47,XYY syndrome is a relatively common sex chromosome aneuploidy that remains largely underdiagnosed. While its somatic phenotype is often mild, growing evidence indicates a substantial burden of neurodevelopmental and psychiatric morbidity. However, the characterization of the neuropsychiatric phenotype across development, particularly during adolescence, and the associated treatment challenges remain incomplete. To provide a comprehensive narrative review of the neuropsychiatric phenotype of 47,XYY syndrome and to illustrate clinical complexity and treatment response through a case series of adolescents. A narrative review of the literature was conducted focusing on genetics, neurodevelopmental and psychiatric features, neuroimaging and neurophysiology findings, clinical course, and management strategies in 47,XYY syndrome. This review is complemented by a case series of adolescents with confirmed 47,XYY karyotype, evaluated for developmental history, psychiatric comorbidity and response to pharmacological and non-pharmacological interventions. The literature consistently describes increased risks of language impairment, executive dysfunction, ADHD, autism spectrum traits, and emotional and behavioral dysregulation in males with 47,XYY syndrome. Psychiatric vulnerability appears to increase during adolescence and adulthood, with elevated rates of mood, psychotic, and substance use disorders. The presented cases illustrate a convergent clinical trajectory marked by early developmental delays, progressive behavioral dysregulation in adolescence and limited or inconsistent response to multiple classes of psychotropic medications, suggesting a pattern of pharmacoresistance in a subset of patients. 47,XYY syndrome is associated with a distinct and heterogeneous neuropsychiatric phenotype that extends beyond early neurodevelopmental disorders. Early diagnosis alone may be insufficient to prevent severe psychiatric outcomes, highlighting the need for long-term monitoring and integrated, multidisciplinary management. Further research is required to identify early predictors of high-risk trajectories and to optimize treatment strategies for this population.

To compare the prevalence of neurodevelopmental and mental health diagnoses in a national sample of youth with sex chromosome trisomies (SCTs) with matched controls. Patients in PEDSnet and a diagnosis code mapping to 47,XXY/Klinefelter syndrome (n = 1171), 47,XYY/Double Y syndrome (n = 243), or 47,XXX/Trisomy X syndrome (n = 262) were matched with controls using propensity scores. Generalized estimating equations computed odds ratios (OR) with 95% confidence intervals (CI) for the prevalence of diagnoses within the neurodevelopmental and mental health composites, psychotropic medication prescriptions, and encounters with behavioral health and therapy providers. Alpha was set at 0.0025 to account for multiple comparisons. Patients with SCTs had higher odds of diagnoses within the neurodevelopmental (OR 6.3, 95% CI, 5.7-7.2) and mental health composites (OR 2.7, 95% CI, 2.3-3.2) compared with matched controls. All neurodevelopmental diagnoses were more prevalent among all SCT groups compared with controls. Within the mental health composite, only the prevalence of anxiety and mood disorder was higher in all SCT groups. A higher proportion of patients with SCTs had psychotropic prescriptions compared with controls (stimulants 13.1% vs 5.2%, selective serotonin reuptake inhibitors 8.7% vs 2.8%, antipsychotics 6.5% vs 2.4%, p < 0.0001 for all). Overall, 48% of patients with SCTs had a clinical encounter with a behavioral health provider vs 16.6% of controls (OR 5.6, 95% CI, 4.1-5.1). Compared with matched controls, youth with SCTs receiving care at US tertiary care pediatric centers have disproportionately high rates of neurodevelopmental and mental health conditions, emphasizing the need for appropriate screening and intervention in these populations.

The 47,XYY syndrome is a genetic condition found in about 1 in 1000 male children. The expected phenotype is male but could vary greatly. Those with genitourinary abnormalities may also present with microphallus, hypoplastic scrotum, cryptorchidism, hypospadias and macroorchidism. This study reports a child with sex ambiguity who possesses an initial 47,XYY karyotype. We also conducted a narrative literature review of 47,XYY individuals and their respective genital phenotype and/or gender identity. The narrative literature review was performed by searching for "47,XYY" in the PubMed database. All studies published in English, Spanish or Portuguese from January 1960 to January 2024 that contained the term "47,XYY" in the title or abstract were included. Studies that did not describe the genital phenotype and/or gender identity of cases were excluded. We also described the case of a 2-month-old patient with the 47,XYY karyotype and sex ambiguity. Our patient underwent additional karyotype testing, resulting in 47,XYY [30] and another 45,X [2]/47,XYY [98] with mosaicism being confirmed by fluorescent in situ hybridization (FISH) on buccal smears (nuc ish (DXZ1 × 1, DYZ3 × 2)[64/100]/(DXZ1 × 1, DYZ3 × 0)[36/100]. A gonadal biopsy revealed an atrophic testis on the left and a streak gonad on the right, with a final diagnosis of mixed gonadal dysgenesis determined. The narrative review revealed 643 articles, of which 350 met the inclusion criteria. However, we excluded 132 articles because they presented no new cases. We included 138 articles, which presented a series containing less than 10 new cases with the 47,XYY karyotype (total of 327 cases), 58 articles presented 4001 cases and 22 articles presented 75 patients with the 47,XYY karyotype in mosaic with 45,X. For all 4403 analyzed cases, 4354 (98.90%) presented a male phenotype, of which 4322 had the 47,XYY karyotype and 32 had mosaicism with 45,X lineage. A further 23 (0.52%) presented a female phenotype, of which four had the 47,XYY karyotype and 19 had mosaicism with 45,X lineage. In addition, 23 (0.52%) cases presented ambiguous genitalia, of which two had the 47,XYY karyotype and 21 had mosaicism with 45,X lineage. Finally, three (0.06%) cases had undefined phenotypes, all with mosaicism with 45,X lineage. Of the six cases with the 47,XYY karyotype and no male phenotype, one had complete androgen insensitivity syndrome (CAIS), one had lipoid congenital adrenal hyperplasia, two had probable CAIS, and two presented an incomplete diagnostic investigation. A female or ambiguous genital phenotype in an individual with 47,XYY karyotype is uncommon and should alert to the presence of the 45,X lineage or association with other causes of disorder/difference of sex development.

To investigate the clinical phenotype and genetic etiology of a patient with tall stature and primary amenorrhea presenting with 47,XYY Disorder of sex development (DSD). A female patient presenting with "tall stature and primary amenorrhea" at Nanjing Drum Tower Hospital in July 2024 was selected as the study subject. A retrospective study design was employed to collect the patient's clinical data. Peripheral venous blood sample was collected. Following the extraction of genomic DNA, genetic testing was performed including chromosomal karyotyping analysis, copy number variation sequencing (CNV-seq), multiplex PCR for the AZF regions and sex-determining genes Y (SRY), and whole-exome sequencing (WES). Candidate variants were validated by Sanger sequencing and classified for pathogenicity based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Nanjing Drum Tower Hospital (Ethics No.: 2022-451-01). The patient had a height of 188 cm and a body weight of 50 kg, in addition with infantile uterus, absent ovaries, and primary amenorrhea. G-banded karyotyping analysis of peripheral blood sample revealed 47,XYY. CNV-seq indicated Seq[GRCh37]Yp11.32q12×2. No deletion was detected in the AZF regions of Y chromosome, and SRY was positive. WES identified a heterozygous c.86C>A (p.Thr29Lys) variant of the NR5A1 gene, leading to substitution of threonine with lysine at position 29 of the encoded protein. Sanger sequencing confirmed the presence of the variant. According to the ACMG guidelines, this variant was classified as variant of uncertain significance (VUS) with supporting evidence (PS3_Moderate+PM5+PP3+PM2_Supporting+PS4_Supporting). Reviewing the nearly 60 years of previously reported cases, all 7 documented 47,XYY DSD patients were assigned a female social gender and presented with abnormal gonadal and external genitalia development. Among them, 5 cases underwent SRY testing, all of which were positive. Only 1 case underwent whole-exome sequencing (WES), but no pathogenic or likely pathogenic variants were identified. This DSD patient presented with the clinical features of tall stature and primary amenorrhea. The NR5A1 gene variant c.86C>A (p.Thr29Lys) probably underlay the Disorder of sex development in this patient. Above finding has enriched the spectrum of pathogenic variants of the NR5A1 gene.

Jacobs (JS) and Klinefelter (KS) syndromes, carrying 47,XYY and 47,XXY chromosomes, respectively, are the most prevalent sex-chromosome aneuploidies in males. JS and KS patients share several clinical features, including sterility, hormonal deficits, neurocognitive delay, and skeletal-muscle defects, although the penetrance of these traits in the two syndromes varies. Despite the high incidence, the molecular mechanisms underlying the clinical manifestations in sex aneuploid male patients are still elusive. In this study, we characterize the inaugural cohort of 47,XYY human induced pluripotent stem cells (iPSCs). We perform a comprehensive transcriptional analysis, including 47,XYY and 46,XY primary fibroblasts, iPSCs, and neural stem cells (NSCs), alongside a comparative analysis of 47,XYY and 47,XXY fibroblasts and iPSC transcriptomes. We reveal a transcriptional feedback mechanism tuning non-PAR X Chromosome gene (NPX) homologs in Y supernumerary cells, a phenomenon not detected in X aneuploid male iPSCs. By ectopically modulating the expression of selected NPY genes, we demonstrate a transcriptional link between the UTY-KDM6A gene pair. Furthermore, our analyses identify a shared transcriptomic signature between JS and KS, discernible already at the iPSC stage, with a notable enrichment for processes related to neurological functions. This transcriptomic convergence underscores potential commonalities in the molecular pathways underpinning the pathophysiology of male sex-chromosome aneuploidies. Finally, through genome-wide DNA methylation profiling of JS iPSCs, we demonstrate that a supernumerary Y Chromosome only minimally impacts the methylation status of 47,XYY cells at the pluripotent stage. Our work reveals critical transcriptional feedback mechanisms and shared gene expression signatures in male sex-chromosome aneuploidies.