Mild liver dysfunction in Klinefelter syndrome is associated with abdominal obesity and elevated lipids but not testosterone treatment.

CONTEXT: Klinefelter syndrome (KS) is associated with hypergonadotropic hypogonadism, which contributes to characteristic phenotypical manifestations including metabolic alterations. Extensive research has demonstrated important associations between androgens and liver function. OBJECTIVES: Investigation of the association between metabolic parameters, sex hormones and liver function in males with KS, both treated (T-KS) and untreated (U-KS) and healthy control males. METHODS: A total of 65 KS males were recruited, of which 32 received testosterone replacement therapy (TRT). Also, 69 healthy controls were recruited. We used alanine aminotransferase (ALAT), alkaline phosphatase and PP (prothrombin-proconvertin time ratio) as the main liver markers. Multivariable regression was performed within the three groups. All statistics were calculated using STATA. Principal component analysis was utilized to demonstrate the interconnected patterns among all measured biomarkers, and to elucidate how the different groups were linked to these patterns. RESULTS: Higher levels of main liver markers were observed in U-KS compared to controls, with no significant differences between U-KS and T-KS. T-KS had lower abdominal fat, total cholesterol, and LDL cholesterol than U-KS. Using multivariable models, variation in ALAT in U-KS was explained by HOMA2%S; in T-KS by BMI and SHBG; and in controls by hip circumference and estradiol. We found no multivariable models explaining variation in PP in U-KS; in T-KS, PP was explained by BMI and LDL cholesterol, and in controls by total cholesterol. Using principal component analysis U-KS was positively associated to D1 (an obese profile, which also included ALAT) and controls negatively associated with D1 (non-obese profile). CONCLUSION: KS males have mild liver dysfunction reflected by a significant increase in the main liver markers and decrease in albumin. The presented data underscore a primary role of metabolic conditions including obesity, insulin resistance and unfavourable lipid profile, in the elevated liver function markers seen in males with KS. Whether TRT can improve liver function in KS warrants further studies. Our findings, highlight that an evaluation of the liver function should be part of the clinical care in males with KS.

Complete or partial loss of the Y chromosome in an unselected cohort of 865 non-vasectomized, azoospermic men.

BACKGROUND: Structural abnormalities as well as minor variations of the Y chromosome may cause disorders of sex differentiation or, more frequently, azoospermia. This study aimed to determine the prevalence of loss of Y chromosome material within the spectrum ranging from small microdeletions in the azoospermia factor region (AZF) to complete loss of the Y chromosome in azoospermic men. RESULTS: Eleven of 865 azoospermic men (1.3%) collected from 1997 to 2022 were found to have a karyotype including a 45,X cell line. Two had a pure 45,X karyotype and nine had a 45,X/46,XY mosaic karyotype. The AZF region, or part of it, was deleted in eight of the nine men with a structural abnormal Y-chromosome. Seven men had a karyotype with a structural abnormal Y chromosome in a non-mosaic form. In addition, Y chromosome microdeletions were found in 34 men with a structural normal Y chromosome. No congenital malformations were detected by echocardiography and ultrasonography of the kidneys of the 11 men with a 45,X mosaic or non-mosaic cell line. CONCLUSIONS: In men with azoospermia, Y chromosome loss ranging from small microdeletions to complete loss of the Y chromosome was found in 6.1% (53/865). Partial AZFb microdeletions may give a milder testicular phenotype compared to complete AZFb microdeletions.

RéSUMé: CONTEXTE: Des anomalies structurelles ainsi que des variations mineures du chromosome Y peuvent provoquer des troubles de la différenciation sexuelle ou, plus fréquemment, une azoospermie. Cette étude visait à déterminer la prévalence de la perte de matériel chromosomique Y dans le spectre allant de petites microdélétions dans la région du facteur d'azoospermie (AZF) à la perte complète du chromosome Y chez les hommes azoospermiques. RéSULTATS: Onze des 865 hommes azoospermiques (1,3 %), collectés entre 1997 et 2022, présentaient un caryotype comprenant une lignée cellulaire 45,X. Deux avaient un caryotype pur 45,X et neuf avaient un caryotype mosaïque 45,X/46,XY. La région AZF, ou une partie de celle-ci, était absente chez huit des neuf hommes présentant un chromosome Y anormal sur le plan structurel. Sept hommes présentaient un caryotype avec un chromosome Y structurellement anormal sous une forme non mosaïque. De plus, des microdélétions du chromosome Y ont été trouvées chez 34 hommes présentant un chromosome Y de structure normale. Aucune malformation congénitale n'a été détectée par échocardiographie et échographie des reins des 11 hommes porteurs d'une lignée cellulaire 45,X mosaïque ou non mosaïque. CONCLUSIONS: Chez les hommes qui ont une azoospermie, une perte du chromosome Y, allant de petites microdélétions à une perte complète du chromosome Y, a été observée chez 6,1 % (53/865). Les microdélétions partielles de la région AZFb peuvent donner un phénotype testiculaire plus doux que les microdélétions complètes de l'AZFb.

Subjective versus objective sleep in men with Klinefelter syndrome.

OBJECTIVES: To investigate sleep among men with Klinefelter syndrome (KS). METHOD: We compared the sleep domains latency, disturbance, and efficiency in 30 men with KS (M age = 36.7 years, SD = 10.6) to 21 age-matched non-KS controls (M age = 36.8 years, SD = 14.4). Actigraphs were used to objectively measure sleep across 7 days and nights. Participants also completed a sleep diary over the same period, and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The mean correlation between the objective and subjective sleep measures was lower for the KS sample (M r = .15) than for controls (M r = .34). Sleep disturbance was significantly larger in the KS sample, as measured by actigraphy (p = .022, d = 0.71) and the PSQI (p = .037, d = 0.61). In regression models predicting sleep domains from KS status, age, educational level, vocational status, IQ, and mental health, KS status was not a significant predictor. Higher age was associated with more actigraphy-measured sleep disturbance. Higher educational level and being employed were associated with better sleep efficiency. CONCLUSIONS: Sleep disturbance may be a particular problem for men with KS and should be measured with complimentary methods.

Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.

An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.

21-hydroxylase autoantibodies are more prevalent in Turner syndrome but without an association to the autoimmune polyendocrine syndrome type I.

Turner syndrome (TS) is associated with an increased frequency of autoimmunity. Frequently observed autoimmune diseases in TS are also seen in the autoimmune polyendocrine syndrome type I (APS I), of which Addison disease is a key component. An overlapping antibody profile between TS and APS I could be considered. The aim of this work was to study women with TS regarding 21-hydroxylase (21-OH) antibodies and interferon omega (IFN-ω) antibodies, a highly specific marker for APS I, to determine if there are immunological overlaps between TS and APS I. Blood samples from 141 TS were assayed for 21-OH antibodies and IFN-ω antibodies using in-vitro-transcribed and translated autoantigen. Indices with a cut-off point of 57 and 200 for 21-OH antibody and IFN-ω antibody were used as reference. The median age of TS was 31·6 years (range = 11·2-62·2). Positive indices of 21-OH antibodies were present in six TS (4%), with a mean of 144·8 (range = 60-535). None had apparent adrenal insufficiency. There was no age difference comparing 21-OH antibody-positive TS (median age = 33·9 years, range = 17·7-44·7) and 21-OH antibody-negative TS (median age = 31·6 years, range = 11·2-62·2) (P = 0·8). No TS was positive for IFN-ω antibodies (mean = 42·4, range = -435-191). No overlapping autoimmune profile between TS and APS I was found. Autoimmunity against 21-OH among TS patients was more prevalent than previously identified, suggesting an increased risk of adrenal failure in TS. However, whether adrenal impairment will develop remains unknown.

Case of successful IVF treatment of an oligospermic male with 46,XX/46,XY chimerism.

INTRODUCTION: We present a case of an infertile male with 46,XX/46,XYchimerism fathering a child after ICSI procedure. METHODS: Conventional cytogenetic analysis on chromosomes, derived from lymphocytes, using standard Q-banding procedures with a 450-550-band resolution and short-tandem-repeat analysis of 14 loci. RESULTS: Analysis of 20 metaphases from lymphocytes indicated that the proband was a karyotypic mosaic with an almost equal distribution between male and female cell lines. In total, 12 of 20 (60%) metaphases exhibited a normal female karyotype 46,XX, while 8 of 20 (40%) metaphases demonstrated a normal male karyotype 46,XY. No structural chromosomal abnormalities were present. Out of 14 STR loci, two loci (D18S51 and D21S11) showed four different alleles in peripheral blood, buccal mucosal cells, conjunctival mucosal cells, and seminal fluid. In three loci (D2S1338, D7S820, and vWA), three alleles were detected with quantitative differences that indicated presence of four alleles. In DNA extracted from washed semen, four alleles were detected in one locus, and three alleles were detected in three loci. This pattern is consistent with tetragametic chimerism. There were no quantitative significant differences in peak heights between maternal and paternal alleles. STR-analysis on DNA from the son confirmed paternity. CONCLUSION: We report a unique case with 46,XX/46,XY chimerism confirmed to be tetragametic, demonstrated in several tissues, with male phenotype and no genital ambiguity with oligospermia fathering a healthy child after IVF with ICSI procedure.

Incidence, prevalence, diagnostic delay, morbidity, mortality and socioeconomic status in males with 46,XX disorders of sex development: a nationwide study.

STUDY QUESTION: What is the epidemiology and trajectory of health and socioeconomic status in males with 46,XX disorders of sex development (DSD)? SUMMARY ANSWER: 46,XX DSD males had an increased overall morbidity compared to male background population controls, and the socioeconomic status was inferior on outcome parameters such as education and long-term income. WHAT IS KNOWN ALREADY: 46,XX DSD males are rare and estimates of prevalence and incidence are limited. An increased morbidity and mortality as well as a negatively affected socioeconomic status are described in males with Klinefelter Syndrome. However, this has never been systematically studied in 46,XX DSD males. STUDY DESIGN, SIZE, DURATION: In this nationwide registry study including 44 males with a verified diagnosis of 46,XX DSD we aimed to estimate incidence, prevalence and diagnostic delay. Further, we aimed to study morbidity, mortality and socioeconomic outcome parameters using the Danish registries. The socioeconomic outcome parameters were education, income, retirement, parenthood and cohabitation. 46,XX DSD males were born during 1908-2012 and follow-up started at birth or at start of registration and ended in 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Potential cases (n = 69) were identified in the Danish Cytogenetic Central Registry and the diagnosis was verified by medical record evaluation (n = 44). A randomly selected age-matched control group of 100 males and 100 females per case was identified by Statistics Denmark. MAIN RESULTS AND THE ROLE OF CHANCE: Among newborn males the prevalence of diagnosed 46,XX DSD males was 3.5-4.7 per 100 000. Median age at diagnosis was 17.0 years (range: 0.0-62.8). Overall morbidity was increased compared to male controls (hazard ratio [HR] = 2.4, 95% CI: 1.8-3.3) but not when excluding endocrine and urogenital diseases as well as congenital malformations (HR = 1.2, 95% CI: 0.8-1.6). Mortality was not increased (HR = 0.6, 95% CI: 0.2-2.5) compared to male controls. 46,XX DSD males had poorer education (HR = 0.1, 95% CI: 0.0-0.9) and fewer fatherhoods (HR = 0.4, 95% CI: 0.2-0.7) than male controls, and their income was reduced for the following age groups; 45-49 years: odds ratio [OR] = 0.4 (95% CI: 0.2-0.7); 50-54 years: OR = 0.1 (95% CI: 0.0-0.6). LIMITATIONS, REASONS FOR CAUTION: The study cohort is rather small, although it is large in comparison to other studies on 46,XX DSD males. Some 46,XX DSD males may have been excluded from the study owing to lack of data in medical records, making the diagnosis impossible to verify. As in all epidemiologic studies a risk of misclassification must be considered when interpreting the study results, and as the study included diagnosed 46,XX DSD males only, conclusions cannot be extended to non-diagnosed 46,XX DSD males. WIDER IMPLICATIONS OF THE FINDINGS: This study provides a new insight into trajectory of health and socioeconomic status of 46,XX DSD males. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by research grants from the Health Research Fund of Central Denmark Region, the A.P. Møller Foundation 'Fonden til Laegevidenskabens Fremme', the Lundbeck Foundation and the Novo Nordisk Foundation (NNF13OC0003234 and NNF15OC0016474). The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Neuropsychology and brain morphology in Klinefelter syndrome - the impact of genetics.

Klinefelter syndrome (KS, 47,XXY) is associated with increased psychiatric morbidity and cognitive disabilities, although the neuropsychological phenotype shows great variability. Androgen receptor polymorphism (CAG repeat length), skewed X-chromosome inactivation and parent-of-origin of the extra X-chromosome have been suggested to influence cognitive function and psychological traits. These issues have not been clarified for KS patients. We studied X-chromosome inactivation pattern, CAG repeat length and parent-of-origin in relation to educational and cohabitation status, personality and autism traits, psychological distress, cognitive function and brain volumes in 73 KS patients and 73 controls. Grey matter (GM) volume of left insula was significantly decreased in KS patients with skewed X-inactivation (z = 5.78) and we observed a borderline significant difference in global brain matter volume where KS patients with skewed X-chromosome inactivation tended to have smaller brains. Skewed X-inactivation, CAG repeat length and parent-of-origin were not correlated with educational and marital status, personality traits, autism traits, and psychological distress, prevalence of depression and anxiety or cognitive function. Interestingly our results regarding brain volumes indicate that X-inactivation has an influence on GM volume in left insula and might also be related to global GM volume, indicating a possible effect of X-linked genes on the development of GM volume in KS patient. Skewed X-inactivation, CAG repeat length and parent-of-origin have no impact on the neuropsychological phenotype in KS (http://www.clinicaltrials.gov (Clinical trial NCT00999310)).

Low INSL3 in Klinefelter syndrome is related to osteocalcin, testosterone treatment and body composition, as well as measures of the hypothalamic-pituitary-gonadal axis.

Klinefelter syndrome (KS) is characterized by infertility and hypogonadism associated with increased prevalence of osteoporosis, diabetes and metabolic syndrome. Insulin-like factor 3 (INSL3) is produced in the Leydig cells. INSL3 has been suggested to play a role in bone health. Here, we studied INSL3 in relation to bone markers, body composition, the metabolic syndrome and diabetes. This was a case-control study. Sex hormones, anthropometric measures, vitamin D metabolites, parathyroid hormone, growth factors, muscle strength, maximal oxygen consumption and BMD were measured. We included 70 adult KS patients and 71 age-matched controls. INSL3 was lower in testosterone-treated KS compared with untreated KS. Correlation analyses showed a positive correlation between INSL3 and osteocalcin among KS, but not in controls; a significant positive correlation between INSL3 and testosterone in controls and in untreated KS, but not in treated KS men. Among controls a negative correlation was found between INSL3 and lipids, and glucose, but not in KS. HOMA2-B and impaired fasting glycaemia was positively correlated with INSL3 in controls. Among KS males we found a negative correlation between INSL3 and BMI, weight and waist/hip ratio, as well as positive correlations between INSL3 and FSH, LH, SHBG and testis volume. Multivariate analyses showed that age, testosterone and HDL cholesterol were the principal independent variables among healthy controls, whereas the determinants of INSL3 concentration among KS were age, LH, current testosterone treatment and testicular volume. INSL3 in KS is influenced by testosterone treatment and INSL3 is correlated with measures of bone metabolism, body composition and the metabolic syndrome. This may suggest that low INSL3 concentration is related to the pathogenesis behind an unfavourable change in body composition and bone metabolism among KS patients.

Mortality in Cushing's syndrome: a systematic review and meta-analysis.

CONTEXT: Data on mortality associated with Cushing's disease (CD) and Cushing's syndrome (CS) are scarce. OBJECTIVE: To perform a systematic review and meta-analysis of mortality studies in patients with CD and CS secondary to a benign adrenal adenoma. DATA SOURCES: A search was performed in seven electronic databases. Sixty-six articles were retrieved for analysis and 7 included in the final study. The main outcome measure was standardized mortality ratio (SMR). STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: Studies reporting SMR for patients diagnosed with CD and/or CS. Outcomes were stratified by subtype of Cushing's syndrome. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies were appraised by two authors and were synthesized using a weighted estimate based on the standard error of the SMR. RESULTS: The weighted mean of SMR for patients with CD was 1.84 (95% confidence interval (CI): 1.28-2.65). CD patients with persistent disease after initial surgery had a SMR of 3.73 (95% CI: 2.31-6.01), whereas mortality of CD patients with initial remission did not differ significantly from the general population (SMR: 1.23 (95% CI: 0.51-2.97)). SMR for patients with a benign adrenal adenoma was 1.90 (95% CI: 0.93-3.91). Age, sex and observation time did not significantly impact mortality. CONCLUSIONS: CD as opposed to CS due to a benign adrenal adenoma is associated with an excess mortality, which is attributed to patients in whom initial surgical cure is not obtained. This underlines the importance of a rigorous and early follow-up of newly operated patients with CD.

Genotype and phenotype in Klinefelter syndrome - impact of androgen receptor polymorphism and skewed X inactivation.

The phenotypic variation of Klinefelter syndrome (KS) is wide and may by caused by various genetic and epigenetic effects. Skewed inactivation of the supra-numerical X chromosome and polymorphism in the androgen receptor (AR) have been suggested as plausible causes. We wanted to describe X-chromosome inactivation patterns and the AR polymorphism and correlate these to clinical findings in KS in a cross-sectional study. To that end, we studied 70 KS patients enrolled from fertility clinics and endocrine clinics and 70 age-matched control subjects. The main outcome was X-chromosome inactivation pattern (skewX), AR polymorphism (CAGn - repeat length) and correlation to anthropometrical, hormonal, metabolic and bone-related variables. Forty-six of 70 KS men were heterozygous for CAGn. The shortest and the longest alleles were equally frequent inactivated and the mean CAGn of the two alleles did not differ significantly from the CAGn from either KS men, homozygous for the CAGn, or from the control subjects (22 vs. 23 vs. 21). SkewX was found in 12 of the 46 informative KS men (26%). In KS, height and arm span correlated positively to CAGn, whereas total cholesterol and haematocrit correlated negatively to CAGn. In controls, bone mineral density at the spine and hip correlated positively with CAGn, whereas adiponectin correlated negatively with CAGn. SkewX did not correlate to any of the investigated parameters. We conclude that CAGn polymorphism in AR explain some of the phenotypic variation in KS, whereas skewed X-chromosome inactivation did not. The impact of CAGn on final height may be caused by later reactivation of the pituitary-gonadal axis.

Bone mineral density in Klinefelter syndrome is reduced and primarily determined by muscle strength and resorptive markers, but not directly by testosterone.

SUMMARY: Klinefelter syndrome (KS) patients have lower bone mineral density (BMD) at the spine, hip and forearm compared to healthy subjects, but frank osteoporosis is not common. Muscle strength and bone markers predicted BMD but KS itself and serum testosterone did not. Low vitamin D and high PTH were frequent among KS. INTRODUCTION: The long-term consequence of KS on bone health is not well described. The objective of this study is to investigate the regional BMD and its determinants in KS. METHODS: This is a cross-sectional study. BMD at the spine, hip and forearm are measured by DXA and correlated to biochemical markers of bone turnover, vitamin D metabolites, PTH, sex hormones, growth factors as well as muscle strength and anthropometric measures. The setting is at a university clinical research centre. The study involves 70 adult KS patients and 71 age-matched healthy subjects. RESULTS: In KS, BMD was universally lowered in all regions. Markers of bone formation or bone resorption were not altered in KS, but 25-OH-Dvitamin was lower (55 vs. 82 nmol/L, p < 0.0001) than in healthy subjects. Significantly more KS patients had low BMD (Z-scores below -2) at the forearm (15 KS vs. two healthy subjects, p = 0.001) but not at the spine or hip. Muscle strength (bicep and quadriceps) was lower among KS patients. Multivariate analysis revealed that muscle strength, treatment with testosterone (ever/never), age at diagnosis, SHBG, bone-specific alkaline phosphatase and 1CTP were all independent predictors of BMD, but androgens was not. CONCLUSIONS: KS patients had lower BMD at the spine, hip and forearm compared to age-matched healthy subjects, but frank osteoporosis was not common. Muscle strength, previous history of testosterone treatment, age at diagnosis and bone markers were predictors of BMD, but testosterone was not. Signs of secondary hyperparathyroidism were present among KS. Dietary intake of vitamin D or sun exposure may be lower in KS patients.

Effect of sex hormone treatment on circulating adiponectin and subforms in Turner and Klinefelter syndrome.

BACKGROUND: Sex hormones have been shown to influence levels of adiponectin. Furthermore, testosterone has been shown to alter the subform distribution of adiponectin, whereas the effects of oestradiol are equivocal. We investigated the impact of sex hormone replacement therapy (HRT) on circulating adiponectin and its subforms, fasting lipids and measures of insulin sensitivity in Turner syndrome (TS) and Klinefelter syndrome (KS) respectively. MATERIALS AND METHODS: We compared eight young TS patients on and off 2 months of HRT vs. eight age- and body mass index (BMI) matched healthy females as well as 19 untreated KS patients vs. 20 testosterone treated KS patients vs. 20 age and BMI matched healthy males. Total adiponectin and adiponectin subforms separated by fast protein liquid chromatography were measured using an in-house assay. In addition, fasting levels of insulin, glucose and homeostasis model assessment estimates were determined. RESULTS: In TS, total adiponectin levels were 10.5 +/- 3.1 (mean +/- SD) vs. 12.8 +/- 3.5 mg L(-1) (P = 0.02) and high molecular weight (HMW) adiponectin 5.8 +/- 2.7 and 6.8 +/- 1.9 mg L(-1) (P = 0.02) on and off HRT respectively. Irrespective of HRT, total adiponectin and HMW adiponectin were similar to control values. In KS, total adiponectin levels were 6.5 (3.0-24.2) (median and range) and 9.3 (4.3-14.3) mg L(-1) (P = NS) and HMW adiponectin was 2.5 (0.5-16.0) and 4.6 (1.3-8.6) mg L(-1) (P = NS) with and without testosterone treatment respectively, and similar to controls. CONCLUSION: Short time HRT suppressed HMW and total adiponectin levels in TS patients. Testosterone treatment in KS patients had no effect on these parameters. In both groups of patients either adiponectin or the HMW subform seems to play no greater role in reflecting or mediating insulin sensitivity. Our data indicates that in patients with TS and KS, sex hormones have different effects on circulating adiponectin and its HMW subform than previously reported in other sex hormone deficient patients and healthy subjects.

Increased prevalence of autoimmunity in Turner syndrome--influence of age.

Individuals with Turner syndrome (TS) are prone to develop autoimmune conditions such as coeliac disease (CD), thyroiditis and type 1 diabetes (T1DM). The objective of the present study was to examine TS of various karyotypes for autoantibodies and corresponding diseases. This was investigated in a prospective cross-sectional study of Danish TS patients (n = 107, median age 36.7 years, range: 6-60 years). A medical history was recorded and a blood sample was analysed for autoantibodies against gliadin, transglutaminase, adrenal cortex, intrinsic factor, anti-thyroid peroxidase (anti-TPO) and glutamic-acid-decarboxylase 65 (GAD-65). Autoantibodies were present in 58% (n = 61) of all patients, whereof 18% (11) had autoantibodies targeting more than one organ. Patients with autoantibodies were significantly older than those without (P = 0.001). Anti-TPO was present in 45% (48) of patients, of whom 33% (16) were hypothyroid. Overall, 18% (19) presented with CD autoantibodies, of whom 26% (five) had CD. Anti-TPO and CD autoantibodies co-existed in 9% (10). Immunoglobulin A deficiency was found in 3% (three) of patients, who all had CD autoantibodies without disease. Among four patients with anti-GAD-65 none had T1DM, but two were classified as having T2DM. One patient had adrenocortical autoantibodies but not adrenal failure. Autoantibodies against intrinsic factor were absent. Anti-GAD-65 was increased in isochromosomal karyotypes (3/23 versus 1/84, P = 0.008) with no other association found between autoantibodies and karyotype. In conclusion, TS girls and women face a high prevalence of autoimmunity and associated disease with a preponderance towards hypothyroidism and CD. Thus, health care providers dealing with this patient group should be observant and test liberally for these conditions even before clinical symptoms emerge.

Left ventricular dysfunction in Klinefelter syndrome is associated to insulin resistance, abdominal adiposity and hypogonadism.

OBJECTIVE: Epidemiological data suggest there is an increased risk of dying from heart disease among patients with Klinefelter syndrome (KS). Due to high prevalence of hypogonadism and metabolic syndrome, we speculated that patients with KS may have subclinical changes in the left ventricular function. Therefore, the aim was to assess left ventricular long axis function by tissue Doppler echocardiography in patients with KS and relate these findings to the metabolic status and testosterone levels. DESIGN: Cross-sectional study. Out-patient clinic. PATIENTS: We investigated 25 unselected patients with KS, recruited from endocrine and fertility clinics. Twenty-five age-matched males served as controls. MEASUREMENTS: Left ventricular systolic long axis function (velocities and strain rate) assessed by tissue Doppler echocardiography related to free testosterone, fasting values of plasma glucose, insulin, homeostasis model assessment (HOMA)-index, cholesterol and triglycerides in addition to dual energy X-ray absorptiometry (DEXA) scan derived assessment of truncal body fat. RESULTS: The long axis function was significantly reduced in patients with KS (peak systolic velocities 4.4 +/- 1.3 vs. 5.3 +/- 1.0 cm/s, P < 0.01 and strain rate -1.3 +/- 0.3 vs.-1.6 +/- 0.3 s(-1), P < 0.01). However, the ventricular dysfunction was mainly attributed KS patients with metabolic syndrome. The peak systolic velocities were significantly correlated to truncal body fat (r = -0.72, P < 0.01) and free testosterone (r = 0.63, P < 0.01), but uncorrelated to plasma glucose, insulin and HOMA-index. CONCLUSION: Systolic long axis function is decreased in patients with KS and metabolic syndrome. The decrease in myocardial systolic function was significantly related to truncal body fat and hypogonadism, but not correlated to insulin sensitivity.

Disproportional geometry of the proximal femur in patients with Turner syndrome: a cross-sectional study.

OBJECTIVE: Patients with Turner syndrome (TS) have altered growth and increased risk of osteoporosis due to oestrogen deficiency and possibly a host of other factors. Thus, TS patients have a 4.9-fold increased risk of femoral neck fractures. Most patients are treated with oestrogen during puberty and adolescence to facilitate pubertal development and prevent secondary osteoporosis. The geometry of the hip is a predictor for hip fractures independent of bone mineral density (BMD). The purpose of the present study was to investigate the variation of the geometry of the hip in patients with TS in comparison with healthy controls. PATIENTS: The study population comprised 58 patients with TS (aged 22-67 years) and 60 age-matched healthy women (aged 21-65 years). MEASUREMENTS: Hip axis length (HAL), neck width (NW), neck shaft angle (NSA), and femoral head-radius (HR) on dual-energy X-ray absorptiometry (DXA) screen images. These parameters related to age of oestrogen supplementation, menarche, and duration of oestrogen exposure. RESULTS: Height was 146.6 +/- 6.9 cm and 167.1 +/- 6.2 cm (P < 0.1) and weight 57.4 +/- 13.9 kg and 62.3 +/- 8.3 kg (P < 0.001) in patients and controls, respectively. After adjustment for differences in height, HAL was not significantly different (9.4 +/- 0.5 vs. 9.5 +/- 0.5 cm; NS) in TS compared with controls while NW was significantly increased (3.5 +/- 0.4 cm vs. 3.3 +/- 0.2 cm, P < 0.001), NSA was similar (129 +/- 4 degrees vs. 130 +/- 4 degrees , NS), and HR was significantly decreased (4.1 +/- 0.4 vs. 4.5 +/- 0.3 cm, P < 0.001). The duration of oestrogen exposure was significantly shorter among TS, but did not correlate significantly with the geometrical parameters in either TS or controls. CONCLUSION: Our data demonstrates that hip geometry is disproportionate in TS compared with normal controls. The altered hip geometry, however, cannot explain the increased risk of hip fracture in TS.