y- to X-chromosome copy numbers. These analyses confirmed the presence of both XX and XY cell lines in the tested tissues, with the highest proportion of the XX line detected in hair follicles. Conclusion: This study demonstrated that tortoiseshell tomcats with XX/XY chimerism can be fertile. Therefore, cytogenetic and molecular analyses of tri-colored male cats are recommended before making decisions regarding their use in breeding.
INTRODUCTION:The pre-B-cell leukemia transcription factor encoded by PBX1 is expressed throughout human embryonic stages. Accumulating cases with differences of sex development (DSDs) have been reported harboring PBX1 variants, suggesting a yet elusive role of PBX1 in the gonadal differentiation and sexual development processes. METHODS:We report a syndromic case of 46,XY DSD presenting severely undervirilized genitalia and gonadal dysgenesis with mixed ovarian and testicular differentiation, where whole-exome sequencing analysis identified a novel missense variant c.710G>C (p.R237T) in the highly conserved nuclear localization sequence in the three-amino acid loop extension domain of PBX1. RESULTS:Compared with wild-type (WT) PBX1, PBX1 p.R237T reduced protein stability and hampered nuclear translocation of PBX1 in the inducible Flp-In TREx HEK293 cells. Induction with tetracycline significantly decreased cell proliferation in both Flp-In HEK293 PBX1 WT and p.R237T cells compared to untransfected HEK293 cells, while adhesive ability was not different. RNA sequencing identified differentially expressed genes in DSD-related genes, including MAP3K4, EMX2, KISS1R, and HOXA13 in cells expressing PBX1 p.R237T when compared to cells expressing WT PBX1. CONCLUSION:Altogether, our results demonstrated the deleterious functional consequences of the rare PBX1 p.R237T variant identified in a Taiwanese proband with 46,XY DSD.
INTRODUCTION:Considering that testicular volume (TV) is probably not an adequate marker of pubertal onset in boys born small for gestational age (SGA), we aimed to describe the progression of pubertal clinical and biochemical characteristics, comparing the trajectory of TV with other parameters as markers of pubertal onset in boys born SGA. METHODS:We performed a retrospective, descriptive study of a cohort of boys born SGA with longitudinal follow-up. We determined the TV at the time when serum AMH decreased ≥30% or LH attained 0.35 IU/L. RESULTS:Thirty boys born SGA were included: 16 of 30 (53.3%) had LH ≥0.35 IU/L and 7 of 24 boys (29.2%) had a decline ≥30% in serum AMH with a TV <4 mL. LH ≥0.35 IU/L and AMH decrease ≥30% were observed at least 1 year before TV 4-5 mL in 11 of 22 (50%) and 3 of 19 (15.8%) boys, respectively. During follow-up, higher serum LH, FSH, and testosterone and lower AMH levels than those expected for TV were observed, indicating that some boys born SGA have a more advanced stage of puberty than their TV suggests. CONCLUSION:We identified a subgroup of boys born SGA in whom hormonal changes typical of initial puberty (serum LH ≥0.35 IU/L and AMH decline ≥30%) occurred before a clinical diagnosis of pubertal onset (TV ≥4 mL) was evident. These results indicate that TV 4 mL is not a reliable clinical sign of pubertal onset in all boys born SGA and that other biomarkers, such as serum LH and AMH, may need to be assessed.
INTRODUCTION:46,XY differences of sex development (DSD) are conditions with extreme phenotypic and genetic heterogeneity. Therefore, their diagnosis remains a major challenge for both clinicians and geneticists. In this study, we aimed to identify the underlying genetic causes of DSD in a series of 3 Moroccan patients with syndromic 46,XY DSD recruited in the BRO Biobank. CASE PRESENTATIONS:Methods: Karyotyping analysis was performed on peripheral blood samples using standard R banding techniques. SRY gene was analyzed using PCR amplification followed by Sanger sequencing. Whole exome sequencing (WES) was performed after unsuccessful conventional genetic analyses. Candidate variants were evaluated by segregation analysis and molecular modeling. RESULTS:WES identified three pathogenic variants in genes encoding various components of the epigenetic machinery: in patient 1, a novel heterozygous frameshift variant c.4072dup (p.Glu1358GlyfsTer29) in the KAT6B gene associated with two clinically distinct syndromes (genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome) was detected; in patient 2, we identified a previously reported de novo heterozygous nonsense variant c.12943C>T (p.Gln4315Ter) in KMT2D responsible for Kabuki syndrome; in patient 3, WES revealed a novel heterozygous missense variant c.4056C>G (p.Phe1352Leu) in CHD7 responsible for CHARGE syndrome. We discuss the genotype-phenotype correlation in these syndromic 46,XY DSD and discuss the relevance of the epigenetic genes in sexual development. CONCLUSION:Our findings highlight the utility of WES in discriminating clinically overlapping syndromic 46,XY DSD to provide an accurate diagnosis, thus allowing better follow-up and appropriate patient management. In addition, our study enriched the mutational spectrum of syndromic 46,XY DSD and confirmed the genotype-phenotype correlations.
INTRODUCTION:The transcription factors Forkhead box L2 (FOXL2) and SRY-box transcription factor 9 (SOX9), among others, are required for embryonic ovarian and testicular differentiation, respectively. In patients with complete androgen insensitivity syndrome (CAIS), the testes are usually undescended and may show histological changes similar to those sometimes seen in patients with undescended testes (UDT). The aim of this study was to explore the expression of FOXL2 and SOX9 in testes from patients with CAIS and UDT. METHODS:Immunohistochemical staining with FOXL2 and SOX9 was performed on samples from 13 patients with CAIS and 20 with UDT. RESULTS:In addition to nuclear SOX9 expression in intratubular Sertoli cells, FOXL2 expression was present in stromal cells in 8 of 9 patients with CAIS and in 1 of 20 with UDT. Moreover, FOXL2 expression was found in the rete testis in three of nine samples that included this region. CONCLUSION:Expression of the ovarian-specific marker FOXL2 in regions of the testes of patients with CAIS and UDT has not previously been documented and suggests partial activation of the female pathway within these testes. Further research is needed, including FOXL2 protein expression studies in larger series and molecular studies, e.g., transcriptome analysis, to understand the pathophysiology and clinical significance of these novel findings.
Background Sexual size dimorphism (SSD), i.e., size difference between sexes, is common in fishes and spans from negligible to extreme body size differences, with both female‑ and male‑biased directions. While evolutionary drivers behind SSD such as sexual selection, fecundity selection and natural selection are increasingly well understood, our understanding of the underlying mechanisms of how sex‑specific growth trajectories develop is less clear. Summary Here we review recent findings of such mechanisms in fishes and reveal that SSD arises from an interplay of sex-linked and autosomal genetic factors. In teleosts, master sex-determining genes and growth regulators such as dmrt1/dmY, sdY, amhr2by, gdf6Y and gsdfY play key roles, while quantitative trait loci (QTL) influence growth and maturation, further contributing to SSD. Essential sex-specific regulation of hormones across brain, pituitary, liver and gonad determines SSD directionality. Epigenetic mechanisms, such as DNA methylation and non-coding RNA further modulate gene expression in growth and reproductive pathways. We identify the basic mechanisms, highlight knowledge gaps, and propose that multi-omics approaches can disentangle sex effects from dimorphism-specific regulation, linking together endocrine, genetic and epigenetic drivers. Key Messages 1. At the mechanistic level, SSD results from an interplay of genetic, endocrine and environmental influences. 2. Sex chromosomes and autosomal loci form the genetic architecture that shapes growth differences between males and females. 3. The somatotropic axis, involving GH/IGF signaling, together with the actions of sex steroids, serves as a central effector system underlying SSD in fish. 4. Epigenetic mechanisms help establish and maintain sex-specific gene expression programs, but integrative multi‑omic approaches are needed to uncover causal relationships and phenotypic plasticity in SSD.
BACKGROUND:The management of 46,XY disorders of sex development (DSD) is challenging due to genetic heterogeneity and phenotypic variability. This study aimed to characterize the clinical and genetic findings in patients with 46,XY DSD, using a targeted next-generation sequencing (NGS) panel for molecular evaluation. METHODS:A targeted DSD gene panel covering 31 genes was applied in 112 patients with nonsyndromic 46,XY DSD. Forty-six patients had previously tested negative for AR and SRD5A2 by Sanger sequencing. Patients were clinically categorized into disorders of gonadal development, androgen synthesis or action. Variant classification was performed according to the ACMG criteria. RESULTS:Among the 38 variants detected, 32 were pathogenic or likely pathogenic. Nineteen (50%) variants were novel. A molecular diagnosis was established in 31 (27.7%) patients and inclusion of previously diagnosed cases would have increased the overall diagnostic yield to 43.8%. The HSD17B3 variants were the most common, followed by NR5A1 and LHCGR. In 8 patients, the genetic findings led to reclassification of their clinical diagnosis, particularly in those initially suspected to have a disorder of androgen action. CONCLUSION:NGS is a valuable diagnostic tool in the evaluation of 46,XY DSD, offering improved diagnostic yield. For patients without molecular diagnosis, more comprehensive genomic analyses, including noncoding regions, are required.
Introduction: Previous research has shown substantial variation in sexual dimorphism of facial structure and skin color across human populations. This study investigates sexual dimorphism in both facial shape and skin color in understudied populations from the Horn of Africa – Somalis and Ethiopians – focusing on the relationship between facial morphology and pigmentation traits. Methods: Standardized frontal and profile photographs were collected from participants and analyzed using geometric morphometrics. Sexual shape dimorphism (SShD) was calculated by projecting each individual's facial shape onto a vector connecting average male and female shapes in Procrustes-aligned morphospace; higher values indicate more masculine morphology. Sexual color dimorphism (SCoD) was computed similarly, by projecting individual skin color values (from forehead and cheeks) onto a vector defined by average male–female difference in the CIE Lab* color space. Trajectory analysis and Bayesian hierarchical modelling were performed to examine associations between SShD and SCoD. Results: Significant sexual dimorphism was detected in both facial shape and skin color across both populations. Male faces tended to be more robust and darker, while female faces were more gracile and lighter-skinned. However, despite group-level sex differences, individual-level associations between facial structure and skin pigmentation were weak or absent. Somali participants exhibited greater dimorphism in skin color compared to Ethiopians, while facial shape dimorphism remained consistent between groups. Conclusion: Both target populations revealed significant sexual dimorphism in both structural and pigmentation facial traits. However, in contrast to previous findings reported in certain West African populations, we found no statistically reliable association between these two traits at the individual level. This decoupling may indicate distinct evolutionary or ecological pressures shaping morphological and pigmentation traits. Our findings suggest that no universal trade-off or consistent relationship exists between morphological and pigmentation components of sexual dimorphism across human populations.
Introduction: Sexual conflict is pervasive and can favor the evolution of differential gene expression patterns between males and females. The evolution of such sex-biased expression patterns is constrained by pleiotropic functions of differentially expressed genes, such as widespread expression across tissues. Methods: We investigated sex-biased gene expression and its relationship to tissue specificity in reproductive and somatic organs in the Northern pipefish, Syngnathus fuscus, a polygynandrous species with extreme paternal care and no evidence of sex chromosomes – conditions ripe for intra-locus sexual conflict. Results: We found patterns of sex-biased expression in the gonads, liver, and gills of the Northern pipefish, with the largest number of sex-biased genes identified in the gonads. In general, sex-biased genes were only more tissue-specific in the reproductive tissues (gonads), but not in either of the somatic tissues (liver or gills). Sex-biased genes with evidence of branch-specific selection were also more tissue specific. Discussion: We highlight the potential for different sex-specific selection pressures to be acting on each tissue type as there were widespread differences in the protein classes represented by sex-biased genes across both organs and sexes, although sex-biased genes did not experience stronger episodic selection than unbiased genes. Furthermore, our results support the hypothesis that broad expression can constrain the molecular evolution of a gene. The work presented here supports the potential for sex-biased gene expression to act as a mechanism for phenotypic differentiation between the sexes and increases our knowledge of patterns of gene expression in an unusual group of fishes.
INTRODUCTION:The Y chromosome-linked gene sult1st6y (a homolog of the estrogen sulfotransferase gene) has recently been identified in Thunnus, a genus characterized by an XX/XY sex determination system. This study examined whether sult1st6y is a sex-determining gene in bluefin tuna (Thunnus orientalis). METHODS:The expression of sult1st6y was examined using polymerase chain reaction analyses and in situ hybridization. Sult1st6y expression in masculinized XX testes produced by aromatase inhibitor administration and the expression profile of the sult1st6y mutant, which was produced using CRISPR/Cas9, were examined. RESULTS:Sult1st6y was specifically expressed in XY gonads during sex differentiation. The onset of sult1st6y expression preceded that of other genes promoting sex differentiation. Sult1st6y expression was not detected in masculinized XX testes, indicating that gonads can differentiate into testes without sult1st6y if estrogens are depleted. The Sult1st6y mutant XY gonad showed a gene expression pattern similar to that of wild-type XX gonads. CONCLUSION:Our results collectively suggest that sult1st6y is at the top of the molecular cascade that regulates gonadal sex differentiation. Sult1st6y may trigger testicular differentiation by deactivating estrogens, although its biochemical activity should be examined. This study provides evidence that sult1st6y is a major candidate sex-determining gene in tuna.
Introduction: SEMA3E is a secreted class 3 semaphorin that, in mice, plays roles in neuronal guidance, cardiovascular morphogenesis, angiogenesis, and vascular homeostasis. Adult male mice lacking SEMA3E exhibit reduced testicular size compared to wild-type littermates, indicating a potential role in reproductive function. In humans, heterozygous missense variants in SEMA3E were initially reported to be associated with CHARGE syndrome and hypogonadotropic hypogonadism with anosmia. However, these associations have since been questioned, and the contribution of SEMA3E variants to human disease is unclear. METHODS:We describe the results of exome sequencing of a 46,XY boy with unexplained bilateral testicular regression syndrome and optic nerve atrophy. RESULTS:Exome sequencing indicates that he carries a heterozygous frameshift variant (c.942del, p.Leu314PheTer11) in the SEMA3E gene. The variant is located within the functional SEMA domain of the protein and is predicted to trigger nonsense-mediated mRNA decay. This is the second reported loss-of-function (LoF) variant in the highly conserved SEMA3E gene. A previously described LoF variant was identified in a child presenting with severe intellectual disability and cognitive regression. CONCLUSION:LoF SEMA3E variants may be associated with a broad and variable spectrum of clinical phenotypes. .
Introduction: Transgender identity is a complex and multifactorial condition shaped by the effects of environmental and cultural factors as well as its biological basis. Genes involved in neurodevelopment and neuroplasticity may contribute to brain sexual differentiation, and rare variants in these genes could play a role in gender diversity. This study aimed to enhance explanations for the genetic component of transgender identity. METHODS:After the filtering process applied to the WES analysis data obtained from eight transgender men (TM), the gene list was generated. Previously reported genes were scanned in the gene list with a detailed literature review and data mining. Functional enrichment, protein classification, pathway, and genetic interaction network analysis were performed to determine the salient genes. RESULTS:A total of 30 variants were detected in 18 genes reported in the literature. The rs879121178 (GOLGA8J) variant, previously reported in 1 TW (transgender woman) and 1 TM, and the rs548940626 (PCDHA8) variant, previously reported in 1 TW, were present in two different individuals (individuals 5 and 6, respectively). In the functional enrichment analysis, the highest enrichment score in biological processes was detected in the cluster related to cell adhesion (enrichment score: 12.91) and the most enriched term was "homophilic cell adhesion via plasma membrane adhesion molecules" with 54 genes (p: 3.1E-11). CONCLUSIONS:Our study shows that rare variants in cell adhesion genes, previously reported in TW, are also prominent in TM. These findings may help guide further investigations into genes that could be relevant to neurodevelopmental pathways, including those involved in brain sexual differentiation. .
Background: 46,XX testicular/ovotesticular disorders of sexual development (T/OT DSD) are infrequent congenital conditions characterized by the presence of functional ovarian and testicular or only testicular parenchyma. OBJECTIVE:The aim of the study was to retrospectively describe clinical, hormonal, and genetic characteristics of 29 patients with 46,XX T/OT DSD (2000-2023), focusing on gonadal function, hormonal production, and long-term follow-up. RESULTS:Most patients (n = 25, 86.2%) presented with atypical genitalia that suggested DSD. Median age at first assessment was 0.38 years. Sex assignment was male in 21 patients without reports of discordant gender identity. Sex assignment was recommended before expert evaluation and without adequate studies in 64% of those patients with atypical genitalia (16/25). The median external masculinization score was 8 (range 4-12). During mini-puberty, LH, testosterone, AMH, and the LH/FSH ratio were above the female reference range and no different from the normal male reference range. Spontaneous puberty was observed in one female and 10 male-assigned subjects. Among the latter, pubertal virilization occurred with signs of hypergonadotropic hypogonadism and gynecomastia. Molecular studies identified the underlying mechanism in 7 patients: SRY gene was identified in two, WT1 gene variations were detected in three others, and 2 syndromic patients harbored complex chromosomal rearrangements. CONCLUSION:Our findings underscore the clinical and biochemical variability in 46,XX T/OT DSD. Expert evaluation and accurate diagnostic work-up are essential prior to sex assignment and to prevent misdiagnosis and inappropriate treatments. Mini-puberty was characterized by a masculinized pattern of gonadotropin secretion. The potential for functional male pubertal development should be taken into account when making sex assignment decisions. .
Introduction: Although maternal microchimerism has been implicated in various disorders in children, its association with the risk of 46,XY disorders of sex development remains unknown. METHODS:We studied 22 boys with hypospadias using highly sensitive quantitative PCR assays. In seven cases with additional anomalies, microarray-based comparative genomic hybridization and whole-exome sequencing confirmed the lack of apparent pathogenic variants. RESULTS:Maternal microchimeric cells were detected in 2 patients (1.9 and 32.0 cells per 106 total cells). The results were comparable to our reference data. CONCLUSION:This study argues against the significant role of maternal microchimerism in the risk of hypospadias. .
