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1.
Ned Tijdschr Geneeskd ; 1642020 05 20.
Artigo em Holandês | MEDLINE | ID: mdl-32749791

RESUMO

In this case series, we describe four children and adolescents with tall stature or growth acceleration to illustrate the diagnostic evaluation of tall stature according to the new Paediatric Association of the Netherlands (NVK) Guideline on growth disorders. A 14-year-old girl with tall stature and a relatively late onset of puberty was diagnosed with idiopathic familial tall stature, and the patient decided not to opt for epiphysiodesis. A 14-year-old boy with prepubertal growth acceleration and a history of behavioural problems was diagnosed with Klinefelter syndrome. A 7-year-old boy with tall stature, arachnodactyly, pectus excavatum and lumbar scoliosis was diagnosed with Marfan syndrome. Finally, a 16-year-old girl with isolated progressive tall stature was diagnosed with growth hormone excess caused by a pituitary somatotroph adenoma. The most clinically relevant conditions associated with tall stature are Klinefelter and Marfan syndrome, and secondary growth disorders such as precocious puberty and growth hormone excess.

3.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31650157

RESUMO

CONTEXT: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. OBJECTIVE: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. PATIENTS, DESIGN, AND SETTING: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. MAIN OUTCOME MEASURES: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. RESULTS: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. CONCLUSIONS: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.


Assuntos
Imunoglobulinas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Membrana/fisiologia , Neurossecreção/fisiologia , Somatotrofos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Hormônio do Crescimento/biossíntese , Humanos , Imunoglobulinas/deficiência , Fator de Crescimento Insulin-Like I/análise , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Masculino , Proteínas de Membrana/deficiência , Camundongos , Pessoa de Meia-Idade
4.
J Clin Res Pediatr Endocrinol ; 12(2): 130-139, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31842524

RESUMO

The serum insulin-like growth factor-I (IGF-I) concentration is commonly used as a screening tool for growth hormone deficiency (GHD), but there is no consensus on the cut-off limit of IGF-I standard deviation score (SDS) to perform GH stimulation tests for confirmation or exclusion of GHD. We argue that the cut-off limit is dependent on the clinical pre-test likelihood of GHD and propose a diagnostic strategy in which the cut-off limit varies between zero to -2 SDS.

5.
Horm Res Paediatr ; 91(5): 293-310, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31302655

RESUMO

Tall stature and/or accelerated growth (TS/AG) in a child can be the result of a primary or secondary growth disorder, but more frequently no cause can be found (idiopathic TS). The conditions with the most important therapeutic implications are Klinefelter syndrome, Marfan syndrome and secondary growth disorders such as precocious puberty, hyperthyroidism and growth hormone excess. We propose a diagnostic flow chart offering a systematic approach to evaluate children referred for TS/AG to the general paediatrician. Based on the incidence, prevalence and clinical features of medical conditions associated with TS/AG, we identified relevant clues for primary and secondary growth disorders that may be obtained from the medical history, physical evaluation, growth analysis and additional laboratory and genetic testing. In addition to obtaining a diagnosis, a further goal is to predict adult height based on growth pattern, pubertal development and skeletal maturation. We speculate that an improved diagnostic approach in addition to expanding use of genetic testing may increase the diagnostic yield and lower the age at diagnosis of children with a pathologic cause of TS/AG.


Assuntos
Acromegalia/diagnóstico , Transtornos do Crescimento/diagnóstico , Puberdade Precoce/diagnóstico , Acromegalia/etiologia , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/etiologia , Humanos , Hipertireoidismo/complicações , Hipertireoidismo/diagnóstico , Síndrome de Klinefelter/complicações , Síndrome de Klinefelter/diagnóstico , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/diagnóstico , Puberdade Precoce/etiologia
6.
Horm Res Paediatr ; 91(4): 223-240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31195397

RESUMO

Based on a recent Dutch national guideline, we propose a structured stepwise diagnostic approach for children with growth failure (short stature and/or growth faltering), aiming at high sensitivity for pathologic causes at acceptable specificity. The first step is a detailed clinical assessment, aiming at obtaining relevant clinical clues from the medical history (including family history), physical examination (emphasising head circumference, body proportions and dysmorphic features) and assessment of the growth curve. The second step consists of screening: a radiograph of the hand and wrist (for bone age and assessment of anatomical abnormalities suggestive for a skeletal dysplasia) and laboratory tests aiming at detecting disorders that can present as isolated short stature (anaemia, growth hormone deficiency, hypothyroidism, coeliac disease, renal failure, metabolic bone diseases, renal tubular acidosis, inflammatory bowel disease, Turner syndrome [TS]). We advise molecular array analysis rather than conventional karyotyping for short girls because this detects not only TS but also copy number variants and uniparental isodisomy, increasing diagnostic yield at a lower cost. Third, in case of diagnostic clues for primary growth disorders, further specific testing for candidate genes or a hypothesis-free approach is indicated; suspicion of a secondary growth disorder warrants adequate further targeted testing.


Assuntos
Determinação da Idade pelo Esqueleto , Variações do Número de Cópias de DNA , Insuficiência de Crescimento , Hormônio do Crescimento Humano , Cariotipagem , Dissomia Uniparental , Criança , Pré-Escolar , Insuficiência de Crescimento/sangue , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino
8.
J Clin Endocrinol Metab ; 104(8): 3157-3171, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30848790

RESUMO

CONTEXT: The phenotype and response to GH treatment of children with an IGF1R defect is insufficiently known. OBJECTIVE: To develop a clinical score for selecting children with short stature for genetic testing and evaluate the efficacy of treatment. DESIGN AND SETTING: Case series with an IGF1R defect identified in a university genetic laboratory. PATIENTS AND INTERVENTIONS: Of all patients with sufficient clinical data, 18 had (likely) pathogenic mutations (group 1) and 7 had 15q deletions including IGF1R (group 2); 19 patients were treated with GH. MAIN OUTCOME MEASURES: Phenotype and response to GH treatment. RESULTS: In groups 1 and 2, mean (range) birth weight, length, and head circumference (HC) SD scores (SDSs) were -2.1 (-3.7 to -0.4), -2.7 (-5.0 to -1.0), and -1.6 (-3.0 to 0.0), respectively. At presentation, height, HC, and serum IGF-1 SDSs were -3.0 (-5.5 to -1.7), -2.5 (-4.2 to -0.5), and +1.2 (-1.3 to 3.2), respectively. Feeding problems were reported in 15 of 19 patients. A clinical score with 76% sensitivity is proposed. After 3 years of GH treatment [1.1 (0.2) mg/m2/d] height gain in groups 1 (n = 12) and 2 (n = 7) was 0.9 SDS and 1.3 SDS (at a mean IGF-1 of 3.5 SDS), less than reported for small for gestational age (1.8 SDS). CONCLUSION: A clinical score encompassing birth weight and/or length, short stature, microcephaly, and IGF-1 is useful for selecting patients for IGF1R analysis. Feeding problems are common and the growth response to GH treatment is moderate.


Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Mutação , Receptor IGF Tipo 1/genética , Adolescente , Adulto , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Fator de Crescimento Insulin-Like I/análise , Masculino , Fenótipo , Estudos Retrospectivos , Adulto Jovem
9.
Horm Res Paediatr ; 92(6): 372-381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32344414

RESUMO

INTRODUCTION: Short stature homeobox-containing gene (SHOX) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on patients with intragenic variants or deletions. However, recent discoveries showed that deletions of the enhancer elements are quite common. The majority of these patients show less body disproportion and respond better to recombinant human growth hormone treatment. We redefined clinical criteria for genetic analysis to facilitate detection of the full spectrum of SHOX haploinsufficiency. METHODS: We analyzed 51 children with SHOX variants or deletions and 25 children with a deletion in its enhancer region. Data were compared to 277 children referred for suspicion of growth failure without endocrine or genetic pathology. RESULTS: Only half of the patients with an enhancer region deletion fulfilled any of the current screening criteria. We propose new clinical criteria based on sitting height to height ratio >1 SDS or arm span ≥3 cm below height, with a sensitivity of 99%. When these criteria are combined with obligatory short stature, the sensitivity to detect SHOX haploinsufficiency is 68.1%, the specificity 80.6%, and the number needed to screen 21 patients. CONCLUSION: Novel clinical criteria for screening for SHOX haploinsufficiency allow the detection of patients within the full genetic spectrum, that is, intragenic variants and enhancer region deletions.


Assuntos
Sequência de Bases , Elementos Facilitadores Genéticos , Transtornos do Crescimento/genética , Haploinsuficiência , Deleção de Sequência , Proteína de Homoeobox de Baixa Estatura/genética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Retrospectivos
10.
Horm Res Paediatr ; 90(4): 247-256, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30408796

RESUMO

OBJECTIVE: Congenital hypothyroidism (CH) per se, when not treated or undertreated, may lead to severe behavioural problems (cretinism), whereas overtreatment of CH seems associated with attention problems. DESIGN AND METHODS: For 55 CH patients, prospectively followed from birth until 11 years, parents rated the Child Behaviour Checklist and teachers the Teacher's Report Form at children's ages 6 and 11 years. We related scores regarding Attention, Delinquency, and Aggression (ADA scores, indicative for attention deficit hyperactivity syndrome, ADHD), and scores regarding Withdrawn, Anxious, Social, and Thought problems (WAST scores, indicative for autism) to the occurrence of over- and undertreatment in five age periods. Over- and undertreatment were defined as free thyroxine (fT4) concentrations above/below the range of the patient's individual fT4 steady state concentration. RESULTS: ADA scores at 6 and 11 years for patients overtreated in the period 1-3 months postnatally were higher than those for patients who were not overtreated. Patients with severe CH undertreated in the period 3-6 months postnatally had higher WAST scores at 6 and 11 years than all other patients. CONCLUSIONS: This is the first study suggesting that permanent ADHD as well as autism in CH patients at ages 6 and 11 years are the result of early overtreatment and undertreatment, respectively.


Assuntos
Hipotireoidismo Congênito/tratamento farmacológico , Hipotireoidismo Congênito/psicologia , Comportamento Problema/psicologia , Criança , Feminino , Humanos , Masculino
11.
PLoS One ; 13(10): e0205318, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30300409

RESUMO

BACKGROUND: A previous single-center study established a mathematical model for predicting the adult height (AH) in girls with idiopathic central precocious puberty (CPP). OBJECTIVE: To perform internal and external validations by comparing the actual AH to the calculated AH established by this model and to update it. METHODS: The original formula, calculated AH (cm) = 2.21 (height at initial evaluation, SD) + 2.32 (target height, SD) - 1.83 (luteinizing hormone/follicle-stimulating hormone peaks ratio) + 159.68, was established in a sample of 134 girls (group 4) and was applied to additional girls with CPP seen in the same center (group 1, n = 35), in Germany (group 2, n = 43) and in the Netherlands (group 3, n = 72). This formula has been updated based on these extended data, and both versions are available at the following location: http://www.kamick.org/lemaire/med/girls-cpp15.html. RESULTS: Despite the differences among the 4 groups in terms of their characteristics at the initial evaluation and the percentages of patients treated with the gonadotropin-releasing hormone analogue, they have similar calculated and actual AHs. The actual AHs are 162.2±7.0, 163.0±7.6, 162.4±7.7 and 162.1±5.6 cm in groups 1 to 4, respectively. They are highly correlated with the AHs calculated by the formula established in the original group (group 4), with R at 0.84, 0.67 and 0.69 in groups 1 to 3, respectively. When the actual AHs and the AHs predicted by the Bayley and Pinneau method are compared, the R is 0.76, 0.51 and 0.64 in groups 1 to 3, respectively. The absolute differences between actual AHs and the calculated AHs are greater than 1 SD (5.6 cm) in 15%, 35% and 28% of the patients in groups 1 to 3, respectively. CONCLUSION: This study validates and updates the previously established formula for predicting AH in girls with CPP. This updated formula can help clinicians to make treatment decisions.


Assuntos
Estatura/fisiologia , Modelos Teóricos , Puberdade Precoce/epidemiologia , Puberdade Precoce/fisiopatologia , Adulto , Criança , Feminino , Hormônio Foliculoestimulante/sangue , Alemanha/epidemiologia , Hormônio Liberador de Gonadotropina/sangue , Humanos , Hormônio Luteinizante/sangue , Países Baixos/epidemiologia , Puberdade Precoce/sangue
12.
Horm Res Paediatr ; 88(2): 127-139, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28689203

RESUMO

BACKGROUND: Information sharing in chronic conditions such as disorders of/differences in sex development (DSD) is essential for a comprehensive understanding by parents and patients. We report on a qualitative analysis of communication skills of fellows undergoing training in paediatric endocrinology. Guidelines are created for the assessment of communication between health professionals and individuals with DSD and their parents. METHODS: Paediatric endocrinology fellows worldwide were invited to study two interactive online cases (www.espe-elearning.org) and to describe a best practice communication with (i) the parents of a newborn with congenital adrenal hyperplasia and (ii) a young woman with 46,XY gonadal dysgenesis. The replies were analysed regarding completeness, quality, and evidence of empathy. Guidelines for structured assessment of responses were developed by 22 senior paediatric endocrinologists worldwide who assessed 10 selected replies. Consensus of assessors was established and the evaluation guidelines were created. RESULTS: The replies of the fellows showed considerable variation in completeness, quality of wording, and evidence of empathy. Many relevant aspects of competent clinical communication were not mentioned; 15% (case 1) and 17% (case 2) of the replies were considered poor/insufficient. There was also marked variation between 17 senior experts in the application of the guidelines to assess communication skills. The guidelines were then adjusted to a 3-level assessment with empathy as a separate key item to better reflect the qualitative differences in the replies and for simplicity of use by evaluators. CONCLUSIONS: E-learning can play an important role in assessing communication skills. A practical tool is provided to assess how information is shared with patients with DSD and their families and should be refined by all stakeholders, notably interdisciplinary health professionals and patient representatives.


Assuntos
Comunicação , Transtornos do Desenvolvimento Sexual/diagnóstico , Empatia , Endocrinologia , Pais/psicologia , Relações Profissional-Família , Humanos , Recém-Nascido , Revelação da Verdade
13.
J Clin Res Pediatr Endocrinol ; 9(4): 366-370, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28588001

RESUMO

Cornelia de Lange syndrome (CdLS) is a both clinically and genetically heterogeneous syndrome. In its classical form, it is characterised by distinctive facial features, intra-uterine growth retardation, short stature, developmental delay, and anomalies in multiple organ systems. NIPBL, SMC1A, SMC3, RAD21 and HDAC8, all involved in the cohesin pathway, have been identified to cause CdLS. Growth hormone (GH) secretion has been reported as normal, and to our knowledge, there are no reports on the effect of recombinant human GH treatment in CdLS patients. We present a patient born small for gestational age with persistent severe growth retardation [height -3.4 standard deviation score (SDS)] and mild dysmorphic features, who was treated with GH from 4.3 years of age onward and was diagnosed 6 years later with CdLS using whole-exome sequencing. Treatment led to a height gain of 1.6 SDS over 8 years. Treatment was interrupted shortly due to high serum insulin-like growth factor-1 serum values. In conclusion, GH therapy may be effective and safe for short children with CdLS.


Assuntos
Síndrome de Cornélia de Lange/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Estatura/efeitos dos fármacos , Criança , Síndrome de Cornélia de Lange/complicações , Nanismo/tratamento farmacológico , Nanismo/etiologia , Terapia de Reposição Hormonal , Humanos , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Masculino , Resultado do Tratamento
14.
J Clin Res Pediatr Endocrinol ; 9(3): 265-273, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28588003

RESUMO

We present a 13-year-old boy who was admitted with complaints of a state of progressive sleepiness and a sudden headache with vomiting and fever. Laboratory testing showed hypoglycemia, multiple pituitary hormonal deficiencies, and an elevated C-reactive protein level. A cranial magnetic resonance imaging (MRI) showed an opaque sphenoid sinus and an intrasellar mass suggesting hemorrhage, so that we suspected pituitary apoplexy (PA) originating from a non-functioning adenoma, although a pituitary abscess could not completely be excluded. The boy was treated with antibiotics, hydrocortisone, and levothyroxine. Due to his rapid clinical improvement, no surgery was performed and we considered the diagnosis of PA as confirmed. At follow-up, the MRI scan showed a small residual lesion. Pituitary deficiencies of growth hormone, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone, and vasopressin persisted. A literature search of all well-documented cases of PA in children or adolescents (n=30, 13 boys and 17 girls) indicated that this condition is rare below 20 years of age but must be considered when a patient experiences headache with or without visual disturbances, even in the presence of clinical and laboratory signals suggestive of pituitary abscess. MRI neuroimaging is helpful in the differential diagnosis. In both conditions, the possibility of ACTH deficiency should always be considered, investigated, and treated. In cases without severe neuro-ophthalmological deficits and/or with a rapid and positive response to acute medical management, one can abstain from surgical treatment.


Assuntos
Adenoma/complicações , Apoplexia Hipofisária/etiologia , Neoplasias Hipofisárias/complicações , Adolescente , Humanos , Masculino
15.
J Hum Genet ; 62(8): 755-762, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28356564

RESUMO

Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96 kb deletion that comprises the first two exons of POU1F1. In three families a homozygous 15.9 kb deletion including complete PROP1 was discovered. Breakpoints map within highly homologous AluY sequences. Haplotype analysis revealed a shared haplotype of 350 kb among PROP1 deletion carriers. For the first time we were able to assign the boundaries of a previously reported PROP1 deletion. This gross deletion shows strong evidence to originate from a common ancestor in patients with Kurdish descent. No CNVs within LHX3, LHX4, HESX1, GH1 and GHRHR were found. Our data prove multiplex ligation-dependent probe amplification to be a valuable tool for the detection of CNVs as cause of pituitary insufficiencies and should be considered as an analytical method particularly in Kurdish patients.


Assuntos
Haplótipos , Proteínas de Homeodomínio/genética , Hipopituitarismo/genética , Deleção de Sequência , Fator de Transcrição Pit-1/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Linhagem
16.
J Clin Endocrinol Metab ; 101(12): 4564-4573, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27603907

RESUMO

CONTEXT: Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the transducin ß-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor-corepressor complex. OBJECTIVE: The objectives of the study were the identification of TBL1X mutations in patients with unexplained isolated CeH, Sanger sequencing of relatives of affected individuals, and clinical and biochemical characterization; in vitro investigation of functional consequences of mutations; and mRNA expression in, and immunostaining of, human hypothalami and pituitary glands. DESIGN: This was an observational study. SETTING: The study was conducted at university medical centers. PATIENTS: Nineteen individuals with and seven without a mutation participated in the study. MAIN OUTCOME MEASURES: Outcome measures included sequencing results, clinical and biochemical characteristics of mutation carriers, and results of in vitro functional and expression studies. RESULTS: Sanger sequencing yielded five additional mutations. All patients (n = 8; six males) were previously diagnosed with CeH (free T4 [FT4] concentration below the reference interval, normal thyrotropin). Eleven relatives (two males) also carried mutations. One female had CeH, whereas 10 others had low-normal FT4 concentrations. As a group, adult mutation carriers had 20%-25% lower FT4 concentrations than controls. Twelve of 19 evaluated carriers had hearing loss. Mutations are located in the highly conserved WD40-repeat domain of the protein, influencing its expression and thermal stability. TBL1X mRNA and protein are expressed in the human hypothalamus and pituitary. CONCLUSIONS: TBL1X mutations are associated with CeH and hearing loss. FT4 concentrations in mutation carriers vary from low-normal to values compatible with CeH.


Assuntos
Perda Auditiva/genética , Hipotireoidismo/genética , Hipófise/metabolismo , Tiroxina/sangue , Transducina/genética , Adolescente , Adulto , Criança , Feminino , Perda Auditiva/etiologia , Heterozigoto , Humanos , Hipotálamo/metabolismo , Hipotireoidismo/sangue , Hipotireoidismo/complicações , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , RNA Mensageiro/metabolismo , Adulto Jovem
17.
Pediatr Res ; 80(6): 816-823, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27494505

RESUMO

BACKGROUND: In congenital hypothyroidism (CH), age-specific reference ranges (asRR) for fT4 and thyrotropine (TSH) are usually used to signal over/under-treatment. We compared the consequences of individual fT4 steady-state concentrations (SSC's) and asRR regarding over-treatment signaling and intelligence quotient at 11 y (IQ11) and the effect of early over-treatment with high L-T4 dosages on IQ11. METHODS: Sixty-one patients (27 severe, 34 mild CH) were psychologically tested at 1.8, 6, and 11 y. Development scores were related to over-treatment in the period 0-24 mo, relative to either individual fT4SSC's or asRR. Three groups were formed, based on severity of over/under-treatment 0-5 mo (severe, mild, and no over/under-treatment). RESULTS: FT4 and TSH asRR missed 41-50% of the over-treatment episodes and consequently 22% of the over-treated patients, classified as such by fT4SSC's. Severe over-treatment 0-5 mo led to lowered IQ11's and to a 5.5-fold higher risk of IQ11 < 85 than other treatment regimes. Under-treatment had no effect on development scores. Initial L-T4 dosages >10 µg/kg resulted in a 3.7-fold higher risk of over-treatment than lower dosages. CONCLUSIONS: Data suggest that asRR, compared to fT4SSC's, signal over-treatment insufficiently. Using fT4SSC's and avoiding over-treatment may optimize cognitive outcome. Lowered IQ11's are usually a late complication of severe early over-treatment.


Assuntos
Cognição/efeitos dos fármacos , Hipotireoidismo Congênito/tratamento farmacológico , Hipotireoidismo Congênito/psicologia , Tiroxina/uso terapêutico , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Hipotireoidismo Congênito/sangue , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Sobremedicalização , Medicina de Precisão , Tireotropina/sangue , Tiroxina/administração & dosagem , Tiroxina/sangue , Resultado do Tratamento
18.
J Clin Res Pediatr Endocrinol ; 8(4): 445-451, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27550850

RESUMO

OBJECTIVE: Although vitamin D levels are not routinely monitored in pediatric fracture patients, identification of children with a vitamin D deficiency may be clinically relevant because of the potential role of vitamin D in fracture healing. This study aimed to determine the prevalence of vitamin D deficiency in a pediatric fracture population and to identify risk factors for deficiency. METHODS: All pediatric patients (<18 years) who were treated for a fracture of the upper or lower extremity from September 2012 to October 2013 in the outpatient setting of a level one trauma center were included in this cross-sectional study. Vitamin D deficiency was defined as a serum calcidiol <50 nmol/L. Potential risk factors for vitamin D deficiency were analysed using multivariable logistic regression analysis. RESULTS: A total of 108 boys (58%) and 79 girls, of a mean age 11.1 years (standard deviation 3.9), who had undergone 189 fractures were included in the study. Sixty-four children (34%) were vitamin D deficient. Of those with follow-up measurements, 74% were no longer deficient after supplementation. Vitamin D status did not influence the occurrence of complications during fracture treatment. Independent risk factors for vitamin D deficiency were older age, season (spring), and a non-Caucasian skin type. CONCLUSION: Clinicians who treat children with a fracture should inform patients and parents on vitamin D supplementation. Vitamin D measurement and supplementation may be needed for children with a non-Caucasian skin type or for those who present with a fracture during spring months.


Assuntos
Fraturas Ósseas/terapia , Pacientes Ambulatoriais/estatística & dados numéricos , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/uso terapêutico , Adolescente , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Criança , Comorbidade , Estudos Transversais , Suplementos Nutricionais , Feminino , Fraturas Ósseas/epidemiologia , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Países Baixos/epidemiologia , Prevalência , Fatores de Risco , Vitamina D/administração & dosagem , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/epidemiologia
19.
Endocrinology ; 157(5): 1914-28, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26982636

RESUMO

IGFs are critical for normal intrauterine and childhood growth and sustaining health throughout life. We showed previously that the production of IGF-1 and IGF-2 requires interaction with the chaperone glucose-regulated protein 94 (GRP94) and that the amount of secreted IGFs is proportional to the GRP94 activity. Therefore, we tested the hypothesis that functional polymorphisms of human GRP94 affect IGF production and thereby human health. We describe a hypomorphic variant of human GRP94, P300L, whose heterozygous carriers have 9% lower circulating IGF-1 concentration. P300L was found first in a child with primary IGF deficiency and was later shown to be a noncommon single-nucleotide polymorphism with frequencies of 1%-4% in various populations. When tested in the grp94(-/-) cell-based complementation assay, P300L supported only approximately 58% of IGF secretion relative to wild-type GRP94. Furthermore, recombinant P300L showed impaired nucleotide binding activity. These in vitro data strongly support a causal relationship between the GRP94 variant and the decreased concentration of circulating IGF-1, as observed in human carriers of P300L. Thus, mutations in GRP94 that affect its IGF chaperone activity represent a novel causal genetic mechanism that limits IGF biosynthesis, quite a distinct mechanism from the known genes in the GH/IGF signaling network.


Assuntos
Proteínas de Choque Térmico HSP70/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Somatomedinas/biossíntese , Alelos , Análise Mutacional de DNA , Frequência do Gene , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Mutação
20.
Horm Res Paediatr ; 85(6): 412-20, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26925581

RESUMO

BACKGROUND: Recessive mutations in the leptin receptor (LEPR) are a rare cause of hyperphagia and severe early-onset obesity. To date, the phenotype has only been described in 25 obese children, some of whom also had altered immune function, hypogonadotropic hypogonadism, reduced growth hormone secretion, hypothalamic hypothyroidism or reduced adult height. We provide a detailed description of the phenotype of 2 affected girls to add to this knowledge. METHODS: Whole-exome sequencing and targeted sequencing were used to detect the LEPR mutations. RNA analysis was performed to assess the effect of splice-site mutations. RESULTS: In 2 unrelated girls with severe obesity, three novel LEPR mutations were detected. Longitudinal growth data show normal childhood growth, and in the older girl, a normal adult height despite hypogonadotropic hypogonadism and the lack of an obvious pubertal growth spurt. Bone age is remarkably advanced in the younger (prepubertal) girl, and bone mineral density (BMD) is high in both girls, which might be directly or indirectly related to leptin resistance. CONCLUSION: The spectrum of clinical features of LEPR deficiency may be expanded with increased BMD. Future observations in LEPR-deficient subjects should help further unravel the role of leptin in human bone biology.


Assuntos
Densidade Óssea , Mutação , Obesidade/genética , Receptores para Leptina/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Obesidade/sangue , Obesidade/patologia , Receptores para Leptina/metabolismo , Índice de Gravidade de Doença
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