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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 pituitary gland is key for childhood growth, puberty, and metabolism. Pituitary dysfunction is associated with a spectrum of phenotypes, from mild to severe. Congenital Hypopituitarism (CH) is the most commonly reported pediatric endocrine dysfunction with an incidence of 1:4000, yet low rates of genetic diagnosis have been reported. OBJECTIVE: We aimed to unveil the genetic etiology of CH in a large cohort of patients from Argentina. METHODS: We performed whole exome sequencing of 137 unrelated cases of CH, the largest cohort examined with this method to date. RESULTS: Of the 137 cases, 19.1% and 16% carried pathogenic or likely pathogenic variants in known and new genes, respectively, while 28.2% carried variants of uncertain significance. This high yield was achieved through the integration of broad gene panels (genes described in animal models and/or other disorders), an unbiased candidate gene screen with a new bioinformatics pipeline (including genes high loss of function intolerance), and analysis of copy number variants. Three novel findings emerged. First, the most prevalent affected gene encodes the cell adhesion factor ROBO1. Affected children had a spectrum of phenotypes, consistent with a role beyond pituitary stalk interruption syndrome. Second, we found that CHD7 mutations also produce a phenotypic spectrum, not always associated with full CHARGE syndrome. Third, we add new evidence of pathogenicity in the genes PIBF1 and TBC1D32, and report 13 novel candidate genes associated with CH (e.g. PTPN6, ARID5B). CONCLUSION: Overall, these results provide an unprecedented insight into the diverse genetic etiology of hypopituitarism.
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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: 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 del Ovario Poliquístico , Pubertad Precoz , Adolescente , Femenino , Humanos , Preescolar , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/epidemiología , Pubertad Precoz/tratamiento farmacológico , Prevalencia , Hiperandrogenismo/complicaciones , Hiperandrogenismo/epidemiología , MenarquiaRESUMEN
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 , Niño , Adolescente , Hidrocortisona/análisis , Estudios Prospectivos , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Saliva/químicaRESUMEN
Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.
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Hipopituitarismo , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/terapia , Niño , Hormonas Adenohipofisarias/deficiencia , Hormonas Adenohipofisarias/metabolismoRESUMEN
Los niños con lesiones selares y/o supraselares pueden presentar diabetes insípida central con posterior secreción inadecuada de hormona antidiurética. Nosotros observamos, en algunos casos, aumento de la incidencia de poliuria, natriuresis e hiponatremia, tríada diagnóstica del síndrome cerebral perdedor de sal. Aquí comunicamos la evolución de 7 pacientes con antecedentes de daño agudo del sistema nervioso central y diabetes insípida central seguida por síndrome cerebral perdedor de sal. Como tratamiento aportamos secuencialmente fluidos salinos parenterales, cloruro de sodio oral, desmopresina, mineralocorticoides e incluso tiazidas. Ante la persistencia de poliuria con hiponatremia, agregamos ibuprofeno. Como resultado de este esquema terapéutico secuencial, este grupo redujo significativamente los valores de diuresis diaria de 10 ml/kg/h a 2 ml/kg/h en un tiempo promedio de 5 días, normalizando también las natremias (de 161 mEq/L a 143 mEq/L) en un tiempo promedio de 9 días. En ningún caso observamos efectos adversos asociados al tratamiento.
Children with sellar and/or suprasellar lesions may develop central diabetes insipidus with subsequent inappropriate antidiuretic hormone secretion. An increased incidence of polyuria, natriuresis, and hyponatremia has been reported in some cases, which make up the diagnostic triad of cerebral salt wasting syndrome. Here we report the clinical course of 7 patients with a history of acute central nervous system injury and central diabetes insipidus followed by cerebral salt wasting syndrome. Treatment included the sequential use of parenteral saline solution, oral sodium chloride, desmopressin, mineralocorticoids, and even thiazides. Due to persistent polyuria and hyponatremia, ibuprofen was added. As a result of this sequential therapeutic regimen, daily urine output reduced significantly from 10 mL/ kg/h to 2 mL/kg/h over an average period of 5 days, together with a normalization of natremia (from 161 mEq/L to 143 mEq/L) over an average period of 9 days. No treatment-related adverse effects were observed in any case.
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Humanos , Preescolar , Niño , Adolescente , Diabetes Insípida Neurogénica , Hiponatremia/etiología , Hiponatremia/tratamiento farmacológico , Poliuria/complicaciones , Poliuria/etiología , Investigación , Ibuprofeno/uso terapéuticoRESUMEN
Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI, however; there have been almost no new therapeutic modalities since the development of diazoxide. Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in 'developed' countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.
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Children with sellar and/or suprasellar lesions may develop central diabetes insipidus with subsequent inappropriate antidiuretic hormone secretion. An increased incidence of polyuria, natriuresis, and hyponatremia has been reported in some cases, which make up the diagnostic triad of cerebral salt wasting syndrome. Here we report the clinical course of 7 patients with a history of acute central nervous system injury and central diabetes insipidus followed by cerebral salt wasting syndrome. Treatment included the sequential use of parenteral saline solution, oral sodium chloride, desmopressin, mineralocorticoids, and even thiazides. Due to persistent polyuria and hyponatremia, ibuprofen was added. As a result of this sequential therapeutic regimen, daily urine output reduced significantly from 10 mL/kg/h to 2 mL/kg/h over an average period of 5 days, together with a normalization of natremia (from 161 mEq/L to 143 mEq/L) over an average period of 9 days. No treatment-related adverse effects were observed in any case.
Los niños con lesiones selares y/o supraselares pueden presentar diabetes insípida central con posterior secreción inadecuada de hormona antidiurética. Nosotros observamos, en algunos casos, aumento de la incidencia de poliuria, natriuresis e hiponatremia, tríada diagnóstica del síndrome cerebral perdedor de sal. Aquí comunicamos la evolución de 7 pacientes con antecedentes de daño agudo del sistema nervioso central y diabetes insípida central seguida por síndrome cerebral perdedor de sal. Como tratamiento aportamos secuencialmente fluidos salinos parenterales, cloruro de sodio oral, desmopresina, mineralocorticoides e incluso tiazidas. Ante la persistencia de poliuria con hiponatremia, agregamos ibuprofeno. Como resultado de este esquema terapéutico secuencial, este grupo redujo significativamente los valores de diuresis diaria de 10 ml/kg/h a 2 ml/kg/h en un tiempo promedio de 5 días, normalizando también las natremias (de 161 mEq/L a 143 mEq/L) en un tiempo promedio de 9 días. En ningún caso observamos efectos adversos asociados al tratamiento.
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Diabetes Insípida Neurogénica , Hiponatremia , Humanos , Niño , Hiponatremia/tratamiento farmacológico , Hiponatremia/etiología , Poliuria/etiología , Poliuria/complicaciones , Ibuprofeno/uso terapéutico , InvestigaciónRESUMEN
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 , Niño , Adolescente , Hormona Folículo Estimulante , Estudios Prospectivos , Semen , Testosterona , Neoplasias Hematológicas/tratamiento farmacológicoRESUMEN
Growth hormone (GH) binding to GH receptor activates janus kinase 2 (JAK2)-signal transducer and activator of transcription 5b (STAT5b) pathway, which stimulates transcription of insulin-like growth factor-1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3) and insulin-like growth factor acid-labile subunit (IGFALS). Although STAT5B deficiency was established as an autosomal recessive disorder, heterozygous dominant-negative STAT5B variants have been reported in patients with less severe growth deficit and milder immune dysfunction. We developed an in vivo functional assay in zebrafish to characterize the pathogenicity of three human STAT5B variants (p.Ala630Pro, p.Gln474Arg and p.Lys632Asn). Overexpression of human wild-type (WT) STAT5B mRNA and its variants led to a significant reduction of body length together with developmental malformations in zebrafish embryos. Overexpression of p.Ala630Pro, p.Gln474Arg or p.Lys632Asn led to an increased number of embryos with pericardial edema, cyclopia and bent spine compared with WT STAT5B. Although co-injection of WT and p.Gln474Arg and WT and p.Lys632Asn STAT5B mRNA in zebrafish embryos partially or fully rescues the length and the developmental malformations in zebrafish embryos, co-injection of WT and p.Ala630Pro STAT5B mRNA leads to a greater number of embryos with developmental malformations and a reduction in body length of these embryos. These results suggest that these variants could interfere with endogenous stat5.1 signaling through different mechanisms. In situ hybridization of zebrafish embryos overexpressing p.Gln474Arg and p.Lys632Asn STAT5B mRNA shows a reduction in igf1 expression. In conclusion, our study reveals the pathogenicity of the STAT5B variants studied.
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Factor de Transcripción STAT5 , Pez Cebra , Animales , Humanos , Pez Cebra/genética , Pez Cebra/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Hormona del Crecimiento , Transducción de Señal/genética , ARN Mensajero , Factor I del Crecimiento Similar a la Insulina/genéticaRESUMEN
Growth hormone deficiency (GHD) is a clinical syndrome that can manifest either as isolated or associated with additional pituitary hormone deficiencies. Although diminished height velocity and short stature are useful and important clinical markers to consider testing for GHD in children, the signs and symptoms of GHD are not always so apparent in adults. Quality of life and metabolic health are often impacted in patients with GHD; thus, making an accurate diagnosis is important so that appropriate growth hormone (GH) replacement therapy can be offered to these patients. Screening and testing for GHD require sound clinical judgment that follows after obtaining a complete medical history of patients with a hypothalamic-pituitary disorder and a thorough physical examination with specific features for each period of life, while targeted biochemical testing and imaging are required to confirm the diagnosis. Random measurements of serum GH levels are not recommended to screen for GHD (except in neonates) as endogenous GH secretion is episodic and pulsatile throughout the lifespan. One or more GH stimulation tests may be required, but existing methods of testing might be inaccurate, difficult to perform, and can be imprecise. Furthermore, there are multiple caveats when interpreting test results including individual patient factors, differences in peak GH cut-offs (by age and test), testing time points, and heterogeneity of GH and insulin-like growth factor 1 assays. In this article, we provide a global overview of the accuracy and cut-offs for diagnosis of GHD in children and adults and discuss the caveats in conducting and interpreting these tests.
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CONTEXT: Insulin-like growth factor (IGF)1 gene mutations are extremely rare causes of pre- and postnatal growth retardation. Phenotype can be heterogenous with varying degrees of neurosensory deafness, cognitive defects, glucose metabolism impairment and short stature. OBJECTIVE: This study describes a 12.6-year-old girl presenting with severe short stature and insulin resistance, but with normal hearing and neurological development at the lower limit of normal. METHODS: DNA was obtained from the proband and both parents for whole exome sequencing (WES). In silico analysis was performed to predict the impact of the IGF1 variant on IGF1 and insulin receptors (IGF1R and IR) signaling. Phosphorylation of the IGF1R at activating Tyr residues and cell proliferation analyses were used to assess the ability of each subject's IGF1 to bind and activate IGF1R. RESULTS: The proband had low immunoreactive IGF1 in serum and WES revealed a novel homozygous IGF1 missense variant (c.247A>T), causing a change of serine 83 for cysteine (p.Ser83Cys; p.Ser35Cys in mature peptide). The proband's parents were heterozygous for this mutation. In silico analyses indicated the pathogenic potential of the variant with electrostatic variations with the potential of hampering the interaction with the IGF1R but strengthening the binding to IR. The mutant IGF1 protein had a significantly reduced activity on in vitro bioassays. CONCLUSION: We describe a novel IGF1 mutation leading to severe loss of circulating IGF1 immunoreactivity and bioactivity. In silico modeling predicts that the mutant IGF1 could interfere with IR signaling, providing a possible explanation for the severe insulin resistance observed in the patient. The absence of significant hearing and neurodevelopmental involvement in the present case is unusual and broadens the clinical spectrum of IGF1 mutations.
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Enanismo , Resistencia a la Insulina , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Resistencia a la Insulina/genética , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Mutación , Mutación Missense , Enanismo/genética , FenotipoRESUMEN
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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Gliomas are the most frequent solid tumors in children. Among these, high-grade gliomas are less common in children than in adults, though they are similar in their aggressive clinical behavior. In adults, glioblastoma is the most lethal tumor of the central nervous system. Insulin-like growth factor 1 receptor (IGF1R) plays an important role in cancer biology, and its nuclear localization has been described as an adverse prognostic factor in different tumors. Previously, we have demonstrated that, in pediatric gliomas, IGF1R nuclear localization is significantly associated with high-grade tumors, worst clinical outcome, and increased risk of death. Herein we explore the role of IGF1R intracellular localization by comparing two glioblastoma cell lines that differ only in their IGF1R capacity to translocate to the nucleus. In vitro, IGF1R nuclear localization enhances glioblastoma cell motility and metabolism without affecting their proliferation. In vivo, IGF1R has the capacity to translocate to the nucleus and allows not only a higher proliferation rate and the earlier development of tumors but also renders the cells sensitive to OSI906 therapy. With this work, we provide evidence supporting the implications of the presence of IGF1R in the nucleus of glioma cells and a potential therapeutic opportunity for patients harboring gliomas with IGF1R nuclear localization.
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Glioblastoma , Glioma , Adulto , Carcinogénesis/metabolismo , Núcleo Celular/metabolismo , Niño , Glioblastoma/metabolismo , Glioma/metabolismo , Humanos , Receptores de Somatomedina/metabolismoRESUMEN
BACKGROUND: 25-hydroxyvitamin D (VD) effects on lung function and immune-modulation might affect respiratory syncytial virus (RSV) infection outcomes. We aimed to assess VD levels on admission and their association with life-threatening RSV disease (LTD). METHODS: A prospective cohort study was conducted during 2017-2019. Previously healthy infants aged <12 months, hospitalized with a first episode of RSV infection, were enrolled. LTD was defined by need for intensive care and ventilatory support. Serum VD levels <20 ng/mL were categorized as deficient, and 20-29.9 ng/mL as insufficient. RESULTS: Of 125 patients studied, 73 (58%) were male. Median age was 4 months. Twenty-two patients developed LTD. No differences in viral load were seen between cases with LTD and controls (P = .94). Patients who developed LTD had significantly lower VD levels: median 18.4 ng/mL (IQR, 15.1-26.9 ng/mL) versus 31.7 ng/mL (IQR, 23.6-42.0 ng/mL), P < .001; 59% of infants with LTD had VD deficiency compared with 12% in those with better outcome. Multivariable regression analysis confirmed VD deficiency as a risk factor (odds ratio, 11.83; 95% confidence interval, 3.89-35.9; P < .001). CONCLUSIONS: These findings provide additional evidence for the development of strategies to prevent severe RSV infections.
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Virus Sincitiales Respiratorios , Índice de Severidad de la Enfermedad , Vitamina DRESUMEN
OBJETIVE: We followed our previously reported algorithm based on intra and postoperative parathyroid hormone (PTH) levels to predict postthyroidectomy hypoparathyroid hypocalcemia. The objective of the study was to assess if this strategy is useful and safe to reduce hypocalcemia, hospitalisation length and postsurgery calcium sampling. DESIGN, PATIENTS, MEASSUREMENTS: We classified our series of 66 patients according to their risk of hypoparathyroidism based on PTH determinations. We treated high-risk patients with calcium and vitamin D1-25 supplementation and obtained routine daily calcium samples to control low-risk patients until 48 h postsurgery. We compared the outcomes and overall results of this new approach with those of a historical control group of patients with equivalent PTH measurements who were treated only if they presented hypocalcemia. RESULTS: In the high-risk subgroup (n = 30), five patients had hypocalcemia within the first 24 h. Compared with the high-risk control subgroup, the incidence of hypocalcemia fell from 100% to 17% (p < .001), and the median hospitalisation length from 6 to 3 days (p < .001). In the low-risk subgroup (n = 36), 28 patients remained normocalcemic with significantly less calcium sampling (p < .001). Eight patients had hypocalcemia; seven of them required neck dissection, which was the only risk factor related to postsurgical hypoparathyroidism (RR: 2.1 [confidence interval 95%: 1.4-3.1]; p < .001). The overall incidence of hypocalcemia decreased by 58% in our patients compared to the control group. CONCLUSIONS: Assessing PTH levels to classify the risk of hypoparathyroidism and to initiate preventive therapy was an effective approach that improved the safety of our paediatric patients by reducing the incidence of hypocalcemia and the length of hospitalisation after thyroidectomy in paediatric patients.
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Hipocalcemia , Hipoparatiroidismo , Calcio , Niño , Humanos , Hipocalcemia/etiología , Hipocalcemia/prevención & control , Hipoparatiroidismo/etiología , Hipoparatiroidismo/prevención & control , Hormona Paratiroidea , Complicaciones Posoperatorias/prevención & control , Tiroidectomía/efectos adversosRESUMEN
Pituitary hormone deficiency occurs in â¼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.
Asunto(s)
Ensayos Analíticos de Alto Rendimiento/métodos , Hipopituitarismo/patología , Mutación , Hormonas Hipofisarias/deficiencia , Empalme del ARN/genética , Factor de Transcripción Pit-1/genética , Adolescente , Adulto , Niño , Preescolar , Humanos , Hipopituitarismo/etiología , Hipopituitarismo/metabolismo , Masculino , LinajeRESUMEN
BACKGROUND: The use of technology to support health and health care has grown rapidly in the last decade across all ages and medical specialties. Newly developed eHealth tools are being implemented in long-term management of growth failure in children, a low prevalence pediatric endocrine disorder. OBJECTIVE: Our objective was to create a framework that can guide future implementation and research on the use of eHealth tools to support patients with growth disorders who require growth hormone therapy. METHODS: A total of 12 pediatric endocrinologists with experience in eHealth, from a wide geographical distribution, participated in a series of online discussions. We summarized the discussions of 3 workshops, conducted during 2020, on the use of eHealth in the management of growth disorders, which were structured to provide insights on existing challenges, opportunities, and solutions for the implementation of eHealth tools across the patient journey, from referral to the end of pediatric therapy. RESULTS: A total of 815 responses were collected from 2 questionnaire-based activities covering referral and diagnosis of growth disorders, and subsequent growth hormone therapy stages of the patient pathway, relating to physicians, nurses, and patients, parents, or caregivers. We mapped the feedback from those discussions into a framework that we developed as a guide to integration of eHealth tools across the patient journey. Responses focused on improved clinical management, such as growth monitoring and automation of referral for early detection of growth disorders, which could trigger rapid evaluation and diagnosis. Patient support included the use of eHealth for enhanced patient and caregiver communication, better access to educational opportunities, and enhanced medical and psychological support during growth hormone therapy management. Given the potential availability of patient data from connected devices, artificial intelligence can be used to predict adherence and personalize patient support. Providing evidence to demonstrate the value and utility of eHealth tools will ensure that these tools are widely accepted, trusted, and used in clinical practice, but implementation issues (eg, adaptation to specific clinical settings) must be addressed. CONCLUSIONS: The use of eHealth in growth hormone therapy has major potential to improve the management of growth disorders along the patient journey. Combining objective clinical information and patient adherence data is vital in supporting decision-making and the development of new eHealth tools. Involvement of clinicians and patients in the process of integrating such technologies into clinical practice is essential for implementation and developing evidence that eHealth tools can provide value across the patient pathway.
Asunto(s)
Hormona del Crecimiento , Telemedicina , Inteligencia Artificial , Niño , Atención a la Salud , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/tratamiento farmacológico , HumanosRESUMEN
PURPOSE: Congenital hypopituitarism (CH) can present in isolation or with other birth defects. Mutations in multiple genes can cause CH, and the use of a genetic screening panel could establish the prevalence of mutations in known and candidate genes for this disorder. It could also increase the proportion of patients that receive a genetic diagnosis. METHODS: We conducted target panel genetic screening using single-molecule molecular inversion probes sequencing to assess the frequency of mutations in known hypopituitarism genes and new candidates in Argentina. We captured genomic deoxyribonucleic acid from 170 pediatric patients with CH, either alone or with other abnormalities. We performed promoter activation assays to test the functional effects of patient variants in LHX3 and LHX4. RESULTS: We found variants classified as pathogenic, likely pathogenic, or with uncertain significance in 15.3% of cases. These variants were identified in known CH causative genes (LHX3, LHX4, GLI2, OTX2, HESX1), in less frequently reported genes (FOXA2, BMP4, FGFR1, PROKR2, PNPLA6) and in new candidate genes (BMP2, HMGA2, HNF1A, NKX2-1). CONCLUSION: In this work, we report the prevalence of mutations in known CH genes in Argentina and provide evidence for new candidate genes. We show that CH is a genetically heterogeneous disease with high phenotypic variation and incomplete penetrance, and our results support the need for further gene discovery for CH. Identifying population-specific pathogenic variants will improve the capacity of genetic data to predict eventual clinical outcomes.