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STUDY QUESTION: Does standardised treatments used in children and adolescents with haematologic malignancies, including acute lymphoblastic (ALL) or myeloid leukaemia (AML) and non-Hodgkin lymphoma (NHL), affect endocrine function of the developing testes? SUMMARY ANSWER: Therapy of haematologic malignancies do not provoke an overt damage of Sertoli and Leydig cell populations, as revealed by normal levels of anti-Müllerian hormone (AMH) and testosterone, but a mild primary testicular dysfunction may be observed, compensated by moderate gonadotropin elevation, during pubertal development. WHAT IS KNOWN ALREADY: Evidence exists on the deleterious effect that chemotherapy and radiotherapy have on germ cells, and some attention has been given to the effects on Leydig and Sertoli cells of the adult gonads, but information is virtually non-existent on the effects of oncologic treatment on testicular somatic cell components during childhood and adolescence. STUDY DESIGN, SIZE, DURATION: A retrospective, analytical, observational study included 97 boys with haematological malignancies followed at two tertiary paediatric public hospitals in Buenos Aires, Argentina, between 2002 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical records of males aged 1-18 years, referred with the diagnoses of ALL, AML or NHL for the assessment of gonadal function, were eligible. We assessed serum levels of AMH and FSH as biomarkers of Sertoli cell endocrine function and testosterone and LH as biomarkers of Leydig cell function. MAIN RESULTS AND THE ROLE OF CHANCE: All hormone levels were normal in the large majority of patients until early pubertal development. From Tanner stage G3 onwards, while serum AMH and testosterone kept within the normal ranges, gonadotropins reached mildly to moderately elevated values in up to 35.9% of the cases, indicating a compensated Sertoli and/or Leydig cell dysfunction, which generally did not require hormone replacement therapy. LIMITATIONS, REASONS FOR CAUTION: Serum inhibin B determination and semen analysis were not available for most patients; therefore, we could not conclude on potential fertility impairment or identify whether primary Sertoli cell dysfunction resulted in secondary depleted spermatogenesis or whether primary germ cell damage impacted Sertoli cell function. WIDER IMPLICATIONS OF THE FINDINGS: The regimens used in the treatment of boys and adolescents with ALL, AML or NHL in the past two decades seem relatively safe for endocrine testicular function; nonetheless, a mild primary testicular endocrine dysfunction may be observed, usually compensated by slightly elevated gonadotropin secretion by the pituitary in adolescents, and not requiring hormone replacement therapy. No clinically relevant risk factor, such as severity of the disease or treatment protocol, could be identified in association with the compensated endocrine dysfunction. STUDY FUNDING/COMPETING INTEREST(S): This work was partially funded by grants PIP 11220130100687 of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and PICT 2016-0993 of Fondo para la Investigación Científica y Tecnológica (FONCYT), Argentina. R.A.R., R.P.G. and P.B. have received honoraria from CONICET (Argentina) for technology services using the AMH ELISA. L.A.A. is part-time employee of CSL Behring Argentina. The other authors have no conflicts of interest to disclose.
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Hormônio Antimülleriano/sangue , Antineoplásicos/efeitos adversos , Hormônio Foliculoestimulante/sangue , Leucemia/terapia , Linfoma não Hodgkin/terapia , Adolescente , Criança , Humanos , Masculino , Estudos RetrospectivosRESUMO
INTRODUCTION: The prevalence of polycystic ovarian syndrome (PCOS) in adolescent girls is between 1 and 4.3%. It remains controversial whether women with a history of idiopathic central precocious puberty (ICPP) are at increased risk for PCOS. Our objective was to assess the prevalence of PCOS in adolescents with a history of ICPP compared with healthy adolescents and the prevalence of PCOS among ICPP girls who have received or not gonadotropin-releasing hormone analogue (GnRHa) treatment. METHODS: We assessed post-menarcheal girls with a history of ICPP. Girls were evaluated at gynecological age ≥2.5 years. Data collected were age at menarche, menstrual cycle characteristics, BMI, clinical hyperandrogenism (HA), total and free testosterone levels. PCOS diagnosis was defined by criteria for adolescents. Subjects were also analyzed regarding whether or not they had received GnRHa treatment. RESULTS: Ninety-four subjects were assessed, and 63 had been treated with GnRHa. Menstrual disorders were found in 29%, clinical HA in 36%, and biochemical HA in 23%. Twelve percent met the diagnostic criteria for PCOS. There was no difference in BMI or in the incidence of menstrual dysfunction or hyperandrogenemia between treated and untreated patients. A higher proportion of clinical HA was found in untreated patients when compared to treated girls. The relative risk (RR) of developing PCOS in ICPP girls was 2.5 compared to a population of healthy adolescents. This RR was not higher in patients who received treatment with GnRHa than in those who did not. CONCLUSION: Adolescent girls with a history of ICPP have an increased risk of PCOS. This risk seems not to be related to GnRHa treatment.
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Hiperandrogenismo , Síndrome do Ovário Policístico , Puberdade Precoce , Adolescente , Feminino , Humanos , Pré-Escolar , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/epidemiologia , Puberdade Precoce/tratamento farmacológico , Prevalência , Hiperandrogenismo/complicações , Hiperandrogenismo/epidemiologia , MenarcaRESUMO
INTRODUCTION: Assessment of the hypothalamic-pituitary-adrenal (HPA) axis is necessary after prolonged glucocorticoid therapy withdrawal. Salivary cortisol reflects 65% of the free circulating cortisol fraction. Saliva collection is non-invasive and child friendly. OBJECTIVE: We aimed to evaluate the diagnostic accuracy of morning salivary cortisol (mSAF) to determine HPA recovery after prolonged corticosteroid therapy in children. METHODS: We conducted a prospective, validation study in 171 paediatric patients (mean ± SD age: 13.0 ± 4.4 years) who received glucocorticoids for >4 weeks (median and interquartile range: 11 [7-14] months) and were referred for therapy withdrawal. Serum and saliva samples were collected between 8 and 9 a.m. on the same day. Cortisol was measured by an electrochemiluminescence immunoassay (ECLIA) 48 h after cessation of glucocorticoid therapy. Serum cortisol ≥193 nmol/L was used as the reference cut-off value for HPA recovery after glucocorticoid withdrawal and mSAF as the index test. RESULTS: The cut-off concentration obtained by ROC for mSAF was ≥5.0 nmol/L. True positive and true negative results were observed in 85/171 and 40/171 children, respectively. The false-positive rate was low (3/171, 1.7%); however, false-negative results were observed in 43/171 (25%) children. The main ROC results (95% CI) were area under curve: 0.98 (0.96-0.99), sensitivity: 0.66 (0.57-0.75), specificity: 0.93 (0.81-0.99), positive predictive value: 0.97 (0.90-0.99), negative predictive value: 0.48 (0.37-0.59), LR+: 9.5, and diagnostic accuracy: 73.1%. CONCLUSION: The present study supports that mSAF ≥5.0 nmol/L by ECLIA is a non-invasive biomarker for the assessment of HPA recovery after prolonged glucocorticoid therapy in paediatric patients, with a positive predictive value of 97%. This proposed cut-off should be further validated using gold standard techniques for steroid quantification such as liquid chromatography-tandem mass spectrometry.
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Glucocorticoides , Hidrocortisona , Humanos , Criança , Adolescente , Hidrocortisona/análise , Estudos Prospectivos , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Saliva/químicaRESUMO
Pubertal delay can be due to hypogonadotropic hypogonadism (HH), which may occur in association with anosmia or hyposmia and is known as Kallmann syndrome (OMIM #308700). Recently, hypogonadotropic hypogonadism has been suggested to overlap with Witteveen-Kolk syndrome (WITKOS, OMIM #613406) associated with 15q24 microdeletions encompassing SIN3A. Whether hypogonadotropic hypogonadism is due to haploinsufficiency of SIN3A or any of the other eight genes present in 15q24 is not known. We report the case of a female patient with delayed puberty associated with intellectual disability, behavior problems, dysmorphic facial features, and short stature, at the age of 14 years. Clinical, laboratory, and imaging assessments confirmed the diagnosis of Kallmann syndrome. Whole-exome sequencing identified a novel heterozygous frameshift variant, NM_001145358.2:c.3045_3046dup, NP_001138830.1:p.(Ile1016Argfs*6) in SIN3A, classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG/AMP) criteria. Reverse phenotyping led to the clinical diagnosis of WITKOS. No other variant was found in the 96 genes potentially related to hypogonadotropic hypogonadism. The analysis of the other contiguous seven genes to SIN3A in 15q24 did not reveal any clinically relevant variant. In conclusion, these findings point to SIN3A as the gene in 15q24 related to the reproductive phenotype in patients with overlapping WITKOS and Kallmann syndrome.
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INTRODUCTION: Cushing's syndrome (CS) constitutes one of the most challenging diagnostic assessments for paediatric endocrinologists. The clinical presentation of some children with exogenous obesity overlaps with those observed in hypercortisolism states. Accurate, non-invasive first-line tests are necessary to avoid false-positive results in the obese. We aimed to evaluate the diagnostic accuracy of salivary cortisol to assess endogenous hypercortisolism in children with obesity and clinical overlapping signs of Cushing's syndrome. METHODS: Case-control study that included children aged 2-18 years, BMI-SDS ≥ 2.0 and a follow-up >2 years. Patients were assigned to three categories: Group A, features strongly indicative of paediatric CS (growth failure combined with increasing weight); Group B, features suggestive of CS (e.g. moon face and striae); and Group C, less specific features overlapping with CS (e.g. hypertension, hirsutism, insulin resistance). Children in categories A and B formed the control group. Ten patients with confirmed CS were the case group. All children collected saliva samples on the same day in the morning between 7 to 8 am (morning salivary cortisol: mSC) and at 11 pm (nocturnal salivary cortisol: nSC). The mSC and nSC results were used to calculate the percentage decrease of cortisol at night (%D). Main outcomes by ROC for nSC and the %D were sensitivity, specificity, positive (P) and Negative (N) predictive values (PV) and their corresponding 95%IC. Salivary cortisol was measured by electrochemiluminiscence assay (lower limit of quantification: 2.0 nmol/L). RESULTS: 75/112 children met the inclusion criteria, whereas 22/75 children were eligible for the control group. Only controls decreased nSC [median and interquartile range: 2.0 (2.0-2.5) nmol/L] compared to mSC [6.9 (4.8-10.4) nmol/L], p< 0.0001. A cut-off for nSC ≥8 nmol/L confirmed CS within a sensitivity: 1.0 (0.69 to 1.0), specificity: 1.0 (0.85 to 1.0), PPV: 1.0 (0.69 to 0.99) and NPV: 1.0(0.85 to 0.99), achieving a diagnostic efficiency of 100%. The cut-off obtained for %D was 50%. No child with CS had a %D ≥50%, but 6/22 children in the control group had a %D below the cut-off, resulting in a lower overall diagnostic accuracy of 81% compared to nSC. CONCLUSION: Salivary cortisol at 11 pm is an accurate, feasible and non-invasive first-line test to assess endogenous hypercortisolism in children with obesity and clinical suspicion of Cushing's syndrome. The nSC was also useful in showing that the circadian rhythm of cortisol was preserved in children with exogenous obesity. In patients with nSC ≥8.0 nmol/L, other biochemical assessments and imaging studies are needed to further confirm the aetiology.
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CONTEXT: The GnRH test is the gold standard to confirm the diagnosis of central precocious puberty (CPP); however, this compound is not always readily available. Diagnostic accuracy of subcutaneous GnRH analogues tests compared to classical GnRH test has not been reported. OBJECTIVE: To evaluate the diagnostic accuracy of Triptorelin test (index test) compared to the GnRH test (reference test) in girls with suspicion of CPP. DESIGN: A prospective, case-control, randomized clinical trial was performed. CPP or precocious thelarche (PT) was diagnosed according to maximal LH response to GnRH test and clinical characteristics during follow-up. PATIENTS AND INTERVENTIONS: Forty-six girls with premature breast development randomly underwent two tests: (i) intravenous GnRH 100 µg, (ii) subcutaneous Triptorelin acetate (0.1 mg/m(2), to a maximum of 0.1 mg) with blood sampling at 0, 3 and 24 h for LH, FSH and estradiol ascertainment. MEASUREMENTS: Gonadotrophins and estradiol responses to Triptorelin test were measured by ultrasensitive assays. RESULTS: Clinical features were similar between CPP (n = 33) and PT (n = 13) groups. Using receiver operating characteristic curves, maximal LH response (LH-3 h) under Triptorelin test ≥ 7 IU/l by immunofluorometric assay (IFMA) or ≥ 8 IU/l by electrochemiluminescence immunoassay (ECLIA) confirmed the diagnosis of CPP with specificity of 1.00 (95% CI: 0.75-1.00) and sensitivity 0.76 (95% CI: 0.58-0.89). Considering either LH-3 h or maximal estradiol response at 24 h (cut-off value, 295 pm), maintaining the specificity at 1.00, the test sensitivity increased to 0.94 (95% CI: 0.80-0.99) and the diagnostic efficiency to 96%. CONCLUSION: The Triptorelin test had high accuracy for the differential diagnosis of CPP vs PT in girls providing a valid alternative to the classical GnRH test. This test also allowed a comprehensive evaluation of the pituitary-ovarian axis.
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Hormônio Liberador de Gonadotropina , Puberdade Precoce/diagnóstico , Pamoato de Triptorrelina , Criança , Pré-Escolar , Feminino , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos , Puberdade Precoce/sangue , Sensibilidade e EspecificidadeRESUMO
In patients with 46,XY disorders of sex development (DSDs), next-generation sequencing (NGS) has high diagnostic efficiency. One contribution to this diagnostic approach is the possibility of applying reverse phenotyping when a variant in a gene associated with multiple organ hits is found. Our aim is to report a case of a patient with 46,XY DSDs in whom the identification of a novel variant in MYRF led to the detection of a clinically inapparent congenital heart defect. A full-term newborn presented with ambiguous genitalia, as follows: a 2 cm phallus, penoscrotal hypospadias, partially fused labioscrotal folds, an anogenital distance of 1.2 cm, and non-palpable gonads. The karyotype was 46,XY, serum testosterone and AMH were low, whereas LH and FSH were high, leading to the diagnosis of dysgenetic DSD. Whole exome sequencing identified a novel, heterozygous, nonsense variant in MYRF, classified as pathogenic according to the ACMG criteria. MYRF encodes a membrane-bound transcriptional factor expressed in several tissues associated with OCUGS syndrome (ophthalmic, cardiac, and urogenital anomalies). In the patient, oriented clinical assessment ruled out ophthalmic defects, but ultrasonography confirmed meso/dextrocardia. We report a novel MYRF variant in a patient with 46,XY DSDs, allowing us to identify a clinically inapparent congenital heart defect by reverse phenotyping.
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Introduction: Hematopoietic malignancies are the most frequent type of cancer in childhood. Recent advances in cancer treatment have significantly improved survival until adulthood. There is an extensive literature on the effects of cancer treatment on the gonadal axis in adult survivors of childhood cancer mainly focused on sperm production, but scarce information exists on the immediate impact of cancer and its treatment in boys. Objectives: In this work, we determined the status of the hypothalamic-pituitary-testicular (HPT) axis function at diagnosis and the immediate impact of chemotherapy at the start of treatment in children and adolescents with hematopoietic malignancies. Subjects and methods: In a prospective study of 94 boys and adolescents with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or non-Hodgkin lymphoma (NHL), we determined serum AMH, inhibin B and FSH to assess the gonadotrophin-Sertoli cell component of the HPT axis, and testosterone and LH to evaluate the gonadotrophin-Leydig cell component, at diagnosis and after 3 months of chemotherapy. Secondarily, the general health state was evaluated. Results: In prepubertal boys, at diagnosis, AMH, inhibin B and FSH were lower compared to the reference population, reflecting an FSH-Sertoli cell axis dysfunction. After 3 months of chemotherapy, all hormone concentrations increased. At pubertal age, at diagnosis, AMH and inhibin B were lower compared to the reference population for Tanner stage, with inappropriately normal FSH, suggesting a primary Sertoli cell dysfunction with insufficient gonadotrophin compensation. The LH-Leydig cell axis was mildly disrupted. After 3 months of chemotherapy, inhibin B and AMH were unchanged while median FSH levels rose to values that exceeded the reference range, indicating a significant impairment of Sertoli cell function. Testosterone normalized concomitantly with an abnormal LH elevation reflecting a compensated Leydig cell impairment. General health biomarkers were impaired at diagnosis and improved after 3 months. Conclusion: The HPT axis function is impaired in boys with hematopoietic malignancies before the initiation of chemotherapy. There is a primary testicular dysfunction and a concomitant functional central hypogonadism that could be due to an impaired overall health. The HPT axis function improves during the initial 3 months of chemotherapy concomitantly with the general health state. However, in pubertal boys the dysfunction persists as shown by elevated gonadotropin levels after 3 months.
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Neoplasias Hematológicas , Neoplasias , Adulto , Humanos , Masculino , Criança , Adolescente , Hormônio Foliculoestimulante , Estudos Prospectivos , Sêmen , Testosterona , Neoplasias Hematológicas/tratamento farmacológicoRESUMO
Pubertal delay in males is frequently due to constitutional delay of growth and puberty, but pathologic hypogonadism should be considered. After general illnesses and primary testicular failure are ruled out, the main differential diagnosis is central (or hypogonadotropic) hypogonadism, resulting from a defective function of the gonadotropin-releasing hormone (GnRH)/gonadotropin axis. Ciliopathies arising from defects in non-motile cilia are responsible for developmental disorders affecting the sense organs and the reproductive system. WDR11-mediated signaling in non-motile cilia is critical for fetal development of GnRH neurons. Only missense variants of WDR11 have been reported to date in patients with central hypogonadism, suggesting that nonsense variants could lead to more complex phenotypes. We report the case of a male patient presenting with delayed puberty due to Kallmann syndrome (central hypogonadism associated with hyposmia) in whom the next-generation sequencing analysis identified a novel heterozygous base duplication, leading to a frameshift and a stop codon in the N-terminal region of WDR11. The variant was predicted to undergo nonsense-mediated decay and classified as probably pathogenic following the American College of Medical Genetics and Genomics (ACMG) criteria. This is the first report of a variant in the WDR11 N-terminal region predicted to lead to complete expression loss that, contrary to expectations, led to a mild form of ciliopathy resulting in isolated Kallmann syndrome.
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The diagnosis of male central (or hypogonadotropic) hypogonadism, typically based on low luteinizing hormone (LH) and testosterone levels, is challenging during childhood since both hormones are physiologically low from the sixth month until the onset of puberty. Conversely, follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH), which show higher circulating levels during infancy and childhood, are not used as biomarkers for the condition. We report the case of a 7-year-old boy with a history of bilateral cryptorchidism who showed repeatedly low FSH and AMH serum levels during prepuberty. Unfortunately, the diagnosis could not be ascertained until he presented with delayed puberty at the age of 14 years. A gonadotropin-releasing hormone (GnRH) test showed impaired LH and FSH response. By then, his growth and bone mineralization were partially impaired. Gene panel sequencing identified a variant in exon 15 of FGFR1, affecting the tyrosine kinase domain of the receptor, involved in GnRH neuron migration and olfactory bulb morphogenesis. Testosterone replacement was started, which resulted in the development of secondary sexual characteristics and partial improvement of bone mineral density. This case illustrates the difficulty in making the diagnosis of central hypogonadism in boys during childhood based on classical criteria, and how serum FSH and AMH assessment may be helpful if it is suspected before the age of puberty, and confirm it using next-generation sequencing. The possibility of making an early diagnosis of central hypogonadism may be useful for a timely start of hormone replacement therapy, and to avoid delays that could affect growth and bone health as well as psychosocial adjustment.
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To determine the influence of age, gestational age, gender and methodological protocol on serum 17OHP and cortisol concentrations. 17OHP in non-extracted (NE) and extracted (E) sera was measured by RIA in 319 full-term (FT) (1 d-5 yr) infants, 38 pre-term (PT) and in 19 neonates with classical CAH at diagnosis. 17OHP (NE- and E-) decreased with age in normal children. The extraction procedure significantly reduced 17OHP by eliminating interfering steroids in children < 1 year. Sexual dimorphism was only observed in NE-17OHP. 17OHP in PT was always higher than in FT up to 2 months of age (p < 0.001). Neither NE- nor E-17OHP in CAH overlapped with those of FT or PT (p < 0.001) allowing to omit the extraction procedure to confirm CAH diagnosis. Cortisol levels were within normal range in neonates with CAH, thus not adding useful information about adrenal function. Chronological and gestational age, gender, and extraction for 17OHP measurement are important factors to know when assessing adrenal function during the first year of life.
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Glândulas Suprarrenais/crescimento & desenvolvimento , Química Clínica/métodos , Química Clínica/normas , Hidrocortisona/sangue , Progesterona/análogos & derivados , Glândulas Suprarrenais/fisiologia , Fatores Etários , Pré-Escolar , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Progesterona/análise , Progesterona/sangue , Valores de ReferênciaRESUMO
Introduction: Practice guidelines cannot recommend establishing a diagnosis of growth hormone deficiency (GHD) without performing growth hormone stimulation tests (GHST) in children with risk factors, due to the lack of sufficient evidence. Objective: Our goal was to generate an evidence-based prediction rule to diagnose GHD in children with growth failure and clinically identifiable risk factors. Methods: We studied a cohort of children with growth failure to build the prediction model, and a second, independent cohort to validate the prediction rule. To this end, we assessed the existence of: pituitary dysgenesis, midline abnormalities, (supra)sellar tumor/surgery, CNS infection, traumatic brain injury, cranial radiotherapy, chemotherapy, genetic GHD, pituitary hormone deficiencies, and neonatal hypoglycemia, cholestasis, or hypogenitalism. Selection of variables for model building was performed using artificial intelligence protocols. Specificity of the prediction rule was the main outcome measure in the validation set. Results: In the first cohort (n=770), the resulting prediction rule stated that a patient would have GHD if (s)he had: pituitary dysgenesis, or two or more anterior pituitary deficiencies, or one anterior pituitary deficiency plus: neonatal hypoglycemia or hypogenitalism, or diabetes insipidus, or midline abnormalities, or (supra)sellar tumor/surgery, or cranial radiotherapy ≥18 Gy. In the validation cohort (n=161), the specificity of the prediction rule was 99.2% (95% CI: 95.6-100%). Conclusions: This clinical rule predicts the existence of GHD with high specificity in children with growth disorders and clinically identifiable risk factors, thus providing compelling evidence to recommend that GHD can be safely diagnosed without recurring to GHST in neonates and children with growth failure and specific comorbidities.
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Algoritmos , Estatura/fisiologia , Hormônio do Crescimento Humano/deficiência , Aprendizado de Máquina/normas , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Nanismo Hipofisário/sangue , Nanismo Hipofisário/diagnóstico por imagem , Feminino , Humanos , Masculino , Guias de Prática Clínica como Assunto/normas , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
BACKGROUND: IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation. RESULTS: We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from -1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth. CONCLUSION: The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.
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Transtornos do Crescimento/genética , Perda Auditiva Neurossensorial/genética , Fator de Crescimento Insulin-Like I/deficiência , Mutação de Sentido Incorreto/genética , Anormalidades Múltiplas/genética , Proliferação de Células , Biologia Computacional , Simulação por Computador , Retardo do Crescimento Fetal/genética , Células HEK293 , Homozigoto , Humanos , Lactente , Fator de Crescimento Insulin-Like I/genética , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Receptor IGF Tipo 1 , Receptores de Somatomedina/genética , Tirosina/genéticaRESUMO
OBJECTIVE: X-linked adrenal hypoplasia congenita (AHC, OMIM 300200) due to mutations in the DAX-1 gene is frequently associated to hypogonadotrophic hypogonadism (HHG, OMIM 238320). Clinical variants with delayed-onset have been recognized. The objective of this study is to assess Sertoli cell function throughout pubertal development in patients with childhood-onset AHC due to stop mutations in the DAX-1 gene. DESIGN: Observational follow-up study of gonadotrophin pulsatility pattern, and serum levels of antimüllerian hormone and inhibin B through pubertal development in these patients. PATIENTS: Three patients belonging to two families with AHC were included in this study. MEASUREMENTS: The gonadotrophic pattern, serum inhibin B and antimüllerian hormone were determined in relation to clinical Tanner stage of pubertal development. RESULTS: One patient showed a marked elevation in serum FSH concomitantly with low inhibin B and antimüllerian hormone levels, indicating a primary testicular dysfunction. The other two patients showed a gonadotrophic pattern of HHG, and their serum levels of inhibin B and antimüllerian hormone also reflected a moderate primary testicular dysfunction. The three patients were azoospermic. CONCLUSIONS: These cases give further insight into the clinical spectrum of phenotypes of the hypothalamic-pituitary-gonadal axis in patients with variants in hypogonadism associated with childhood-onset X-linked AHC due to DAX-1 mutations.
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Hiperplasia Suprarrenal Congênita/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Hipogonadismo/fisiopatologia , Túbulos Seminíferos/fisiopatologia , Adolescente , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/genética , Insuficiência Adrenal , Hormônio Antimülleriano/sangue , Criança , Pré-Escolar , Receptor Nuclear Órfão DAX-1/genética , Hormônio Foliculoestimulante/sangue , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Hipoadrenocorticismo Familiar , Hipogonadismo/sangue , Hipogonadismo/genética , Inibinas/sangue , Masculino , MutaçãoRESUMO
OBJECTIVE: To precisely characterize the chronology of testicular endocrine function impairment during childhood and adolescence in patients with Klinefelter syndrome. Design Retrospective chart review. Patients A total of 29 boys with Klinefelter syndrome with up to 12.3 years follow-up. MEASUREMENTS: Clinical features and serum hormone levels were analysed during follow-up. RESULTS: Of the 29 patients, 16 were prepubertal and 13 had already entered puberty at their first visit. Fifteen patients were followed up through late puberty. Before puberty, LH, FSH, testosterone, anti-Müllerian hormone (AMH) and inhibin B were within the expected range in almost all cases. However, levels of the inhibin alpha-subunit precursor Pro-alphaC were in the lowest levels of the normal range in most cases. During puberty, FSH levels increased earlier and more markedly than LH. Inhibin B and AMH declined to abnormally low or undetectable levels in advanced pubertal stages. Although testosterone and Pro-alphaC levels were within the reference ranges in most cases, they were abnormally low for the observed LH values. CONCLUSIONS: In Klinefelter syndrome, a mild Leydig cell dysfunction is present from early childhood in most cases and persists throughout puberty. Sertoli cell function is normal until mid puberty, when a dramatic impairment is observed.
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Síndrome de Klinefelter/genética , Síndrome de Klinefelter/fisiopatologia , Puberdade/sangue , Testículo/fisiopatologia , Adolescente , Animais , Hormônio Antimülleriano , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Humanos , Lactente , Recém-Nascido , Inibinas/sangue , Cariótipo , Células Intersticiais do Testículo/patologia , Hormônio Luteinizante/sangue , Masculino , Precursores de Proteínas/sangue , Testículo/metabolismo , Testículo/patologia , Testosterona/sangueRESUMO
UNLABELLED: Some adolescents with a history of idiopathic central precocious puberty (ICPP) develop hyperandrogenism. HYPOTHESIS: Luteinizing hormone (LH) hypersecretion could be a common mechanism underlying ICPP and polycystic ovary syndrome. AIM: To explore the GnRH-LH axis in those patients. DESIGN: To compare overnight LH secretion in 7 healthy adolescents (CG) with that in patients with prior ICPP [5 with (CPPA) and 7 without (CPPB) hyperandrogenism]. To analyze daytime LH secretion in those patients. METHODS: LH secretion was quantified by immunofluorometry and deconvolution analysis. RESULTS: Nighttime mean LH (international units/liter) was higher in CPPA (6.9 +/- 1.5) than in CPPB (3.2 +/- 0.4, p < 0.05) and CG (2.9 +/- 0.4, p < 0.01). Deconvolution analysis revealed a greater nighttime LH frequency (pulses/hour) both in CPPA (0.91 +/- 0.06, p < 0.01) and CPPB (0.74 +/- 0.02, p < 0.05) than in CG (0.45 +/- 0.07). CPPA patients maintained a higher frequency than CPPB. Pulsatile LH production was greater in CPPA than in CG (50 +/- 12 vs. 18 +/- 3 IU/l/day, p < 0.01). Daytime mass of LH released per burst and pulsatile production rate were significantly greater in CPPA than in CPPB patients. CONCLUSIONS: Hyperandrogenic adolescents with prior ICPP show increased pulsatile LH secretion. Augmentation of LH pulsatility may predispose to or cause hyperandrogenism in some adolescents with a history of precocious puberty.
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Hiperandrogenismo/complicações , Hiperandrogenismo/metabolismo , Hormônio Luteinizante/sangue , Puberdade Precoce/complicações , Puberdade Precoce/metabolismo , Adolescente , Androstenodiona/sangue , Estrona/sangue , Feminino , Fluorimunoensaio , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/metabolismo , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/metabolismo , Testosterona/sangueRESUMO
INTRODUCTION: Androstenedione (A4) is an adrenal and gonadal steroid biomarker, useful in the assessment of children in whom steroidogenic disorders are suspected. The first key step in the evaluation of a diagnostic test resides on confident reference intervals (RI). The lack of updated A4-RI with current methods in pediatrics may mislead A4 results and limit its diagnosis accuracy. AIM: To provide A4 reference ranges in healthy children. METHODS: Prospective, descriptive study. 283 children aged 4 days to 18 years were included. In children < 1 yr, A4 was measured directly in serum (NE-A4) and postorganic solvent extraction (E-A4) for the assessment of interfering steroids. The influence of chronological age (CA), gender, and Tanner stage (T) were investigated. RESULTS: In the neonatal period, E-A4 was significantly lower than NE-A4; boys had higher NE-A4; sexual dimorphism disappeared after extraction procedure. In children older than 4 months, A4 concentration remained low until the age of 5 years. Thereafter, A4 increased significantly in association with CA and T (r2 = 0.65; p < 0.001), obtaining the highest concentrations in children within pubertal ages without sexual dimorphism. CONCLUSION: We recommend to perform solvent extraction in neonates and to take into account age and sexual development to properly interpret A4 results in childhood.
Assuntos
Androstenodiona/sangue , Adolescente , Androstenodiona/normas , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
OBJECTIVE: To investigate the occurrence of abnormally elevated values of biomarkers of growth hormone (GH) action in short children on recombinant human GH (rhGH) therapy. METHODS: Sixty-three prepubertal short children were examined: 31 with GH deficiency (GHD), 25 small for gestational age (SGA), and 9 with Turner syndrome (TS). The main outcomes were the following: standard deviation score (SDS) values of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio before, at the 1st and at the 2nd year on rhGH and Δheight (Ht)-SDS to evaluate GH treatment efficacy (adequate 1st-year ΔHt SDS: >0.4 SDS for GHD and >0.3 SDS for non-GHD). RESULTS: Seventy-eight percent of GHD, 78% of SGA and 55% of TS children had adequate 1st-year ΔHt SDS. In GHD, 88% of IGF-I SDS and IGFBP-3 SDS that were ≤-2.0 SDS at baseline normalized on treatment. Abnormal IGF-I values >+2.0 SDS were observed in 52% of SGA and in 55% of TS patients on rhGH. Within each group, the IGF-I/IGFBP-3 molar ratio increased significantly from pretreatment and throughout therapy, remaining within normal range for most patients. ΔIGF-I/IGFBP-3 molar ratio SDS were significantly higher in children with an adequate response (p < 0.01). CONCLUSION: Non-GHD groups presented markedly elevated concentrations of GH biomarkers on rhGH and normal IGF-I/IGFBP-3 molar ratio in most patients. Since there is a lack of consensus regarding the molar ratio usefulness, we think that interventions towards a more physiological IGF-I serum profile should be implemented.
Assuntos
Estatura/efeitos dos fármacos , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Recombinantes/uso terapêutico , Adolescente , Estatura/fisiologia , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/sangue , Hormônio do Crescimento Humano/farmacologia , Humanos , Lactente , Masculino , Proteínas Recombinantes/farmacologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Estradiol at baseline or after a classical gonadotropin-releasing hormone test did not reflect ovarian steroidogenesis in central precocious puberty (CPP) girls. AIMS: To evaluate estradiol response to depot triptorelin, both at start and during therapy to determine how active ovarian steroidogenesis is at pubertal stage and under therapy. METHODS: A prospective study was performed in 43 CPP girls. Serum luteinizing hormone and follicle-stimulating hormone at 3 h (LH-3h, FSH-3h) and estradiol at 24 h (E2-24h) after injection of depot triptorelin 3.75 mg were measured, at first dose and at 3, 6, 12, 18 and 24 months of treatment. RESULTS: E2-24h after depot triptorelin was >100 pg/ml after the first dose. Estradiol response (E2-24h) fell to levels <14 pg/ml in 78 out of 82 follow-up visits along 2 years of therapy. Concomitantly, LH-3h and FSH-3h were <4.0 and <6.3 IU/l, respectively. In 4 patients with inadequate treatment, E2-24h, LH-3h and FSH-3h rose to pubertal values similar to those observed at first dose. CONCLUSION: Estradiol (<14 pg/ml) assessment 24 h after depot triptorelin administration is a reliable and simple manner to confirm ovarian suppression in CPP girls during treatment.
Assuntos
Estradiol/sangue , Puberdade Precoce/sangue , Puberdade Precoce/tratamento farmacológico , Pamoato de Triptorrelina/administração & dosagem , Criança , Feminino , Seguimentos , Humanos , Estudos ProspectivosRESUMO
BACKGROUND: Combined pituitary hormone deficiency (CPHD) presents a wide spectrum of pituitary gland disorders. The postnatal gonadotropic surge provides a useful period to explore the gonadotropic axis for assessing the presence of congenital hypogonadotropic hypogonadism (CHH). AIM: To explore the functioning of the hypothalamic-pituitary-gonadal axis in the postnatal gonadotropic surge for an early diagnosis of CHH in newborns or infants suspected of having CPHD. SUBJECTS AND METHODS: A cohort of 27 boys under 6 months and 19 girls under 24 months of age with suspected hypopituitarism was studied. Serum concentrations of LH, FSH, testosterone, inhibin B, anti-Müllerian hormone (AMH) and estradiol were measured, and male external genitalia were characterized as normal or abnormal (micropenis, microorchidism and/or cryptorchidism). RESULTS: CPHD was confirmed in 36 out of 46 patients. Low LH and testosterone levels were found in 66% of the hypopituitary males, in significant association with the presence of abnormal external genitalia. This abnormality had a positive predictive value of 93% for CHH. No significant association was observed between serum FSH, AMH and inhibin B and the patient's external genitalia. CONCLUSION: In newborn or infant boys with CPHD, LH and testosterone concentrations measured throughout the postnatal gonadotropic surge, together with a detailed evaluation of the external genital phenotype, facilitate the diagnosis of CHH at an early stage.