To assess the population-based incidence, prevalence, and age at diagnosis of individuals with 45,X/46,XY mosaicism (and associated variants) and describe the associated mortality pattern. In ...addition, a systematic literature review of papers providing prevalence data of 45,X/46,XY mosaicism was performed.
A population-based epidemiological study of all individuals diagnosed with 45,X/46,XY mosaicism between 1960 and 2019. Mortality was analyzed using data from the Danish Causes of Death Register. One-hundred randomly age- and sex-matched general population controls per case were identified for comparison.
One-hundred-thirty-seven males and 46 females with 45,X/46,XY mosaicism were identified. The apparent prevalence was 5.6 per 100,000 liveborn males and 2.1 per 100,000 liveborn females. The incidence of males with 45,X/46,XY increased during the study (P > .0001) but was stable for females (P = .4). Males were significantly older than females when diagnosed (median age = 29.1, interquartile range: 3.4-41.3) years versus 13.3 (interquartile range: 2.1-19.1) years, P = .002). All-cause mortality was doubled in males with 45,X/46,XY (Hazard Ratio = 2.0, 95% confidence interval: 1.2-3.3) and quadrupled in females (Hazard Ratio = 4.0, confidence interval: 2.0-7.9).
The apparent population-based prevalence of males and females with 45,X/46,XY is 5.6 and 2.1 per 100,000 liveborn males and females, respectively. Diagnosis of males with 45,X/46,XY males is increasing. 45,X/46,XY mosaicism is associated with an increased all-cause mortality.
Klinefelter syndrome is highly underdiagnosed and diagnosis is often delayed. With the introduction of non-invasive prenatal screening, the diagnostic pattern will require an updated description of ...the clinical and biochemical presentation of infants with Klinefelter syndrome. In the first months of life, the hypothalamic-pituitary-gonadal (HPG)-axis is transiently activated in healthy males during the so-called minipuberty. This period represents a "window of opportunity" for evaluation of the HPG-axis before puberty and without stimulation tests. Infants with Klinefelter syndrome present with a hormonal surge during the minipuberty. However, only a limited number of studies exist, and the results are contradictory. Further studies are needed to clarify whether infants with Klinefelter syndrome present with impaired testosterone production during the minipuberty. The aim of this review is to describe the clinical and biochemical characteristics of the neonate and infant with Klinefelter syndrome with special focus on the minipuberty and to update the clinical recommendations for Klinefelter syndrome during infancy.
Klinefelter syndrome (KS) is the leading genetic cause of primary hypogonadism and infertility in men. The clinical phenotype has expanded beyond the original description of infertility, small ...testes, and gynecomastia. Animal models, epidemiologic studies, and clinical research of male subjects with KS throughout the lifespan have allowed the better characterization of the variable phenotype of this condition. This review provides an overview on what is known of the epidemiology, clinical features, and pathophysiology of KS, followed by a more focused discussion of testicular development and the clinical management of hypogonadism and fertility in boys and men with KS.
Cardiometabolic health in Turner syndrome Davis, Shanlee M; Geffner, Mitchell E
American journal of medical genetics. Part C, Seminars in medical genetics,
March 2019, Letnik:
181, Številka:
1
Journal Article
Odprti dostop
Individuals with Turner syndrome (TS) have a higher morbidity and mortality compared to the general population. Diabetes and cardiovascular disease are the major contributors to this burden. ...Precursors to diabetes and cardiovascular disease make up what is known as metabolic syndrome, including abdominal obesity, hypertension, dyslipidemia, and elevated fasting glucose. These features of poor cardiometabolic health are also prevalent among women with TS. Youth with TS also exhibit many of these features, indicating that the pathogenesis of these cardiometabolic conditions may begin early in life. The etiology of the increased risk of cardiometabolic conditions in TS is likely multifactorial, involving genetics, epigenetics, hypogonadism, medical comorbidities, medications, and lifestyle. Counseling for the increased risk of cardiometabolic diseases as well as efforts to prevent or lower this risk should be routinely provided in the care of all patients with TS. Clinical practice guidelines are now available to guide screening and treatment of cardiometabolic conditions in girls and women with TS.
Background Sex differences in body composition are appreciated throughout the lifespan with probable contributions from sex steroids: testosterone and estrogen. The purpose of this longitudinal ...observational study was to determine if sex differences in body composition emerge during the first months of life in healthy infants, corresponding to the age at which male infants produce endogenous testosterone. Methods Linear growth and body composition parameters using air displacement plethysmography were obtained from 602 healthy infants after birth and again at 5 months of age. Rate of change in body composition parameters were compared between sexes. Results Sex differences in length, total mass, fat free mass (FFM), and percent fat mass (%FM) were present both at birth and at 5 months (p < 0.001 for all), with males having greater total mass and FFM but lower %FM. Gain in %FM over the first 5 months was significantly lower in males (p = 0.0004). This difference was secondary to a gain of 17 g/week more in FFM in males compared to females. Conclusions Sex differences in body composition emerge in the first months of life, with lower adiposity accumulation in males. Endogenous testosterone production in males ~1-4 months of age may account for findings and may have lifelong implications for sex differences in body composition.
Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosome abnormality in males (150 per 100,000 males). The condition leads to hypergonadotropic hypogonadism and ever since the condition ...was described approximately 80 years ago, testosterone treatment has been the cornerstone in care for individuals with KS. However, KS is associated with an array of health-related and socioeconomic challenges and it is becoming progressively clear that proper care for boys and men with KS reaches far beyond simply supplementing with testosterone. There are no widely implemented guidelines for KS care, and studies investigating crucial aspects of testosterone treatment in individuals with KS, including both beneficial and potentially adverse effects, have only begun to emerge during the last decades. For this descriptive review, we present an overview of literature describing health-related outcomes of testosterone treatment in KS and outline the clinical applications of testosterone treatment in KS. Collectively, beneficial effects of testosterone treatment on overall health in KS are described with few apparent adverse effects. However, larger randomized studies in adult and pediatric patients are warranted to elucidate key aspects of treatment. We stress the implementation of centralized multidisciplinary clinics and the need for a dedicated international guideline to ensure optimal care of boys and men with KS.
Girls with Turner syndrome (TS) often have features that have been associated with obstructive sleep-disordered breathing (oSDB). However, little is known about oSDB in TS. Herein, we aimed to ...characterize oSDB in young patients with TS and identify associated risk factors.
Retrospective cross-sectional study.
Tertiary care pediatric hospital.
We reviewed medical records for patients diagnosed with TS seen at our institution between October 1, 2007 and December 31, 2019 with the first outpatient visit before age 6 years. The prevalence of oSDB was compared to the general pediatric population with 1-sample binomial proportion tests. Clinical characteristics were compared between those diagnosed with oSDB and those without oSDB, and risk factors for oSDB were identified.
Of 151 patients with TS, 73 (48%) were diagnosed with oSDB which is 4-fold higher than the general pediatric population (12%, P < 0.0001). In the multivariable model, adenoid, tonsillar, and inferior turbinate hypertrophy, birthweight, failure to thrive, and older age at the last clinic visit were all associated with increased odds for oSDB.
Young children with TS have a high prevalence of oSDB and thus should be screened for oSDB. Polysomnography should be performed in those with associated risk factors and symptoms oSDB. Treatment of oSDB is imperative as individuals with TS are already at increased risk of behavioral problems, neurocognitive deficits, and growth impairment that may be worsened with oSDB.
Diabetes and cardiovascular diseases are common among men with Klinefelter syndrome (KS) and contribute to high morbidity and mortality.
To determine if cardiometabolic-related diagnoses are more ...prevalent among youth with KS than matched controls in a large population-based cohort.
Secondary data analysis of electronic health records from 6 pediatric institutions in the United States (PEDSnet). Patients included all youth with KS in the database (n = 1080) and 4497 youth without KS matched for sex, age (mean 13 years at last encounter), year of birth, race, ethnicity, insurance, site, and duration of care (mean 7 years). The main outcome measures were prevalence of 5 cardiometabolic-related outcomes: overweight/obesity, dyslipidemia, dysglycemia, hypertension, and liver dysfunction.
The odds of overweight/obesity (OR 1.6; 95% CI 1.4-1.8), dyslipidemia (3.0; 2.2-3.9), and liver dysfunction (2.0; 1.6-2.5) were all higher in KS than in controls. Adjusting for covariates (obesity, testosterone treatment, and antipsychotic use) attenuated the effect of KS on these outcomes; however, boys with KS still had 45% greater odds of overweight/obesity (95% CI 1.2-1.7) and 70% greater odds of liver dysfunction (95% CI 1.3-2.2) than controls, and both dyslipidemia (1.6; 1.1-2.4) and dysglycemia (1.8; 1.1-3.2) were higher in KS but of borderline statistical significance when accounting for multiple comparisons. The odds of hypertension were not different between groups.
This large, population-based cohort of youth with KS had a higher odds of most cardiometabolic-related diagnoses than matched controls.
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 ...receptor (CRF1R) antagonism may decrease adrenal androgen production.
This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD.
This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.
Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios.
Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.
Klinefelter syndrome (KS) is a common genetic condition in which males have an extra X chromosome. KS is associated with testosterone deficiency, neurodevelopmental delays, and cardiometabolic ...disorders. There has been recent interest in prepubertal androgen treatment; however, the effects on puberty and gonadal function are unknown.
To compare onset of puberty and testicular function in prepubertal boys treated with 2 years of oxandrolone (Ox) vs placebo (Pl).
Double-blind, randomized, controlled trial.
Single tertiary care referral center.
Eighty prepubertal boys with KS; mean age: 8.0 ± 2.2 years (range: 4 to 12).
Ox 0.05 mg/kg vs identical-appearing Pl capsule given for 2 years.
Onset of gonadarche (testicular volume ≥4 mL) and onset of pubarche (Tanner 2 pubic hair); change in testicular hormone concentrations.
Ox-treated group had 20.5 times higher odds of reaching gonadarche (OR 95% CI: 6.5, 77.8) and 28.1 times higher odds of reaching pubarche (OR 95% CI: 8.8, 110.4) during the 2-year study period after adjusting for baseline age. Gonadarche and pubarche both occurred at a younger age in the Ox group (gonadarche: 9.8 ± 1.5 vs 12.1 ± 1.0 years, P < 0.001; pubarche: 10.2 ± 1.1 vs 11.6 ± 1.3 years, P = 0.02). Serum concentrations of testicular hormones and gonadotropins were not different between groups.
Two years of Ox treatment in prepubertal boys with KS results in an increased risk of early gonadarche, on average 2 years earlier than in Pl-treated boys. Ox did not affect serum concentrations of testicular hormones.
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