Generation of functional oocytes from male mice in vitro.

Sex chromosome disorders severely compromise gametogenesis in both males and females. In oogenesis, the presence of an additional Y chromosome or the loss of an X chromosome disturbs the robust production of oocytes1-5. Here we efficiently converted the XY chromosome set to XX without an additional Y chromosome in mouse pluripotent stem (PS) cells. In addition, this chromosomal alteration successfully eradicated trisomy 16, a model of Down's syndrome, in PS cells. Artificially produced euploid XX PS cells differentiated into mature oocytes in culture with similar efficiency to native XX PS cells. Using this method, we differentiated induced pluripotent stem cells from the tail of a sexually mature male mouse into fully potent oocytes, which gave rise to offspring after fertilization. This study provides insights that could ameliorate infertility caused by sex chromosome or autosomal disorders, and opens the possibility of bipaternal reproduction.

Current and future therapies for haemophilia-Beyond factor replacement therapies.

Some non-factor products that work by facilitating the coagulation pathway (emicizumab) and blocking the anticoagulant pathway (fitusiran, concizumab and marstacimab) for patients with haemophilia (H) have been developed, and clinical trials using these products are currently ongoing. Prophylaxis using non-factor products by subcutaneous administration provides marked reductions of bleeding episodes in patients with HA or HB, regardless of the presence of inhibitor. Emicizumab has already been approved globally. Emicizumab alters the phenotype of patients with HA from severe to mild by maintaining trough levels of equivalent factor VIII activity (15-20 iu/dl). Phase 3 clinical trials and long-term observations assessing emicizumab revealed tolerable safety and efficacy. However, thrombotic events have occurred in patients receiving these non-factor products. Furthermore, monitoring of the haemostatic function of these products with concomitant therapy is also required in clinical practice. These products have promising haemostatic efficiency, but wider clinical experience is needed to provide optimal therapeutic strategies in the future.

Maternal input to children with sex chromosome trisomies.

BACKGROUND: Although language difficulties are one of the most distinctive characteristics of the neuropsychological profile of children with sex chromosome trisomies (SCT), the analysis of the maternal input addressed to them is a neglected topic. AIMS: The present study aims to analyse the lexical, morphosyntactic, and functional features of the input addressed to children with SCT comparing them with those of the input directed to typically developing children (TD). METHODS & PROCEDURES: Participants were 38 mothers and their 8-month-old children, 19 with SCT and 19 TD children. Maternal utterances, collected during video-recorded play sessions, have been transcribed and coded. OUTCOMES & RESULTS: No significant differences between groups have been found in the lexical and syntactic characteristics of maternal input. However, considering the input functional features, the proportion of directives and questions was significantly higher in the maternal input addressed to children with SCT than in the input addressed to TD children whereas the opposite pattern was found in the proportion of affect-salient speech. CONCLUSIONS & IMPLICATIONS: The awareness of a possible delay in their children's language development could influence the way the mothers speak to them. In particular, the functional features of maternal input could be affected. Support groups for parents of children with SCT at the preverbal stage could be useful to reassure the mothers about their role in their children's language development. What this paper adds What is already known on the subject Studies in the literature identified a high percentage of language delays or impairments in children with SCT. To date, according to our knowledge, there are no studies that analyse the linguistic input addressed to these children. What this study adds The lexical and syntactic features of maternal input addressed to 8-month-old children with SCT are adequate to the children's communicative skills. However, the mothers of children with SCT seem to provide additional scaffolding in their verbal input, using a lower proportion of affect-salient speech and a higher proportion of questions. In addition, a higher proportion of directives suggests the use of a more demanding style. Clinical implications of this study The awareness of possible language delays could influence the functional features of input leading mothers to use a more supportive and demanding input. Support groups for parents of children with SCT at the preverbal stage could be useful to reassure the mothers about their role in their children's language development.

Case report of 49,XXXXY syndrome with cleft palate, diabetes, hypothyroidism, and cataracts.

RATIONALE: The karyotype 49,XXXXY is a rare form of Klinefelter syndrome usually presenting with ambiguous genitalia, facial dysmorphism, mental retardation, and a combination of cardiac, skeletal, and other malformations. PATIENT CONCERNS: We describe a 19-year-old man, whose chromosomal analysis of peripheral blood revealed a karyotype of 49,XXXXY. His mental development and motor ability were significantly delayed. At the age of 19, he had failed to develop secondary sexual characteristics. His random blood glucose level was 19.61 mmol/L, and he showed dry mouth, polydipsia, and polyuria. He had a characteristic facial appearance with prognathism, widened nasal bridge, and strabismus. His bilateral elbow rotation was limited. He had atrophic testes with micropenis. Ophthalmic examination revealed a polar cataract in both eyes. DIAGNOSIS: He was diagnosed with Klinefelter syndrome associated with cleft palate, hypothyroidism, cataracts, diabetes, and other anomalies. INTERVENTIONS: After the initial diagnosis, the patient received intensive insulin therapy to correct hyperglycemia, and he received calcium and vitamin D supplements. The patient also received testosterone and thyroid hormone replacement therapy for primary hypogonadism. OUTCOMES: The patient was discharged 12 days after receiving treatment; meanwhile, there were no clinical symptoms of dry mouth, polyuria and polyuria, and his blood glucose level was controlled. LESSONS: The combination of cleft palate, hypothyroidism, cataracts, diabetes, and osteoporosis in 49,XXXXY syndrome has not yet been reported. Early treatment and appropriate care can significantly improve the patient's quality of life and prevent serious consequences.

Abnormal Auditory Mismatch Fields in Children and Adolescents with 47,XYY Syndrome.

47,XYY syndrome (XYY) is one of the common forms of sex chromosome aneuploidy in males. XYY males tend to have tall stature, early speech, motor delays, social and behavioral challenges, and a high rate of language impairment. Recent studies indicate that 20-40% of males with XYY meet diagnostic criteria for autism spectrum disorder (ASD; the rate in the general population is 1-2%). Although many studies have examined the neural correlates of language impairment in ASD, few similar studies have been conducted on individuals with XYY. Studies using magnetoencephalography (MEG) in idiopathic ASD (ASD-I) have demonstrated delayed neurophysiological responses to changes in the auditory stream, revealed in the mismatch negativity or its magnetic counterpart, the mismatch field (MMF). This study investigated whether similar findings are observed in XYY-associated ASD and whether delayed processing is also present in individuals with XYY without ASD. MEG measured MMFs arising from the left and the right superior temporal gyrus during an auditory oddball paradigm with vowel stimuli (/a/ and /u/) in children/adolescents with XYY both with and without a diagnosis of ASD, as well as in those with ASD-I and in typically developing controls (TD). Ninety male participants (6-17 years old) were included in the final analyses (TD, n = 38, 11.50 ± 2.88 years; ASD-I, n = 21, 13.83 ± 3.25 years; XYY without ASD, n = 15, 12.65 ± 3.91 years; XYY with ASD, n = 16, 12.62 ± 3.19 years). The groups did not differ significantly in age (p > 0.05). There was a main effect of group on MMF latency (p < 0.001). Delayed MMF latencies were found in participants with XYY both with and without an ASD diagnosis, as well as in the ASD-I group compared to the TD group (ps < 0.001). Furthermore, participants with XYY (with and without ASD) showed a longer MMF latency than the ASD-I group (ps < 0.001). There was, however, no significant difference in MMF latency between individuals with XYY with ASD and those with XYY without ASD. Delayed MMF latencies were associated with severity of language impairment. Our findings suggest that auditory MMF latency delays are pronounced in this specific Y chromosome aneuploidy disorder, both with and without an ASD diagnosis, and thus may implicate the genes of the Y chromosome in mediating atypical MMF activity.

Auditory evoked response delays in children with 47,XYY syndrome.

47,XYY syndrome (XYY) is a male sex chromosome disorder where individuals have an X chromosome and two copies of the Y chromosome. XYY is associated with a physical phenotype and carries increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Latencies of auditory evoked responses measured by magnetoencephalography have shown atypical prolongations in several neuropsychiatric and genetic disorders; specifically, delayed auditory responses have been observed in ASD. In this study, we investigated the associations of genotype and clinical phenotype with auditory processing. Whole cortex magnetoencephalography recorded during a passive auditory paradigm (500 Hz tones) was used to assess the auditory evoked response in three groups of male children: idiopathic ASD, typically developing, and XYY boys. Response waveforms were computed for left and right auditory cortex and latencies of the ∼50 ms (M50) and ∼100 ms (M100) components were determined. M50 latencies were significantly delayed compared with typically developing controls in children with ASD in the right hemisphere only, and in children with XYY in the left hemisphere only, irrespective of whether they met diagnostic criteria for ASD. Findings on the later M100 component trended in the same directions but did not attain significance, due to increased variance. Replicating previous findings, decreased M50 and M100 latencies with age were observed bilaterally. Overall, while XYY shares an electrophysiological phenotype (delayed evoked response latency) with idiopathic ASD, the hemispheric differences warrant further investigation.

Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome.

BACKGROUND: XYY syndrome is a sex chromosome aneuploidy that occurs in ~ 1/850 male births and is associated with increased risk for neurodevelopmental difficulties. However, the profile of neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD) in XYY remains poorly understood. This gap in knowledge has persisted in part due to lack of access to patient cohorts with dense and homogeneous phenotypic data. METHODS: We evaluated a single-center cohort of 64 individuals with XYY aged 5-25 years, using a standardized battery of cognitive and behavioral assessments spanning developmental milestones, IQ, adaptive behavior, academic achievement, behavioral problems, and gold-standard diagnostic instruments for ASD. Our goals were to (i) detail the neurodevelopmental profile of XYY with a focus on ASD diagnostic rates and symptom profiles, (ii) screen phenotypes for potential ascertainment bias effects by contrasting pre- vs. postnatally diagnosed XYY subgroups, and (iii) define major modules of phenotypic variation using graph-theoretical analysis. RESULTS: Although there was marked inter-individual variability, the average profile was characterized by some degree of developmental delay, and decreased IQ and adaptive behavior. Impairments were most pronounced for language and socio-communicative functioning. The rate of ASD was 14%, and these individuals exhibited autism symptom profiles resembling those observed in ASD without XYY. Most neurodevelopmental dimensions showed milder impairment among pre- vs. postnatally diagnosed individuals, with clinically meaningful differences in verbal IQ. Feature network analysis revealed three reliably separable modules comprising (i) cognition and academic achievement, (ii) broad domain psychopathology and adaptive behavior, and (iii) ASD-related features. CONCLUSIONS: By adding granularity to our understanding of neurodevelopmental difficulties in XYY, these findings assist targeted clinical assessment of newly identified cases, motivate greater provision of specialized multidisciplinary support, and inform future efforts to integrate behavioral phenotypes in XYY with neurobiology. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls."

Somatically Acquired Isodicentric Y and Mosaic Loss of Chromosome Y in a Boy with Hypospadias.

Isodicentric Y chromosome [idic(Y)] represents a relatively common subtype of Y chromosomal rearrangements in the germline; however, limited evidence supports the postzygotic occurrence of idic(Y). Here, we report a boy with hypospadias and somatically acquired idic(Y). The 3.5-year-old boy has been identified in our previous study for patients with hypospadias. In the present study, cytogenetic analysis including FISH revealed a 45,X[5]/46,X,idic(Y)[7]/46,XY[8] karyotype. MLPA showed a mosaic deletion involving PPP1R12BP1 and RBMY2DP. The idic(Y) was likely to have been formed through aberrant recombination between P1 palindromes and subsequently underwent mosaic loss. The patient's phenotype was attributable to deletion of some Y chromosomal genes and/or mosaic loss of chromosome Y (mLOY). The results suggest that idic(Y) can originate in postzygotic cells via palindrome-mediated crossovers. Moreover, our data indicate that somatically acquired idic(Y) can trigger mLOY, which usually appears as an aging-related phenomenon in elderly men.

Cataract in a patient with 47,XYY sex chromosome aneuploidy. / Catarata congénita en un paciente con aneuploidía cromosómica 47,XYY.

CASE REPORT: The case concerns a 16 year-old boy with a history of high myopia and unilateral congenital cataract, tall stature for age, facial dysmorphism, hypermobile metacarpal-phalangeal joints, as well as behavioural problems. The mother had a history of recurrent pregnancy loss. Chromosomal analysis of the peripheral blood lymphocytes reported 47,XYY. DISCUSSION: Patients with sex chromosome aneuploidy 47,XYY have higher risk of congenital malformations, although ophthalmological anomalies are unusual. Evaluation of patients with tall stature and behavioural problems should include a chromosomal analysis in order to determine the aetiology.

[Insufficient knowledge of the relationship between sex chromosome abnormalities and psychiatric diagnoses]. / Otillräcklig kunskap om samband mellan könskromosom­­avvikelser och psykiatriska diagnoser - Viktigt att barn och unga utreds och får rätt omhändertagande.

Sex chromosome abnormalities are among the most common genetic changes. The manifestations vary and may include growth abnormalities, specific appearance features, and other endocrinological and physical disorders, but also delayed psychomotor development, learning disabilities, and psychiatric conditions including ADHD and autism spectrum disorders. Increased knowledge about the relationship between sex chromosome abnormalities, development and psychiatric conditions would enable improved care of these patients.

When to Perform Karyotype Analysis in Infertile Men? Validation of the European Association of Urology Guidelines with the Proposal of a New Predictive Model.

Known genetic alterations play a major role in perturbing male reproductive health. We sought to retrospectively validate the European Association of Urology (EAU) guidelines for karyotype analysis (KA) in a homogenous cohort of 1168 White European men presenting for primary couple's infertility (noninterracial infertile couples only) and to develop a novel nomogram capable of predicting karyotype alterations. Overall, 742 (63.5%) patients would have deserved KA according to the EAU guidelines. Of those, 48 (6.9% of the assessable patients according to EAU guidelines) displayed any kind of alteration at KA. Conversely, hypothetically relying on the EAU criteria, 12 (20%) out of 60 patients with karyotype abnormalities would not have been candidates for the same genetic assessment. Overall, 694 (62.6%) patients would have been candidates for genetic workup despite having a normal karyotype. As a whole, the EAU guideline sensitivity, specificity, and discrimination were 80%, 37%, and 59%, respectively. We developed a novel nomogram, with a 2% probability cut-off, which allows for a more careful detection of KA alterations. PATIENT SUMMARY: The application of the European Association of Urology guidelines for karyotype analysis does not ensure an adequate diagnostic process. In this regard, we propose a novel diagnostic tool to improve detection of alterations at karyotype analysis.

Xq26.1-26.2 gain identified on array comparative genomic hybridization in bilateral periventricular nodular heterotopia with overlying polymicrogyria.

Periventricular nodular heterotopia (PNH) with overlying polymicrogyria (PMG) is a recently described, developmental brain malformation; however, the causative genes of this malformation have not yet been identified. We report on a 5-year-old Japanese male with bilateral PNH with overlying PMG. He had mild intellectual disability, distinctive facial features, short stature, and microcephaly, with cardiac disorders. No mutation was identified in Sanger sequences for FLNA and ARFGEF2; however, array comparative genomic hybridization revealed an approximately 0.8Mb gain at Xq26.1-26.2, which included three genes: IGSF1, OR13H1, and FIRRE. We identified the same 3-copy gain in his mother; despite identifying the same abnormality in the mother, it must still be considered as a possible cause for the abnormalities, as X-inactivation in the mother could have led to her not expressing the same phenotype. This case may provide important clues for identifying the genes responsible and help in the understanding of the pathogenesis of this disorder.

Dosage effects of X and Y chromosomes on language and social functioning in children with supernumerary sex chromosome aneuploidies: implications for idiopathic language impairment and autism spectrum disorders.

BACKGROUND: Supernumerary sex chromosome aneuploidies (X/Y-aneuploidies), the presence of extra X and/or Y chromosomes, are associated with heightened rates of language impairments and social difficulties. However, no single study has examined different language domains and social functioning in the same sample of children with tri-, tetra-, and pentasomy X/Y-aneuploidy. The current research sought to fill this gap in the literature and to examine dosage effects of X and Y chromosomes on language and social functioning. METHODS: Participants included 110 youth with X/Y-aneuploidies (32 female) and 52 with typical development (25 female) matched on age (mean ∼12 years; range 4-22) and maternal education. Participants completed the Wechsler intelligence scales, and parents completed the children's communication checklist-2 and the social responsiveness scale to assess language skills and autistic traits, respectively. RESULTS: Both supernumerary X and Y chromosomes were related to depressed structural and pragmatic language skills and increased autistic traits. The addition of a Y chromosome had a disproportionately greater impact on pragmatic language; the addition of one or more X chromosomes had a disproportionately greater impact on structural language. CONCLUSIONS: Given that we link extra X chromosomes with structural language impairments and an extra Y chromosome with pragmatic language impairments, X/Y-aneuploidies may provide clues to genetic mechanisms contributing to idiopathic language impairment and autism spectrum disorders.

Transient hydrops fetalis in a prenatally diagnosed pentasomy X?

Numerical abnormalities of sex chromosomes are seen approximately 1 in 400 live births. Pentasomy X is a very rare chromosomal abnormality and it is defined as presence of five X chromosomes instead of two. Prenatal sonographic features have rarely been described in the literature before. Here we present a non-immune fetal hydrops diagnosed during the 17th week of gestation. Ultrasonographic examination revealed subcutaneous edema, pleural effusion and ascites, and also clinodactyly of the fifth fingers of both hands. The fetal karyotype was assessed as 49,XXXXX (pentasomy X) in two different culture flasks. Hydropic signs regressed at 21 weeks' gestation. Prenatal diagnosis may not be possible usually for this rare chromosomal abnormality. Every anomaly detected prenatally, such as transient hydrops, may help us to diagnose pentasomy X.

Cryptic x; autosome translocation in a boy--delineation of the phenotype.

Chromosome X-to-autosome translocations [t(X;A)] are rare rearrangements with an estimated occurrence of 1 to 3 per 10,000 live births. Occurrences of Xq duplications have been observed in male and female subjects in whom the X chromosome segment escapes inactivation and results in functional disomy. We report a case of X;6 translocation in a 7-year-old boy with severe mental retardation, hypotonia, and recurrent respiratory tract infections. High-resolution chromosome analyses (fluorescence in situ hybridization, multiplex ligation probe-dependent amplification, and whole-genome array) revealed a terminal duplication of chromosome X at q28-qter (approximately 3.246 Mb in size) involving gene MECP2 and a terminal deletion (approximately 1.89 Mb) with the breakpoint at 6q27. This is the second report of a boy with a cryptic unbalanced Xq-autosome translocation. This case increases our understanding of mental disability caused by terminal Xq duplication.

A man with 47,XYY karyotype, prolactinoma and a history of first trimester recurrent miscarriages in his wife.

UNLABELLED: The clinical and laboratory features as well as the diagnostic and therapeutic approach of men with XYY syndrome have not been fully described. A 41-year-old infertile man was diagnosed as having a 47,XYY karyotype and a micro-prolactinoma. His 32-year-old wife had a history of five spontaneous pregnancies, all resulting in first trimester miscarriages. Three in-vitro fertilization (IVF) attempts were made with no biochemical pregnancy. During the third attempt, a pre-implantation genetic diagnosis (PGD) was performed by fluorescent in-situ hybridization (FISH) technique. Only one out of six (16%) embryos had normal karyotype. CONCLUSIONS: (1) Karyotypic analysis of both partners is a sine qua non investigation for recurrent miscarriages; (2) the XYY syndrome results in high frequency of embryo aneuploidy; (3) PGD by FISH can contribute to the transferring of chromosomally normal embryos in cases of parental chromosomal defects; (4) investigation for a prolactinoma should be considered in men with XYY syndrome.

Prenatal diagnosis of an epignathus associated with a 49,XXXXY karyotype--a case report.

BACKGROUND: Epignathus is a rare form of congenital teratoma, originating from the base of the skull, most commonly the hard palate, or mandible. It has been associated with a poor prognosis due to complications including polyhydramnios and respiratory compromise at birth as a consequence of upper airway obstructions. It is usually not associated with chromosomal aberrations. We present a case of prenatally diagnosed epignathus associated with a gonosomal pentasomy 49,XXXXY. CASE: A 34-year-old gravida 1, para 0 was referred to our unit with a sonographically suspected gastroschisis at 26+6 weeks' gestation. A detailed ultrasound scan revealed a large mixed echogenic mass seen in continuation with the mouth in the midline. Based on the appearance, an epignathus was suspected. No other fetal anomalies were detected. Karyotyping showed a 49,XXXXY karyotype of the fetus. The couple decided to continue the pregnancy after detailed counseling about results and prognosis. A cesarean section was necessary and performed at 29+0 weeks' gestation due to a pathological Doppler and cardiotocogram. Because of the enormous epignathus intubation of the newborn was not possible. A tracheostomy was performed for ventilation and oxygenation, which failed and the newborn died 30 min after birth. CONCLUSION: Prenatal diagnosis by ultrasound has improved perinatal management. This should include assessment of the tumor size and spread in order to establish an accurate prognosis and to anticipate likely problems which are to be encountered during pregnancy or at the time of delivery. To our knowledge, this is the first reported case of a prenatally diagnosed epignathus with a gonosomal pentasomy 49,XXXXY.

Underlying karyotype abnormalities in IVF/ICSI patients.

Cytogenetic investigations are performed in couples asking for IVF or intracytoplasmic sperm injection (ICSI) treatment. These serve a diagnostic purpose because male or female infertility might have a chromosomal origin. Chromosomal aberrations found in these patients include numerical abnormalities, such as Klinefelter syndrome, XYY karyotype or Turner syndrome and its variants; sex reversions, such as XX males or XY females; and also structural abnormalities, such as Robertsonian or reciprocal translocations and inversions. Finding the chromosomal origin of infertility in a patient also has a prognostic value because it aids the management of pregnancies obtained after IVF or ICSI and may lead to a proposal of prenatal or preimplantation genetic diagnosis.