Klinefelter Syndrome: What should we tell prospective parents?

Klinefelter syndrome (KS) or 47,XXY is the most common sex chromosome aneuploidy (SCA), occurring at a prevalence of 1 in 600 male pregnancies. Historically, only 25% of individuals with KS came to medical attention, for a range of issues across the life course including under-virilisation at birth, developmental and social concerns in childhood, absence, delay or arrest of puberty in adolescence or infertility in adulthood. Our understanding of the phenotypic spectrum of KS has been largely influenced by this ascertainment bias. With increasing uptake of antenatal noninvasive prenatal testing (NIPT), a corresponding increase in identification of KS has been documented. Population-based longitudinal data from infancy to adulthood on these individuals is lacking, which impedes balanced antenatal genetic counselling and raises issues for prospective parents and clinicians alike.

State-wide increase in prenatal diagnosis of klinefelter syndrome on amniocentesis and chorionic villus sampling: Impact of non-invasive prenatal testing for sex chromosome conditions.

BACKGROUND: To analyze population-based trends in the prenatal diagnosis of sex chromosome aneuploidy (SCA) since the availability of non-invasive prenatal testing (NIPT). METHODS: Retrospective state-wide data for all prenatal diagnoses performed <25 weeks gestation from 2005 to 2020 in Victoria, Australia. Non-invasive prenatal testing became locally available from 2012. The prenatal diagnosis rates of SCA as proportions of all prenatal diagnostic tests and all births were calculated. Statistical significance was assessed with the χ2 test for trend, with p < 0.05 considered significant. RESULTS: 46,518 amniocentesis and chorionic villus sampling were performed during the study period, detecting 617 SCAs. There was a significant increase in the rate of prenatal SCAs from 5.8 per 10,000 births in 2005 to 8.7 per 10,000 births in 2020 (p < 0.0001). This increase was predominantly due to 47,XXY cases, 91% of which were ascertained via positive NIPT for this condition in 2020. The prenatal diagnosis rate of 47,XXY significantly increased from 0.8 per 10,000 births in 2005 to 4.3 per 10,000 births in 2020 (p < 0.0001). CONCLUSION: Screening for SCAs using NIPT has directly led to an increase in their prenatal diagnosis on a population-wide basis, especially 47,XXY. This has implications for clinician education, genetic counselling, and pediatric services.

Body composition, trabecular bone score and vertebral fractures in subjects with Klinefelter syndrome.

BACKGROUND: Klinefelter syndrome (KS) frequently causes skeletal fragility characterized by profound alterations in bone microstructure with increased risk of fractures. Increased body fat mass associated with decreased body lean mass are frequent features of KS with possible detrimental effects on skeletal health. In this cross-sectional study, we evaluated the associations between body composition parameters, vertebral fractures (VFs) and trabecular bone score (TBS) in adult subjects with KS. METHODS: Seventy-one adult males (median age 41 years, range 18-64) with 47, XXY KS were consecutively enrolled by two Endocrinology and Andrology Units (IRCCS Humanitas Research Hospital in Milan and ASST Spedali Civili in Brescia). Dual-energy X-ray absorptiometry (DXA) was performed to assess bone mineral density (BMD) at lumbar spine, femoral neck and total hip, TBS and body composition. Prevalence of VFs was assessed by quantitative morphometry on lateral spine X-rays. RESULTS: VFs were detected in 14 patients (19.7%), without significant association with low BMD (p = 0.912). In univariate logistic regression analysis, VFs were significantly associated with truncal/leg fat ratio (OR 2.32 per tertile; 95% CI 1.05-5.15; p = 0.038), whereas impaired TBS (detected in 23.4% of subjects) was associated with older age at study entry (p = 0.001) and at diagnosis of disease (p = 0.015), body mass index (BMI; p = 0.001), waist circumference (p = 0.007), fat mass index (FMI; p < 0.001), FMI/lean mass index (LMI) ratio (p = 0.001). Prevalence of VFs was not significantly different between subjects with impaired TBS as compared to those with normal TBS (26.7 vs. 18.4%; p = 0.485). Skeletal end-points were not significantly associated with duration of testosterone replacement therapy and serum testosterone and 25hydroxyvitamin D values. CONCLUSION: Body composition might influence bone quality and risk of VFs in subjects with KS.

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.

Clinical features and prevalence of Klinefelter syndrome in transgender individuals: A systematic review.

OBJECTIVE: Previous studies have suggested a higher prevalence of Klinefelter syndrome amongst transgender individuals. We undertook a systematic review to determine the prevalence of Klinefelter syndrome amongst transgender individuals presumed male at birth and summarize the clinical features and potential treatment implications for individuals with Klinefelter syndrome commencing gender-affirming hormone therapy. DESIGN: Using preferred reporting items for systematic review and meta-analysis guidelines, we searched EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to 31 December 2021. All studies reporting on the prevalence or clinical features of transgender individuals with Klinefelter syndrome were included. This study is registered with the International Prospective Register of Systematic Reviews, number CRD42021227916. RESULTS: Our search strategy retrieved 11 cohort studies comprising 1376 transgender individuals. In all, 14 of 1376 (1.02%) individuals were diagnosed with Klinefelter syndrome. Based on the seven studies in which karyotype was undertaken in all individuals, the prevalence is 9/1013 (0.88%; 95% CI, 0.41%-1.68%). Case reports highlight unique treatment considerations in this population, including azoospermia, venous thromboembolism, and monitoring of breast cancer and bone health. CONCLUSIONS: Compared to the general population, observational studies document a higher prevalence of Klinefelter syndrome amongst transgender individuals, though underdiagnosis in the general population limits conclusions. Routine karyotype in transgender people initiating gender-affirming hormone therapy is not supported unless clinical features of Klinefelter syndrome, such as small testicular volume, or hypergonadotropic hypogonadism are present. Transgender individuals with Klinefelter syndrome need to manage a unique risk profile if they desire feminizing gender-affirming hormone therapy.

First baseline data of the Klinefelter ItaliaN Group (KING) cohort: clinical features of adult with Klinefelter syndrome in Italy.

BACKGROUND: Klinefelter syndrome (KS) is frustratingly under-diagnosed. KS have a broad spectrum of clinical features, making it difficult to identify.  OBJECTIVE: We describe KS clinical presentation in a large Italian cohort. DESIGN: This is the first observational cohort study within a national network, the Klinefelter ItaliaN Group (KING). Primary outcomes were to describe the basic clinical features and the actual phenotype of KS in Italy. Secondary outcomes were to determine age at diagnosis and geographical distribution. METHODS: We performed a basic phenotyping and evaluation of the hormonal values of 609 adult KS patients. RESULTS: Mean age at diagnosis was 37.4 ± 13.4 years. The overall mean testicular size was 3 ml, and 2.5 ml in both testes in untreated KS group. BMI was 26.6 ± 5.8 kg/m2, and 25.5% of KS had metabolic syndrome (MetS). LH and FSH were increased, and mean total testosterone were 350 ± 9.1 ng/dl. A descriptive analysis showed that 329 KS patients were evaluated in Northern Italy, 76 in Central and 204 in Southern Italy. Analysis of variance demonstrated significant statistical differences (p < 0001) between the age at diagnosis of the three geographical groups. Compared with the expected number among male patients matched for age in Italy, only 16% of KS patients received a diagnosis. CONCLUSIONS: These data are the results of the only national database available that collects the clinical and hormonal data of the KS patients, currently referred at the KING centers. In Italy the typical KS patient is overweight, with small testes, and elevated LH and FSH. Only 25.5% of them are diagnosed with MetS. Early detection and timely treatment are mandatory.

49,XXXXY syndrome: A study of neurological function in this uncommon X and Y chromosomal disorder.

49,XXXXY is a rare chromosomal variation characterized by deficits in motor, language, and cognitive domains. This study reports on the neurological function and dysmorphic features in the largest cohort to date. Seventy-two boys with 49,XXXXY were evaluated on a variety of domains including a neurological examination and neuromotor assessments including the Beery Buktenica Developmental Test of Visual-Motor Integration, Sixth Edition, the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), and the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition. Results supported previous literature by describing high occurrences of truncal and extremity hypotonia, which significantly impacts on motor milestones and ambulation in this population. The boys presented with dysmorphic features including epicanthal folds, frontal bossing, and synophrys. Visual perception skills were mildly impaired and cranial nerves were typically intact, however capabilities in motor coordination and fine motor precision were greatly delayed, supporting deficits in refined and controlled hand movements versus widespread visual deficits. Preschool boys treated with testosterone replacement had significantly increased scores when compared to the untreated group on the BSID-III Psychomotor Development Index, further supporting previous research indicating that testosterone replacement may have a positive impact on neurodevelopmental outcomes in males with additional X chromosomes. Boys with 49,XXXXY may benefit from hormonal treatment in conjunction with early intervention services to address their significant motor deficits.

Glucose metabolic disorder in Klinefelter syndrome: a retrospective analysis in a single Chinese hospital and literature review.

BACKGROUND: We aimed to investigate the clinical characteristics and islet ß-cell function in patients with Klinefelter syndrome (KS) and hyperglycemia. METHODS: This is a retrospective study. In total, 22 patients diagnosed with KS were identified from the electronic medical record system, including 9 patients with hyperglycemia (total patients with hyperglycemia, THG-KS group) and 5 hyperglycemic KS patients with oral glucose tolerance test (OGTT) results (HG-KS group). An additional 5 subjects with hyperglycemia and 5 normal glucose tolerance (NGT) subjects matched based on body mass index were included as the HG group and NGT group, respectively. Data from clinical and laboratory examinations were collected. We further performed a literature review of KS and hyperglycemia. RESULTS: We found that KS patients developed abnormal glucose metabolism earlier in life than those without KS, and the median age was 17 years, ranging from 10 years to 19 years. Six of 17 (35.3%) patients were diagnosed with diabetes mellitus and 3 of 17 (17.6%) patients were diagnosed with prediabetes. Among 10 patients with both fasting blood glucose and insulin results recorded, there were 8 out of 17 (47.1%) KS patients had insulin resistance. The prevalence of hypertension and dyslipidemia was higher in patients with hyperglycemia and KS than in patients with NGT KS. Compared with the HG group, insulin sensitivity levels were lower in HG-KS group, whereas homeostasis model assessment of ß-cell function levels (p = 0.047) were significantly, indicating higher insulin secretion levels in the HG-KS group. CONCLUSIONS: KS patients develop hyperglycemia earlier in life than those without KS and show lower insulin sensitivity and higher insulin secretion. These patients also have a higher prevalence of other metabolic diseases and may have different frequencies of developing KS-related symptoms.

Quality of life in Klinefelter patients on testosterone replacement therapy compared to healthy controls: an observational study on the impact of psychological distress, personality traits, and coping strategies.

PURPOSE: We aimed to verify if 1 year-testosterone-replacement therapy could produce a psychopathological recovery and a satisfactory quality of life in Klinefelter syndrome (KS) patients compared to matched healthy controls. Further, we analyzed personality traits and coping strategies, an issue not yet examined in androgen-treated KS patients. We also enquired whether any of the sociodemographic and psychological variables might predict a patient's general and sexual life satisfaction. METHODS: The Quality of Life Enjoyment and Satisfaction Questionnaire and the Temperament and Character Inventory-Revised were administered to both 23 KS patients and matched healthy subjects. Psychopathology was investigated by the Symptom Checklist-90-Revised (SCL-90-R) and the Mini-mental State Examination. The COPE Inventory was used to identify cognitive and behavioral strategies to manage disease-related distress. RESULTS: In testosterone-treated KS patients, when compared with controls, SCL-90-R subscales analysis evidenced high psychological distress, mainly presented as obsessive thoughts, hanger-hostility, phobias, and psychoticism. Self-directedness and self-transcendence, along with the prevalent use of emotion-focused coping strategies, outlined the personality of our KS patients. Depression and somatization proved to be predictors of general life dissatisfaction. Depression, anger-hostility, and paranoid ideation, instead, emerged as predictors of sexual life dissatisfaction. CONCLUSION: Endocrinologists should cooperate with mental health providers to foster a better outcome of the disease in KS patients.

[Klinefelter syndrome: Advances in research].

Klinefelter syndrome (KS) is a most common chromosome abnormality and frequently leads to male infertility. In recent years, deeper insights have been gained into the treatment of KS in children, clinical manifestations of KS, as well as reproductive problems and pre- and postnatal screening of the disease. This article presents an overview of the epidemiology, clinical manifestations, pathophysiological mechanism, laboratory examination, drug therapy and application of assisted reproductive technology, and KS screening, aiming to provide some reference for KS-related clinical practice.

Hormone-related diseases and prostate cancer: An English national record linkage study.

Insulin-like growth factor-I (IGF-I) and testosterone may be related to prostate cancer risk. Acromegaly is associated with clinically high IGF-I concentrations. Klinefelter's syndrome, testicular hypofunction and hypopituitarism are associated with clinically low testosterone concentrations. We aimed to investigate whether diagnosis with these conditions was associated with subsequent prostate cancer diagnosis and mortality. We used linked English national Hospital Episode Statistics and mortality data from 1999 to 2017 to construct and follow-up cohorts of men aged ≥35 years diagnosed with (i) acromegaly (n = 2,495) and (ii) hypogonadal-associated diseases (n = 18,763): Klinefelter's syndrome (n = 1,992), testicular hypofunction (n = 8,086) and hypopituitarism (n = 10,331). We estimated adjusted hazard ratios (HRs) and confidence intervals (CIs) for prostate cancer diagnosis and death using Cox regression in comparison with an unexposed reference cohort of 4.3 million men, who were admitted to hospital for a range of minor surgeries and conditions (n observed cases = 130,000, n prostate cancer deaths = 30,000). For men diagnosed with acromegaly, HR for prostate cancer diagnosis was 1.33 (95% CI 1.09-1.63; p = 0.005; n observed cases = 96), HR for prostate cancer death was 1.44 (95% CI 0.92-2.26; p = 0.11; n deaths = 19). Diagnosis with Klinefelter's syndrome was associated with a lower prostate cancer risk (HR = 0.58, 95% CI 0.37-0.91; p = 0.02; n observed cases = 19) and hypopituitarism was associated with a reduction in prostate cancer death (HR = 0.53, 95% CI 0.35-0.79; p = 0.002; n deaths = 23). These results support the hypothesised roles of IGF-I and testosterone in prostate cancer development and/or progression. These findings are important because they provide insight into prostate cancer aetiology.

Rare sex chromosome variation 48,XXYY: An integrative review.

While the most common Sex Chromosome Aneuploidy (SCA) is 47,XXY, other variations, such as 48,XXYY, are less studied, perhaps due to its rarity. 48,XXYY occurs with an estimated prevalence of 1:18,000-40,000 male births. This SCA is associated with a variety of complex physical, psychological, and neuroanatomical findings. The purpose of this integrative review is to summarize the available evidence related to 48,XXYY and identify gaps in the literature. This study utilized integrative review and PRISMA-guided methodology to search six databases for information pertaining to 48,XXYY. There were no exclusion criteria related to design methodology, given the paucity of available research. Among 397 articles reviewed for potential inclusion, 30 articles remained after inclusion and exclusion criteria were applied. Seven of these articles concentrated solely on participants with 48,XXYY. Literature was summarized into categories of physical phenotype, psychosocial, behavioral, neurocognitive, and brain function. Clinical description of 48,XXYY has evolved over time to develop a deeper understanding of this complex disorder. Large gaps remain, especially a lack of experimental studies, clinical guidelines, and treatments. Additionally, few studies explore methodologies such as interviews or self-report surveys in this population. 48,XXYY presents with a wide spectrum of physical, psychological, and neurocognitive symptoms, and frequently requires complex interdisciplinary care. In order to better understand this disorder and to appropriately treat the individuals affected by it, future research should focus on experimental studies and research that utilizes a variety of methods, including participant interviews and patient-report surveys.

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.

Metabolic and cardiovascular risk factors in Klinefelter syndrome.

Klinefelter syndrome (KS), which normally presents with a 47,XXY karyotype, is the most common sex chromosome disorder in males. It is also the most common genetic cause of male infertility. KS subjects are typically tall, with small and firm testes, gynecomastia, broad hips, and sparse body hair, although a less evident presentation is also possible. KS is also characterized by a high prevalence of hypogonadism, metabolic syndrome (MetS) and cardiovascular disease. The aim of this article is to systematically review metabolic and the cardiovascular risk factors in KS patients. Hypogonadism has an important role in the pathogenesis of the changes in body composition (particularly visceral obesity) and hence of insulin resistance and MetS, but the association between KS and MetS may go beyond hypogonadism alone. From childhood, KS patients may show an increase in visceral fat with a reduction in lean body mass and an increase in glucose and impaired fat metabolism. Their increased incidence of congenital anomalies, epicardial adipose tissue, and thromboembolic disease suggests they have a higher risk of cardiovascular disease. There is conflicting evidence on the effects of testosterone therapy on body composition and metabolism.

High prevalence of cardiometabolic risk features in adolescents with 47,XXY/Klinefelter syndrome.

Klinefelter syndrome (KS) occurs in 1:600 males and is associated with high morbidity and mortality due to diabetes and cardiovascular disease. Up to 50% of men with KS have metabolic syndrome, a cluster of features conferring increased risk for diabetes and cardiovascular disease. These cardiometabolic (CM) risk features have not been studied in adolescents with KS. The objective of this cohort study was to compare CM risk features in adolescents with KS to controls matched for sex, age, and BMI z score. Fifty males with KS (age 10-17 years) were well-matched to male controls (n = 50) for age (14.0 ± 1.7 vs. 14.0 ± 1.5 years) and BMI z score (0.3 ± 1.3 vs. 0.4 ± 1.2). Three CM risk features were present in 30% of adolescents with KS compared to 12% of controls (RR 2.5, 95% CI 1.1-5.9, p = .048). The KS group had significantly lower HDL cholesterol (p = .006), higher triglycerides (p < .001), and greater waist circumference percentile (p < .001). Despite a normal BMI, the prevalence of CM risk features was very high in adolescents with KS, particularly for central adiposity and dyslipidemia. The pathophysiology of this metabolic profile independent of obesity needs further investigation to facilitate prevention of the high morbidity of cardiovascular disease and diabetes in this population. ClinicalTrials.gov identifiers: NCT01585831 and NCT02723305.

Behavioral phenotype of 49,XXXXY syndrome: Presence of anxiety-related symptoms and intact social awareness.

49,XXXXY is a rare X and Y chromosome variation that occurs in 1:85,000 to 1:100,000 live male births and is notable for variable motor, speech, and behavioral deficits. Case studies have described boys with this disorder as shy, impulsive, and aggressive with low frustration tolerances; however, previous studies have been limited due to cohort size. This study reports on the largest cohort of boys with 49,XXXXY to date with an emphasis on the prevalence of anxiety-related symptoms and sociability from preschool to adolescence. The Child Behavior Checklist, Behavior Rating Inventory of Executive Function, 2nd edition, and Social Responsiveness Scale, 2nd edition were completed by parents on a cohort of 69. The cohort demonstrated deficits in social cognition and communication beginning in preschool, however, presented with consistent social awareness and motivation for social activities not previously appreciated in this disorder. In addition, signs of anxiety presented during preschool years and increased in severity with age, particularly in internalizing problems. Boys with 49,XXXXY presented with wide behavioral variability across all ages and domains. Further research into the potential influences of culture, birth order, biological treatment, and frequency of services is needed to better define the behavioral phenotype of children with this disorder.

Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis.

PURPOSE: Low testosterone (T) in Klinefelter's syndrome (KS) can contribute to typical features of the syndrome such as reduced bone mineral density, obesity, metabolic disturbances and increased cardiovascular risk. The aim of the present study is to review and meta-analyze all available information regarding possible differences in metabolic and bone homeostasis profile between T treated (TRT) or untreated KS and age-matched controls. METHODS: We conducted a random effect meta-analysis considering all the available data from observational or randomized controlled studies comparing TRT-treated and untreated KS and age-matched controls. Data were derived from an extensive MEDLINE, Embase, and Cochrane search. RESULTS: Out of 799 retrieved articles, 21 observational and 22 interventional studies were included in the study. Retrieved trials included 1144 KS subjects and 1284 healthy controls. Not-treated KS patients showed worse metabolic profiles (including higher fasting glycemia and HOMA index as well as reduced HDL-cholesterol and higher LDL-cholesterol) and body composition (higher body mass index and waist circumference) and reduced bone mineral density (BMD) when compared to age-matched controls. TRT in hypogonadal KS subjects was able to improve body composition and BMD at spinal levels but it was ineffective in ameliorating lipid and glycemic profile. Accordingly, TRT-treated KS subjects still present worse metabolic parameters when compared to age-matched controls. CONCLUSION: TRT outcomes observed in KS regarding BMD, body composition and glyco-metabolic control, are similar to those observed in male with hypogonadism not related to KS. Moreover, body composition and BMD are better in treated than untreated hypogonadal KS. Larger and longer randomized placebo-controlled trials are advisable to better confirm the present data, mainly derived from observational studies.

Klinefelter syndrome comorbidities linked to increased X chromosome gene dosage and altered protein interactome activity.

Klinefelter syndrome (KS) (47,XXY) is the most common male sex chromosome aneuploidy. Diagnosis and clinical supervision remain a challenge due to varying phenotypic presentation and insufficient characterization of the syndrome. Here we combine health data-driven epidemiology and molecular level systems biology to improve the understanding of KS and the molecular interplay influencing its comorbidities. In total, 78 overrepresented KS comorbidities were identified using in- and out-patient registry data from the entire Danish population covering 6.8 million individuals. The comorbidities extracted included both clinically well-known (e.g. infertility and osteoporosis) and still less established KS comorbidities (e.g. pituitary gland hypofunction and dental caries). Several systems biology approaches were applied to identify key molecular players underlying KS comorbidities: Identification of co-expressed modules as well as central hubs and gene dosage perturbed protein complexes in a KS comorbidity network build from known disease proteins and their protein-protein interactions. The systems biology approaches together pointed to novel aspects of KS disease phenotypes including perturbed Jak-STAT pathway, dysregulated genes important for disturbed immune system (IL4), energy balance (POMC and LEP) and erythropoietin signalling in KS. We present an extended epidemiological study that links KS comorbidities to the molecular level and identify potential causal players in the disease biology underlying the identified comorbidities.

Mental Health of a Large Group of Adults With Disorders of Sex Development in Six European Countries.

OBJECTIVE: The aim of the study was to evaluate psychiatric symptoms among 1022 persons with various disorders of sex development (DSDs). METHODS: The study was a European multicenter cross-sectional clinical evaluation in six countries. The mean (SD) age of participants was 32.1 (13.4) years. The cohort consisted of 325 individuals with Turner syndrome, 219 individuals with Klinefelter syndrome (KS), female individuals with various XY-DSD conditions (107 with and 67 without androgenization), 87 male individuals with XY-DSD conditions, and 221 female individuals with congenital adrenal hyperplasia. The Hospital Anxiety and Depression Scale, the Short Autism Spectrum Quotient, the Adult Attention-Deficit/Hyperactivity Disorder Self-Report Scale, and self-reported mental health history were used to assess psychiatric symptoms. RESULTS: Across the six DSD diagnostic groups, clinical cutoff symptom scores were reached in 19.5% of participants for anxiety, in 7.1% for depression, in 4.1% for attention-deficit/hyperactivity disorder, and in 9.1% for autism. The mean depression and anxiety scores were higher compared with population norms in men with KS and men with XY-DSD. Compared with participants with other DSD conditions, men with KS reported significantly more mental health symptoms. Self-esteem, satisfaction with care, body dissatisfaction, and experiences of shame were associated with psychiatric symptoms in many DSD conditions. CONCLUSIONS: A substantial minority of adults with DSD, with KS in particular, experience psychiatric morbidity. Across DSD conditions, adults may share feelings of shame. Developing a positive self-esteem and body image may be challenging. Multidisciplinary DSD care that involves specialized mental health support can be of important value. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006072.

High-level language competencies and Theory of Mind in a group of children with Klinefelter syndrome.

Klinefelter syndrome (KS) is a genetic anomaly involving the presence of one or more supernumerary X chromosomes in male individuals. In the cognitive profile of these individuals, strengths are found in nonverbal abilities, whereas weaknesses are observed in executive function, language, and academic performance. Our study is based on a comparison between eight children diagnosed with KS (47,XXY) (age range: 9-13 years; IQ range: 80-123), with no delay in language development, and eight typically developing (TD) controls. We explored a range of high-level language competencies and Theory of Mind (ToM) in addition to basic language competency. High-level language competencies were assessed by a battery that measures pragmatic language skills and a metaphor comprehension test (MCT). To assess ToM, we administered the corresponding subtest of the NEPSY II. Basic language competence was assessed by the NEPSY II Comprehension of Instructions subtest. Although basic language performance did not differentiate the individuals with KS from the TD controls, relevant differences appeared in some of the high-level language competencies as well as in the ToM task. All tasks in which the individuals with KS performed less well were characterized by complex inferential processes. Some possible clinical and educational implications are discussed.