Mixed Gonadal Dysgenesis: A Narrative Literature Review and Clinical Primer for the Urologist.

PURPOSE: Mixed gonadal dysgenesis is a difference of sex development that is often confused with other conditions. Individuals have a 45,X/46,XY karyotype. Gonads are characterized by a streak gonad and a dysgenetic testis at varying levels of descent. Persistent Müllerian structures are typical (eg, hemi-uterus). There is significant phenotypic heterogeneity of the internal and external genitalia that, together with different interpretations of the definition, have contributed to a poor understanding of the condition among pediatric urologists. Mixed gonadal dysgenesis is one manifestation of the 45,X/46,XY karyotype. 45,X/46,XY mosaicism can also be associated with typical female or male external genitalia. This review aims to clarify the mixed gonadal dysgenesis definition and to provide urologists with diagnostic and management considerations for affected individuals. MATERIALS AND METHODS: We searched 3 medical databases for articles related to mixed gonadal dysgenesis. Two hundred eighty-seven full-text abstracts and manuscripts were reviewed for content pertinent to: (1) clarifying the definition of mixed gonadal dysgenesis, and (2) describing the following related to the care of affected individuals: prenatal and neonatal evaluation and management, genital surgery, gonadal malignancy risk and management, fertility, gender dysphoria/incongruence, puberty and long-term outcomes, systemic comorbidities, and transitional care. RESULTS: Fifty articles were included. Key points and implications for each of the above topics were summarized. CONCLUSIONS: Mixed gonadal dysgenesis exists on a wide phenotypic spectrum and management considerations reflect this heterogeneity. Care for individuals with mixed gonadal dysgenesis is complex, and decisions should be made in a multidisciplinary setting with psychological support.

Expanding the phenotype of neurofibromatosis type 1 microdeletion syndrome.

Neurofibromatosis type 1 (NF-1) microdeletion syndrome accounts for 5 to 11% of individuals with NF-1. The aim of our study was to characterize a large cohort of individuals with NF-1 microdeletion syndrome and expand its natural history. We conducted a retrospective chart review from 1994 to 2024 of individuals with NF-1 microdeletion syndrome followed at two large Neurofibromatosis Clinics. This cohort consists of 57 individuals with NF-1 microdeletion syndrome (28 type-1, 4 type-2, 2 type-3, 9 atypical deletions, and 14 indeterminate). We note 38/56 (67.9%) with describable facial features, 25/57 (43.8%) with plexiform neurofibromas, and 3/57 (5.2%) with malignant peripheral nerve sheath tumors within the observed period. The most reported neurodevelopmental manifestations from school-age or older individuals included 39/49 (79.6%) with developmental delays, 35/49 (71.4%) with expressive and/or receptive speech delays, 33/41 (80.5%) with learning difficulties, and 23/42 (54.8%) with attention-deficit/hyperactivity disorder. Full-scale IQ testing data was available for 22 individuals (range: 50-96). Of the 21 adults in this cohort, 14/21 (66.7%) graduated from high school, and 4/21 (19.0%) had some college experience. Many individuals received academic support (i.e., special education, individual education plan). In this cohort, neurocognitive outcomes in adults varied more than typically reported in the literature.

Turner Syndrome With Y Chromosome and Germ Cells: A Case Report Highlighting the Need to Prioritize Individualized Care.

Turner syndrome (TS) is a genetic condition in phenotypic females in which the individual has 1 intact X chromosome and the second sex chromosome is absent or structurally altered Components of Y chromosome (eg, 45,X/46,XY) have been found in 5%-15% of patients with TS; these patients are often referred to as having "Turner syndrome with Y" (TS+Y). The presence of Y chromosome material increases risk for development of gonadal tumors. Historically, prophylactic gonadectomy has been recommended in this population to prevent malignancy, and patients were presumed infertile due to the presence of streak gonads with no germ cells (GCs). More recently, studies have reported on spontaneous puberty and menarche in TS+Y patients suggesting the presence of viable GC and ovarian function. Our institution offers patients with TS+Y the option of experimental gonadal tissue cryopreservation (GTC) at the time of gonadectomy. We present a unique case of a young girl with TS+Y who had GCs present in her gonads and underwent experimental GTC at the time of gonadectomy.

Outcomes and Associated Extracardiac Malformations in Neonates from Colombia with Severe Congenital Heart Disease.

Congenital heart disease (CHD) is a common structural anomaly, affecting ~ 1% of live births worldwide. Advancements in medical and surgical management have significantly improved survival for children with CHD, however, extracardiac malformations (ECM) continue to be a significant cause of morbidity and mortality. Despite clinical significance, there is limited literature available on ECM in neonates with CHD, especially from Latin America. A cross-sectional study of neonates with severe CHD evaluated by the medical-surgical board team at Fundación Cardiovascular de Colombia from 2014 to 2019 was completed to characterize morbidity, mortality, surgical outcomes, and ECM. Demographics and surgical outcomes were compared between neonates with and without ECM. Medical record data were abstracted and descriptive statistical analysis was performed. Of 378 neonates with CHD, 262 had isolated CHD (69.3%) and 116 had ECM (30.7%). The most common ECM was gastrointestinal (n = 18, 15.5%) followed by central nervous system (n = 14, 12%). Most neonates required a biventricular surgical approach (n = 220, 58.2%). Genetic testing was performed more often for neonates with ECM (n = 65, 56%) than neonates with isolated CHD (n = 14, 5.3%). Neonates with ECM had lower birth weight, longer hospital stays, and higher postsurgical complications rates. There was no difference in survival between groups. Overall, Screening for ECM in neonates with CHD is important and identification of ECM can guide clinical decision-making. These findings have important implications for pediatric healthcare providers, especially in low- and middle-income countries, where the burden of CHD is high and resources for managing CHD and extracardiac malformations may be limited.

Clinical utility of early rapid genome sequencing in the evaluation of patients with differences of sex development.

Establishing an early and accurate genetic diagnosis among patients with differences of sex development (DSD) is crucial in guiding the complex medical and psychosocial care they require. Genetic testing routinely utilized in clinical practice for this population is predicated upon physical exam findings and biochemical and endocrine profiling. This approach, however, is inefficient and unstandardized. Many patients with DSD, particularly those with 46,XY DSD, never receive a molecular genetic diagnosis. Rapid genome sequencing (rGS) is gaining momentum as a first-tier diagnostic instrument in the evaluation of patients with DSD given its ability to provide greater diagnostic yield and timely results. We present the case of a patient with nonbinary genitalia and systemic findings for whom rGS identified a novel variant of the WT1 gene and resulted in a molecular diagnosis within two weeks of life. This timeframe of diagnosis for syndromic DSD is largely unprecedented at our institution. Rapid GS expedited mobilization of a multidisciplinary medical team; enabled early understanding of clinical trajectory; informed planning of medical and surgical interventions; and guided individualized psychosocial support provided to the family. This case highlights the potential of early rGS in transforming the evaluation and care of patients with DSD.

Workflow for Management of Gonadal Neoplasm in 2 Patients with Differences of Sex Development Enrolled in an Experimental Gonadal Tissue Cryopreservation Protocol.

OBJECTIVE: To outline our experimental gonadal tissue cryopreservation (GTC) protocol that does not disrupt the standard of care in medically-indicated gonadectomy for patients with differences of sex development, including highlighting the multidisciplinary collaborative protocol for when neoplasm is discovered in these cases. METHODS: Two patients with complete gonadal dysgenesis who were undergoing medically-indicated prophylactic bilateral gonadectomy elected to pursue GTC. Both were found to have germ cell neoplasia in situ on initial pathologic analysis, requiring recall of the gonadal tissue, which had been cryopreserved. RESULTS: Cryopreserved gonadal tissue was successfully thawed and transferred to pathology for complete analysis. No germ cells were identified in either patient nor were found to have malignancy, so further treatment beyond gonadectomy was not indicated. Pathologic information was communicated to each family, including that long-term GTC was no longer possible. CONCLUSION: Organizational planning and coordination between the clinical care teams, GTC laboratory, and pathology were key to handling these cases with neoplasia. Processes that anticipated the possibility of discovering neoplasia within tissue sent to pathology and the potential need to recall GTC tissue to complete staging included (1) documenting the orientation and anatomical position of tissue processed for GTC, (2) defining parameters in which tissue will be recalled, (3) efficiently thawing and transferring GTC tissue to pathology, and (4) coordinating release of pathology results with verbal communication from the clinician to provide context. GTC is desired by many families and at the time of gonadectomy and is (1) feasible for patients with DSD, and (2) did not inhibit patient care in 2 patients with GCNIS.

Cardiovascular Manifestations of Turner Syndrome: Phenotypic Differences Between Karyotype Subtypes.

Turner syndrome (TS) is a genetic disorder presenting in phenotypic females with total or partial monosomy of the X chromosome. Cardiovascular abnormalities are common, including congenital heart defects (CHD) and aortic dilation. Although mosaic TS is suspected to have less severe phenotype as compared to non-mosaic TS, differences in cardiovascular manifestations between karyotypes are not well studied. This is a single-center retrospective cohort study including patients with TS seen from 2000 to 2022. Demographic data, chromosomal analysis, and imaging were reviewed. Karyotypes were categorized as monosomy X (45X), 45X mosaicism, isochromosome Xq, partial X deletions, ring X (r(X)), TS with Y material, and others. Prevalence of CHD and aortic dilation were compared between monosomy X and other subtypes using Pearson's chi-square test and Welch two-sample t-test. We included 182 TS patients with median age 18 (range 4-33) years. CHD was more common in monosomy X as compared with others (61.4% vs. 26.8%, p < 0.001), including bicuspid aortic valve (44.3% vs. 16.1%, p < 0.001), partial anomalous pulmonary venous return (12.9% vs. 2.7%, p = 0.023), persistent left superior vena cava (12.9% vs. 1.8%, p = 0.008), and coarctation of the aorta (20.0% vs. 4.5%, p = 0.003). Cardiac surgery (24.3% vs. 8.9%, p = 0.017) was more prevalent in the monosomy X group. There was no statistically significant difference for presence of aortic dilation (7.1% vs 1.8%, p = 0.187). Although CHD and need for cardiac surgery are more common in TS with monosomy X as compared to others, all TS subtypes may have similar risk of developing aortic dilation. All TS patients should have similar cardiovascular surveillance testing to monitor for aortic dilation.