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Background: Childhood primary brain tumors (CPBT) are the second largest group of childhood malignancies and associated with a high risk for endocrine late effects. Objective: To assess endocrine late effects and their relevance for the development of osteopathologies in survivors. Methods: This single center cross sectional study investigated data from 102 CPBT survivors with a mean age of 13.0 years and a mean age at diagnosis of 8.7 years. Clinical, biochemical, radiographic, and anamnestic data regarding endocrine and bone health were obtained at study visits. In addition, data regarding tumor stage and therapy was obtained by chart review. An expert opinion was applied to define presence of osteopathologies. Results: Impaired bone health, defined by at least one pathological screening parameter, was present in 65% of patients. 27.5% were found to have overt osteopathologies per expert opinion. 37.8% displayed a severe vitamin D deficiency (25-OH vitamin D < 10 ng/ml) and 11% a secondary hyperparathyroidism. Patients with osteopathologies had lower 25-OH vitamin D levels compared to patients without osteopathologies. Multiple endocrine late effects were present: diabetes insipidus in 10.8%, aberrant pubertal development in 13.7%, central hypocortisolism in 14.9%, thyroid dysfunction in 23.8% and growth hormone deficiency in 21.8%. A total of 31.3% of survivors displayed any endocrinopathy. Tumors located near hypothalamic structures and patients who received irradiation had a higher likelihood of endocrine morbidity. Conclusion: This study indicates that endocrine deficiencies are common in pediatric survivors of CPBTs. Osteopathologies are present in this cohort. A prominent effect of hormonal deficiencies on bone health was not detected, possibly because patients were sufficiently treate for their endocrine conditions or indicating resilience of the childhood bone remodeling process. Vitamin D deficiency is frequent and should be treated as recommended.
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In ultra-rare bone diseases, information on growth during childhood is sparse. Juvenile Paget disease (JPD) is an ultra-rare disease, characterized by loss of function of osteoprotegerin (OPG). OPG inhibits osteoclast activation via the receptor activator of nuclear factor-κB (RANK) pathway. In JPD, overactive osteoclasts result in inflammatory-like bone disease due to grossly elevated bone resorption. Knowledge on the natural history of JPD, including final height and growth, is limited. Most affected children receive long-term antiresorptive treatment, mostly with bisphosphonates, to contain bone resorption, which may affect growth. In this study, we report the follow-up of height, growth velocity, and skeletal maturation in a 16-year-old female patient with JPD. The patient was treated with cyclic doses of pamidronate starting at 2.5 years of age and with 2 doses of denosumab at the age of 8 years, when pamidronate was paused. In the following years, a sustainable decline in a height z-score and a stunted pubertal growth spurt; despite appropriate maturation of the epiphyseal plates of the left hand, the proximal right humerus and both femora were observed. Whether this reflects the growth pattern in JPD or might be associated to the antiresorptive treatments is unclear, since there is very limited information available on the effect of bisphosphonates and denosumab on growth and the growth plate in pediatric patients. Studies are needed to understand the natural history of an ultra-rare bone disease and to assess the effects of antiresorptive treatment on the growing skeleton.
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Denosumab/administração & dosagem , Fêmur , Lâmina de Crescimento , Úmero , Osteíte Deformante , Pamidronato/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Fêmur/crescimento & desenvolvimento , Fêmur/metabolismo , Fêmur/fisiopatologia , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/fisiopatologia , Humanos , Úmero/crescimento & desenvolvimento , Úmero/fisiopatologia , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/metabolismo , Osteíte Deformante/fisiopatologia , Osteoprotegerina/metabolismoRESUMO
OBJECTIVE: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumours (TART) in young males with congenital adrenal hyperplasia (CAH). DESIGN: Combined cross-sectional and retrospective clinical study. METHODS: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as 'poor', 'moderate' or 'medium'. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes. RESULTS: Semen quality was similar in males with CAH and controls (P = 0.066), however patients with 'poor' past control and large TART, or with 'poor' current CAH control had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was 'poor' (1.8 ± 0.9 U/L; 'good': 3.9 ± 2.2 U/L); P = 0.015); luteinizing hormone was decreased if it was 'poor' (1.8 ± 0.9 U/L; P = 0.041) or 'moderate' (1.9 ± 0.6 U/L; 'good': 3.0 ± 1.3 U/L; P = 0.025). None of the males with 'good' past CAH control, 50% of those with 'moderate' past control and 80% with 'poor past control had bilateral TART. The prevalence of TART in males with severe (class null or A) CYP21A2 mutations was 53% and 25% and 0% in those with milder class B and C mutations, respectively. CONCLUSIONS: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TART. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.
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Corticosteroides/uso terapêutico , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Tumor de Resto Suprarrenal/epidemiologia , Terapia de Reposição Hormonal/métodos , Análise do Sêmen , Neoplasias Testiculares/epidemiologia , Adolescente , Glândulas Suprarrenais/patologia , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/fisiopatologia , Tumor de Resto Suprarrenal/patologia , Adulto , Androgênios/sangue , Humanos , Estudos Longitudinais , Masculino , Mutação , Puberdade , Espermatogênese , Neoplasias Testiculares/patologia , Ultrassonografia , Adulto JovemRESUMO
Background: Impaired bone health is a late effect of childhood malignancies which can be difficult to detect in juvenile survivors. It may, however, lead to compromised quality of life, or even permanent disability later in life due to osteoporosis, pain or fractures if left untreated. Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy with an over 85% five-year survival. ALL and its treatment cause bone alterations in adults, but little information on the bone health status in juvenile survivors is available. Objective: To report data on skeletal late effects in juvenile survivors of childhood ALL based on a comprehensive assessment of bone health and to assess the influence of a vitamin D deficiency on bone health in this cohort. Methods: In a single center cross sectional study 128 pediatric patients (11.9 ± 4.76 years) with a mean follow up of 5.88 ± 3.75 years after diagnosis of ALL were recruited. The bone health status of the survivors was assessed based on clinical examination, review of medical records, biochemical and radiographic analyses, by clinical experts. A score which utilized 8 different parameters was formed and used to assess the effect of a vitamin D deficiency on bone health. Results: In this cohort, 18% of survivors displayed overt osteopathologies as defined by clinical expert assessment. Impaired bone health, defined by at least one pathological screening parameter, was detected in 77%. Despite recommendations for adequate vitamin D supplementation, 15% displayed a vitamin D deficiency associated with hyperparathyroidism. The applied score identified survivors with osteopathologies with high sensitivity and specificity. The median score did not differ between patients without and with severe vitamin D deficiency. Conclusion: Our findings suggest that impaired bone health and osteopathologies are common skeletal late effects following treatment of childhood ALL. Major contributing factors are BMT, irradiation and older age at diagnosis. Vitamin D deficiency likely accounts for hyperparathyroidism in some patients but does not seem to further affect bone health in this cohort. Survivors of ALL need thorough surveillance to investigate bone health, since bone morbidity is common and still poorly understood. Early detection and appropriate intervention may improve bone health.
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AIM: The aim of this official guideline published by the German Society of Gynecology and Obstetrics (DGGG) and coordinated with the German Society of Urology (DGU) and the German Society of Reproductive Medicine (DGRM) is to provide consensus-based recommendations, obtained by evaluating the relevant literature, on counseling and fertility preservation for prepubertal girls and boys as well as patients of reproductive age. Statements and recommendations for girls and women are presented below. Statements or recommendations for boys and men are not the focus of this guideline. METHODS: This S2k guideline was developed at the suggestion of the guideline commission of the DGGG, DGU and DGRM and represents the structured consensus of representative members from various professional associations (n = 40). RECOMMENDATIONS: The guideline provides recommendations on counseling and fertility preservation for women and girls which take account of the patient's personal circumstances, the planned oncologic therapy and the individual risk profile as well as the preferred approach for selected tumor entities.
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Introduction: Juvenile Paget's disease (JPD), an ultra-rare, debilitating bone disease due to loss of functional osteoprotegerin (OPG), is caused by recessive mutations in TNFRFSF11B. A genotype-phenotype correlation spanning from mild to very severe forms is described. Aim: This study aimed to describe the complexity of the human phenotype of OPG deficiency in more detail and to investigate heterozygous mutation carriers for clinical signs of JPD. Patients: We investigated 3 children with JPD from families of Turkish, German, and Pakistani descent and 19 family members (14 heterozygous). Results: A new disease-causing 4 bp-duplication in exon 1 was detected in the German patient, and a microdeletion including TNFRFSF11B in the Pakistani patient. Skeletal abnormalities in all affected children included bowing deformities and fractures, contractures, short stature and skull involvement. Complex malformation of the inner ear and vestibular structures (2 patients) resulted in early deafness. Patients were found to be growth hormone deficient (2), displayed nephrocalcinosis (1), and gross motor (3) and mental (1) retardation. Heterozygous family members displayed low OPG levels (12), elevated bone turnover markers (7), and osteopenia (6). Short stature (1), visual impairment (2), and hearing impairment (1) were also present. Conclusion: Diminished OPG levels cause complex changes affecting multiple organ systems, including pituitary function, in children with JPD and may cause osteopenia in heterozygous family members. Diagnostic and therapeutic measures should aim to address the complex phenotype.
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Mutação/genética , Osteíte Deformante/genética , Osteoprotegerina/genética , Adolescente , Adulto , Idoso , Biomarcadores/análise , Criança , Pré-Escolar , Éxons/genética , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Osteíte Deformante/patologia , Linhagem , Fenótipo , PrognósticoRESUMO
Survivors of childhood cancer frequently suffer from endocrine late effects, which are, at least partly, attributed to toxic effects of chemotherapy. Treatment of retinoblastoma typically involves chemotherapy at a very young age. The authors conducted a cross-sectional study to assess bone health in a pediatric cohort of 33 survivors of retinoblastoma (mean age: 4.4 years) who had undergone chemotherapy treatment at an especially young age (mean age: 0.76 years). Of these patients, 14 had unilateral and 19 bilateral retinoblastoma. Polychemotherapy consisted of treatment with cyclophosphamide, etoposide, vincristine, and carboplatin. Ten patients had undergone external beam radiotherapy. Clinical and biochemical parameters of growth, pubertal development, and bone health were obtained. A vitamin D deficiency was found in 51.7% of the patients, and 13.7% of patients displayed severe vitamin D deficiency. Secondary hyperparathyroidism and altered readings for bone formation or resorption markers were present in 15%. Nine percent reported bone pain or experienced fractures of the long bones after primary diagnosis. No difference between children with bilateral and unilateral disease or irradiated versus nonirradiated children was observed. The parameters of thyroid function, growth, and pubertal development were within age-appropriate norms in almost all children. In conclusion, altered parameters of bone health can be present in survivors of retinoblastoma at a young age and warrant regular follow-up in these children. The endocrine hypothalamic-pituitary axes, however, were not impaired at this early age in this group of survivors of retinoblastoma.
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Protocolos de Quimioterapia Combinada Antineoplásica , Fraturas Ósseas , Retinoblastoma , Sobreviventes , Deficiência de Vitamina D , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Pré-Escolar , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Fraturas Ósseas/induzido quimicamente , Fraturas Ósseas/metabolismo , Fraturas Ósseas/patologia , Humanos , Masculino , Retinoblastoma/tratamento farmacológico , Retinoblastoma/metabolismo , Retinoblastoma/patologia , Fatores de Risco , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Deficiência de Vitamina D/induzido quimicamente , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/patologiaRESUMO
OBJECTIVE: To investigate whether celiac disease (CD) associated with type 1 diabetes increases the risk of microvascular complications. RESEARCH DESIGN AND METHODS: Patients (n = 56,514) aged >10 years with diabetes duration <20 years from 392 centers in Germany and Austria were assigned to one of three categories (n): no CD (50,933), biopsy-confirmed CD (812), or suspected CD (4,769; clinical diagnosis or positive antibodies). The confirmed and suspected groups were combined and analyzed for retinopathy or nephropathy. Cox proportional hazards regression was used to adjust for potential confounders (glycated hemoglobin [HbA1c], age at diabetes onset, sex, smoking, dyslipidemia, and hypertension). RESULTS: Kaplan-Meier analysis revealed that retinopathy and nephropathy occurred earlier in the presence versus absence of CD: retinopathy at age 26.7 years (95% CI 23.7-30.2) in 25% of patients with CD vs. age 33.7 years (33.2-34.4) in 25% without CD and microalbuminuria at age 32.8 years (29.7-42.5) vs. 42.4 years (41.4-43.3). The adjusted risk for both retinopathy (hazard ratio 1.263 [95% CI 1.078-1.481]) and nephropathy (1.359 [1.228-1.504]) was higher in patients with diabetes and CD versus those without CD. Cox regression revealed CD as an independent risk factor for microvascular complications after adjustment for confounders. CONCLUSIONS: CD is an independent risk factor for retinopathy and nephropathy in patients with type 1 diabetes. Our study therefore supports the recommendation for regular serologic testing for CD, even in the absence of clinical CD. Further prospective studies are required to investigate whether a gluten-free diet might reduce the risk of microvascular disorders in patients with diabetes and CD.
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Doença Celíaca/complicações , Diabetes Mellitus Tipo 1/etiologia , Angiopatias Diabéticas/etiologia , Adulto , Idade de Início , Albuminúria/epidemiologia , Albuminúria/etiologia , Áustria , Doença Celíaca/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Angiopatias Diabéticas/epidemiologia , Dieta Livre de Glúten , Dislipidemias/complicações , Dislipidemias/epidemiologia , Feminino , Alemanha , Hemoglobinas Glicadas/metabolismo , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Incidência , Estimativa de Kaplan-Meier , Masculino , Microvasos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
INTRODUCTION: Sickle cell anemia and thalassemia result in impaired bone health in both adults and youths. Children with other types of chronic hemolytic anemia may also display impaired bone health. STUDY DESIGN: To assess bone health in pediatric patients with chronic hemolytic anemia, a cross-sectional study was conducted involving 45 patients with different forms of hemolytic anemia (i.e., 17 homozygous sickle cell disease and 14 hereditary spherocytosis patients). Biochemical, radiographic and anamnestic parameters of bone health were assessed. RESULTS: Vitamin D deficiency with 25 OH-vitamin D serum levels below 20 ng/ml was a common finding (80.5%) in this cohort. Bone pain was present in 31% of patients. Analysis of RANKL, osteoprotegerin (OPG) and osteocalcin levels indicated an alteration in bone modeling with significantly elevated RANKL/OPG ratios (control: 0.08+0.07; patients: 0.26+0.2, Pâ=â0.0007). Osteocalcin levels were found to be lower in patients compared with healthy controls (68.5+39.0 ng/ml vs. 118.0+36.6 ng/ml, Pâ=â0.0001). Multiple stepwise regression analysis revealed a significant (P<0.025) influence of LDH (partial r2â=â0.29), diagnosis of hemolytic anemia (partial r2â=â0.05) and age (partial r2â=â0.03) on osteocalcin levels. Patients with homozygous sickle cell anemia were more frequently and more severely affected by impaired bone health than patients with hereditary spherocytosis. CONCLUSION: Bone health is impaired in pediatric patients with hemolytic anemia. In addition to endocrine alterations, an imbalance in the RANKL/OPG system and low levels of osteocalcin may contribute to this impairment.
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Anemia Hemolítica/sangue , Anemia Hemolítica/fisiopatologia , Osso e Ossos/fisiopatologia , Adolescente , Densidade Óssea/fisiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Osteocalcina/sangue , Osteoprotegerina/sangue , Ligante RANK/sangueRESUMO
BACKGROUND: Total body irradiation (TBI) treatment eradicates malignant cells and suppresses the immune system before hematopoietic stem cell transplantation (HSCT). The radiation dose is limited by its toxicity to healthy organs. Many reports describe long-term sequelae from TBI in adults, but comparable data for pediatric patients are scarce. PROCEDURES: We evaluated late effects of a cohort of survivors after at least 2 years from 106 children treated with TBI and HSCT between 1985 and 2008. Follow-up was available from 39 patients with a mean duration of 8.3 (range 2.0-21.9) years. We examined cardiac, pulmonary and renal function, longitudinal growth, weight development, endocrinological parameters, and gastrointestinal problems. RESULTS: Initial remission status and overall survival were significantly correlated. None of the 39 patients experienced cardiac dysfunction or changes in pulmonal function, but 5 exhibited renal impairment. Gastrointestinal problems were reported by 4 patients, and 10 patients had severe growth impairment. Altogether, our follow-up of pediatric patients who survived TBI-containing conditioning regimens for more than 2 years showed no cardiac morbidity or pulmonary aggravation, but mild renal sequelae and growth impairment. CONCLUSION: The adverse long-term effects of TBI in our cohort of children surviving at least 2 years after TBI and HSCT seem to be within a tolerable range. Future studies are required to investigate whether conditioning regimens lacking TBI result in a better ratio of benefits to overall side effects.
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Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Neoplasias/terapia , Sobreviventes/estatística & dados numéricos , Irradiação Corporal Total/efeitos adversos , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Tempo , Adulto JovemRESUMO
CONTEXT: Juvenile Paget's disease (JPD) is an extremely rare, yet painful and debilitating bone disease with onset occurring during early childhood. JPD can be caused by loss of function of osteoprotegerin, resulting in subsequent stimulation of osteoclasts via the receptor activator of nuclear factor-κB (RANK) pathway. Increased bone turnover and lack of bone modeling lead to severe deformities, frequent fractures, short stature, and loss of hearing. SETTING: The treatment for JPD is challenging and has previously been based on administration of either calcitonin or bisphosphonates. However, with the development of denosumab, a receptor activator of nuclear factor-κB-ligand (RANKL) antibody, a treatment targeting the pathophysiology of JPD may be available. We report the effects of denosumab treatment on an 8-year-old girl with a severe form of JPD. PATIENT: Before starting the denosumab treatment regimen, the patient had been treated for 3.5 years with iv pamidronate. INTERVENTION AND OUTCOME: The administration of denosumab resulted in improved disease control compared with bisphosphonate, as assessed by monitoring markers of bone turnover. Alkaline phosphatase levels dropped within the normal range and remained at normal levels for 5 months after the final dose of denosumab. Additionally, bone pain was more efficiently controlled with denosumab. However, concomitant with the first injection, severe hypocalcemia developed, for which the patient was hospitalized and iv calcium supplementation was required for 13 days. CONCLUSIONS: Denosumab appears to be significantly effective for osteoclast inhibition for the treatment of JPD. However, in our patient, denosumab administration was associated with severe hypocalcemia, indicating that close monitoring of calcium levels is required during treatment.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Remodelação Óssea , Osteíte Deformante/tratamento farmacológico , Ligante RANK/antagonistas & inibidores , Fosfatase Alcalina/sangue , Aminoácidos/urina , Biomarcadores , Criança , Colágeno Tipo I/urina , Denosumab , Feminino , Humanos , Osteíte Deformante/metabolismo , Hormônio Paratireóideo/sangue , Peptídeos/urinaRESUMO
BACKGROUND: Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disease caused by mutations in the genes encoding the human mineralocorticoid receptor (MR) or the α (SCNN1A), ß (SCNN1B) or γ (SCNN1G) subunit of the epithelial Na(+) channel (ENaC). While autosomal dominant mutation of the MR cause renal PHA1, autosomal recessive mutations of the ENaC lead to systemic PHA1. In the latter, affected children suffer from neonatal onset of multi-organ salt loss and often exhibit cystic fibrosis-like pulmonary symptoms. OBJECTIVE: We searched for underlying mutations in seven unrelated children with systemic PHA1, all offsprings of healthy consanguineous parents. METHODS AND RESULTS: Amplification of the SCNN1A gene and sequencing of all 13 coding exons unraveled mutations in all of our patients. We found five novel homozygous mutations (c.587_588insC in two patients, c.1342_1343insTACA, c.742delG, c.189C>A, c.1361-2A>G) and one known mutation (c.1474C>T) leading to truncation of the αENaC protein. All parents were asymptomatic heterozygous carriers of the respective mutations, confirming the autosomal recessive mode of inheritance. Five out of seven patients exhibited pulmonary symptoms in the neonatal period. CONCLUSION: The α subunit is essential for ENaC function and mutations truncating the pore-forming part of the protein leading to systemic PHA1. Based on current knowledge, the pulmonary phenotype cannot be satisfactorily predicted.
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Canais Epiteliais de Sódio/genética , Pseudo-Hipoaldosteronismo/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Linhagem , Fenótipo , Pseudo-Hipoaldosteronismo/fisiopatologiaRESUMO
BACKGROUND: Bardet-Biedl syndrome (BBS) is a genetic disorder with obesity as one of the major phenotypic criterion, which is proposed to be of neuroendocrine origin. Therefore, disturbances in appetite-regulating hormones have been considered as causative factors. Acyl ghrelin is an orexigenic hormone, whereas its desacylated form, obestatin, and leptin have the opposite functions. Ghrelin is negatively regulated in relation to nutritional status. The aim of this study was to evaluate the impact of hormone alterations on obesity development in BBS patients. METHODS: Total and acylated ghrelin, obestatin, leptin and adiponectin were measured in eight children with BBS. The results were analyzed in relation to auxological parameters [body mass index (BMI), height]. RESULTS: The mean BMI was significantly increased in BBS patients compared to the controls. Plasma levels of acylated ghrelin, total ghrelin and obestatin were slightly elevated in BBS patients compared to controls, as was the acyl/total ghrelin ratio. Leptin levels were significantly elevated in BBS patients. CONCLUSION: BBS patients lack the negative regulatory mechanisms of appetite-regulating hormones with respect to nutritional status and exhibit resistance to anorexigenic leptin. This results in a shift towards the orexigenic effects of this self-regulating system. These alterations may in part be responsible for the disturbed appetite regulation in BBS patients.
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Regulação do Apetite , Síndrome de Bardet-Biedl/sangue , Obesidade/sangue , Hormônios Peptídicos/sangue , Acilação , Adiponectina/sangue , Adolescente , Análise de Variância , Síndrome de Bardet-Biedl/diagnóstico , Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/fisiopatologia , Síndrome de Bardet-Biedl/psicologia , Estatura , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Pré-Escolar , Retroalimentação Fisiológica , Comportamento Alimentar , Feminino , Grelina/sangue , Humanos , Leptina/sangue , Masculino , Estado Nutricional , Obesidade/diagnóstico , Obesidade/genética , Obesidade/fisiopatologia , Obesidade/psicologia , Transdução de SinaisRESUMO
BACKGROUND: Patients with renal insufficiency often suffer from cachexia and growth retardation due to low appetite and increased resting metabolic rate. The neuroendocrine hormone ghrelin, a growth hormone secretagogue, enhances food intake, but its role in the development of a cachectic state in renal insufficiency is unclear. Objective. The aim of our study was to investigate the plasma concentration of total ghrelin and other hormones involved in appetite regulation in children with preterminal chronic renal failure (CRF, n = 24), children undergoing dialysis (n = 19), children after renal transplantation (RTx, n = 59) and healthy controls (n = 10). RESULTS: Total ghrelin was significantly elevated in CRF patients (1370 +/- 182 pg/ml; mean +/- SEM) when compared to control subjects (682 +/- 106 pg/ml; P = 0.016) or patients following RTx (859 +/- 51 pg/ml; P = 0.002). Furthermore, a negative correlation between glomerular filtration rate and total ghrelin was observed in CRF and transplant recipients (r = 0.36, P = 0.0006). BMI SDS (standard deviation score) is lower in CRF patients compared to the other groups (P < 0.0001). Leptin, adiponectin, blood glucose, insulin, IGF-I, IGFBP-3 and growth hormone concentrations did not differ among groups. CONCLUSIONS: We observed elevated ghrelin levels in uraemic patients despite poor appetite, but the underlying reasons remain unclear. Normal ghrelin levels can be re-achieved following RTx.
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Regulação do Apetite/fisiologia , Grelina/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Adiponectina/sangue , Adolescente , Caquexia/sangue , Caquexia/etiologia , Estudos de Casos e Controles , Criança , Transtornos da Nutrição Infantil/sangue , Transtornos da Nutrição Infantil/etiologia , Pré-Escolar , Feminino , Taxa de Filtração Glomerular , Hormônio do Crescimento Humano/sangue , Humanos , Lactente , Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Falência Renal Crônica/complicações , Transplante de Rim/fisiologia , Masculino , Uremia/sangue , Uremia/complicações , Uremia/terapiaRESUMO
BACKGROUND: Childhood GH deficiency, suspected in the presence of decreased height velocity and short stature, is usually characterized by low IGF-I and IGF-binding protein-3 (IGFBP-3) serum concentrations and is conventionally confirmed by diminished GH peak responses to pharmacological stimuli. OBJECTIVE: We evaluated the agreement between different IGF-I (IGFBP-3) assays in predicting GH deficiency and tested whether variability between growth factor screening and pharmacological testing could be diminished by reassessment of growth factor and GH peak concentrations in a single laboratory. DESIGN: Using the Tuebingen IGF-I (IGFBP-3) RIA, 317 (321) sera from children evaluated for growth disorders in 19 centers were reanalyzed. In 103 children with insulin hypoglycemia and arginine tests, we evaluated how the association between the outcome of growth factor screening and functional testing would change if different assays were employed. RESULTS: Locally measured IGF-I correlated better than IGFBP-3 with the results of the central laboratory (Tuebingen) assay (slope of the regression curve 1.05; 95% confidence interval (95% CI) 1.01-1.1 versus 1.18; 95% CI 1.09-1.3). Agreement between local and central laboratory assays in predicting GH deficiency was better for IGF-I than for IGFBP-3 assays (kappa =0.59 versus kappa =0.47). The poor agreement between growth factor screening and GH pharmacological testing was not improved when hormone concentrations were remeasured in the central laboratory (kappa local=-0.0031, central=0.12). CONCLUSIONS: In children with impaired growth, growth factor screening reflects different aspects of GH insufficiency than does functional testing. Agreement between these approaches is poor and could not be improved by reduction of assay-related variability.
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Instituições de Assistência Ambulatorial/normas , Assistência Ambulatorial/normas , Transtornos do Crescimento/sangue , Hormônio do Crescimento Humano/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Programas de Rastreamento/normas , Criança , Técnicas de Laboratório Clínico/normas , Feminino , Transtornos do Crescimento/diagnóstico , Humanos , Masculino , Sensibilidade e EspecificidadeRESUMO
Defects in long-range regulatory elements have recently emerged as previously underestimated factors in the genesis of human congenital disorders. Léri-Weill dyschondrosteosis is a dominant skeletal malformation syndrome caused by mutations in the short stature homeobox gene SHOX. We have analysed four families with Léri-Weill dyschondrosteosis with deletions in the pseudoautosomal region but still with an intact SHOX coding region. Using fluorescence in situ hybridization and single nucleotide polymorphism studies, we identified an interval of approximately 200 kb that was deleted in all tested affected family members but retained in the unaffected members and in 100 control individuals. Comparative genomic analysis of this interval revealed eight highly conserved non-genic elements between 48 and 215 kb downstream of the SHOX gene. As mice do not have a Shox gene, we analysed the enhancer potential in chicken embryos using a green fluorescent protein reporter construct driven by the beta-globin promoter, by in ovo electroporation of the limb bud. We observed cis-regulatory activity in three of the eight non-genic elements in the developing limbs arguing for an extensive control region of this gene. These findings are consistent with the idea that the deleted region in the affected families contains several distinct elements that regulate Shox expression in the developing limb. Furthermore, the deletion of these elements in humans generates a phenotype apparently undistinguishable to those patients identified with mutations in the SHOX coding region and, for the first time, demonstrates the potential of an in vivo assay in chicken to monitor putative enhancer activity in relation to human disease.
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Anormalidades Múltiplas/genética , Sequência Conservada/genética , DNA Intergênico/genética , Regulação da Expressão Gênica , Membro Posterior/metabolismo , Proteínas de Homeodomínio/genética , Osteocondrodisplasias/genética , Deleção de Sequência/genética , Adolescente , Adulto , Idoso , Animais , Sequência de Bases , Estatura/genética , Embrião de Galinha , Criança , Mapeamento Cromossômico , Análise Mutacional de DNA , Primers do DNA , Eletroporação , Feminino , Componentes do Gene , Genômica/métodos , Membro Posterior/embriologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Proteína de Homoeobox de Baixa Estatura , SíndromeRESUMO
CONTEXT: Fasting levels of plasma ghrelins are grossly elevated in children with Prader-Willi syndrome (PWS). The cause of this elevation and the regulation of ghrelins in PWS is largely unknown. The regulatory role of individual nutritional components and of GH is not well characterized. OBJECTIVE: We investigated the influence of GH on acylated (aGhr) and total ghrelin (tGhr) concentrations before and after an oral glucose load, and on insulin resistance in PWS children. DESIGN, PATIENTS, AND INTERVENTIONS: In a clinical follow-up study, plasma ghrelins were measured during an oral glucose tolerance test, and parameters of insulin resistance were determined in 28 PWS children before and/or 1.18 (0.42-9.6) yr (median, range) after start of GH therapy (0.035 mg/kg body weight per day). MAIN OUTCOME MEASURES: Fasting and postglucose concentrations of aGhr and tGhr and homeostasis model assessment 2 insulin resistance were the main outcome measures. SETTING: The study was conducted in a single center (University Children's Hospital). RESULTS: High fasting [1060 +/- 292 (sd) pg/ml; n = 12] and postglucose trough (801 +/- 303 pg/ml; n = 10) tGhr concentrations in GH-untreated PWS children were found to be decreased in the GH-treated group (fasting 761 +/- 247 pg/ml, n = 24, P = 0.006; postglucose 500 +/- 176 pg/ml, n = 20; P = 0.006). In contrast, aGhr concentrations and insulin resistance were not changed by GH treatment. Both aGhr and tGhr concentrations were decreased by oral carbohydrate administration, independent of the GH treatment status. CONCLUSIONS: Our results indicate that, in PWS children, aGhr and tGhr are differentially regulated by GH.
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Glicemia/fisiologia , Hormônio do Crescimento/farmacologia , Hormônio do Crescimento/uso terapêutico , Resistência à Insulina , Hormônios Peptídicos/sangue , Síndrome de Prader-Willi/sangue , Síndrome de Prader-Willi/tratamento farmacológico , Acilação , Adolescente , Criança , Pré-Escolar , Feminino , Grelina , Teste de Tolerância a Glucose , Humanos , Masculino , Hormônios Peptídicos/metabolismoAssuntos
Hipogonadismo/tratamento farmacológico , Síndrome de Kallmann/genética , Puberdade/genética , Proteínas Supressoras de Tumor/metabolismo , Administração Cutânea , Estradiol/administração & dosagem , Feminino , Humanos , Kisspeptinas , Puberdade/efeitos dos fármacos , Puberdade/fisiologia , Proteínas Supressoras de Tumor/genética , Síndrome de Turner/tratamento farmacológicoRESUMO
A prospective, multicenter study of patients with Ullrich-Turner syndrome (UTS) was conducted to estimate the prevalence of autoantibodies to tissue transglutaminase (tTg), thyroid stimulating hormone receptor (TSH-R), thyroglobulin (TG) and thyroid peroxidase (TPO) in relation to adult height after long-term growth hormone (GH) treatment. Out of 347 near-adult (> 16 years) patients with UTS from 96 German centers, whose longitudinal growth was documented within the Pharmacia International Growth Study (KIGS), 188 returned for a standardized follow-up visit at a median chronological age of 18.7 (16.0-23.6) years (bone age > 15 years). Serum samples of 120 patients were obtained for central measurements of TSH, thyroxine (T4) and free T4 and autoantibodies by standard immunoassays. Information regarding thyroid disease, karyotype and anthropometric data was extracted from the KIGS database. Thirty-six percent of the patients with UTS had positive TG and/or TPO autoantibodies and 4% had positive tTg autoantibodies, whereas 2% had positive TG and/or TPO autoantibodies as well as positive tTg autoantibodies. TSH-R autoantibodies were undetectable in all patients. The detection of autoantibodies was unrelated to a specific karyotype. Median height standard deviation scores (SDS, UTS) at start of GH treatment (0.43; -1.07, 1.85) and at follow-up (1.36; -0.11, 2.57) were comparable in all patients independent of their antibody status. The total deltaheight SDS, however, was higher in patients with negative autoantibody titers (1.08; -0.03, 2.25) compared to those with positive antibody titers (0.68; -0.44, 1.82; p < 0.01). Our study confirms the high prevalence of autoantibodies in patients with UTS predisposing them to autoimmune thyroid disease and celiac disease, and indicates for the first time that autoimmune pathologies may interfere with GH therapy and thus compromise final height. Therefore, medical care for patients with UTS should routinely include screening for these autoimmune disorders in order to assure early detection and appropriate treatment.