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1.
Pediatr Transplant ; 28(5): e14767, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38895795

RESUMO

BACKGROUND: Sarcopenia predicts morbidity and mortality in end-stage chronic liver disease (ESCLD). Here, we describe changes in body composition in children with ESCLD before and after liver transplantation (LT). METHODS: Retrospective analysis of whole body DXA scans performed before and after LT over 4 years. Appendicular and whole-body fat mass and lean mass were expressed as fat mass (FMI) and lean mass (LMI) index z-scores. Sarcopenia was defined as leg LMI z-score <-1.96. RESULTS: Eighty-three DXA scans of children before or after LT were studied. Sarcopenia had a positive correlation with weight (0.8, p < .01), height (0.48, p < .05), and BMI z-score (0.77, p < .01), as well as arm, trunk, and total mean mass indices. It correlated negatively with indices of hypersplenism: PLTs (-0.57, p < .01), Neu (-0.50, p < .05), WCC (-0.44, p < .05), and days to discharge (-0.46, p < .05). At baseline: 13/25 (52%) children were sarcopenic and stayed in the hospital after LT for longer. Eight were stunted with a higher WCC and Ne/Ly ratio. All had normal FM indices. One year after LT, 12/26 children remained sarcopenic. Seven were stunted. Two years after LT, 5/15 were sarcopenic, and 5 were stunted. Three years after LT, 1/10 was sarcopenic, and 2 were stunted. By 4 years after LT, 1/7 was sarcopenic, and the same one was stunted. FM indices remained normal. CONCLUSIONS: Sarcopenic patients stayed longer in the hospital after LT. Lean mass indices were mostly within the normal range by 4 years after LT. 32% of children were stunted, and markers of inflammation were correlated with stunting. Fat mass was preserved at the cost of lean mass.


Assuntos
Composição Corporal , Doença Hepática Terminal , Transplante de Fígado , Sarcopenia , Humanos , Estudos Retrospectivos , Masculino , Feminino , Criança , Doença Hepática Terminal/cirurgia , Doença Hepática Terminal/complicações , Sarcopenia/etiologia , Pré-Escolar , Adolescente , Absorciometria de Fóton , Tecido Adiposo , Lactente
3.
Arch Dis Child ; 108(11): 871-878, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37045585

RESUMO

Adrenal insufficiency (AI) is characterised by lack of cortisol production from the adrenal glands. This can be a primary adrenal disorder or secondary to adrenocorticotropic hormone deficiency or suppression from exogenous glucocorticoids. Symptoms of AI in children may initially be non-specific and include growth faltering, lethargy, poor feeding, weight loss, abdominal pain, vomiting and lingering illnesses. AI is treated with replacement doses of hydrocortisone. At times of physiological stress such as illness, trauma or surgery, there is an increased requirement for exogenous glucocorticoids, which if untreated can lead to an adrenal crisis and death. There are no unified guidelines for those <18 years old in the UK, leading to substantial variation in the management of AI. This paper sets out guidance for intercurrent illness, medical, dental and surgical procedures to allow timely and appropriate recognition and treatment of AI and adrenal crisis for children and young people.


Assuntos
Insuficiência Adrenal , Diabetes Mellitus , Criança , Humanos , Adolescente , Consenso , Insuficiência Adrenal/tratamento farmacológico , Insuficiência Adrenal/diagnóstico , Hidrocortisona/uso terapêutico , Glucocorticoides/uso terapêutico , Diabetes Mellitus/tratamento farmacológico
4.
J Endocr Soc ; 7(4): bvad021, 2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36824585

RESUMO

Context: Recurrent hypoglycemia can result in significant neurological impairments in children and continuous glucose monitoring (CGM) technology has been shown to reduce recurrent hypoglycemia in conditions such as type 1 diabetes. In the United Kingdom, CGM devices are currently only recommended by the National Institute of Clinical Excellence (NICE) for patients with diabetes and not for other diagnoses. Objective: To examine access to CGM technology for children and young people with recurrent hypoglycemia in the United Kingdom. Methods: In 2021, the British Society of Paediatric Endocrinology and Diabetes (BSPED) conducted a national health professional survey in England, Wales, Scotland, and Northern Ireland looking at CGM access to funding for children and young people with recurrent hypoglycemia, without the diagnosis of diabetes. The UK Children's Hyperinsulinism Charity (UK CHC) also conducted a national patient survey. Results: Responses from BSPED were received from 55 units while the UK CHC received 69 responses from individual families, the largest response to a survey carried out by the charity. The results of the BSPED and UK CHC surveys found that funding streams for CGM were highly variable. Only 29% were able to access CGM for recurrent hypoglycemia and from these, 65% were self-funding CGM. Quality of life benefits were evident from the UK CHC survey on the utility of CGM in reducing worry, improving sleep, lessening the burden of frequently finger-pricking and reducing out-of-hours appointments as a result of hypoglycemia. Patient-reported utilization rates of blood glucose test strips per week were significantly reduced. Conclusion: BSPED and UK CHC national surveys support a call and a consideration for CGM access to be widened to patients who suffer from recurrent hypoglycemia such as those with hyperinsulinism or metabolic conditions. The prevention of recurrent hypoglycemia and improving quality of life for patients and carers remain a cornerstone management for people who suffer from frequent hypoglycemia. CGM education is critical to support its use and understand its limitations. Further research is warranted to determine the safety and efficacy of CGM in detection and reduction of hypoglycemic events, impact of hospital stay, and long-term neurological outcomes in those who suffer from recurrent hypoglceamia.

6.
Arch Dis Child ; 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35851291

RESUMO

INTRODUCTION: The destination of transgender and gender variant young people referred by the National Health Service (NHS) Gender Identity Development Service (GIDS) to, and discharged from the two English paediatric endocrine liaison clinics is not known. METHODS: 1151 young people referred after full assessment by the GIDS; 827 to University College London Hospital since 2008; 324 to Leeds Children's Hospital since 2013. Discharge categorisation was by agreed criteria. Eleven emigrated and 51 self-discharged. 1089 had known outcomes. RESULTS: 999/1089 (91.7%) continued identifying as gender variant. 867/999 (86.8%) were discharged to adult gender identity clinics (GICs). 166/867 (19.1%) of these were <16 years and 701/867 (80.9%) ≥16 years at initial endocrine referral. No sex differences were seen. 38/999 (3.8%) opted for non-NHS services.90/1089 ceased identifying as gender variant. In 32/1089 (2.9%), this was subsequent to their first clinic appointment.58/1089 (5.3%) stopped treatment either with the gonadotropin releasing hormone analogue (GnRHa) or gender-affirming hormones (GAH) and reverted to their birth gender: <16 years (20/217; 9.2%); ≥16 years (38/872; 4.4%).Subdividing further, 16/217 (7.4%) <16 years ceased GnRHa and 4/217 (1.8%) after GAH. Of those ≥16 years, 33/872 (3.8%) ceased GnRHa and 5/872 (0.6%) GAH. CONCLUSIONS: At discharge, 91.7% continued as transgender or gender variant, 86.8% sought ongoing care through NHS GICs. 2.9% ceased identifying as transgender after an initial consultation prior to any endocrine intervention and 5.3% stopped treatment either with GnRHa or GAH, a higher proportion in the <16 year compared with the ≥16 year groups.

7.
J Clin Endocrinol Metab ; 106(11): e4716-e4733, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34136918

RESUMO

CONTEXT: Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding. OBJECTIVE: We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH-IGF-I axis defects. METHODS: Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing, whole exome sequencing, array comparative genomic hybridization, and a targeted whole genome short stature gene panel. RESULTS: Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH-IGF-I axis defects (GHR n = 40, IGFALS n = 4, IGFIR n = 1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n = 10) (OBSL1 n = 7, CUL7 n = 2, and CCDC8 n = 1), Noonan syndrome (n = 4) (PTPN11 n = 2, SOS1 n = 1, and SOS2 n = 1), Silver-Russell syndrome (n = 2) (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n = 10), and disorders not previously associated with GHI (n = 9) (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, and Bloom syndrome). CONCLUSION: We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management.


Assuntos
Biomarcadores/análise , Estatura , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Transtornos do Crescimento/patologia , Síndrome de Laron/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Testes Genéticos , Transtornos do Crescimento/complicações , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Hormônio do Crescimento Humano/metabolismo , Humanos , Lactente , Fator de Crescimento Insulin-Like I/metabolismo , Síndrome de Laron/complicações , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Masculino , Prognóstico , Adulto Jovem
8.
Clin Endocrinol (Oxf) ; 95(6): 818-840, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34031907

RESUMO

It is paramount that any child or adolescent with a suspected difference or disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD and is discussed with the regional DSD service. In most cases, the paediatric endocrinologist within this service acts as the first point of contact but involvement of the regional multidisciplinary service will also ensure prompt access to specialist psychology and nursing care. The underlying pathophysiology of DSD and the process of delineating this should be discussed with the parents and affected young person with all diagnostic tests undertaken in a timely fashion. Finally, for rare conditions such as these, it is imperative that clinical experience is shared through national and international clinical and research collaborations.


Assuntos
Transtornos do Desenvolvimento Sexual , Endocrinologia , Adolescente , Criança , Transtornos do Desenvolvimento Sexual/diagnóstico , Humanos , Pais , Desenvolvimento Sexual , Reino Unido
9.
Eur J Med Genet ; 64(2): 104141, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33450337

RESUMO

Multiple endocrine neoplasia type 2 (MEN2) is a dominantly inherited condition with defined correlations between the genetic variant and clinical presentations. The location of pathogenic variants in the RET gene is a significant determinant of disease presentation and is associated with variable gene activation. Heterozygous pathogenic variants in codon 634 result in earlier onset of medullary thyroid carcinoma and higher incidence of phaeochromocytoma. Here we describe a consanguineous family with MEN2A that includes two children homozygous for the established pathogenic variant p. Cys634Trp. Both parents and a sibling were confirmed to being heterozygotes. Previous reports of biallelic or multiple RET variants have been limited to weakly activating variants. We present the first report of individuals homozygous for the highly activating RET p. Cys634Trp pathogenic variant and discuss disease severity and onset in this rare occurrence.


Assuntos
Neoplasia Endócrina Múltipla Tipo 2a/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-ret/genética , Adolescente , Adulto , Criança , Consanguinidade , Feminino , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Linhagem
10.
Arch Dis Child Educ Pract Ed ; 105(5): 311-314, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32371419

RESUMO

You are seeing an 11-year-old boy in a general paediatric clinic referred with short stature. His height is below the 0.4th centile. The mid-parental height is on 50th centile. Baseline investigations, including renal and liver function, coeliac screen and thyroid function tests are normal. You have a suspicion of growth hormone deficiency. Should you check an insulin-like growth factor-1 level or proceed with a growth hormone provocation test? The current paper will aim to give an overview of these tests and factors to consider when interpreting the results.


Assuntos
Transtornos do Crescimento , Fator de Crescimento Insulin-Like I , Estatura , Criança , Hormônio do Crescimento , Humanos , Masculino
11.
PLoS One ; 15(2): e0228417, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027664

RESUMO

Congenital hyperinsulinism (CHI) is a significant cause of hypoglycaemia in neonates and infants with the potential for permanent neurologic injury. Accurate calculations of the incidence of rare diseases such as CHI are important as they inform health care planning and can aid interpretation of genetic testing results when assessing the frequency of variants in large-scale, unselected sequencing databases. Whilst minimal incidence rates have been calculated for four European countries, the incidence of CHI in the UK is not known. In this study we have used referral rates to a central laboratory for genetic testing and annual birth rates from census data to calculate the minimal incidence of CHI within the UK from 2007 to 2016. CHI was diagnosed in 278 individuals based on inappropriately detectable insulin and/or C-peptide measurements at the time of hypoglycaemia which persisted beyond 6 months of age. From these data, we have calculated a minimum incidence of 1 in 28,389 live births for CHI in the UK. This is comparable to estimates from other outbred populations and provides an accurate estimate that will aid both health care provision and interpretation of genetic results, which will help advance our understanding of CHI.


Assuntos
Hiperinsulinismo Congênito/epidemiologia , Testes Genéticos/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Doenças Raras/epidemiologia , Encaminhamento e Consulta/estatística & dados numéricos , Pré-Escolar , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/cirurgia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Nascido Vivo/epidemiologia , Masculino , Triagem Neonatal/métodos , Pancreatectomia/estatística & dados numéricos , Doenças Raras/diagnóstico , Doenças Raras/genética , Reino Unido/epidemiologia
12.
Endocr Connect ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061156

RESUMO

OBJECTIVES: The homozygous GH receptor (GHR) pseudoexon (6Ψ) mutation leads to growth hormone insensitivity (GHI) with clinical and biochemical heterogeneity. We investigated whether transcript heterogeneity (6Ψ-GHR to WT-GHR transcript ratio) and/or concurrent defects in other short stature (SS) genes contribute to this. METHODS: 6Ψ-GHR and WT-GHR mRNA transcripts of 4 6Ψ patient (height SDS -4.2 to -3.1) and 1 control fibroblasts were investigated by RT-PCR. Transcripts were quantified by qRT-PCR and delta delta CT analysis and compared using ANOVA with Bonferroni correction. In eleven 6Ψ patients, 40 genes known to cause GHI/SS were analysed by targeted next generation sequencing. RESULTS: RT-PCR confirmed 6Ψ-GHR transcript in the 6Ψ patients but not control. 6Ψ-GHR transcript levels were comparable in patients 1 and 3 but significantly different among all other patients. The mean 6Ψ:WT transcript ratios ranged from 29-71:1 for patients 1-4 and correlated negatively with height SDS (R=-0.85; p<0.001). Eight deleterious variants in 6 genes were detected but the number of gene hits did not correlate with the degree of SS in individual 6Ψ patients. CONCLUSION: Variable amounts of 6Ψ- and WT-GHR transcripts were identified in 6Ψ patients but no 6Ψ transcript was present in the control. Higher 6Ψ:WT GHR transcript ratio correlated with SS severity and may explain the phenotypic variability. Analysis of known SS genes suggested that phenotypic variation is independent of the genetic background. This is the first report of transcript heterogeneity producing a spectrum of clinical phenotypes in different individuals harbouring an identical homozygous genetic mutation.

13.
J Pediatr Endocrinol Metab ; 32(9): 959-967, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31301676

RESUMO

Background Type I pseudohypoaldosteronism (PHA1) is a rare condition characterised by profound salt wasting, hyperkalaemia and metabolic acidosis due to renal tubular resistance to aldosterone (PHA1a) or defective sodium epithelial channels (PHA1b or systemic PHA). Our aim was to review the clinical presentation related to the genotype in patients with PHA1. Methods A questionnaire-based cross-sectional survey was undertaken through the British Society of Paediatric Endocrinology and Diabetes (BSPED) examining the clinical presentation and management of patients with genetically confirmed PHA1. We also reviewed previously reported patients where genotypic and phenotypic information were reported. Results Genetic confirmation was made in 12 patients with PHA1; four had PHA1a, including one novel mutation in NR3C2; eight had PHA1b, including three with novel mutations in SCNN1A and one novel mutation in SCNN1B. It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile. Patients presenting with missense mutations of SCNN1A and SCNN1B had a less marked rise in serum aldosterone suggesting preservation in sodium epithelial channel function. Conclusions We advocate early genetic testing in patients with presumed PHA1, given the challenges in differentiating between patients with PHA1a and PHA1b. Clinical course differs between patients with NR3C2 and SCNN1A mutations with a poorer prognosis in those with multisystem PHA. There were no obvious genotype-phenotype correlations between mutations on the same gene in our cohort and others, although a lower serum aldosterone may suggest a missense mutation in SCNN1 in patients with PHA1b.


Assuntos
Biomarcadores/análise , Canais Epiteliais de Sódio/genética , Mutação de Sentido Incorreto , Pseudo-Hipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , Aldosterona/sangue , Criança , Pré-Escolar , Estudos Transversais , Feminino , Seguimentos , Estudos de Associação Genética , Genótipo , Humanos , Recém-Nascido , Masculino , Fenótipo , Prognóstico , Pseudo-Hipoaldosteronismo/classificação , Pseudo-Hipoaldosteronismo/patologia
14.
Eur J Endocrinol ; 178(5): 481-489, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29500309

RESUMO

BACKGROUND: Patients with homozygous intronic pseudoexon GH receptor (GHR) mutations (6Ψ) have growth hormone insensitivity (GHI) (growth failure, IGF1 deficiency and normal/elevated serum GH). We report 9 patients in addition to previously described 11 GHR 6Ψ patients and their responses to rhIGF1 therapy. METHODS: 20 patients (12 males, 11 families, mean age 4.0 ± 2.2 years) were diagnosed genetically in our centre. Phenotypic data and responses to rhIGF1 treatment were provided by referring clinicians. Continuous parametric variables were compared using Student t-test or ANOVA. RESULTS: 10/20 (50%) had typical facial features of GHI, 19/20 (95%) from consanguineous families and 18/20 (90%) of Pakistani origin. At diagnosis, mean height SDS: -4.1 ± 0.95, IGF1 SDS: -2.8 ± 1.4; IGFBP3 SDS: -3.0 ± 2.1 and mean basal and peak GH levels: 11.9 µg/L and 32.9 µg/L, respectively. 1/12 who had IGF1 generation test, responded (IGF1: 132-255 ng/mL). 15/20 (75%; 11M) received rhIGF1 (mean dose: 114 µg/kg twice daily, mean duration: 5.3 ± 2.5 years). Mean baseline height velocity of 4.7 ± 1.1 cm/year increased to 7.4 ± 1.8 cm/year (P = 0.001) during year 1 of therapy. Year 3 mean height SDS (-3.2 ± 1.0) was higher than pre-treatment height SDS (-4.3 ± 0.8) (P = 0.03). Mean cumulative increase in height SDS after year 5 was 1.4 ± 0.9. Difference between target height (TH) SDS and adult or latest height SDS was less than that of TH SDS and pre-treatment height SDS (2.1 ± 1.2 vs 3.0 ± 0.8; P = 0.02). CONCLUSION: In addition to phenotypic heterogeneity in the cohort, there was mismatch between clinical and biochemical features in individual patients with 6Ψ GHR mutations. rhIGF1 treatment improved height outcomes.


Assuntos
Transtornos do Crescimento/prevenção & controle , Fator de Crescimento Insulin-Like I/uso terapêutico , Síndrome de Laron/tratamento farmacológico , Mutação Puntual , Receptores da Somatotropina/agonistas , Receptores da Somatotropina/genética , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Consanguinidade , Resistência a Medicamentos , Inglaterra , Saúde da Família , Feminino , Transtornos do Crescimento/etiologia , Homozigoto , Humanos , Fator de Crescimento Insulin-Like I/genética , Íntrons , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Síndrome de Laron/fisiopatologia , Masculino , Paquistão/etnologia , Receptores da Somatotropina/metabolismo , Proteínas Recombinantes/uso terapêutico
15.
Am J Med Genet A ; 170(12): 3303-3307, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27549894

RESUMO

Prompt and accurate diagnosis of skeletal dysplasias can play a crucial role in ensuring appropriate counseling and management (both antenatal and postnatal). When a skeletal dysplasia is detected during the antenatal period, especially early in the pregnancy, it can be associated with a poor prognosis. It is important to make a diagnosis in antenatal presentation of skeletal dysplasias to inform diagnosis, predict prognosis, provide accurate recurrence risks, and options for prenatal genetic testing in future pregnancies. Prenatal ultrasound scanning is a useful tool to detect several skeletal dysplasias and sonographic measurements serve as reliable indicators of lethality. The lethality depends on various factors including gestational age at which features are identified, size of the chest and progression of malformations. Although, it is important to type the skeletal presentation as accurately as possible, this is not always possible in an antenatal presentation and it is important to acknowledge this uncertainty. In the case of a live birth, it is always important to reassess the infant. Osteogenesis imperfecta (OI) is a heterogeneous group of disorders characterized by fragile bones. Here, we report an infant with severe OI born following a twin pregnancy in whom the bone disease is caused by a heterozygous pathogenic mutation, c.4160C >T, p.(Ala1387Val) located in the C-propeptide region of COL1A1. An assumption of lethality antenatally complicated his management in early life. We discuss this patient with particular emphasis on the neonatal presentation of a severe skeletal dysplasia and the lessons that may be learned in such situations. © 2016 Wiley Periodicals, Inc.


Assuntos
Colágeno Tipo I/genética , Heterozigoto , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Alelos , Substituição de Aminoácidos , Pré-Escolar , Cadeia alfa 1 do Colágeno Tipo I , Fácies , Estudos de Associação Genética , Testes Genéticos , Humanos , Masculino , Fenótipo , Exame Físico , Radiografia
16.
Arch Dis Child Educ Pract Ed ; 100(4): 180-4, 203, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25855216

RESUMO

Short stature can be a cause of distress for children and families. It is not usually pathological, but it is important to identify treatable conditions. This article presents a systematic approach to the evaluation of a child with short stature, covering differential diagnoses, first line investigations and indications for treatment with growth hormone.


Assuntos
Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/etiologia , Adolescente , Estatura/fisiologia , Criança , Pré-Escolar , Transtornos do Crescimento/fisiopatologia , Transtornos do Crescimento/terapia , Hormônio do Crescimento/deficiência , Hormônio do Crescimento/uso terapêutico , Humanos
17.
J Clin Endocrinol Metab ; 94(9): 3191-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19567534

RESUMO

CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.


Assuntos
Testes Genéticos , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/genética , Mutação , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Proteínas de Homeodomínio/genética , Humanos , Lactente , Região de Controle de Locus Gênico , Linhagem , Fatores de Transcrição SOXB1/genética
18.
Growth Horm IGF Res ; 17(5): 435-9, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17590365

RESUMO

OBJECTIVE: To determine if glucocorticoids and proinflammatory cytokines inhibit bone growth through a common mechanism involving impaired IGF-I signalling. DESIGN: IGF-I (100 ng/ml), dexamethasone (dex) (10(-6)M) and IL-1beta (10 ng/ml) with inhibitors of the PI3K (LY294002) and Erk 1/2 (PD98059 and UO126) IGF-I pathways (all 10 microM) were studied using the ATDC5 chondrocyte cell line and murine fetal metatarsal cultures. RESULTS: IGF-I stimulated ATDC5 chondrocyte proliferation (322%; P < 0.001 versus control). Addition of PD or LY individually to IGF-I supplemented ATDC5 cultures partially reduced proliferation by 32% (P < 0.001), and 66% (P < 0.001), respectively. PD and LY in combination blocked all IGF-I stimulated ATDC5 proliferation. LY significantly reversed IGF-I stimulatory effects on metatarsal growth (P < 0.001), whereas PD and UO treatment had no effect. IGF-I induced ATDC5 proliferation was further decreased when Dex (24%; P < 0.01) or IL-1beta (33%; P < 0.001) were added to PD but not LY cultures. Metatarsal growth inhibition by LY was unaltered by Dex or IL-1beta addition. CONCLUSIONS: Both the PI3K and Erk 1/2 pathways contributed independently to IGF-I mediated ATDC5 proliferation. However in metatarsal cultures, the Erk 1/2 pathway was not required for IGF-I stimulated growth. Dex and IL-1beta may primarily inhibit IGF-I induced bone growth through the PI3K pathway.


Assuntos
Desenvolvimento Ósseo/fisiologia , Condrócitos/fisiologia , Dexametasona/farmacologia , Fator de Crescimento Insulin-Like I/fisiologia , Interleucina-1beta/farmacologia , Transdução de Sinais/fisiologia , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Linhagem Celular , Condrócitos/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Ossos do Metatarso/efeitos dos fármacos , Ossos do Metatarso/embriologia , Camundongos , Técnicas de Cultura de Órgãos , Transdução de Sinais/efeitos dos fármacos
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