RESUMEN
Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.
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Envejecimiento/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Epigénesis Genética , Trastornos del Crecimiento/genética , Mutación , Anomalías Múltiples/genética , Adolescente , Adulto , Amish/genética , Niño , Metilación de ADN , ADN Metiltransferasa 3A , Cara/anomalías , Enfermedades Hematológicas/genética , Humanos , Discapacidad Intelectual/genética , Leucemia Mieloide Aguda/genética , Masculino , Metiltransferasas , Morfogénesis/genética , Síndrome , Enfermedades Vestibulares/genética , Adulto JovenRESUMEN
OBJECTIVE: To evaluate whether optimized and standardized diagnostic procedures would improve detection of germ cell neoplasia in situ (GCNIS) in the contralateral testis of patients with testicular germ cell tumour (TGCT) and decrease the rate of metachronous tumours, which in a nationwide Danish study was estimated to be 1.9%. PATIENTS AND METHODS: This was a retrospective analysis of outcomes in 655 patients with TGCT who underwent contralateral biopsies (1996-2007) compared with those in 459 non-biopsied TGCT controls (1984-1988). The biopsies were performed using a standardized procedure with immunohistochemical GCNIS markers and assessed by experienced evaluators. Initial histopathology reports were reviewed, and pathology and survival data were retrieved from national Danish registers. In 604/608 patients diagnosed as GCNIS-negative (four were lost to follow-up), the cumulative incidence of metachronous TGCT was estimated in a competing risk setting using the Grey method. All cases of metachronous TGCT were re-examined using immunohistochemistry. RESULTS: Germ cell neoplasia in situ was found in 47/655 biopsied patients (7.2%, 95% confidence interval [CI] 5.4-9.5%). During the follow-up period (median 17.3 years) five of the 604 GCNIS-negative patients developed a TGCT. In 1/5 false-negative biopsies, GCNIS was found on histological revision using immunohistochemistry and 2/5 biopsies were inadequate because of too small size. The estimated cumulative incidence rate of second tumour after 20 years of follow-up was 0.95% (95% CI 0.10%-1.8%) compared with 2.9% (95% CI 1.3%-4.4%) among the non-biopsied TGCT patients (P = 0.012). The estimates should be viewed with caution due to the small number of patients with metachronous TGCT. CONCLUSIONS: Optimized diagnostic procedures improved the detection rate of GCNIS in patients with TGCT and minimized their risk of developing metachronous bilateral cancer. Urologists should be aware of the importance of careful tissue excision (to avoid mechanical compression) and the need of adequate biopsy size. Performing contralateral biopsies is beneficial for patients' care and should be offered as a part of their management.
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Neoplasias de Células Germinales y Embrionarias , Neoplasias Primarias Secundarias , Neoplasias Testiculares , Masculino , Humanos , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/epidemiología , Testículo/patología , Estudios Retrospectivos , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Testiculares/patología , Biopsia , Células Germinativas/patologíaRESUMEN
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.
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Sistema Hipotálamo-Hipofisario/metabolismo , Síndrome de Klinefelter/diagnóstico , Pruebas Prenatales no Invasivas , Pubertad/genética , Humanos , Sistema Hipotálamo-Hipofisario/diagnóstico por imagen , Recién Nacido , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patología , Masculino , Pubertad/fisiologíaRESUMEN
STUDY QUESTION: What is the course of the LH/FSH ratio from infancy into adulthood in healthy individuals and in patients with Differences of Sex Development (DSD)? SUMMARY ANSWER: The LH/FSH ratio had a marked overlap between the sexes after infancy and onwards throughout adulthood in healthy individuals and it was not a marker of hypogonadism in DSD patients. WHAT IS KNOWN ALREADY: The LH/FSH ratio is a distinct marker of sex during minipuberty. No study has evaluated the LH/FSH ratio from infancy into adulthood. STUDY DESIGN, SIZE, DURATION: This was a combined study of prospective longitudinal and cross-sectional cohorts of healthy individuals totaling 6417 males and females aged 0-80 years. Retrospective data from a single, tertiary center on 125 patients with DSD was also included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the healthy males (n = 3144) and females (n = 3273) aged 0-80 years, reference ranges for LH, FSH and the LH/FSH ratio were established from infancy (after minipuberty) and onwards. LH, FSH, and the LH/FSH ratio in 125 patients with DSD not undergoing treatment were compared to the reference ranges. Included DSD diagnoses were: Klinefelter syndrome including mosaic variants (males: n = 14), Turner syndrome including mosaic variants without Y-chromosome material (females: n = 48), 45,X/46,XY mosaicism (males: n = 24 and females: n = 6), partial androgen insensitivity syndrome (males: n = 11), complete androgen insensitivity syndrome (females: n = 13) and anorchia (males: n = 9). MAIN RESULTS AND THE ROLE OF CHANCE: An overlap was observed in the LH/FSH ratio reference curves between males and females. However, when comparing the sexes at specific time points, the LH/FSH ratio was significantly higher in healthy males during childhood and adulthood and significantly higher in healthy females during puberty. When compared with healthy participants, male patients with anorchia and 45,X/46,XY mosaicism had significantly lower ratios, while patients with androgen insensitivity, regardless of sex, had significantly higher ratios. LIMITATIONS, REASONS FOR CAUTION: The limitations of this study include that; (i) all healthy individuals were Caucasian, so conclusions may not apply to non-Caucasians; (ii) the calculated LH/FSH ratios were restricted to the specific analytical method used and may not be applicable to other laboratories; (iii) the samples from healthy individuals were stored for varying amounts of time up to 20 years which may affect the durability; and (iv) DSD diagnoses are heterogeneous thus making sturdy conclusions across diagnoses impossible. WIDER IMPLICATIONS OF THE FINDINGS: In this study of combined cohorts of healthy participants, the largest normative ranges of LH, FSH, and the LH/FSH ratio to date were created. These reference ranges provide the opportunity for clinical as well as research use for all three markers. However, the previously rather undescribed LH/FSH ratio was not a distinct marker of sex after infancy nor a new marker of hypogonadism. Although there were significant differences between subgroups of DSD patients compared to healthy controls, the clinical significance of the LH/FSH ratio after infancy lacked. However, it can be speculated whether there are other areas of clinical application not investigated in this article, for example as a marker of fertility in select patient groups. As gonadotropin assays are readily available and gonadotropin measurements are part of regular workups, the LH/FSH ratio can easily be explored in further research without additional costs. STUDY FUNDING/COMPETING INTEREST(S): M.L.L. was funded by the Absalon Foundation. Cohort 1 was funded by the European Commission, through the Biomed 2 Program (BMH4-CT96-0314), Environmental Reproductive Health (QLK4-CT1999-01422) and EXPORED (QLK4-2001-00269), by the Danish Council for Independent Research (9700833 and 9700909), and by the Svend Andersens Foundation. Cohort 2 was funded by the Danish Environmental Research Program (96.01.015.16.05). Cohort 3 was funded by Kirsten and Freddy Johansens Foundation. TRIAL REGISTRATION NUMBER: NA. DATE OF FIRST PATIENT'S ENROLMENT: June 1990 (the launch of the department from which this project stems).
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Hormona Folículo Estimulante , Hormona Luteinizante , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: The aim of this clinical study was to determine the prevalence of SHOX haploinsufficiency in a population of short stature patients and describe their anthropometric measurements. METHODS: 574 short statured patients were evaluated in a single center (1992-2015). SHOX copy number was detected by quantitative polymerase chain reaction (qPCR) in 574 subjects, followed by multiplex ligation-dependent probe amplification (MLPA) and DNA sequencing in subjects with SHOX haploinsufficiency. We evaluated anthropometric measurements at birth, and at first examination. Skeletal abnormalities were recorded for patients with SHOX haploinsufficiency. RESULTS: Thirty-two patients were excluded due to Turner syndrome (n = 28), SRY-positive 46,XX male karyotype (n = 1), or lacked clinical follow-up information (n = 3). The prevalence of SHOX haploinsufficiency was 9 out of 542 (1.7%). The nine children had decreased height -2.85 (0.6) SD scores (SDS) (mean (SD)) and weight -2.15 (1.36) SDS, P < 0.001 and P = 0.001, respectively. The sitting height/height ratio was increased, P = 0.04. Madelung deformity was diagnosed in three patients. Mean height was -2.9 (0.4) SDS at baseline and increased by 0.25 (0.2) SDS, P = 0.046, after 1 y of growth hormone (GH) treatment. CONCLUSION: The prevalence of SHOX haploinsufficiency was 1.7%. The clinical findings indicating SHOX haploinsufficiency among the nine children were disproportionate short stature and forearm anomalies.
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Trastornos del Crecimiento/epidemiología , Trastornos del Crecimiento/genética , Haploinsuficiencia , Proteína de la Caja Homeótica de Baja Estatura/genética , Adolescente , Estatura , Niño , Preescolar , Femenino , Eliminación de Gen , Trastornos del Crecimiento/complicaciones , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Lactante , Recién Nacido , Cariotipificación , Masculino , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/epidemiología , Mutación Puntual , Reacción en Cadena de la Polimerasa , Prevalencia , Estudios Retrospectivos , Análisis de Secuencia de ADNRESUMEN
AIM: The short stature homeobox-containing gene (SHOX) plays an important role in short stature, but has not been explored in detail in a tall stature population before. This study explored the prevalence of SHOX aberrations in girls diagnosed with idiopathic tall stature with a normal karyotype. METHODS: We studied SHOX aberrations in 81 girls with a median age of 10.43 (7.17-12.73) years diagnosed with tall stature who were referred to our clinic at Copenhagen University Hospital, Denmark, between 2003 and 2013. SHOX copy variations were analysed by quantitative polymerase chain reaction, and aberrations were confirmed by multiplex ligation probe-dependent amplification. RESULTS: One extra SHOX copy was found in three (3.7%) of the 81 girls with tall stature, and their heights were 2.87, 3.71 and 3.98 standard deviation scores (SDS) and above the median height SDS of the girls with two SHOX copies. Their sitting height/height ratios (-3.08, -2.00 and -2.18 SDS) were all lower than the population mean. Despite these SHOX duplications, the three girls were clinically and biochemically comparable to the 78 girls with two SHOX copies. CONCLUSION: This study was the first to demonstrate SHOX duplications in three girls with tall stature and normal karyotypes.
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Estatura/genética , Proteína de la Caja Homeótica de Baja Estatura/genética , Adolescente , Niño , Estudios de Cohortes , Femenino , Humanos , CariotipoRESUMEN
A 30-yr-old woman presented with 2 consecutive miscarriages within 7 mo. Histopathologic examination of the placental tissue showed intracytoplasmic inclusion vacuoles with a strong reaction in Periodic acid-Schiff staining and a slightly pallor reaction in alcian blue staining. Additional molecular genetic analyses confirmed glycogen storage disease Type IV with the finding of compound heterozygosity for 2 mutations (c.691+2T>C and c.1570C>T, p.R524X) in the GBE1 gene. We conclude that glycogen storage disease Type IV can cause early miscarriage and that diagnosis can initially be made on histopathologic examination. Genetic analysis is required to confirm the diagnosis and to offer prenatal genetic testing in future pregnancies.
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Sistema de la Enzima Desramificadora del Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno Tipo IV/diagnóstico , Aborto Espontáneo , Adulto , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Enfermedad del Almacenamiento de Glucógeno Tipo IV/genética , Humanos , Mutación , Placenta/patología , Embarazo , Diagnóstico Prenatal , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. AIMS/METHODS: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. RESULTS: We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only). CONCLUSIONS: The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.
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Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Encefalopatías Metabólicas/diagnóstico , Glutaril-CoA Deshidrogenasa/deficiencia , Hiperamonemia/diagnóstico , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/diagnóstico , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Adolescente , Adulto , Anciano , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual , Masculino , Persona de Mediana Edad , Sistema de Registros , Vómitos , Adulto JovenRESUMEN
OBJECTIVE: Pubertal gynaecomastia is a very common condition. Although the underlying aetiology is poorly understood, it is generally accepted that excess of oestrogens and deficit of androgens are involved in the pathogenesis. Furthermore, adiposity as well as the GH/IGF-I axis may play a role. In this study, we elucidate the association of adiposity and levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), testosterone, oestrogen, IGF-I and IGFBP-3 with the presence of pubertal gynaecomastia in a large cohort of healthy boys. PATIENTS: A total of 501 healthy Danish school boys (aged 6·1-19·8 year) from the COPENHAGEN Puberty Study. MEASUREMENTS: Anthropometry and pubertal stages (PH1-6 and G1-5) were evaluated, and the presence of gynaecomastia was assessed. Body fat percentage was calculated by means of four skin folds and impedance. Nonfasting blood samples were analysed for FSH, LH, testosterone, SHBG, oestradiol, IGF-I, IGFBP-3 and prolactin. RESULTS: We found that 23% (31/133) of all pubertal boys had gynaecomastia. More specifically, 63% (10/16) of boys in genital stage 4 had gynaecomastia. Boys with gynaecomastia had significantly higher IGF-I levels compared with controls (IGF-I SD-score 0·72 vs -0·037, P < 0·001). This difference was maintained after adjusting for confounders (age and pubertal stage). Sex steroid levels, oestradiol/testosterone ratio or free testosterone were not associated with the presence of gynaecomastia with or without adjustment for confounders. CONCLUSIONS: IGF-I levels were elevated in healthy boys with pubertal gynaecomastia compared with boys without gynaecomastia, whereas sex steroid levels did not differ. We speculate that the GH-IGF-I axis may be involved in the pathogenesis of pubertal gynaecomastia.
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Ginecomastia/sangre , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Esteroides/sangre , Tejido Adiposo , Adiposidad , Adolescente , Andrógenos/sangre , Antropometría , Niño , Estudios de Cohortes , Dinamarca , Estradiol/sangre , Hormona Folículo Estimulante/sangre , Humanos , Hormona Luteinizante/sangre , Masculino , Prevalencia , Testosterona/sangre , Adulto JovenRESUMEN
AIM: To construct new Danish growth charts for 0- to 20-year-olds and to compare them with Danish references from 1982 and with World Health Organization (WHO) standards for children aged 0-5 years from 2006, by applying similar inclusion and exclusion criteria. METHODS: Anthropometric data from three contemporary Danish population-based studies were combined. References for height were based on healthy Caucasian children born at term. A total of 12,671 height measurements (8055 in boys and 4616 in girls) were included. Reference charts were developed using the generalised additive models for location, scale and shape. RESULTS: From prepubertal ages, a secular increase in height was observed for both genders. The differences were most pronounced in puberty, and final heights were increased by 1.4 cm in boys and 2.9 cm in girls compared to 1982 references. In boys, but not girls an upward shift in body mass index (BMI) above median levels was found. Reference curves for height were superimposable with standard curves based on the selective WHO criteria. Danish children were longer/taller and heavier and they had larger head circumferences than those reported in the recent multiethnic WHO standards. CONCLUSION: We recommend national implementation of these contemporary 2014 Danish references for anthropometric measurements.
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Estatura , Índice de Masa Corporal , Peso Corporal , Gráficos de Crecimiento , Adolescente , Antropometría , Niño , Preescolar , Dinamarca , Femenino , Humanos , Lactante , Masculino , Valores de Referencia , Adulto JovenRESUMEN
BACKGROUND: Endogenous sex steroids influence the pubertal growth spurt and adult height. However, the impact of puberty suppression and sex steroids on growth in transgender adolescents is sparsely studied. AIM: We investigated pubertal growth, serum IGF-I and IGFBP-3, and adult height of transgender adolescents receiving hormone therapy. METHODS: Observational study of a national cohort (2016-2023) comprising 219 transgender adolescents <18 years of age. Treatment consisted of gonadotropin-releasing hormone agonist (GnRHa) combined with estradiol or testosterone (adjusted to serum concentrations between 0 and +2 standard deviations (SDs) corresponding to the gender identity). RESULTS: Adult height was within ±2 SD for sex assigned at birth.Most trans girls reached adult height within references of girls. For trans girls (bone age ≤15 years before treatment), a growth spurt was observed during estradiol therapy. IGF-I and height SDS declined during oral estradiol administration (-0.13 SDS per month, p=0.059, and -0.02 SDS, p=0.001, respectively). We observed significantly lower adult height compared to target height for trans girls (-2.7 cm, p=0.01), and significant differences between height SDS before treatment and at adult height (-0.35 SDS, p<0.001).Half of the trans boys remained short (<-2 SD) compared to references for boys, and most completed growth spurt before initiation of treatment. IGFBP-3 declined following testosterone treatment. There was a significant difference between height SDS before treatment and at adult height (-0.17 SDS, p<0.001). DISCUSSION AND CONCLUSION: The minor reduction in adult height of trans girls after hormone treatment may be beneficial to some, whereas trans boys did not experience height gain.
RESUMEN
Klinefelter syndrome (47,XXY) causes infertility with a testicular histology comprising two types of Sertoli cell-only tubules, representing mature and immature-like Sertoli cells, and occasionally focal spermatogenesis. Here, we show that the immature-like Sertoli cells highly expressed XIST and had two X-chromosomes, while the mature Sertoli cells lacked XIST expression and had only one X-chromosome. Sertoli cells supporting focal spermatogenesis also lacked XIST expression and the additional X-chromosome, while the spermatogonia expressed XIST despite having only one X-chromosome. XIST was expressed in Sertoli cells until puberty, where a gradual loss was observed. Our results suggest that a micro-mosaic loss of the additional X-chromosome is needed for Sertoli cells to mature and to allow focal spermatogenesis.
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Síndrome de Klinefelter , ARN Largo no Codificante , Células de Sertoli , Espermatogénesis , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patología , Síndrome de Klinefelter/metabolismo , Masculino , Células de Sertoli/metabolismo , Células de Sertoli/patología , Espermatogénesis/genética , Animales , Humanos , Ratones , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Cromosomas Humanos X/genética , Cromosoma X/genéticaRESUMEN
BACKGROUND: Reference intervals covering the whole life span for all the metabolites in the steroid hormone biosynthesis quantified by sensitive and robust analytical methods are sparse or not existing. OBJECTIVE: To develop a state-of-the-art LC-MS/MS method for simultaneous quantification of multiple steroid metabolites and to establish detailed sex- and age-specific reference intervals for 16 steroid metabolites. MATERIALS AND METHOD: An isotope diluted LC-MS/MS method was developed for simultaneous quantitation of 16 steroid hormones. Serum samples from cross-sectional cohorts of healthy infants, children, adolescents, and adults aged 0.17 months to 77 years (n = 2458) were analysed. RESULTS: With this novel, specific, and sensitive LC-MS/MS method, it was possible to quantify progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione, testosterone, dihydrotestosterone, 11-deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol, and cortisone in ≥90 % of the samples, while estrone sulfate, aldosterone and dehydroepiandrosterone were quantified in 77 %, 75 % and 60 % of the samples, respectively. 21-deoxycortisol was only detectable in 2.5 % of samples from healthy subjects. Sex- and age-dependent fluctuations observed in minipuberty, puberty and adulthood including the menopausal transition were modelled. This enabled us to establish valid reference intervals from birth to late adult life for both males and females. CONCLUSION: Detailed sex- and age-specific reference intervals of multiple, simultaneously quantified steroid metabolites by a novel and specific LC-MS/MS method provides a valuable tool for clinical practice and for future research.
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Esteroides , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/normas , Lactante , Masculino , Femenino , Preescolar , Niño , Adolescente , Adulto , Cromatografía Liquida/normas , Valores de Referencia , Adulto Joven , Anciano , Persona de Mediana Edad , Esteroides/sangre , Recién Nacido , Voluntarios Sanos , Factores de Edad , Estudios Transversales , Factores Sexuales , Cromatografía Líquida con Espectrometría de MasasRESUMEN
OBJECTIVE: To describe the natural history of inhibin B throughout life according to sex, age, and pubertal development. METHODS: Based on serum samples from 2707 healthy controls aged 0 to 80 years, sex- and age-specific reference ranges of inhibin B concentrations were constructed. Concentrations were evaluated according to pubertal development and use of oral contraceptives (OCs). Also, measurements from 42 patients with Klinefelter syndrome were included. RESULTS: In both sexes, inhibin B concentrations were high during minipuberty, decreased in childhood, and increased significantly from Tanner stages B1 to B3 (peak: B4) in females and from G1 to G3 (peak: G3) in males. Despite variations in menstruating females, inhibin B concentrations remained relatively constant after puberty, until becoming unmeasurable at menopause. Despite a modest decrease, the inhibin B concentration in males remained relatively high from puberty onwards. At any age, males had highest concentrations. Inhibin B standard deviation (SD) scores were lower in OC-users (median SD score = -0.88) than in non-users (SD score = 0.35), p < 0.001. In patients with Klinefelter syndrome, inhibin B concentrations spanned the reference range until around 15 years of age, where they decreased to subnormal or unmeasurable levels. CONCLUSION: Valuable sex- and age-specific reference data for inhibin B concentrations were provided. In OC-users, decreased concentrations of inhibin B underlined the ovaries as the only place of inhibin B production. In patients with Klinefelter syndrome, the decline in inhibin B concentrations at puberty underlined the shift in regulation of inhibin B production at pubertal onset.
RESUMEN
47,XXY (Klinefelter syndrome) is the most frequent sex chromosomal disorder and affects approximately one in 660 newborn boys. The syndrome is characterized by varying degrees of cognitive, social, behavioral, and learning difficulties and in adulthood additionally primary testicular failure with small testes, hypergonadotropic hypogonadism, tall stature, and eunuchoid body proportions. The phenotype is variable ranging from "near-normal" to a significantly affected individual. In addition, newborns with Klinefelter syndrome generally present with a normal male phenotype and the only consistent clinical finding in KS is small testes, that are most often not identified until after puberty. Decreased awareness of this syndrome among health professionals and a general perception that all patients with 47,XXY exhibit the classic textbook phenotype results in a highly under-diagnosed condition with up to 75% of the patients left undetected. Typically, diagnosis is delayed with the majority of patients identified during fertility workup in adulthood, and only 10% of patients diagnosed prior to puberty. Early detection of this syndrome is recommended in order to offer treatment and intervention at the appropriate ages and stages of development for the purpose of preventing osteopenia/osteoporosis, metabolic syndrome, and other medical conditions related to hypogonadism and to the XXY as well as minimizing potential learning and psychosocial problems. The aim of this review is to present the clinical aspects of XXY and the age-specific recommendations for medical management. © 2013 Wiley Periodicals, Inc.
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Envejecimiento/genética , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/fisiopatología , Síndrome de Klinefelter/terapia , Humanos , Masculino , Fenotipo , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/diagnóstico , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/genéticaRESUMEN
Paediatric reference intervals based on samples from healthy children are difficult to establish and consequently data are often from hospitalized children. Furthermore, biases may present in published data due to differences in the analytical methods employed. Blood samples from 1429 healthy Danish children were collected for establishing reference intervals for 21 common biochemical properties (Alanine transaminase, Albumin, Alkaline phosphatase, Aspartate transaminase, Bilirubin, Calcium, Cholesterol, Creatinine, Creatine kinase, HDL-Cholesterol, Iron, Lactate dehydrogenase, LDL- Cholesterol, Magnesium, Phosphate, Potassium, Protein, Sodium, Transferrin, Triglycerides and Urate). Samples were analyzed on a Roche-Modular-P/ISE-system. The NORIP reference material (NFKK Reference Serum X) was included in all the analytical runs. Reference values were recalculated according to the target values of X for the properties and statistical calculations carried out as performed in the NORIP study. Thus commutable (regarding analytical method) reference intervals for 20 properties were established and for LDL-Cholesterol reference intervals were reported for the specific analytical method employed. The data were compared to previous studies and to those obtained from the youngest age group in the NORIP study. Marked age differences were observed for most of the properties. Several properties also showed gender-related differences, mainly at the onset of puberty. Data are presented as suggested intervals for combined age groups, but can be accessed via the NORIP home page if more detailed division according to age or gender is desired.
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Valores de Referencia , Adolescente , Adulto , Niño , Dinamarca , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Objective: Klinefelter syndrome (KS) is the most common sex chromosome disorder and genetic cause of infertility in males. A highly variable phenotype contributes to the fact that a large proportion of cases are never diagnosed. Typical hallmarks in adults include small testes and azoospermia which may prompt biochemical evaluation that typically shows extremely high follicle-stimulating hormone and low/undetectable inhibin B serum concentrations. However, in prepubertal KS individuals, biochemical parameters are largely overlapping those of prepubertal controls. We aimed to characterize clinical profiles of prepubertal boys with KS in relation to controls and to develop a novel biochemical classification model to identify KS before puberty. Methods: Retrospective, longitudinal data from 15 prepubertal boys with KS and data from 1475 controls were used to calculate age- and sex-adjusted standard deviation scores (SDS) for height and serum concentrations of reproductive hormones and used to infer a decision tree classification model for KS. Results: Individual reproductive hormones were low but within reference ranges and did not discriminate KS from controls. Clinical and biochemical profiles including age- and sex-adjusted SDS from multiple reference curves provided input data to train a 'random forest' machine learning (ML) model for the detection of KS. Applied to unseen data, the ML model achieved a classification accuracy of 78% (95% CI, 61-94%). Conclusions: Supervised ML applied to clinically relevant variables enabled computational classification of control and KS profiles. The application of age- and sex-adjusted SDS provided robust predictions irrespective of age. Specialized ML models applied to combined reproductive hormone concentrations may be useful diagnostic tools to improve the identification of prepubertal boys with KS.
RESUMEN
Adult patients with Klinefelter syndrome (KS) are characterized by a highly variable phenotype, including tall stature, obesity, and hypergonadotropic hypogonadism, as well as an increased risk of developing insulin resistance, metabolic syndrome, and osteoporosis. Most adults need testosterone replacement therapy (TRT), whereas the use of TRT during puberty has been debated. In this retrospective, observational study, reproductive hormones and whole-body dual-energy x-ray absorptiometry-derived body composition and bone mineral content were standardized to age-related standard deviation scores in 62 patients with KS aged 5.9-20.6 years. Serum concentrations of total testosterone and inhibin B were low, whereas luteinizing hormone and follicle-stimulating hormone were high in patients before TRT. Despite normal body mass index, body fat percentage and the ratio between android fat percentage and gynoid fat percentage were significantly higher in the entire group irrespective of treatment status. In patients evaluated before and during TRT, a tendency toward a more beneficial body composition with a significant reduction in the ratio between android fat percentage and gynoid fat percentage during TRT was found. Bone mineral content (BMC) did not differ from the reference, but BMC corrected for bone area was significantly lower when compared to the reference. This study confirms that patients with KS have an unfavorable body composition and an impaired bone mineral status already during childhood and adolescence. Systematic studies are needed to evaluate whether TRT during puberty will improve these parameters.
RESUMEN
Congenital adrenal hyperplasia (CAH) is a recessive condition that affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well as the testicular, steroidogenic cells. In this European two-center study, we evaluated the function of Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylase deficiency. Despite conventional hormone replacement therapy, our results indicated a significant reduction in serum concentrations of both Leydig cell-derived hormones (i.e. insulin-like factor 3 (INSL3) and testosterone) and Sertoli cell-derived hormones (i.e. inhibin B and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3 were particularly reduced in those with testicular adrenal rest tumors. To our knowledge, this is the first study to evaluate circulating INSL3 as a candidate biomarker to monitor Leydig cell function in patients with CAH.
RESUMEN
BACKGROUND: In adult women, the circulating level of anti-Müllerian hormone (AMH) is a novel marker of ovarian function, as it reflects the number of remaining ovarian follicles. Therefore, AMH has gained widespread attention in fertility clinics, and a low AMH is believed to predict impaired fertility and imminent menopause. However, the natural course of circulating AMH levels during female childhood and adolescence is not known. METHODS: Serum levels of AMH and FSH were measured in girls participating in The COPENHAGEN Puberty Study. Longitudinal part: 85 healthy girls and adolescents were examined, and blood samples were drawn every 6 months for an average of 3 years: median (range) number of samples per girl was 6 (2-10), age at baseline was 9.2 (5.9-12.9) years. Cross-sectional part: 224 prepubertal girls (age 8.3, 5.6-11.7 years) were examined and each girl had one blood sample drawn. RESULTS: The individual mean AMH levels in girls followed longitudinally ranged from 5 to 54 pmol/l (median 18 pmol/l). The mean intra-individual coefficient of variation of AMH was 22% (range 0-54%). Overall, each girl maintained her AMH level throughout childhood and adolescence although minor, but significant, changes occurred during pubertal transition. In prepubertal girls, AMH was negatively correlated with FSH (r = -0.31, P < 0.001). Twelve per cent (10/85) had mean AMH below a cut-off value of 8 pmol/l, indicating that the interpretation of low AMH as a marker of approaching menopause may not apply to pre- and peri-pubertal girls. CONCLUSIONS: Circulating AMH exhibits only minor fluctuations during childhood and adolescence, and a random AMH measurement seems representative for a given girl. The negative AMH-FSH correlation in prepubertal girls supports the notion that AMH is a quantitative marker of ovarian follicles even in young girls.