49,XXXYY is an extremely rare sex chromosomal aneuploidy (SCA), with only seven cases reported worldwide to date. Among these cases, only three have been documented into adulthood. Moreover, no cases of 49,XXXYY have been reported in Japan. This SCA has been identified in two scenarios: in vitro fertilization and abortion. Similar to 47,XXY, this aneuploidy is a type of Klinefelter syndrome. Aneuploidy of the X chromosome can lead to various progressive complications due to excess X chromosomes. Herein, we present the case of a Japanese man with 49,XXXYY. He exhibited developmental delays and external genitalia abnormalities since early infancy but was not closely monitored for these symptoms until the age of 3 years old. At that time, a chromosome test revealed his karyotype to be 49,XXXYY. Subsequent examinations were conducted due to various symptoms, including delayed motor development, intellectual disability, facial dysmorphisms, forearm deformities, hip dysplasia, cryptorchidism, micropenis, primary hypogonadism, and essential tremor. Since reaching puberty, he has undergone testosterone replacement therapy for primary hypogonadism, experiencing no complications related to androgen deficiency to date. He has maintained normal lipid and glucose metabolism, as well as bone density, for a prolonged period. There are no other reports on the long-term effects of testosterone treatment for the SCA. Appropriate testosterone replacement therapy is recommended for individuals with 49,XXXYY to prevent complications. This report will contribute to an enhanced understanding of the 49,XXXYY phenotype, aiding in the diagnosis, treatment, and genetic counseling of future cases.

BACKGROUND: The diagnosis of supernumerary X & Y chromosome variations has increased following the implementation of genetic testing in pediatric practice. Empirical evidence suggests that the delivery of the diagnosis has a lasting impact on how affected individuals and their parents perceive and adapt to the diagnosis. The purpose of this review is to synthesize the literature to obtain useful recommendations for delivering a pediatric diagnosis of a sex chromosome multisomy (SCM) based upon a growing body of quantitative and qualitative literature on patient experiences.
METHODS: We conducted an integrative literature review using PubMed, Web of Science and CINAHL employing keywords \"genetic diagnosis delivery,\" \"genetic diagnosis disclosure,\" \"sex chromosome aneuploidy,\" \"Klinefelter syndrome\" or \"\"47, XXY,\" \"Jacob syndrome\" or \"47, XYY,\" \"Trisomy X,\" \"Triple X\" or \"47, XXX,\" and \"48 XXYY from January 1, 2000, to October 31, 2023.
RESULTS: Literature supports that patients and parents value the provision of up-to-date information and connection with supportive resources. Discussion of next steps of care, including relevant referrals, prevents perceptions of provider abandonment and commitment to ongoing support. Proactively addressing special concerns such as disclosing the diagnosis to their child, family, and community is also beneficial. Tables are provided for useful information resources, medical specialties that may be required to support patients, and common misconceptions that interfere with accurate information about the diagnosis.
CONCLUSIONS: Patient experiences suggest there should be heightened attention to diagnosis delivery, in reference to the broader ethical and social impacts of a SCM diagnosis. We present recommendations for optimal disclosure of a SCM diagnosis in early and late childhood, adolescence, and young adulthood.

The aim was to determine the accuracy of cell-free DNA testing (cfDNA) for detecting sex chromosome aneuploidies (SCA) in singleton pregnancies.
A systematic review and meta-analysis was performed to assess cfDNA accuracy for prenatal detection of 45,X, 47,XXY, 47,XXX and 47,XYY. Inclusion was restricted to studies published between January 2010 and December 2021 reporting both cfDNA and confirmatory diagnostic test results.
For 45,X, the sensitivity was 98.8% (95%CI 94.6%-100%), specificity 99.4% (95%CI 98.7%-99.9%) and positive predictive value (PPV) 14.5% (95%CI 7.0%-43.8%). For 47,XXY, the sensitivity was 100% (95%CI 99.6%-100%), specificity 100% (95%CI 99.9%-100%) and PPV 97.7% (95%CI 78.6%-100%). For 47,XXX, the sensitivity was 100% (95%CI 96.9%-100%), specificity 99.9% (95%CI 99.7%-100%) and PPV 61.6% (95%CI 37.6%-95.4%). For 47,XYY, the sensitivity was 100% (95%CI 91.3%-100%), specificity 100% (95% CI 100%-100%) and PPV 100% (95%CI 76.5%-100%). All four SCAs had estimated negative predictive values (NPV) exceeding 99.99%, though false negatives were reported.
This analysis suggests that cfDNA is a reliable screening test for SCA, though both false negatives and false positives were reported. These estimates of test performance are derived from pregnancies at high pretest risk for aneuploidy, limiting the generalisability to average risk pregnancies.

Although cell-free DNA screening for sex chromosome abnormalities is increasingly used in clinical practice, its diagnostic accuracy and clinical utility remain unclear. This systematic review and meta-analysis aimed to determine the performance of cell-free DNA in the detection of sex chromosome abnormalities.
Medline and PubMed, Embase, and Web of Science were searched from inception to January 2022 for articles relating to cell-free DNA screening for sex chromosome abnormalities.
Original articles, randomized control trials, conference abstracts, cohort and case-control studies, and case series with more than 10 cases with diagnostic confirmation were considered for inclusion.
Quality assessment of each included publication was performed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. The positive predictive value was calculated as the proportion of true positive cases among those who tested positive and underwent diagnostic testing. Sensitivity and specificity were pooled, and a summary receiver operating characteristic curve was produced using bivariate models that included studies that had diagnostic confirmation for high- and low-risk women.
The search identified 7553 results. Of these, 380 proceeded to the full-text screening, of which 94 articles were included in the meta-analysis with a total of 1,531,240 women tested. All studies reported a confirmatory genetic test. The pooled positive predictive value was 49.4% (95% confidence interval, 45.8-53.1). The pooled positive predictive value was 32.0% (95% confidence interval, 27.0%-37.3%) for monosomy X, 67.6% (95% confidence interval, 62.5%-72.5%) for XXY, 57.5% (95% confidence interval, 51.7%-63.1%) for XXX, and 70.9% (95% confidence interval, 63.9%-77.1%) for XYY. The pooled sensitivity and specificity of cell-free DNA for sex chromosome abnormalities were 94.1% (95% confidence interval, 90.8%-96.3%) and 99.5% (95% confidence interval, 99.0%-99.7%), respectively, with an area under the summary receiver operating characteristic curve of 0.934 (95% confidence interval, 0.907-0.989).
Although the sensitivity and specificity of cell-free DNA for sex chromosome abnormalities are high, the positive predictive value was approximately 50%. The positive predictive value was higher for sex chromosome abnormalities with a supernumerary Y chromosome and lower for monosomy X. Clinicians should inform couples about these findings when offering cell-free DNA for sex chromosome abnormalities.

BACKGROUND: The cause of systemic lupus erythematosus is not completely clear so far, but the prevalence of systemic lupus erythematosus is significantly increased in people with additional X chromosomes.
METHODS: We report a 17-year-old Chinese female patient with systemic lupus erythematosus complicated with trisomy X, accompanied by lupus nephritis, pancytopenia, hemolytic anemia, and multiserous effusion. The patient recovered well after treatment and returned regularly. We review the previously reported cases to summarize the clinical characteristics of these patients.
CONCLUSIONS: The additional X chromosome is related to the development of systemic lupus erythematosus. Whether it is a subtype of systemic lupus erythematosus remains to be further confirmed.

Noninvasive prenatal screening (NIPS) using cell-free DNA has been assimilated into prenatal care. Prior studies examined clinical validity and technical performance in high-risk populations. This systematic evidence review evaluates NIPS performance in a general-risk population.
Medline (PubMed) and Embase were used to identify studies examining detection of Down syndrome (T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies, rare autosomal trisomies, copy number variants, and maternal conditions, as well as studies assessing the psychological impact of NIPS and the rate of subsequent diagnostic testing. Random-effects meta-analyses were used to calculate pooled estimates of NIPS performance (P < .05). Heterogeneity was investigated through subgroup analyses. Risk of bias was assessed.
A total of 87 studies met inclusion criteria. Diagnostic odds ratios were significant (P < .0001) for T21, T18, and T13 for singleton and twin pregnancies. NIPS was accurate (≥99.78%) in detecting sex chromosome aneuploidies. Performance for rare autosomal trisomies and copy number variants was variable. Use of NIPS reduced diagnostic tests by 31% to 79%. Conclusions regarding psychosocial outcomes could not be drawn owing to lack of data. Identification of maternal conditions was rare.
NIPS is a highly accurate screening method for T21, T18, and T13 in both singleton and twin pregnancies.

Tectocerebellar dysraphia (TCD) is a rare sporadic malformation associated with severe neurodevelopmental morbidity and high infant mortality. The presence of other ciliopathies worsens the prognosis. Joubert syndrome (JS) is a ciliopathy associated with gene mutations, consisting of midbrain and cerebellum malformations, markedly lack fiber decussation at the level of the pontomesencephalic junction.
We report the case of a child who was born term with occipital encephalocele (OE), diagnosed with TCD and JS spectrum through computed tomography (CT), magnetic resonance (MR), diffuse tensor imaging (DTI), and clinical findings. She had the OE surgically corrected after spontaneous rupture on the second day after delivery. She developed postoperative ventriculitis, meningitis, and hydrocephalus, successfully treated with intravenous antibiotics and cysto-ventriculostomy, cysto-cisternostomy, third ventriculostomy, and choroid plexus coagulation. G-band karyotyping showed 47, XXX, in all analyzed cells (trisomy X). The infant was followed up for 18 months, presenting, so far, a relatively good outcome.
This is the first case reported in the literature of the association of TCD/OE/JS spectrum (JSS) with trisomy X (XXX).

A total of 551 pregnancies with positive results for noninvasive prenatal testing (NIPT) using traditional karyotyping and chromosomal microarray analysis were analyzed. Confirmatory results, positive predictive values, etiology exploration of false-positive results, and pregnancy outcomes were recorded. The study demonstrated that NIPT performed better in predicting trisomy 21 and trisomy 18 for pregnancies with advanced maternal age than for pregnancies with young maternal age; as for trisomy 13 and sex chromosomal aneuploidy (SCA) prediction, there was no significant difference between the two groups. The positive predictive values for trisomy 21, trisomy 18, trisomy 13, and SCA showed no significant upward trend when compared based on specific age categories (an interval of 5 years), which suggested that NIPT-positive result deserves equal attention from both providers and patients regardless of maternal age. In addition, the termination rates of 45,X, 47,XXY, 47,XXX, and 47,XYY were 100% (2/2), 92.9% (26/28), 33.3% (5/15), and 9.5% (2/21), respectively, which demonstrated that the decision-making regarding pregnancies varied greatly according to the types of SCAs, and further reinforce the importance of confirmatory prenatal diagnosis. The current study also supported the viewpoint that confined placental mosaicism and maternal mosaicism were the important etiology of false-positive results.

BACKGROUND: Patients with 46, XY disorder of sex development (DSD) are predisposed to the development of gonadal tumors, particularly germ cell tumors and gonadoblastoma. However, to the best of our knowledge, there are no publications in the existing literature that refer to the coexistence of 46, XY DSD and serous tumors in the ovary.
METHODS: Here, we report the case of a 23-year-old female (social gender) patient with 46, XY DSD presenting with primary amenorrhea. Imageology revealed a huge mass in the left adnexa. Subsequent pathological analysis revealed a serous borderline tumor of the ovary.
CONCLUSIONS: Gonadal tumors of patients with 46, XY DSD are not necessarily malignant tumors and can coexist with borderline tumors with primitive corded gonads. The coexistence of DSD and serous borderline tumors is rare. Clearly, an early and accurate diagnosis plays an important role in the treatment of these patients. Although there may not be a clear correlation between the two lesions, it is vital that we specifically analyze the mechanisms involved so that we can determine whether patients with DSD are associated with an increase of developing serous borderline tumors of the gonad.

Eight years have passed since noninvasive prenatal testing (NIPT) was clinically evaluated and data on NIPT for trisomy 21, 18 and 13 were collected. The data revealed that NIPT is more accurate than conventional first-trimester screening. However, there is still insufficient data regarding the clinical use of NIPT results in detecting sex chromosome aneuploidies or whole-genome regions. NIPT is already being used as a clinical screening method globally. However, it is an unconfirmed diagnostic test and the results must be interpreted with caution as they may yield false negatives, false positives or inconclusive results. Therefore, the aim of this review is to highlight the current status of information, including the different methodologies, shortcomings and implications, regarding NIPT after its adoption worldwide. It is important to include genetic counseling when implementing NIPT. Going forward, the knowledge obtained to date, including the associated shortcomings, must be considered in evaluating the effectiveness of NIPT in detecting genetic abnormalities.