Postural tremor and sexual chromosome aneuploidies: case report and review of literature.

PURPOSE: To examine the link between tremor and sex chromosome abnormalities, emphasizing the necessity of comprehensive physical examination. CASE DESCRIPTION: An 18-year-old man exhibited an isolated action tremor in both hands. Despite having no familial history of tremors and no identifiable secondary causes, his tall stature and learning difficulties suggested a genetic origin. His karyotype confirmed the diagnosis of Jacob's syndrome (XYY syndrome). Therapies with primidone and propranolol were ineffective for his tremor. CONCLUSIONS: Tremor can be caused by various conditions, and aneuploidies might often be overlooked as a cause. They should be considered in young patients with concrete phenotypes and negative familiar history of tremors. Karyotyping is a cost-effective diagnostic tool crucial for genetic counselling. Common treatments for tremors often yield unsatisfactory results in these cases.

Incidence of sex chromosome aneuploidy in a prenatal population: 27-year longitudinal study in Northern Italy.

OBJECTIVES: The availability of cell-free (cf) DNA as a prenatal screening tool affords an opportunity for non-invasive identification of sex chromosome aneuploidy (SCA). The aims of this longitudinal study were to investigate the evolution and frequency of both invasive prenatal diagnostic testing, using amniocentesis and chorionic villus sampling (CVS), and the detection of SCA in cfDNA samples from a large unselected cohort in Northern Italy. METHODS: The results of genetic testing from CVS and amniotic fluid samples received from public and private centers in Italy from 1995 to 2021 were collected. Chromosomal analysis was performed by routine Q-banding karyotype. Regression analyses and descriptive statistics were used to determine population data trends regarding the frequency of prenatal diagnostic testing and the identification of SCA, and these were compared with the changes in indication for prenatal diagnostic tests and available screening options. RESULTS: Over a period of 27 years, there were 13 939 526 recorded births and 231 227 invasive procedures were performed, resulting in the prenatal diagnosis of 933 SCAs. After the commercial introduction of cfDNA use in 2015, the frequency of invasive procedures decreased significantly (P = 0.03), while the frequency of prenatal SCA detection increased significantly (P = 0.007). Between 2016 and 2021, a high-risk cfDNA result was the indication for 31.4% of detected sex chromosome trisomies, second only to advanced maternal age. CONCLUSIONS: Our findings suggest that the inclusion of SCA in prenatal cfDNA screening tests can increase the prenatal diagnosis of affected individuals. As the benefits of early ascertainment are increasingly recognized, it is essential that healthcare providers are equipped with comprehensive and evidence-based information regarding the associated phenotypic differences and the availability of targeted effective interventions to improve neurodevelopmental and health outcomes for affected individuals. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Study on Absorption, Distribution and Excretion of a New Candidate Compound XYY-CP1106 against Alzheimer's Disease in Rats by LC-MS/MS.

XYY-CP1106, a candidate compound synthesized from a hybrid of hydroxypyridinone and coumarin, has been shown to be remarkably effective in treating Alzheimer's disease. A simple, rapid and accurate high-performance liquid chromatography coupled with the triple quadrupole mass spectrometer (LC-MS/MS) method was established in this study to elucidate the pharmacokinetics of XYY-CP1106 after oral and intravenous administration in rats. XYY-CP1106 was shown to be rapidly absorbed into the blood (Tmax, 0.57-0.93 h) and then eliminated slowly (T1/2, 8.26-10.06 h). Oral bioavailability of XYY-CP1106 was (10.70 ± 1.72)%. XYY-CP1106 could pass through the blood-brain barrier with a high content of (500.52 ± 260.12) ng/g at 2 h in brain tissue. The excretion results showed that XYY-CP1106 was mainly excreted through feces, with an average total excretion rate of (31.14 ± 0.05)% in 72 h. In conclusion, the absorption, distribution and excretion of XYY-CP1106 in rats provided a theoretical basis for subsequent preclinical studies.

Detection and characterization of male sex chromosome abnormalities in the UK Biobank study.

PURPOSE: The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes. METHODS: We analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data. RESULTS: Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = -3.8 nmol/L, all P < 2 × 10-8), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P < 7 × 10-6). CONCLUSION: KS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking.

A patient with 47, XYY mosaic karyotype and congenital absence of bilateral vas deferens: a case report and literature review.

BACKGROUND: The incidence of 47, XYY syndrome in live-born male infants is 1/1000. Due to its variable clinical symptoms, the diagnosis is easy to miss. The incidence of congenital bilateral absence of the vas deferens (CBAVD) in infertile men is 1-2%. The main cause is the mutation of CFTR and ADGAG2 genes. CASE PRESENTATION: The patient was a 33-year-old man who visited a doctor 5 years ago due to infertility. The investigation revealed that the patient's secondary sexual characteristics, testicular, and penis development were normal, and there was no gynecomastia, but the bilateral vas deferens and epididymis were not palpable. Transrectal ultrasound showed that the left seminal vesicle was missing, and the right seminal vesicle was atrophied. No abnormality was observed in Y chromosome microdeletion. Karyotype analysis indicated that the patient was 46, XY/47, XYY mosaic. Genetic testing found heterozygous mutations at two sites of CFTR (c263T > G and c2249C > T). CONCLUSIONS: Herein, we report the rare case of a male patient with clinical manifestations of infertility, chromosome 46, XY/47, XXY mosaic type, simultaneously manifested as the absence of bilateral vas deferens. Two pathogenic heterozygous CFTR gene mutations were found. Given the low genetic risk of the disease, we recommend that patients undergo intracytoplasmic sperm injection (ICSI) for fertility assessment.

Early neurodevelopmental and medical profile in children with sex chromosome trisomies: Background for the prospective eXtraordinarY babies study to identify early risk factors and targets for intervention.

Sex chromosome trisomies (SCT), including Klinefelter syndrome/XXY, Trisomy X, and XYY syndrome, occur in 1 of every 500 births. The past decades of research have resulted in a broadening of known associated medical comorbidities as well as advances in psychological research. This review summarizes what is known about early neurodevelopmental, behavioral, and medical manifestations in young children with SCT. We focus on recent research and unanswered questions related to the risk for neurodevelopmental disorders that commonly present in the first years of life and discuss the medical and endocrine manifestations of SCT at this young age. The increasing rate of prenatal SCT diagnoses provides the opportunity to address gaps in the existing literature in a new birth cohort, leading to development of the eXtraordinarY Babies Study. This study aims to better describe and compare the natural history of SCT conditions, identify predictors of positive and negative outcomes in SCT, evaluate developmental and autism screening measures commonly used in primary care practices for the SCT population, and build a rich data set linked to a bank of biological samples for future study. Results from this study and ongoing international research efforts will inform evidence-based care and improve health and neurodevelopmental outcomes.

Testicular function in boys with 47,XYY and relationship to phenotype.

An additional Y chromosome occurs in ~1 in 1,000 males, resulting in the karyotype 47,XYY. The phenotype includes tall stature, hypotonia, neuropsychiatric comorbidities, and an increased risk of infertility in adulthood. Little is known about testicular function in childhood and adolescence in 47,XYY. This cross-sectional study aimed to assess testicular function serum biomarkers, including total testosterone, inhibin B, and anti-mullerian hormone (AMH), in 82 boys with XYY (11.3 ± 3.8 years) compared with 66 male controls (11.6 ± 3.8 years). The association of testicular hormones with physical features, neuropsychological phenotype, and magnetoencephalography (MEG) was assessed with multiple linear regression models. Results indicate males with XYY have significantly lower inhibin B (median 84 pg/ml vs. 109 pg/ml, p = .004) and higher AMH (median 41 ng/ml vs. 29 ng/ml, p = .011); however, testosterone, testicular volume, and stretched penile length were not different from controls. In the exploratory analysis of relationships between hormone concentrations and phenotypic assessments, higher inhibin B concentrations were positively correlated with lower BMI and better cognitive, academic, and behavioral outcomes in the XYY group. Testosterone concentrations were positively associated with better behavioral outcomes in boys with XYY. Higher testosterone and inhibin B concentrations were also associated with shorter auditory latencies measured using magnetoencephalography (MEG) in XYY. With a few exceptions, testicular hormones were not associated with phenotypic outcomes in controls. In conclusion, there is evidence of subtle impaired testicular function in boys with XYY and a newly described relationship between measures of testicular function and some aspects of the XYY phenotype.

The epidemiology of sex chromosome abnormalities.

Sex chromosome abnormalities (SCAs) are characterized by gain or loss of entire sex chromosomes or parts of sex chromosomes with the best-known syndromes being Turner syndrome, Klinefelter syndrome, 47,XXX syndrome, and 47,XYY syndrome. Since these syndromes were first described more than 60 years ago, several papers have reported on diseases and health related problems, neurocognitive deficits, and social challenges among affected persons. However, the generally increased comorbidity burden with specific comorbidity patterns within and across syndromes as well as early death of affected persons was not recognized until the last couple of decades, where population-based epidemiological studies were undertaken. Moreover, these epidemiological studies provided knowledge of an association between SCAs and a negatively reduced socioeconomic status in terms of education, income, retirement, cohabitation with a partner and parenthood. This review is on the aspects of epidemiology in Turner, Klinefelter, 47,XXX and 47,XYY syndrome.

Morbidity in 47,XYY syndrome: a nationwide epidemiological study of hospital diagnoses and medication use.

PURPOSE: A systematic description of morbidity in 47,XYY syndrome based on nationwide registry data of hospital diagnoses and prescribed medication. METHODS: All males in Denmark diagnosed with 47,XYY syndrome during 1960-2014 were identified. Each was matched with 100 male controls from the general population. Diagnoses related to hospital encounters (1977-2014) and prescriptions (1996-2014) were analyzed by negative binominal regression and Cox regression, respectively. RESULTS: 47,XYY syndrome was associated with a significantly increased overall incidence of hospital diagnoses (incidence rate ratio = 2.30, confidence interval [CI]: 1.99-2.65), including a significantly increased incidence of diagnoses associated with congenital malformations and genetic disorders as well as with psychiatric, neurologic, respiratory, urogenital, endocrine, circulatory, gastrointestinal, and musculoskeletal system disorders. Diagnoses associated with infections, skin and eye disorders were significantly increased as well. 47,XYY syndrome was associated with a significantly increased occurrence of prescriptions overall (hazard ratio = 1.25, CI: 1.10-1.44), with sex hormones and medication related to the urogenital system, blood, and nervous system being most prominently increased. CONCLUSION: 47,XYY syndrome is associated with a significantly increased morbidity owing to a wide variety of diseases. Increased awareness of the diverse morbidity in 47,XYY syndrome may help guide clinicians assessing 47,XYY males, thereby improving long-term health outcomes.

A review of neurocognitive functioning of children with sex chromosome trisomies: Identifying targets for early intervention.

Sex chromosome trisomies (SCT) are among the most common chromosomal duplications in humans. Due to recent technological advances in non-invasive screening, SCT can already be detected during pregnancy. This calls for more knowledge about the development of (young) children with SCT. This review focused on neurocognitive functioning of children with SCT between 0 and 18 years, on domains of global intellectual functioning, language, executive functioning, and social cognition, in order to identify targets that could benefit from early treatment. Online databases were used to identify peer-reviewed scientific articles using specific search terms. In total 18 studies were included. When applicable, effect sizes were calculated to indicate clinical significance. Results of the reviewed studies show that although traditionally, the focus has been on language and intelligence (IQ) in this population, recent studies suggest that executive functioning and social cognition may also be significantly affected already in childhood. These findings suggest that neuropsychological screening of children diagnosed with SCT should be extended, to also include executive functioning and social cognition. Knowledge about these neurocognitive risks is important to improve clinical care and help identify targets for early support and intervention programs to accommodate for the needs of individuals with SCT.

A patient with 46,XY/47,XYY karyotype and female phenotype: a case report.

BACKGROUND: 47,XYY is a chromosomal abnormality syndrome that is typically observed in patients with a male phenotype. Few patients with XYY syndrome will have infertility. We here report a case of 46,XY/47,XYY syndrome diagnosed in a patient with a female phenotype. CASE PRESENTATION: A 15-year-old patient with a female phenotype visited our hospital owing to a chief complaint of short stature as of the age of 6 years. She was diagnosed with dwarf syndrome at the age of 10, but no change was noted after 2 months of growth hormone treatment. The patient's height was 136 cm and the weight was 29 kg, both of which were below the third percentile for her age/gender. In addition to short stature, the 4th and 5th metacarpals were short and there was no significant sex development. Karyotype analysis showed 47,XYY, and chromosomal microarray examination showed a chimera of 46,XY/47,XYY. CONCLUSION: This is an extremely rare case of 47,XYY abnormality in a patient with a female phenotype, with only one such known case reported previously. Since the cause is unknown, and symptoms of this syndrome are highly atypical and variable in childhood, clinicians should be aware of this possibility to avoid misdiagnosis and offer counseling and hormone therapy as needed to patients and their parents to improve their quality of life.

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.

Selective advantage of euploid spermatocytes I in an azoospermic 47,XYY man with gonadal mosaicism.

Although most XYY men have normal sperm counts and are fertile (supposedly due to the loss of the extra Y before meiosis), there is a minority who are infertile. In these cases, the XYY spermatocytes are able to enter meiosis and form different synaptic configurations. With regard to mosaics, there is scarce well-defined information on the presence of the second Y and its meiotic behaviour. In this study, the chromosome constitution and the synaptic behaviour of pachytene spermatocytes from an azoospermic man with testicular hypotrophy and non-mosaic 47,XYY karyotype were analysed. Furthermore, we determined the chromosome constitution of the somatic Sertoli cells. Five karyotypically normal men with obstructive azoospermia, but having complete spermatogenesis, were included as controls. Immuno-FISH using specific protein markers of synapsis and recombination (SYCP3, SYCP1, BRCA1, MLH1, CREST) and a specific Yq12 DNA probe were used. In addition, we used the newly developed Super-Resolution Structured Illumination Microscopy (SR-SIM) to clearly define the synaptic configurations. FISH analysis was also performed on Sertoli cells. The histopathological analysis showed variable degrees of spermatogenesis development in the testicular tissue of the propositus. Immuno-FISH analysis showed that most of the primary spermatocytes were euploid 46, XY. The use of SR-SIM confirmed the existence of this euploidy. Only a few pachytene spermatocytes showed an aneuploid X + YY constitution. Sertoli cells showed two different populations with one or two Y chromosomes, in similar proportions. Thus an abnormal niche of sex-trisomic Sertoli cells should be also considered when searching for the origin of spermatogenesis failure in XYY men.

Y chromosome gene copy number and lack of autism phenotype in a male with an isodicentric Y chromosome and absent NLGN4Y expression.

We describe a unique male with a dicentric Y chromosome whose phenotype was compared to that of males with 47,XYY (XYY). The male Y-chromosome aneuploidy XYY is associated with physical, behavioral/cognitive phenotypes, and autism spectrum disorders. We hypothesize that increased risk for these phenotypes is caused by increased copy number/overexpression of Y-encoded genes. Specifically, an extra copy of the neuroligin gene NLGN4Y might elevate the risk of autism in boys with XYY. We present a unique male with the karyotype 46,X,idic(Y)(q11.22), which includes duplication of the Y short arm and proximal long arm and deletion of the distal long arm, evaluated his physical, behavioral/cognitive, and neuroimaging/magnetoencephalography (MEG) phenotypes, and measured blood RNA expression of Y genes. The proband had tall stature and cognitive function within the typical range, without autism features. His blood RNA showed twofold increase in expression of Yp genes versus XY controls, and absent expression of deleted Yq genes, including NLGN4Y. The M100 latencies were similar to findings in typically developing males. In summary, the proband had overexpression of a subset of Yp genes, absent NLGN4Y expression, without ASD findings or XYY-MEG latency findings. These results are consistent with a role for NLGN4Y overexpression in the etiology of behavioral phenotypes associated with XYY. Further investigation of NLGN4Y as an ASD risk gene in XYY is warranted. The genotype and phenotype(s) of this subject may also provide insight into how Y chromosome genes contribute to normal male development and the male predominance in ASD.

Sleep Problems and Life Satisfaction as Predictors of Health in Men with Sex Chromosome Aneuploidies.

More knowledge is needed about men with sex chromosome aneuploidies (SCA). We present self-reported data from 53 men with SCA (Mage = 36.8 years, SD = 12.3, range 19-67). The Health Survey-Short Form (SF-36) measured eight health domains (physical functioning, role-physical, role-emotional, vitality, emotional health, social functioning, pain, general health). The Pittsburgh Sleep Quality Index measured sleep problems. The Personal Wellbeing Index measured satisfaction with eight life domains. Compared to norms, SCA reported poorer health (mean d = -0.80) and more sleep problems (mean d = -0.85). Differences between SCA and norms on personal well-being were small, except lower health satisfaction in SCA (d = -1.06). Seven of eight regression models predicting the SF-36 domains from life satisfaction and sleep problems were significant (explained variance 12.2% to 46.2%), except physical functioning (ns). Clinical assessment/intervention for a broad range of health and sleep problems is indicated for men with SCA.

An opportune life: 50 years in human cytogenetics.

This article is one person's view of human cytogenetics over the past 50 years. The flowering of human cytogenetics led the way to the establishment of clinical genetics as one of the most important developments in medicine in the twentieth century. The article is written from the viewpoint of a scientist who never tired of analyzing the images of dividing cells on the light microscope and interpreting the wealth of information contained in them.

Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory.

BACKGROUND: Since its debut in 2011, cell-free fetal DNA screening has undergone rapid expansion with respect to both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this screening tool, both for the originally included common autosomal and sex-chromosomal aneuploidies as well as the more recently added chromosomal microdeletion syndromes, have lagged behind. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations of this screening tool to inform pre- and posttest counseling, pre/perinatal decision making, and medical risk assessment/management. OBJECTIVE: The objective of this study was to determine the positive predictive value and false-positive rates for different chromosomal abnormalities identified by cell-free fetal DNA screening using a large data set of diagnostic testing results on invasive samples submitted to the laboratory for confirmatory studies. STUDY DESIGN: We tested 712 patient samples sent to our laboratory to confirm a cell-free fetal DNA screening result, indicating high risk for a chromosome abnormality. We compiled data from all cases in which the indication for confirmatory testing was a positive cell-free fetal DNA screen, including the common trisomies, sex chromosomal aneuploidies, microdeletion syndromes, and other large genome-wide copy number abnormalities. Testing modalities included fluorescence in situ hybridization, G-banded karyotype, and/or chromosomal microarray analysis performed on chorionic villus samples, amniotic fluid, or postnatally obtained blood samples. Positive predictive values and false-positive rates were calculated from tabulated data. RESULTS: The positive predictive values for trisomy 13, 18, and 21 were consistent with previous reports at 45%, 76%, and 84%, respectively. For the microdeletion syndrome regions, positive predictive values ranged from 0% for detection of Cri-du-Chat syndrome and Prader-Willi/Angelman syndrome to 14% for 1p36 deletion syndrome and 21% for 22q11.2 deletion syndrome. Detection of sex chromosomal aneuploidies had positive predictive values of 26% for monosomy X, 50% for 47,XXX, and 86% for 47,XXY. CONCLUSION: The positive predictive values for detection of common autosomal and sex chromosomal aneuploidies by cell-free fetal DNA screening were comparable with other studies. Identification of microdeletions was associated with lower positive predictive values and higher false-positive rates, likely because of the low prevalence of the individual targeted microdeletion syndromes in the general population. Although the obtained positive predictive values compare favorably with those seen in traditional screening approaches for common aneuploidies, they highlight the importance of educating clinicians and patients on the limitations of cell-free fetal DNA screening tests. Improvement of the cell-free fetal DNA screening technology and continued monitoring of its performance after introduction into clinical practice will be important to fully establish its clinical utility. Nonetheless, our data provide valuable information that may aid result interpretation, patient counseling, and clinical decision making/management.

[Social cognition disorders in Klinefelter syndrome: A specific phenotype? (KS)]. / Troubles de la cognition sociale dans le syndrome de Klinefelter : un trait phénotypique ?

INTRODUCTION: The Klinefelter syndrome (KS) is a genetic condition characterized by an X supernumerary sex chromosome in males. The syndrome is frequently associated with cognitive impairment. Indeed, the different areas of the executive sphere can be affected such as inhibition, cognitive flexibility but also attentional and visual-spatial domain. Social cognition disorders, predominantly on emotional recognition processes, have also been documented. In addition, the syndrome may be associated with psychiatric symptoms. MATERIAL AND METHOD: Our study aims to characterize of the various components of social cognition in the SK: facial emotional recognition, theory of mind and attributional style. For this two groups (SK group versus control group) of participants (n=16) matched for age and sociocultural level were recruited. Participants with intellectual disabilities, psychiatric or neurological disorders were excluded. Three social cognition tests were available: the TREF, the MASC, the AIHQ. Neurocognitive functions were assessed by the fNart, the subtest "logical memory" of the MEM-III, the subtests of the two VOSP battery, the d2, the TMT and the Stroop test. RESULTS: The SK group had specific social cognition disorders in comparison to the control group. Two emotions in particular were less well recognized: fear and contempt. In addition, the SK group had significantly lower results in theory of mind. Regarding the hostile attribution bias, no significant difference was found. Finally, the results showed correlations between specific attentional disorders and facial emotional recognition. DISCUSSION-CONCLUSION: Our study emphasizes social cognition disorders in SK. These disorders could be considered as a phenotypic trait in the syndrome. The interest of better characterizing the cognitive phenotype of genetic disorders that can affect the neurodevelopment is to offer specific cognitive remediation strategies.

Rare genomic rearrangement in a boy with Williams-Beuren syndrome associated to XYY syndrome and intriguing behavior.

Williams-Beuren syndrome (WBS) is caused by a hemizygous contiguous gene microdeletion of 1.55-1.84 Mb at 7q11.23 region. Approximately, 28 genes have been shown to contribute to classical phenotype of SWB with presence of dysmorphic facial features, supravalvular aortic stenosis (SVAS), intellectual disability, and overfriendliness. With the use of Microarray-based comparative genomic hybridization and other molecular cytogenetic techniques, is possible define with more accuracy partial or atypical deletion and refine the genotype-phenotype correlation. Here, we report on a rare genomic structural rearrangement in a boy with atypical deletion in 7q11.23 and XYY syndrome with characteristic clinical signs, but not sufficient for the diagnosis of WBS. Cytogenetic analysis of G-banding showed a karyotype 47,XYY. Analysis of DNA with the technique of MLPA (Multiplex Ligation-dependent Probe Amplification) using kits a combination of kits (P064, P036, P070, and P029) identified an atypical deletion on 7q11.23. In addition, high resolution SNP Oligonucleotide Microarray Analysis (SNP-array) confirmed the alterations found by MLPA and revealed others pathogenic CNVs, in the chromosomes 7 and X. The present report demonstrates an association not yet described in literature, between Williams-Beuren syndrome and 47,XYY. The identification of atypical deletion in 7q11.23 concomitant to additional pathogenic CNVs in others genomic regions allows a better comprehension of clinical consequences of atypical genomic rearrangements.

Ovotesticular disorder of sexual development due to 47,XYY/46,XY/45,X mixed gonadal dysgenesis in a phenotypic male presenting as cyclical haematuria: clinical presentation and assessment of long-term outcomes.

Ovotesticular disorder of sexual differentiation (OTDSD) is a rare cause of disorder of sexual differentiation predominantly having 46,XX karyotype, female phenotype and ambiguous genitalia. We report a 15-year-old having male body habitus, axillary and pubic hair, well-developed penis and right-descended testis with history of penoscrotal hypospadias correction, presenting with three episodes of cyclical haematuria, who biochemically had normal serum testosterone (338 ng dl(-1) ) which increased following hCG stimulation (614 ng dl(-1) ), elevated estradiol (17.35 pg ml(-1) ) along with elevated luteinising hormone (11.3 mIU l(-1) ) and follicle-stimulating hormone (31 mIU l(-1) ). Ultrasonography followed by micturating cystourethrogram and cystoscopy confirmed the presence of prostate, uterus, cervix and vagina draining into the urogenital sinus continuing till the penile urethra and left intra-abdominal gonad. Patient underwent hysterectomy and left gonadectomy. Histopathologic study of resected gonad confirmed presence of ovotestis. Low estradiol (1.2 pg ml(-1) ) following gonadectomy confirmed the ovotestis origin of estradiol. Chromosomal analysis revealed complex karyotype predominant being 47,XYY (50%) followed by 46,XY (26%) and 45,X (24%). This is perhaps the first report of 47,XYY/46,XY/45,X causing OTDSD in a phenotypic male.