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OBJECTIVE: Structured transition of adolescents and young adults with a chronic endocrine disease from paediatric to adult care is important. Until now, no data on time and resources required for the necessary components of the transition process and the associated costs are available. DESIGN, PATIENTS AND MEASUREMENTS: In a prospective cohort study of 147 patients with chronic endocrinopathies, for the key elements of a structured transition pathway including (i) assessment of patients' disease-related knowledge and needs, (ii) required education and counselling sessions, (iii) compiling an epicrisis and a transfer appointment of the patient together with the current paediatric and the future adult endocrinologist resource consumption and costs were determined. RESULTS: One hundred and forty-three of 147 enroled patients (97.3%) completed the transition pathway and were transferred to adult care. The mean time from the decision to start the transition process to the final transfer consultation was 399 ± 159 days. Transfer consultations were performed in 143 patients, including 128 patients jointly with the future adult endocrinologist. Most consultations were performed by a multidisciplinary team consisting of a paediatric and adult endocrinologist, psychologist, nurse, and a social worker acting also as a case manager with a median of three team members and lasted 87.6 ± 23.7 min. The mean cumulative costs per patient of all key elements were 519 ± 206 Euros. In addition, costs for case management through the transition process were 104.8 ± 28.0 Euros. CONCLUSIONS: Using chronic endocrine diseases as an example, it shows how to calculate the time and cost of a structured transition pathway from paediatric to adult care, which can serve as a starting point for sustainable funding for other chronic rare diseases.
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Doenças do Sistema Endócrino , Transição para Assistência do Adulto , Humanos , Adolescente , Doenças do Sistema Endócrino/terapia , Doenças do Sistema Endócrino/economia , Transição para Assistência do Adulto/economia , Masculino , Feminino , Adulto Jovem , Adulto , Estudos Prospectivos , Doença Crônica/economia , Criança , Custos de Cuidados de SaúdeRESUMO
Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive multisystem disease. The pathophysiological origin is a dysfunction of the primary cilium. Clinical symptoms are heterogeneous and variable: retinal dystrophy, obesity, polydactyly, kidney abnormalities, hypogenitalism and developmental delays are the most common features. By the approval of the melanocortin 4 receptor agonist setmelanotide, a drug therapy for BBS-associated hyperphagia and obesity can be offered for the first time. Hyperphagia and severe obesity represent a considerable burden and are associated with comorbidity and increased mortality risk. Due to the limited experience with setmelanotide in BBS, a viable comprehensive therapy concept is to be presented. Therapy decision and management should be conducted in expert centers. For best therapeutic effects with setmelanotide adequate information of the patient about the modalities of the therapy (daily subcutaneous injection) and possible adverse drug events are necessary. Furthermore, the involvement of psychologists, nutritionists and nursing services (support for the application) should be considered together with the patient. The assessment of therapy response should be carried out with suitable outcome measurements and centrally reported to an adequate register.
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BACKGROUND: Genes, hormones and factors such as nutrition and psychosocial environment affect growth. OBJECTIVE: What is the significance of various psychosocial factors on growth? METHODS: Evaluation of results of a working meeting of paediatric endocrinologist with current literature research. RESULTS: Psychosocial deprivation in children can be associated with growth hormone deficiency (GHD) and short stature. GHD can be reversed by a change of environment and psychosocial support. War and migration are often associated with underweight, growth disturbances and poor health care. These factors can improve after the end of conflicts, but children often remain too short. Consumption of alcohol or opiates during pregnancy are associated with lower birth weight and increased risk of early and small for gestational age (SGA) childbirth. Children with attention deficit hyperactivity disorder show a slight slowdown in growth after they started stimulant therapy. However, they reach normal adult height. CONCLUSIONS: In children with idiopathic short stature, psychosocial causes should be taken into account in the differential diagnosis. Notably there is an increased risk of growth disturbances in children from conflict regions or after prenatal drug exposure.
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Estatura , Desenvolvimento Infantil , Transtornos do Crescimento , Psicologia , Transtorno do Deficit de Atenção com Hiperatividade , Criança , Feminino , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/etiologia , Hormônio do Crescimento Humano/deficiência , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Estresse PsicológicoRESUMO
Neonatal screening for congenital primary hypothyroidism (CH) may not distinguish between transient (TCH) and permanent dysfunction (PCH), causing potential overtreatment and concerns in affected families. To specify the indication for interruption of therapy, we analysed the German registry "HypoDok" for infants with CH, which oversees 1625 patients from 49 participating centres in Germany and Austria from 1997 until today. A total of 357 patients with a thyroid gland in loco typico were identified and retrospectively grouped according to cessation (TCH, n = 24) or continuation (PCH, n = 333) of L-thyroxine (L-T4) treatment at 2 years of age. The receiver operating characteristic (ROC) analysis was performed to identify cutoffs predicting TCH by screening TSH concentrations and L-T4 dosages. Gestational ages, birth weights and prevalence of associated malformations were comparable in both groups. The cutoff screening TSH concentration was 73 mU/L. The cutoff daily L-T4 dosage at 1 year was 3.1 µg/kg (90% sensitivity, 63% specificity; 36 µg/day) and at 2 years of age 2.95 µg/kg (91% sensitivity, 59% specificity; 40 µg/day). At 2 years of age, specificity (71%) increased when both of these parameters were considered together.Conclusion: The decision to continue or cease L-T4 treatment at 2 years of age in CH patients diagnosed in neonatal screening may be based on their screening TSH concentrations and individual L-T4 dosages at 1 and 2 years of age. Thus, TCH and PCH may be distinguished; overtreatment avoided; and affected families reassured. What is Known: ⢠The course of congenital primary hypothyroidism may be transient, causing potential overtreatment. ⢠The dose of l-thyroxine at 1 or 2 years of age may predict a transient course of primary congenital hypothyroidism. What is New: ⢠TSH screening concentration and l-thyroxine dosages at 1 and 2 years of age represent reliable predictors for transient congenital primary hypothyroidism with higher sensitivity and specificity when considered together in order to select eligible patients who qualify for treatment withdrawal.
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Hipotireoidismo Congênito , Áustria , Pré-Escolar , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/tratamento farmacológico , Hipotireoidismo Congênito/epidemiologia , Alemanha/epidemiologia , Humanos , Lactente , Recém-Nascido , Triagem Neonatal , Sistema de Registros , Estudos Retrospectivos , Tireotropina , TiroxinaRESUMO
INTRODUCTION: We evaluated sequelae of disease and therapy in adolescents with chronic endocrinopathies using a medical and psychological workup to record health-related quality of life (HRQoL), near final height (NFH) and body compositions during the transition period from paediatric to adult care. METHODS: Near final height, weight, body mass index (BMI), grip strength (GS), hip and waist circumference (HC; WC), skin folds (SF) and HRQoL T-scores by KIDSCREEN and DISABKIDS were assessed in 134 patients (70 females and 64 males) from May 2010 to March 2016 diagnosed with congenital adrenal hyperplasia (CAH; n = 22), multiple pituitary hormone deficiency (MPHD; n = 17), growth hormone deficiency (GHD; n = 37), Turner syndrome (TS; n = 27), SGA-short stature (SGA; n = 20) and Klinefelter syndrome (KS; n = 11). RESULTS: Median HRQoL T-scores for KIDSCREEN (50.6-56.5) and DISABKIDS (52.7-58.9) ranged within references with considerable variations but without significant deficit in any diagnosis. Median-corrected height SDS (CoH-SDS: NFH-SDS-TH [target height]-SDS) was >-1, except in KS (SDS + 1.3) and in TS (SDS - 1.9; P < .0001) without correlations with HRQoL. Median BMI was below 25 kg/m2 in all patients except MPHD (26.5 kg/m2 ; SDS 1.5; P = .006). BMI correlated negatively in CAH females with self-perception (rs = -.64, P = .0338), physical well-being (rs = -.8; P = .0086), social exclusion rs = -.65; P = .031) and emotions (rs = -.7; P = .0169). CONCLUSION: Health-related quality of life and body compositions were similar to those of healthy adolescents. Lower scores in HRQoL dimensions as self-perception, physical well-being, social exclusion and emotions were detected and correlated negatively with BMI. Treatment strategies and psychological support should consider HRQoL and adapted in specific treatment guidelines.
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Nanismo Hipofisário , Hormônio do Crescimento Humano , Transição para Assistência do Adulto , Adolescente , Adulto , Composição Corporal , Estatura , Criança , Feminino , Humanos , Masculino , Qualidade de VidaRESUMO
PURPOSE: Combined pituitary hormone deficiency (CPHD) is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases. METHODS: To identify novel genetic causes for congenital hypopituitarism, we performed exome-sequencing studies on 10 patients with CPHD and their unaffected parents. Two candidate genes were sequenced in further 200 patients. Genotype data of known hypopituitary genes are reviewed. RESULTS: We discovered 51 likely damaging variants in 38 genes; 12 of the 51 variants represent de novo events (24%); 11 of the 38 genes (29%) were present in the E12.5/E14.5 pituitary transcriptome. Targeted sequencing of two candidate genes, SLC20A1 and SLC15A4, of the solute carrier membrane transport protein family in 200 additional patients demonstrated two further variants predicted as damaging. We also found combinations of de novo (SLC20A1/SLC15A4) and transmitted variants (GLI2/LHX3) in the same individuals, leading to the full-blown CPHD phenotype. CONCLUSION: These data expand the pituitary target genes repertoire for diagnostics and further functional studies. Exome sequencing has identified a combination of rare variants in different genes that might explain incomplete penetrance in CPHD.
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Proteínas de Transporte/genética , Hipopituitarismo/genética , Proteínas do Tecido Nervoso/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Adolescente , Adulto , Proteínas de Transporte/metabolismo , Criança , Família , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso/metabolismo , Fatores de Risco , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo , Fatores de Transcrição/genética , Sequenciamento do Exoma/métodosRESUMO
NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.
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Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Minociclina/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Antibacterianos/administração & dosagem , Encéfalo/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Minociclina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagemRESUMO
OBJECTIVE: During the process of transition from paediatric to adult health care, counselling concerning fertility is an important issue and is based mainly on serum markers of gonadal function. Here, we analysed these markers in adolescents with various underlying endocrine diseases at the time of transition. METHODS: After reaching near adult height and late puberty (girls: bone age [BA] ≥14 years, and boys: BA ≥16 years), we assessed stages of puberty according to Tanner and measured testes or ovarian volumes and serum markers of gonadal function (anti-Mullerian hormone [AMH], inhibin B, 17ß-estradiol, testosterone). RESULTS: One hundred and ten patients (56 females and 54 males) were included from May 2010 to March 2016 with multiple pituitary hormone deficiency (MPHD; n = 17), growth hormone deficiency (GHD; n = 35), Turner syndrome (TS; n = 27), short stature after being born small for gestational age (SGA; n = 20) and Klinefelter syndrome (KS; n = 11). Female and male adolescents exhibited mature secondary sexual characteristics. The levels of serum inhibin B and AMH were lower in TS and female MPHD than in GHD and SGA, each independently (p < 0.05). The levels of serum AMH were higher whereas serum inhibin B were lower in male MPHD and KS (p < 0.05). Ovary volumes were significantly smaller in patients with TS, and testicular volumes were smaller in patients with KS. CONCLUSIONS: After current established treatments with sex steroids, the development of secondary sexual characteristics was mature. However, impaired markers of fertility have been identified in patients with TS, KS and MPHD, reflecting gonadal dysgenesis in TS and KS, but gonadal immaturity in MPHD as gonadal gonadotropin stimulation is lacking throughout development. Consequently, in patients with MPHD, these markers cannot reliably predict individual fertility, which warrants consideration and incorporation in future treatment concepts.
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Hormônio Antimülleriano , Biomarcadores , Fertilidade , Transição para Assistência do Adulto , Humanos , Adolescente , Feminino , Masculino , Biomarcadores/sangue , Hormônio Antimülleriano/sangue , Inibinas/sangue , Adulto , Adulto Jovem , Doenças do Sistema Endócrino/etiologia , Testosterona/sangue , Síndrome de Turner/fisiopatologia , Doença Crônica , Estradiol/sangue , Puberdade/fisiologia , Síndrome de KlinefelterRESUMO
OBJECTIVES: The aim of our study was the longitudinal assessment of bone health index (BHI) in short-statured children during growth hormone (GH) treatment to estimate changes in their bone health. METHODS: 256 short-statured children (isolated GH deficiency (IGHD) n=121, multiple pituitary hormone deficiency (MPHD) n=49, intrauterine growth retardation (small for gestational age (SGA)) n=52, SHOX (short stature homeobox gene) deficiency n=9, Ullrich Turner syndrome (UTS) n=25) who started with GH between 2010 and 2018 were included. Annual bone ages (Greulich and Pyle, GP) and BHI were, retrospectively, analysed in consecutive radiographs of the left hand (BoneXpert software) from GH therapy start (T0) up to 10â¯years (T10) thereafter, with T max indicating the individual time point of the last available radiograph. The results are presented as the median (25â¯%/75â¯% interquartile ranges, IQR) and statistical analyses were performed using non-parametric tests as appropriate. RESULTS: The BHI standard deviation scores (SDS) were reduced (-0.97, -1.8/-0.3) as bone ages were retarded (-1.6â¯years, -2.31/-0.97) in all patients before start of GH and were significantly lower in patients with growth hormone deficiency (GHD) (-1.04, -1.85/-0.56; n=170) compared to non-GHD patients (-0.79, -1.56/-0.01; n=86; p=0.022). BHI SDS increased to -0.17 (-1/0.58) after 1â¯year of GH (T1, 0.5-1.49, p<0.001) and to -0.20 (-1/-0.50, p<0.001) after 5.3â¯years (T max, 3.45/7.25). CONCLUSIONS: BHI SDS are reduced in treatment-naive short-statured children regardless of their GH status, increase initially with GH treatment while plateauing thereafter, suggesting sustained improved bone health.
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Nanismo Hipofisário , Hormônio do Crescimento Humano , Hipopituitarismo , Humanos , Criança , Hormônio do Crescimento , Hormônio do Crescimento Humano/uso terapêutico , Estudos Retrospectivos , Densidade Óssea , Hipopituitarismo/tratamento farmacológico , Nanismo Hipofisário/tratamento farmacológico , Estatura/genética , Transtornos do Crescimento/tratamento farmacológico , Proteína de Homoeobox de Baixa EstaturaRESUMO
INTRODUCTION: Diagnosis of central diabetes insipidus (CDI) remains challenging. Water deprivation testing and hypertonic saline infusion, as established diagnostic tests, are mentally and physically demanding for patients. Arginine-stimulated copeptin has been shown as a putative parameter for the differential diagnosis of CDI in adults. METHODS: In this single-centre retrospective study, we identified paediatric patients with suspected pituitary disorders who underwent standard arginine-testing. Patients with CDI, matched controls and primary polydipsia (PP) were identified. Diagnoses were confirmed retrospectively using comprehensive clinical and diagnostic characteristics. Serum copeptin concentrations were measured using a commercially available automated immunofluorescence assay (B.R.A.H.M.S Copeptin-proAVP KRYPTOR®) in samples stored for a median of 4.6 years (1.3-10.84) and collected before and 60 minutes after arginine-infusion. Cut-off analyses were performed using ROC curves. RESULTS: Serum samples from 32 patients with CDI, 32 matched controls and 5 patients with PP (n=69; 51 males, 18 females) were available for analysis. Median copeptin concentrations increased from 4.47 pmol/l (IQR: 3.47-8.36) to 6.96 pmol/l (IQR: 4.51-12.89; p<0.001) in controls, from 1.46 pmol/l (IQR: 1.21-2.12) to 1.44 (IQR: 1.10-1.87; p=0.645, ns) in CDI and from 4.40 pmol/l (3.95-6.33) to 9.58 pmol/l (8.19-11.42; p<0.001) in PP. The published cut-off value of 3.8 pmol/l revealed a sensitivity of 100 % and a specificity of 86.5 % in confirming CDI. CONCLUSION: Our results suggest that arginine-stimulated serum copeptin concentrations are a sensitive and specific diagnostic tool for CDI in paediatric patients, which may replace and simplify the conventional diagnostic pathway of water deprivation testing and hypertonic saline infusion.
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BACKGROUND: Endocrine disorders are heterogeneous and include a significant number of rare monogenic diseases. METHODS: We performed exome sequencing (ES) in 106 children recruited from a single center within the TRANSLATENAMSE project. They were categorized into subgroups: proportionate short stature (PSS), disproportionate short stature (DSS), hypopituitarism (H), differences in sexual development (DSD), syndromic diseases (SD) and others. RESULTS: The overall diagnostic yield was 34.9% (n = 37/106), including 5 patients with variants in candidate genes, which have contributed to collaborations to identify gene-disease associations. The diagnostic yield varied significantly between subgroups: PSS: 16.6% (1/6); DSS: 18.8% (3/16); H: 17.1% (6/35); DSD: 37.5% (3/8); SD: 66.6% (22/33); others: 25% (2/8). Confirmed diagnoses included 75% ultrarare diseases. Three patients harbored more than one disease-causing variant, resulting in dual diagnoses. CONCLUSIONS: ES is an effective tool for genetic diagnosis in pediatric patients with complex endocrine diseases. An accurate phenotypic description, including comprehensive endocrine diagnostics, as well as the evaluation of variants in multidisciplinary case conferences involving geneticists, are necessary for personalized diagnostic care. Here, we illustrate the broad spectrum of genetic endocrinopathies that have led to the initiation of specific treatment, surveillance, and family counseling.
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The ability to transmit genetic information through generations depends on the preservation of genome integrity. Genetic abnormalities affect cell differentiation, causing tissue specification defects and cancer. We addressed genomic instability in individuals with Differences of Sex Development (DSD), characterized by gonadal dysgenesis, infertility, high susceptibility for different types of cancer, especially Germ Cell Tumors (GCT), and in men with testicular GCTs. Whole proteome analysis of leukocytes, supported by specific gene expression assessment, and dysgenic gonads characterization, uncovered DNA damage phenotypes with altered innate immune response and autophagy. Further examination of DNA damage response revealed a reliance on deltaTP53, which was compromised by mutations in the transactivation domain in DSD-individuals with GCT. Accordingly, drug-induced rescue of DNA damage was achieved by autophagy inhibition but not by stabilization of TP53 in DSD-individuals' blood in vitro. This study elucidates possibilities for prophylactic treatments of DSD-individuals, as well as new diagnostic approaches of GCT.
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Growth hormone (GH) is widely prescribed for children with short stature across a range of growth disorders. Recombinant human (rh) insulin-like growth factor-1 (rhIGF-1) therapy is approved for severe primary IGF-I deficiency - a state of severe GH resistance. Evidence is increasing for an unacceptably high rate of poor or unsatisfactory response to growth-promoting therapy (i.e. not leading to significant catch up growth) in terms of change in height standard deviation score (SDS) and height velocity (HV) in many approved indications. Consequently, there is a need to define poor response and to prevent or correct it by optimizing treatment regimens within accepted guidelines. Recognition of a poor response is an indication for action by the treating physician, either to modify the therapy or to review the primary diagnosis leading either to discontinuation or change of therapy. This review discusses the optimal investigation of the child who is a candidate for GH or IGF-1 therapy so that a diagnosis-based choice of therapy and dosage can be made. The relevant parameters in the evaluation of growth response are described together with the definitions of poor response. Prevention of poor response is addressed by discussion of strategy for first-year management with GH and IGF-1. Adherence to therapy is reviewed as is the recommended action following the identification of the poorly responding patient. The awareness, recognition and management of poor response to growth-promoting therapy will lead to better patient care, greater cost-effectiveness and increased opportunities for clinical benefit.
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Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento/uso terapêutico , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Transtornos do Crescimento/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/uso terapêutico , Resultado do TratamentoAssuntos
Antibacterianos/uso terapêutico , Encéfalo/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Tetraciclinas/uso terapêutico , Fatores Etários , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Citoproteção , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Fatores de RiscoRESUMO
BACKGROUND: Iatrogenic Cushing's syndrome induced by oral and parenteral glucocorticoid administration is a well-known complication. Immediate withdrawal from exogenous steroids can lead to life-threatening adrenal insufficiency. However, Cushing's syndrome caused by topical treatment with glucocorticoids, such as dexamethasone eye drops or dermal application, is rarely recognized. Young infants in particular are at high risk of suffering from iatrogenic Cushing's syndrome when treated with highly potent topical glucocorticoids. CASE PRESENTATION: We present a 6-month-old Syrian boy with cushingoid face after dermal clobetasol cream treatment and a 2-year-old Iranian girl with severe growth retardation after application of dexamethasone eye drops. Both families have a migration background and language barriers. In both cases no endogenous cortisol secretion was initially detected in serum and in 24-hour collected urine. After dose reduction of glucocorticoids, severity of symptoms was reversible and serum cortisol was detectable. DISCUSSION AND CONCLUSION: Young infants are at high risk of developing Cushing's syndrome from topically applied highly potent glucocorticoids. Precise recommendations of treatment dosage, duration, and frequency must be given to the parents, and if necessary, with the help of an interpreter. Monitoring of height and weight as well as regular pediatric follow-ups should be scheduled. Physicians should be aware of potential adrenal insufficiency following withdrawal from long-term topical glucocorticoid treatment, and hydrocortisone treatment should be considered.
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Insuficiência Adrenal , Síndrome de Cushing , Humanos , Criança , Lactente , Pré-Escolar , Síndrome de Cushing/induzido quimicamente , Glucocorticoides/efeitos adversos , Irã (Geográfico) , Insuficiência Adrenal/induzido quimicamente , Soluções Oftálmicas , Dexametasona/efeitos adversosRESUMO
OBJECTIVES: To validate adult height predictions (BX) using automated and Greulich-Pyle bone age determinations in children with chronic endocrine diseases. METHODS: Heights and near-adult heights were measured in 82 patients (48 females) with chronic endocrinopathies at the age of 10.45 ± 2.12 y and at time of transition to adult care (17.98 ± 3.02 y). Further, bone age (BA) was assessed using the conventional Greulich-Pyle (GP) method by three experts, and by BoneXpert™. PAH were calculated using conventional BP tables and BoneXpert™. RESULTS: The conventional and the automated BA determinations revealed a mean difference of 0.25 ± 0.72 y (p = 0.0027). The automated PAH by BoneXpert™ were 156.26 ± 0.86 cm (SDS - 2.01 ± 1.07) in females and 171.75 ± 1.6 cm (SDS - 1.29 ± 1.06) in males, compared to 153.95 ± 1.12 cm (SDS - 2.56 ± 1.5) in females and 169.31 ± 1.6 cm (SDS - 1.66 ± 1.56) in males by conventional BP, respectively and in comparison to near-adult heights 156.38 ± 5.84 cm (SDS - 1.91 ± 1.15) in females and 168.94 ± 8.18 cm (SDS - 1.72 ± 1.22) in males, respectively. CONCLUSION: BA ratings and adult height predictions by BoneXpert™ in children with chronic endocrinopathies abolish rater-dependent variability and enhance reproducibility of estimates thereby refining care in growth disorders. Conventional methods may outperform automated analyses in specific cases.
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Determinação da Idade pelo Esqueleto , Estatura , Doenças do Sistema Endócrino , Transtornos do Crescimento , Adulto , Determinação da Idade pelo Esqueleto/métodos , Criança , Doença Crônica , Doenças do Sistema Endócrino/complicações , Feminino , Previsões , Humanos , Masculino , Reprodutibilidade dos TestesRESUMO
Congenital primary hypothyroidism (CH) and congenital adrenal hyperplasia (CAH) are targeted by the German and Austrian newborn screening. For both diseases, there are registries for quality improvement, based on standardized observational data from long-term patient follow-up, under the auspices of the DGKED study group. By September 2021, the CH registry HypoDOK includes datasets from 23,348 visits of 1,840 patients, and the CAH registry contains datasets from 36,237 visits of 1,976 patients. Here, we report on the recruitment process, patient characteristics, and research contributions from the registries, and underline that the registries are an important tool to improve patient care and outcomes. Registries for rare conditions should thus be considered as an important public health measure and they should be adequately institutionalized and funded.
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"Differences of Sexual Development (DSD)," individuals with rearranged Y chromosome breaks in their 46,XY cells are reported with male and female gender phenotypes and differences in germ cell tumour (GCT) risk. This raised the question of whether male or female gender and GCT risk depends on the site of the break and/or rearrangement of the individual´s Y chromosome. In this paper, we report molecular mapping of the breakpoint on the aberrant Y chromosome of 22 DSD individuals with a 45,X/46,XY karyotype reared with a different gender. Their Y chromosome breaks are found at different sites on the long and short Y arms. Our data indicate that gender rearing is, neither dependent on the site of Y breakage, nor on the amount of 45,X0 cells in the individuals' leukocytes. Most prominent are secondary rearrangements of the Y chromosome breaks forming di-centric Y-structures ("dic-Y"). Duplications of the short Y arm and the proximal part of the long Y arm are the results. A putative GCT risk has been analysed with immunohistochemical experiments on some dysgenetic gonadal tissue sections. With specific antibodies for OCT3/4 expression, we marked the pluripotent germ cell fraction being potential tumour precursor cells. With specific antibodies for DDX3Y, TSPY, and UTY we analyzed their putative Gonadoblastoma Y (GBY) tumour susceptibility function in the same specimen. We conclude GBY expression is only diagnostic for GCT development in the aberrant germ cells of these DSD individuals when strong OCT3/4 expression has marked their pluripotency.
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Gonadoblastoma , Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual , Quebra Cromossômica , Cromossomos Humanos Y/metabolismo , RNA Helicases DEAD-box/genética , Feminino , Gonadoblastoma/genética , Gonadoblastoma/metabolismo , Gonadoblastoma/patologia , Humanos , Masculino , Antígenos de Histocompatibilidade Menor , Neoplasias Ovarianas/genética , FenótipoRESUMO
BACKGROUND: There has been controversy in recent years on whether the d3 polymorphism of the GH receptor is associated with a better growth response to GH in idiopathic short children born small for gestational age (SGA). METHODS: In this prospective study, we evaluated exon 3-GHR polymorphisms in 142 (62 f, 80 m) short prepubertal children born SGA (birth length and/or weight of ≤-2 SD for GA) and treated with rhGH (mean dose of 0·30 mg/kg/week) in 24 centres in Germany. A growth prediction for the first year of therapy was calculated for each child according to Ranke and co-workers. The index of responsiveness (IOR) was calculated by dividing the response (observed growth minus predicted growth) by the standard error of the prediction. All analyses were performed in one centre on samples collected and shipped on filter paper. The DNA fragment containing or missing exon 3 of the GHR was amplified by multiplex PCR. RESULTS: The fl-GHR isoform was most common with a frequency of 47·8%, followed by the d3/fl isoform with 38% and the d3-GHR isoform with 14·2%. There were no significant differences regarding gestational age, birth weight and birth length, mid parental height-SDS, chronological age at start of therapy, height-SDS, BMI-SDS, height velocity and GH dose between the different subgroups according to the genotype. After the first treatment year, height (H)-SDS (P < 0·05), height velocity (HV) (P < 0·01), HV-SDS (P < 0·001) and delta-H-SDS (P < 0·05) were significantly higher in patients with d3-GHR than in those with fl-GHR. The mean IOR was above 0 in children with at least one d3 allele, and highest, with 0·54, in those with the d3-GHR isoform. After the second year on GH, no differences between the different GHR-isoforms were found. CONCLUSIONS: According to our results, the exon 3-deleted GHR explains the better growth response to GH only for the first and not for the second year.
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Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/genética , Hormônio do Crescimento/uso terapêutico , Polimorfismo Genético/genética , Receptores da Somatotropina/genética , Pré-Escolar , Éxons/genética , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Estudos ProspectivosRESUMO
Congenital primary hypothyroidism (CH; OMIM 218700) is characterized by an impaired thyroid development, or dyshormonogenesis, and can lead to intellectual disability and growth retardation if untreated. Most of the children with congenital hypothyroidism present thyroid dysgenesis, a developmental anomaly of the thyroid. Various genes have been associated with thyroid dysgenesis, but all known genes together can only explain a small number of cases. To identify novel genetic causes for congenital hypothyroidism, we performed trio whole-exome sequencing in an affected newborn and his unaffected parents. A predicted damaging de novo missense mutation was identified in the ZBTB26 gene (Zinc Finger A and BTB Domain containing 26). An additional cohort screening of 156 individuals with congenital thyroid dysgenesis identified two additional ZBTB26 gene variants of unknown significance. To study the underlying disease mechanism, morpholino knock-down of zbtb26 in Xenopus laevis was carried out, which demonstrated significantly smaller thyroid anlagen in knock-down animals at tadpole stage. Marker genes expressed in thyroid tissue precursors also indicated a specific reduction in the Xenopus ortholog of human Paired-Box-Protein PAX8, a transcription factor required for thyroid development, which could be rescued by adding zbtb26. Pathway and network analysis indicated network links of ZBTB26 to PAX8 and other genes involved in thyroid genesis and function. GWAS associations of ZBTB26 were found with height. Together, our study added a novel genetic risk factor to the list of genes underlying congenital primary hypothyroidism and provides additional support that de novo mutations, together with inherited variants, might contribute to the genetic susceptibility to CH.