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1.
Brain ; 142(11): 3382-3397, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31637422

RESUMO

CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain.

2.
JCI Insight ; 3(7)2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29618660

RESUMO

BACKGROUND: The effect of gene expression data on diagnosis remains limited. Here, we show how diagnosis and classification of growth hormone deficiency (GHD) can be achieved from a single blood sample using a combination of transcriptomics and random forest analysis. METHODS: Prepubertal treatment-naive children with GHD (n = 98) were enrolled from the PREDICT study, and controls (n = 26) were acquired from online data sets. Whole blood gene expression was correlated with peak growth hormone (GH) using rank regression and a random forest algorithm tested for prediction of the presence of GHD and in classification of GHD as severe (peak GH <4 µg/l) and nonsevere (peak ≥4 µg/l). Performance was assessed using area under the receiver operating characteristic curve (AUC-ROC). RESULTS: Rank regression identified 347 probe sets in which gene expression correlated with peak GH concentrations (r = ± 0.28, P < 0.01). These 347 probe sets yielded an AUC-ROC of 0.95 for prediction of GHD status versus controls and an AUC-ROC of 0.93 for prediction of GHD severity. CONCLUSION: This study demonstrates highly accurate diagnosis and disease classification for GHD using a combination of transcriptomics and random forest analysis. TRIAL REGISTRATION: NCT00256126 and NCT00699855. FUNDING: Merck and the National Institute for Health Research (CL-2012-06-005).


Assuntos
Perfilação da Expressão Gênica , Transtornos do Crescimento/diagnóstico , Hormônio do Crescimento Humano/deficiência , Aprendizado de Máquina , Adolescente , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Conjuntos de Dados como Assunto , Feminino , Redes Reguladoras de Genes , Transtornos do Crescimento/sangue , Transtornos do Crescimento/genética , Voluntários Saudáveis , Hormônio do Crescimento Humano/sangue , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Análise de Componente Principal , Curva ROC , Índice de Gravidade de Doença , Transcriptoma/genética
3.
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
4.
Lancet Diabetes Endocrinol ; 6(7): 564-574, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29397377

RESUMO

Short stature is a common presentation to paediatric endocrinologists. After exclusion of major endocrine or systemic disease, most children with short stature are diagnosed based on a description of their growth pattern and the height of their parents (eg, familial short stature). Height is a polygenic trait and genome-wide association studies have identified many of the associated genetic loci. Here we review the application of genetic studies, including copy number variant analysis, targeted gene panels, and whole-exome sequencing in children with idiopathic short stature. We estimate 25-40% of children diagnosed with idiopathic short stature could receive a molecular diagnosis using these technologies. A molecular diagnosis for short stature is important for affected individuals and their families and might inform treatment decisions surrounding use of growth hormone or insulin-like growth factor 1 therapy.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Criança , Dosagem de Genes , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Mutação , Sequenciamento Completo do Exoma
5.
Endocr Connect ; 7(3): R126-R134, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29483159

RESUMO

OBJECTIVE: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. PARTICIPANTS: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. EVIDENCE: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. CONSENSUS PROCESS: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. CONCLUSIONS: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly.

6.
Arch Dis Child ; 103(10): 984-986, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29330170

RESUMO

BACKGROUND: A subnormal cortisol response (30 min level (C30min)<550 nmol/L) to synthetic adrenocorticotrophic hormone/Synacthen test (SDST) in all infants does not necessarily indicate underlying or persistent hypothalamic-pituitary-adrenal axis pathology. METHODS: We retrospectively evaluated the diagnoses and outcomes in 68 infants who had a SDST at age <6 months from 2011 to 2014. RESULTS: 29 (43%) infants had a subnormal SDST. Causative pathology was identified in 9/29 (31%). In 20/29 (69%) with no identified pathology, repeat SDST was normal in 18/20 (90%) at median age 0.6 (range 0.1-3.2) years but persistently subnormal in 2. Those with a transient abnormality were more likely to be small for gestational age (P=0.03) and had higher initial SDST C30min (390 nmol/L vs 181 nmol/L, P=0.01) than those with pathology. CONCLUSION: Specific aetiology can be identified in a third of infants with a subnormal SDST. When the aetiology remains elusive, adrenal function should be reassessed as the problem can be transient.


Assuntos
Insuficiência Adrenal , Cosintropina/farmacologia , Técnicas de Diagnóstico Endócrino , Recém-Nascido Prematuro/sangue , Córtex Suprarrenal/metabolismo , Insuficiência Adrenal/sangue , Insuficiência Adrenal/diagnóstico , Diagnóstico Diferencial , Feminino , Idade Gestacional , Hormônios/farmacologia , Humanos , Lactente , Masculino
7.
Endocr Dev ; 32: 74-86, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28873385

RESUMO

Ghrelin is a pleiotropic hormone, whose effect on growth hormone secretion, through the growth hormone secretagogue (GHS) receptor, is one of its many actions. Relationships between GHS receptor gene variants and human height, both in healthy individuals and in patients with growth disorders have been identified. These include constitutional delay in growth and puberty, idiopathic short stature, and isolated growth hormone deficiency. In this review, we provide an overview of the role of ghrelin in growth.


Assuntos
Grelina/fisiologia , Crescimento/fisiologia , Adolescente , Animais , Estatura/genética , Criança , Pré-Escolar , Variação Genética , Grelina/sangue , Grelina/genética , Transtornos do Crescimento/genética , Hormônio Liberador de Hormônio do Crescimento , Hormônio do Crescimento Humano/metabolismo , Humanos , Hormônios Peptídicos , Puberdade Tardia/genética , Receptores de Grelina/genética , Receptores de Grelina/fisiologia , Maturidade Sexual
8.
Cell Death Dis ; 8(6): e2875, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28617445

RESUMO

BRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse. We modeled acquired cross-linker resistance with an FA-derived BRCA2-mutated acute myeloid leukemia (AML) platform. Associated with acquired cross-linker resistance was the expression of a functional BRCA2 protein variant lacking exon 5 and exon 7 (BRCA2ΔE5+7), implying a role for BRCA2 splicing for acquired chemo-resistance. Integrated network analysis of transcriptomic and proteomic differences for phenotyping of BRCA2 disruption infers impact on transcription and chromatin remodeling in addition to the DNA damage response. The striking overlap with transcriptional profiles of FA patient hematopoiesis and BRCA mutation associated ovarian cancer helps define and explicate the 'BRCAness' profile.


Assuntos
Processamento Alternativo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Resistencia a Medicamentos Antineoplásicos , Genes BRCA2 , Mutação , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Dano ao DNA , Éxons , Anemia de Fanconi/tratamento farmacológico , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Íntrons , Células K562 , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fenótipo , Processamento de RNA , Transcrição Genética
9.
Eur J Endocrinol ; 176(3): 359-369, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28073908

RESUMO

OBJECTIVES: The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades. METHODS: Meta-data was retrospectively reviewed over two periods before (1973-2000 (Group A: n = 100)) and after (1998-2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre. RESULTS: Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P < 0.001) and panhypopituitarism (P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged. CONCLUSION: The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes.


Assuntos
Craniofaringioma/patologia , Craniofaringioma/cirurgia , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Hipotálamo/cirurgia , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Reino Unido
10.
JRSM Open ; 7(11): 2054270416653522, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27895928

RESUMO

Vitamin D supplementation for all children <5 is recommended by the UK Department of Health for its skeletal effects. Vitamin D is also linked with a number of extra-skeletal effects; one of them being protection against type 1 diabetes. With a rapid increase in the incidence of type 1 diabetes and the associated costs, measures of curtailing the rapid increase of type 1 diabetes are needed. In this review, we look at type 1 diabetes using a statistical method (PIN-ER-t) and published data in an attempt to quantify the impact on the population of babies born in 2012 of increasing vitamin D supplementation rates. Calculations show that for the population of 729,674 babies born in England and Wales in 2012, 374 cases of type 1 diabetes (out of 1357 total predicted) could be prevented over 18 years if all were supplemented with vitamin D. This could lead to savings in excess of £62 million for the cohort. This piece of work adds to the argument for studying the potential link between vitamin D supplementation and type 1 diabetes further.

11.
J Med Genet ; 53(9): 634-41, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27091925

RESUMO

BACKGROUND: Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis. METHODS: Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed. RESULTS: We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (<9th centile) and similar facial features including a prominent forehead, smooth philtrum and deep-set eyes associated with a recurrent homozygous c.64T>C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly. CONCLUSIONS: Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features-particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry-should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations.


Assuntos
Nanismo/genética , Complexo I de Transporte de Elétrons/genética , Mitocôndrias/genética , Doenças Mitocondriais/genética , Mutação/genética , Criança , Pré-Escolar , Exoma/genética , Facies , Feminino , Estudos de Associação Genética/métodos , Homozigoto , Humanos , Lactente , Masculino , Linhagem , Fenótipo
12.
Pediatr Res ; 80(2): 299-305, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27057740

RESUMO

BACKGROUND: Later life metabolic dysfunction is a well-recognized consequence of being born small for gestational age (SGA). This study has applied metabolomics to identify whether there are changes in these pathways in prepubertal short SGA children and aimed to compare the intracellular and extracellular metabolome in fibroblasts derived from healthy children and SGA children with postnatal growth impairment. METHODS: Skin fibroblast cell lines were established from eight SGA children (age 1.8-10.3 y) with failure of catch-up growth and from three healthy control children. Confluent cells were incubated in serum-free media and the spent growth medium (metabolic footprint), and intracellular metabolome (metabolic fingerprint) were analyzed by gas-chromatography mass spectrometry. RESULTS: Nineteen metabolites were significantly altered between SGA and control cell lines. The greatest fold difference (FD) was seen for alanine (fingerprint FD, SGA: control 0.3, P = 0.01 and footprint FD = 0.19, P = 0.01), aspartic acid (fingerprint FD = 5.21, P = 0.01), and cystine (footprint FD = 1.66, P = 0.02). Network analysis of the differentially expressed metabolites predicted inhibition of insulin as well as growth (ERK) signaling in SGA cells. CONCLUSION: This study indicates that changes in cellular metabolism associated with both growth failure and insulin insensitivity are present in prepubertal short children born SGA.


Assuntos
Aminoácidos/metabolismo , Glicólise , Transtornos do Crescimento/sangue , Recém-Nascido Pequeno para a Idade Gestacional , Alanina/metabolismo , Ácido Aspártico/metabolismo , Estatura , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Idade Gestacional , Transtornos do Crescimento/complicações , Homozigoto , Humanos , Lactente , Insulina/metabolismo , Resistência à Insulina , Masculino , Metaboloma , Metabolômica , Mutação , Pele/metabolismo
13.
Am J Hum Genet ; 98(2): 363-72, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26833329

RESUMO

Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families, and there was dramatic phenotypic overlap among affected individuals who were independently ascertained without bias from clinical features. Analysis of the deletions revealed a ∼350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function. Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area. We show that this finding is consistent with the expression patterns of POU3F2 and related genes in the human brain. Our work helps to further delineate the neuro-endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.


Assuntos
Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Obesidade/genética , Fatores do Domínio POU/genética , Deleção de Sequência , Adolescente , Adulto , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Índice de Massa Corporal , Linhagem Celular , Criança , Pré-Escolar , Cromossomos Humanos Par 6/genética , Modelos Animais de Doenças , Metabolismo Energético , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Hipotálamo/metabolismo , Masculino , Pessoa de Meia-Idade , Ocitocina/metabolismo , Fatores do Domínio POU/metabolismo , Linhagem , Fenótipo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Adulto Jovem , Peixe-Zebra
14.
Artigo em Inglês | MEDLINE | ID: mdl-26903946

RESUMO

BACKGROUND: Congenital hyperinsulinism (CHI) is a rare but severe disorder of hypoglycemia in children, often complicated by brain injury. In CHI, the long-term prevention of hypoglycemia is dependent on reliable enteral intake of glucose. However, feeding problems (FPs) often impede oral glucose delivery, thereby complicating the management of hypoglycemia. FPs have not been systematically characterized in follow-up in a cohort with CHI. AIMS: We aimed to determine the prevalence, types, and persistence of FPs in a cohort of children with CHI and investigate potential causal factors. METHODS: FPs were defined as difficulty with sucking, swallowing, vomiting, and food refusal (or a combination) in an observational study in 83 children in a specialized CHI treatment center. The prevalence of FPs at diagnosis, 6, and 12 months after diagnosis were noted. Genetic mutation status and markers of severity of CHI were tested for association with FPs. RESULTS: A third of children with CHI had FPs (n = 28), of whom 93% required antireflux medication and 75% required nasogastric and gastrostomy tube feeding. Sucking and swallowing problems were present at diagnosis but absent later. Vomiting was present in 54% at 6 months, while food refusal was present in 68% at 6 months and 52% at 12 months. The age at commencing and stopping nasogastric tube feeding did not correlate with FPs frequency at 6 and 12 months. Children with FPs had severe hypoglycemia at diagnosis and required glucagon infusion more often [odds ratio (OR) (95% confidence intervals) (95% CI) 28.13 (2.6-300.1), p = 0.006] to normalize glucose levels. FPs were more frequent in those with diffuse CHI undergoing subtotal pancreatectomy [n (%) = 10 (35%) vs. 0 (0%), p < 0.001], in contrast to those with spontaneous resolution [6 (22%) vs. 32 (58%), p = 0.002]. Those undergoing focal lesionectomy also had reduced FPs at 6 months after diagnosis [OR (95% CI) 0.01 (0.0-0.2), R (2) = 0.42, p = 0.004]. These observations suggest that persistence of hyperinsulinism was associated with FPs. CONCLUSION: FPs occur in a significant proportion of children with CHI. Severe hyperinsulinism, rather than nasogastric tube feeding or medications, is the main factor associated with FPs.

15.
J Pediatr ; 166(1): 191-4, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25444530

RESUMO

Congenital hyperinsulinism causes profound hypoglycemia, which may persist or resolve spontaneously. Among 13 children with congenital hyperinsulinism, elevated incretin hormone concentrations were detected in 2 with atypical, persistent disease. We suggest that incretin biomarkers may identify these patients, and that elevated hormone levels may contribute to their pathophysiology.


Assuntos
Biomarcadores/sangue , Hiperinsulinismo Congênito/sangue , Incretinas/sangue , Canais KATP/genética , Pré-Escolar , Hiperinsulinismo Congênito/genética , Humanos , Lactente , Recém-Nascido , Mutação , Reino Unido
16.
J Mol Endocrinol ; 52(3): 333-44, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24711643

RESUMO

Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.


Assuntos
Antígenos CD/genética , Proteínas de Transporte/genética , Proteínas Culina/genética , Proteínas do Citoesqueleto/genética , Nanismo/genética , Hipotonia Muscular/genética , Receptor de Insulina/genética , Coluna Vertebral/anormalidades , Processamento Alternativo/genética , Proteínas de Transporte/biossíntese , Linhagem Celular Tumoral , Proteínas Culina/biossíntese , Proteínas do Citoesqueleto/biossíntese , Fibroblastos , Perfilação da Expressão Gênica , Transtornos do Crescimento/genética , Células HEK293 , Hormônio do Crescimento Humano/genética , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like II/deficiência , Fator de Crescimento Insulin-Like II/genética , Proteína Supressora de Tumor p53/genética , Ubiquitinação/genética
17.
Eur J Endocrinol ; 170(5): 741-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24599222

RESUMO

BACKGROUND: Insulinomas are a rare cause of hyperinsulinaemic hypoglycaemia (HH) in children. The clinical features, investigations, management and histology of these rare pancreatic tumours in children have not been described in a large cohort of patients. METHODS: We conducted a retrospective review of cases diagnosed between 2000 and 2012, presenting to two referral centres in the United Kingdom. Clinical, biochemical, imaging (magnetic resonance imaging (MRI) and 6-L-¹8F-fluorodihydroxyphenylalanine (¹8F-DOPA) PET/CT scanning) and histological data were collected. RESULTS: Nine children (age range 2-14.5 years) were diagnosed during the study period at Great Ormond Street Hospital (n=5) and Royal Manchester Children's Hospital (n=4). The combination of abdominal MRI scan (7/8) and ¹8F-DOPA PET/CT scan (2/4) correctly localised the anatomical location of all insulinomas. Before surgery, diazoxide therapy was used to treat hypoglycaemia, but only four patients responded. After surgical resection of the insulinoma, hypoglycaemia resolved in all patients. The anatomical localisation of the insulinoma in each patient was head (n=4), uncinate process (n=4) and tail (n=2, one second lesion) of the pancreas. Histology confirmed the diagnosis of insulinoma with the presence of sheets and trabeculae of epithelioid and spindle cells staining strongly for insulin and proinsulin, but not for glucagon or somatostatin. Two children were positive for MEN1, one of whom had two separate insulinoma lesions within the pancreas. CONCLUSIONS: We describe a cohort of paediatric insulinoma patients. Although rare, insulinomas should be included in the differential diagnosis of HH, even in very young children. In the absence of a single imaging modality in the preoperative period, localisation of the tumour is achieved by combining imaging techniques, both conventional and functional.


Assuntos
Insulinoma/cirurgia , Pâncreas/cirurgia , Neoplasias Pancreáticas/cirurgia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Registros Eletrônicos de Saúde , Inglaterra , Feminino , Hospitais Pediátricos , Hospitais Urbanos , Humanos , Hiperinsulinismo/etiologia , Hiperinsulinismo/prevenção & controle , Hipoglicemia/etiologia , Hipoglicemia/prevenção & controle , Insulinoma/diagnóstico , Insulinoma/patologia , Insulinoma/fisiopatologia , Masculino , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/fisiopatologia , Proteínas Proto-Oncogênicas/metabolismo , Cintilografia , Encaminhamento e Consulta , Indução de Remissão , Estudos Retrospectivos , Ultrassonografia
18.
Artigo em Inglês | MEDLINE | ID: mdl-24659984

RESUMO

OBJECTIVE: Congenital hyperinsulinism (CHI) is a rare condition of hypoglycemia where therapeutic options are limited and often complicated by side-effects. Omega-3-polyunsaturated fatty acids (PUFA), which can suppress cardiac myocyte electrical activity, may also reduce ion channel activity in insulin-secreting cells. PUFA supplements in combination with standard medical treatment may improve glucose profile and may reduce glycemic variability in diazoxide-responsive CHI. DESIGN: Open label pilot trial with MaxEPA(R) liquid (eicosapentaenoic and docosahexaenoic acid) PUFA (3 ml/day for 21 days) in diazoxide-responsive CHI patients (https://eudract.ema.europa.eu/, EudraCT number 201100363333). METHODS: Glucose levels were monitored pre-treatment, end of treatment, and at follow-up by subcutaneous continuous glucose monitoring systems (CGMS) in 13 patients (7 girls) who received PUFA. Outcome measures were an improved glucose profile, reduced glycemic variability quantified by a reduction in the frequency of glucose levels <4 and >10 mmol/l, and safety of PUFA. All children were analyzed either as intention to treat (n = 13) or as per protocol (n = 7). RESULTS: Mean (%) CGMS glucose levels increased by 0.1 mmol/l (2%) in intention to treat and by 0.4 mmol/l (8%) in per protocol analysis (n = 7). The frequency of CGMS <4 mmol/l was significantly less at the end of treatment than in the pre-treatment period [556 (7%) vs. 749 (10%)]. Similarly, the frequency of CGMS >10 mmol/l, was also less at the end of treatment [27 (0.3%) vs. 49 (0.7%)]. Except for one child with increased LDL cholesterol, all safety parameters were normal. CONCLUSION: MaxEPA(R) was safe and reduced glycemic variability, but did not increase glucose profiles significantly in diazoxide-responsive CHI. The supplemental value of PUFA should be evaluated in a comprehensive clinical trial.

19.
Arch Dis Child ; 99(2): 158-64, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24225272

RESUMO

OBJECTIVE: Congenital adrenal hyperplasia (CAH) is not currently included in the UK newborn screening programme. We investigated the hypothesis that, owing to non-specificity of symptoms, a proportion of males affected by salt-wasting (SW) CAH have died in infancy without being diagnosed. DESIGN: Stored newborn screening blood spot samples were analysed for 17α-hydroxyprogesterone (17-OHP) in the following groups: Infants born in the North West of England, 1994 to 2006, who had died by 6 months age; (n=1198), a neonatal reference group (full-term n=100; preterm n=100) and a CAH positive control group. A newborn blood spot sample collected before diagnosis was available in 29/61 CAH patients recruited. SW CAH was present in 18/29 patients (16 males and 2 females). Samples from the deceased group with elevated 17-OHP were analysed for 8 common mutations in the 21-hydroxylase gene (CYP21A2). SETTING: North West of England. RESULTS: Grouped by gestational age, mean (maximum) blood spot 17-OHP in nmol/L was as follows. Deceased full-term n=279, 6 (107); deceased premature n=365, 28 (251); deceased unknown gestational age n=553, 13 (>394). In the SW positive control group, the lowest level of 17-OHP was 179 nmol/L and 14 had levels greater than the highest standard (>268 to >420 nmol/L). All samples from the deceased group with 17-OHP results >179 nmol/L (n=6) and a further 13 samples underwent mutation analysis. No mutations were identified. CONCLUSIONS: Our findings do not support the hypothesis that, in our unscreened population, males affected by SW CAH are dying prior to diagnosis.


Assuntos
17-alfa-Hidroxiprogesterona/sangue , Hiperplasia Suprarrenal Congênita/diagnóstico , Triagem Neonatal/estatística & dados numéricos , Mutação Puntual , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/mortalidade , Análise Mutacional de DNA , Inglaterra , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
20.
Hypertension ; 63(1): 167-72, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24126169

RESUMO

We established a maternal birth cohort in Ibadan, Nigeria, where malaria is hyperendemic, to assess how intrauterine exposure to malaria affected infant blood pressure (BP) development. In a local maternity hospital, healthy pregnant women had regular blood films for malaria parasites from booking to delivery. Growth and BP were measured on 318 babies, all followed from birth to 3 and 12 months. Main outcomes were standardized measures of anthropometry and change in BP to 1 year. Babies exposed to maternal malaria were globally smaller at birth, and boys remained smaller at 3 months and 1 year. Change in systolic BP (SBP) during the year was greater in boys than in girls (20.9 versus 15.7 mm Hg; P=0.002) but greater in girls exposed to maternal malaria (18.7 versus 12.7 mm Hg; 95% confidence interval, 1-11 mm Hg; P=0.02). Eleven percent of boys (greater than twice than expected) had a SBP ≥95th percentile (hypertensive, US criteria), of whom 68% had maternal malaria exposure. On regression analysis (ß coefficients, mm Hg), sex (boys>girls; ß=4.4; 95% confidence interval, 1.1-7.7; P=0.01), maternal malaria exposure (3.64; 0.3-6.9; P=0.03), and weight change (2.4; 0.98-3.8/1 standard deviation score; P=0.001) all independently increased SBP change to 1 year, whereas increase in length decreased SBP (-1.98; -3.6 to -0.40). In conclusion, malaria-exposed boys had excess hypertension, whereas malaria-exposed girls a greater increase in SBP. Intrauterine exposure to malaria had sex-dependent effects on BP, independent of infant growth. Because infant-child-adult BP tracking is powerful, a malarial effect may contribute to the African burden of hypertension.


Assuntos
Desenvolvimento Infantil , Hipertensão/etiologia , Malária/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Antropometria , Peso ao Nascer , Pressão Sanguínea , Feminino , Humanos , Lactente , Malária/complicações , Gravidez , Fatores Sexuais
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