RESUMEN
BACKGROUND: Type 2 diabetes in young people is an aggressive disease with a greater risk of complications leading to increased morbidity and mortality during the most productive years of life. Prevalence in the UK and globally is rising yet experience in managing this condition is limited. There are no consensus guidelines in the UK for the assessment and management of paediatric type 2 diabetes. METHODS: Multidisciplinary professionals from The Association of Children's Diabetes Clinicians (ACDC) and the National Type 2 Diabetes Working Group reviewed the evidence base and made recommendations using the Grading Of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. RESULTS AND DISCUSSION: Young people with type 2 diabetes should be managed within a paediatric diabetes team with close working with adult diabetes specialists, primary care and other paediatric specialties. Diagnosis of diabetes type can be challenging with many overlapping features. Diabetes antibodies may be needed to aid diagnosis. Co-morbidities and complications are frequently present at diagnosis and should be managed holistically. Lifestyle change and metformin are the mainstay of early treatment, with some needing additional basal insulin. GLP1 agonists should be used as second-line agents once early ketosis and symptoms are controlled. Glycaemic control improves microvascular but not cardiovascular risk. Reduction in excess adiposity, smoking prevention, increased physical activity and reduction of hypertension and dyslipidaemia are essential to reduce major adverse cardiovascular events. CONCLUSIONS: This evidence-based guideline aims to provide a practical approach in managing this condition in the UK.
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Diabetes Mellitus Tipo 2 , Metformina , Adulto , Humanos , Niño , Adolescente , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/terapia , Comorbilidad , Obesidad , Reino Unido/epidemiologíaRESUMEN
AIMS: To estimate the incidence of Type 2 diabetes in children aged <17 years, compare this with similar data 10 years ago, and characterize clinical features at diagnosis in the UK and Republic of Ireland. METHODS: Using the British Paediatric Surveillance Unit reporting framework, cases of Type 2 diabetes diagnosed in children aged <17 years between 1 April 2015 and 30 April 2016 were reported each month. RESULTS: A total of 106 cases were reported, giving a UK incidence of 0.72/100 000 (95% CI 0.58-0.88). Children from ethnic minorities had significantly higher incidence compared with white children (0.44/100 000) with rates of 2.92/100 000 and 1.67/100 000, in Asian and BACBB (black/African/Caribbean/black British) children respectively. Sixty-seven percent were girls and 81% had a family history of Type 2 diabetes. The mean BMI sd score at diagnosis was 2.89 (2.88, girls; 2.92, boys); 81% were obese. Children of Asian ethnicity had a significantly lower BMI sd score compared with white children (P<0.001). There was a trend in increased incidence from 2005 to 2015, with a rate ratio of 1.35 (95% CI 0.99-1.84), although this was not statistically significant (P=0.062). There was statistical evidence of increased incidence among girls (P=0.03) and children of South-Asian ethnicity (P=0.01) when comparing the 2005 and 2015 surveys. CONCLUSIONS: Type 2 diabetes remains far less common than Type 1 diabetes in childhood in the UK, but the number of cases continues to rise, with significantly increased incidence among girls and South-Asian children over a decade. Female gender, family history, non-white ethnicity and obesity were found to be strongly associated with the condition.
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Diabetes Mellitus Tipo 2/epidemiología , Adolescente , Asia/etnología , Índice de Masa Corporal , Niño , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/etnología , Femenino , Humanos , Incidencia , Irlanda/epidemiología , Masculino , Obesidad Infantil/epidemiología , Obesidad Infantil/etnología , Estudios Prospectivos , Distribución por Sexo , Encuestas y Cuestionarios , Reino Unido/epidemiología , Indias Occidentales/etnología , Población Blanca/etnologíaRESUMEN
Wolcott-Rallison Syndrome is the commonest cause of neonatal diabetes in consanguineous families. It is associated with liver dysfunction, epiphyseal dysplasia, and developmental delay. It is caused by mutations in eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3).We report 4 children with WRS and Os Odontoideum resulting in significant neurological compromise. This cervical spine abnormality has not previously been described in this syndrome. This additional evidence broadens the clinical spectrum of this syndrome and confirms the role of EIF2AK3 in skeletal development. Furthermore, Os Odontoideum needs to be actively screened for in WRS patients to prevent neurological and respiratory compromise.
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Diabetes Mellitus Tipo 1/diagnóstico , Epífisis/anomalías , Osteocondrodisplasias/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Diabetes Mellitus Tipo 1/diagnóstico por imagen , Diabetes Mellitus Tipo 1/genética , Epífisis/diagnóstico por imagen , Exones/genética , Femenino , Humanos , Lactante , Masculino , Mutación , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/genética , Radiografía , Adulto Joven , eIF-2 Quinasa/genéticaRESUMEN
Thyroid hormones are essential for the normal growth and development of the fetus, and even small alterations in maternal thyroid hormone status during early pregnancy may be associated with neurodevelopmental abnormalities in childhood. Mutations in the novel and specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) have been associated with severe neurodevelopmental impairment. However, the mechanism by which MCT8 influences neural development remains poorly defined. We have therefore investigated the effect of wild-type (WT) MCT8, and the previously reported L471P mutant, on the growth and function of human neuronal precursor NT2 cells as well as MCT8-null JEG-3 cells. HA-tagged WT MCT8 correctly localized to the plasma membrane in NT2 cells and increased T(3) uptake in both cell types. In contrast, L471P MCT8 was largely retained in the endoplasmic reticulum and displayed no T(3) transport activity. Transient overexpression of WT and mutant MCT8 proteins failed to induce endoplasmic reticular stress or apoptosis. However, MCT8 overexpression significantly repressed cell proliferation in each cell type in both the presence and absence of the active thyroid hormone T(3) and in a dose-dependent manner. In contrast, L471P MCT8 showed no such influence. Finally, small interfering RNA depletion of endogenous MCT8 resulted in increased cell survival and decreased T(3) uptake. Given that T(3) stimulated proliferation in embryonic neuronal NT2 cells, whereas MCT8 repressed cell growth, these data suggest an entirely novel role for MCT8 in addition to T(3) transport, mediated through the modulation of cell proliferation in the developing brain.
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Transportadores de Ácidos Monocarboxílicos/fisiología , Neuronas/citología , Neuronas/metabolismo , Transporte Biológico/genética , Transporte Biológico/fisiología , Western Blotting , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular , Proliferación Celular , Supervivencia Celular/genética , Cristalinas/genética , Retículo Endoplásmico , Técnica del Anticuerpo Fluorescente , Vectores Genéticos , Humanos , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Musculares/genética , Proteínas Musculares/fisiología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/fisiología , Simportadores , Triyodotironina/metabolismo , Cristalinas muRESUMEN
OBJECTIVE: To report the 1-year outcome for children newly diagnosed as having type 2 diabetes in the UK. DESIGN: Follow-up study of a UK national cohort. SUBJECTS: All children under the age of 17 years diagnosed as having type 2 diabetes from 1 October 2004 to 31 October 2005 (inclusive). RESULTS: Follow-up data were available for 73 of the 76 cases. The mean age at follow-up was 14.5 years, with mean duration of diabetes 1 year. The revised incidence of type 2 diabetes in the UK in children under 17 years is 0.6/100 000/year. The mean body mass index (BMI) SDS at diagnosis was 2.89, and mean change at 1 year was -0.11 (range -1.53 to +1.37). At 1 year, only 58% achieved the American Diabetes Association/European Association for the Study of Diabetes recommended treatment target (glycated haemoglobin < or =7.0%). There was no relation between improvement in BMI and improvement in glycated haemoglobin. There was wide variation in choice of treatments and regimens. Hypertension is a common comorbidity (34%), whereas early nephropathy appears to be rare (4%). Evidence of polycystic ovarian disease was common in girls (26%). 22% of children had not been screened for nephropathy or retinopathy during the first year after diagnosis. CONCLUSIONS: The 3.8% mean reduction in BMI SDS in the first year after diagnosis indicates that many children find it hard to make the necessary lifestyle changes needed to positively affect metabolic health. Physicians are using a wide variety of treatment regimens, which are relatively effective in achieving glycaemic targets, but systematic screening for complications is incomplete. There is an urgent need to develop an evidence base for effective treatment and management protocols to reduce the risks of long-term microvascular and macrovascular complications.
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Diabetes Mellitus Tipo 2/terapia , Adolescente , Índice de Masa Corporal , Niño , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Quimioterapia Combinada , Métodos Epidemiológicos , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipertensión/epidemiología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Irlanda/epidemiología , Masculino , Metformina/uso terapéutico , Síndrome del Ovario Poliquístico/epidemiología , Resultado del Tratamiento , Reino Unido/epidemiología , Pérdida de PesoRESUMEN
AIMS: Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes where correct diagnosis alters treatment, prognosis and genetic counselling. The first UK survey of childhood MODY identified 20 White, but no Asian children with MODY. We hypothesized that MODY causes diabetes in UK Asians, but is underdiagnosed. METHODS: Children with dominant family histories of diabetes were recruited. Direct sequencing for mutations in the two most common MODY genes; HNF1A (TCF1) and GCK was performed in autoantibody-negative probands. We also compared MODY testing data for Asian and White cases from the Exeter MODY database, to 2001 UK census data. RESULTS: We recruited 30 families and identified three Asian families with MODY gene mutations (two HNF1A, one GCK) and three White UK families (two HNF1A, one GCK). Heterozygous MODY phenotypes were similar in Asians and Whites. Only eight (0.5%) of 1369 UK referrals for MODY testing were known to be Asian, but in 2001 Asians represented 4% of the English/Welsh population and have a higher prevalence of diabetes. CONCLUSIONS: We identified three cases of childhood MODY in UK Asians and demonstrated reduced rates of MODY testing in Asians, which has negative implications for treatment. It is unclear why this is. MODY should be considered in autoantibody-negative Asian diabetes patients lacking evidence of insulin resistance.
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Pueblo Asiatico/genética , Diabetes Mellitus Tipo 2/diagnóstico , Glucoquinasa/genética , Factor Nuclear 1-alfa del Hepatocito/genética , Mutación/genética , Polimorfismo Genético , Adolescente , Niño , Preescolar , Diabetes Mellitus Tipo 2/genética , Femenino , Humanos , Masculino , LinajeRESUMEN
CONTEXT: Alström syndrome (AS) is a monogenic form of infancy-onset obesity and insulin resistance, caused by ALMS1 mutations. The natural history of the insulin resistance is unknown, in particular how this relates to changes in body composition. It is also unclear how ALMS1 mutations relate to the characteristic phenotype. OBJECTIVES: Our objectives were to characterize body composition and metabolic parameters, to establish ALMS1 mutation spectrum of United Kingdom AS patients, and to determine whether a genotype-phenotype correlation exists. DESIGN AND PATIENTS: We conducted a cross-sectional cohort study of 12 unrelated subjects with AS. Age-standardized body composition was assessed by anthropometry and dual-energy x-ray absorptiometry and insulin sensitivity by homeostasis model assessment. The exons and intron-exon boundaries of ALMS1 were directly sequenced. SETTING: The study was performed during the annual Alström Syndrome UK multidisciplinary screening clinic. RESULTS: AS patients have early-onset obesity, but body mass index, waist circumference, and body fat from dual-energy x-ray absorptiometry were negatively correlated with age (r = -0.37, P = 0.2; r = -0.84, P = 0.002; and r = -0.6, P = 0.05). Despite this, insulin resistance increased, demonstrated by raised fasting insulin and fall in homeostasis model assessment insulin sensitivity with age (r = -0.64, P = 0.02). ALMS1 mutations were identified in 10 of 12 patients, with a potential founder mutation in exon 16 present in five [np 10775del (C); Del3592fs/ter3597]. No genotype-phenotype correlation was observed. CONCLUSIONS: We identified mutations in ALMS1 in more than 80% of patients with no genotype-phenotype correlation. In AS, severe childhood obesity, waist circumference, and body fat decrease with age, whereas insulin resistance increases. The abdominal obesity, insulin resistance, diabetes, hypertriglyceridemia, and hypertension suggest that AS could represent a monogenic model for the metabolic syndrome.
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Envejecimiento , Composición Corporal , Diabetes Mellitus/genética , Mutación , Obesidad/genética , Proteínas/genética , Absorciometría de Fotón , Tejido Adiposo , Adolescente , Adulto , Antropometría , Índice de Masa Corporal , Proteínas de Ciclo Celular , Niño , Preescolar , Análisis Mutacional de ADN , Diabetes Mellitus/fisiopatología , Femenino , Efecto Fundador , Genotipo , Pérdida Auditiva Sensorineural/genética , Humanos , Hiperinsulinismo/genética , Hipertensión/genética , Hipertrigliceridemia/genética , Resistencia a la Insulina/genética , Masculino , Obesidad/fisiopatología , Fenotipo , Síndrome , Reino UnidoRESUMEN
AIMS/HYPOTHESIS: Alström syndrome is a rare monogenic disorder characterised by retinal dystrophy, deafness and obesity. Patients also have insulin resistance, central obesity and dyslipidaemia, thus showing similarities with type 2 diabetes. Rare mutations in the ALMS1 gene cause severe gene disruption in Alström patients; however, ALMS1 gene polymorphisms are common in the general population. The aim of our study was to determine whether common variants in ALMS1 contribute to susceptibility to type 2 diabetes in the UK population. METHODS: Direct sequencing was performed on coding regions and intron/exon boundaries of the ALMS1 gene in 30 unrelated probands with type 2 diabetes. The linkage disequilibrium (LD; D' and r2) and haplotype structure were examined for the identified variants. The common (minor allele frequency [MAF] >5%) single-nucleotide polymorphisms tagging the common haplotypes (tagged SNPs [tSNPs]) were identified and genotyped in 1985 subjects with type 2 diabetes, 2,047 control subjects and 521 families. RESULTS: We identified 18 variants with MAF between 6 and 38%. Three SNPs efficiently tagged three common haplotypes (rs1881245, rs3820700 and rs1320374). There was no association (all p > 0.05) between the tSNPs and type 2 diabetes in the case-control study and minor alleles of the tSNPs were not overtransmitted to probands with type 2 diabetes in the family study. CONCLUSIONS/INTERPRETATION: Common variations in the ALMS1 gene were not associated with type 2 diabetes in a large study of a white UK population.
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Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Variación Genética , Proteínas/genética , Adulto , Proteínas de Ciclo Celular , Sordera/genética , Dislipidemias/genética , Exones , Femenino , Humanos , Resistencia a la Insulina/genética , Masculino , Persona de Mediana Edad , Obesidad/genética , Síndrome , Reino Unido , Población Blanca/genéticaRESUMEN
AIM: To measure the relationship between perceived child competence, parental self-efficacy, and children's glycaemic control. METHODS: Cross-sectional outpatient based questionnaire survey of 78 parents of children aged 6-12 years with insulin dependent diabetes mellitus, diagnosed for at least one year. Parental perceptions of their child's competence were assessed, together with parental perceptions of their own self-efficacy in managing their child's diabetes. Glycaemic control was assessed by the average annual HbA1C level. RESULTS: The response rate was 64.5% (51 parents); 82% were mothers and the socioeconomic class and ethnicity spread was representative of the general population. The mean age of the children was 10 years and duration of diabetes 4.4 years. Poorer glycaemic control was associated with higher perceived child competence, together with lower perceived age of responsibility, lower perceived seriousness, and less frequent blood tests. Higher parental self-efficacy and higher perceived child competence predicted a higher level of normalisation, as did lower perceived seriousness, a lower perceived parental responsibility for management, and a less protective style of parenting. CONCLUSION: Parents' perceptions of their children's diabetes are significantly related to glycaemic control; however, those who appear more competent at managing diabetes may overestimate their child's capabilities, leading to poorer glycaemic control.
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Actitud , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus/terapia , Padres/psicología , Niño , Estudios Transversales , Diabetes Mellitus/psicología , Femenino , Humanos , Masculino , Relaciones Padres-Hijo , AutoeficaciaRESUMEN
AIM: To assess the factors determining patient choice of GH device, and whether offering free patient choice improves compliance with GH therapy. METHODS: A prospective cross-sectional study performed on patients offered free choice of GH device in a regional growth clinic. In a subgroup having home delivery, GH compliance was assessed using ampoule counts. RESULTS: 125 patients (74 (59%) male), median (range) 9.30 (1.0-18.3) years were commenced on GH from January 2001 to March 2004, and offered free choice of device. 68 (54%) chose a needled device, and 57 (46%) needle-free. There was no statistical difference in age, sex or diagnostic category between the two groups. Light blue devices were more likely to be chosen by males (p=0.056). Questionnaires giving reasons for choosing a device were available in 40, and a further 50 gave reasons for both choosing a specific device and not choosing others. Other than choice of needled/needle-free device, the factor most likely to determine choice was 'ease of use'. Only 6 (4.8%) subsequently changed device, and compliance remained high but unchanged at approximately 90%. CONCLUSIONS: There are no specific features which determine what GH device a patient will choose. For those units offering free patient choice, a wide range of different devices should be made available.
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Terapia de Reemplazo de Hormonas/métodos , Hormona de Crecimiento Humana/administración & dosificación , Adolescente , Niño , Preescolar , Conducta de Elección , Estudios de Cohortes , Femenino , Humanos , Lactante , Inyecciones Subcutáneas , Masculino , Cooperación del Paciente , Estudios ProspectivosRESUMEN
BACKGROUND: Diabetic ketoacidosis (DKA) is a common mode of presentation of diabetes mellitus in children, accounting for 26% of new cases. Rarely, children with diabetes may develop other forms of metabolic decompensation associated with hyperglycaemia and hyperosmolality. Hyperglycaemia and hyperosmolality without ketoacidosis has high mortality in adults, although there is no data on mortality in children. CASE REPORTS: We describe three children who presented to Birmingham Children's Hospital and were initially suspected to have DKA. Each child was severely hyperglycaemic and hyperosmolar but without significant ketosis or acidosis. In two of the three children, the hyperosmolar state was associated with the ingestion of large volumes of high calorie fluids preceding the presentation. These children were exquisitely sensitive to insulin and may be at a significantly higher risk of cerebral oedema in view of their hyperosmolar state. CONCLUSIONS: Hyperosmolar hyperglycaemia is a serious and rare complication at presentation of diabetes in children, and should be distinguished from DKA. These children are at an increased risk of cerebral oedema compared with DKA, and one should have a low threshold for suspicion of this complication.
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Diabetes Mellitus Tipo 1/complicaciones , Coma Hiperglucémico Hiperosmolar no Cetósico/terapia , Adolescente , Edema Encefálico/prevención & control , Cetoacidosis Diabética/diagnóstico , Femenino , Humanos , Coma Hiperglucémico Hiperosmolar no Cetósico/complicaciones , Coma Hiperglucémico Hiperosmolar no Cetósico/diagnóstico , Masculino , Resultado del TratamientoRESUMEN
Type 2 diabetes mellitus is caused by a combination of insulin resistance and beta cell failure. The polygenic nature of type 2 diabetes has made it difficult to study. Although many candidate genes for this condition have been suggested, in most cases association studies have been equivocal. Monogenic forms of diabetes have now been studied extensively, and the genetic basis of many of these syndromes has been elucidated, leading to greater understanding of the functions of the genes involved. Common variations in the genes causing monogenic disorders have been associated with susceptibility to type 2 diabetes in several populations and explain some of the linkage seen in genome-wide scans. Monogenic disorders are also helpful in understanding both normal and disordered glucose and insulin metabolism. Three main areas of defect contribute to diabetes: defects in insulin signalling leading to insulin resistance; defects of insulin secretion leading to hypoinsulinaemia; and apoptosis leading to decreased beta cell mass. These three pathological pathways are reviewed, focusing on rare genetic syndromes which have diabetes as a prominent feature. Apoptosis seems to be a final common pathway in both type 1 and type 2 diabetes. Study of rare forms of diabetes may help ion determining new therapeutic targets to preserve or increase beta cell mass and function.
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Homeostasis , Resistencia a la Insulina , Células Secretoras de Insulina/metabolismo , Animales , Apoptosis , Variación Genética , Humanos , Síndrome Metabólico/patología , Modelos Biológicos , Transducción de Señal , SíndromeRESUMEN
We describe a novel homozygous missense glucokinase mutation (R397L) resulting in insulin-treated neonatal diabetes in an infant from a consanguineous Asian family. Both parents were heterozygous for R397L and had mild hyperglycemia. Glucokinase mutations should be considered in infants of all ethnic groups with neonatal diabetes and consanguinity.
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Pueblo Asiatico , Diabetes Mellitus Tipo 1/genética , Glucoquinasa/genética , Mutación Missense/genética , Consanguinidad , Femenino , Homocigoto , Humanos , Recién Nacido , Pakistán/etnología , LinajeRESUMEN
OBJECTIVES: Mutations in the genes encoding the transcription factors PROP1 and POUF-1 (Pit-1) have been reported as common causes of combined pituitary hormone deficiency (CPHD), and HESX1 mutations have been identified in children with septo-optic dysplasia (SOD). There are few data on UK children. We have performed mutation analysis in a large cohort of affected children within the West Midlands region to assess the feasibility of a screening strategy for molecular diagnosis in CPHD and SOD. DESIGN AND PATIENTS: The three coding exons of PROP1, and six exons of POUF-1 in 27 children from 26 families with CPHD, and three exons of HESX1 in 23 children from 22 families with SOD were directly sequenced from a well-characterized regional cohort. RESULTS: We identified a C to T transition in exon 6 of POUF-1, resulting in a known missense mutation (R271W) in a mother and daughter from one family with CPHD. We also found a novel homozygous T to C transition in exon 6 of POUF-1, resulting in a missense mutation (F233L) in a twin with CPHD. This mutation was excluded in 100 ethnically matched control alleles. We did not identify any mutations in the PROP1 gene or HESX1. The median maternal age at delivery for the CPHD children was 27 years, compared to 21 years for the mothers of SOD children (P = 0.04). CONCLUSIONS: Mutations in POUF-1, PROP1 and HESX1 are rare causes of CPHD and SOD, respectively, in children from the West Midlands. In particular, we did not confirm the reported 'hotspot' in PROP1. A screening strategy that targets familial cases is highly likely to increase the mutation yield. The young maternal age at conception of children with SOD and potential teratogen exposure indicate the predominance of environmental factors in this condition compared with CPHD.
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Proteínas de Unión al ADN/genética , Proteínas de Homeodominio/genética , Hormonas Hipofisarias/deficiencia , Polimorfismo Genético , Displasia Septo-Óptica/genética , Factores de Transcripción/genética , Niño , Preescolar , Análisis Mutacional de ADN , Inglaterra , Femenino , Humanos , Hipopituitarismo/genética , Hipopituitarismo/patología , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Edad Materna , Hipófisis/patología , Estudios Prospectivos , Displasia Septo-Óptica/patología , Teratógenos/toxicidad , Factor de Transcripción Pit-1RESUMEN
Over the past 30 years it has become apparent that not all diabetes presenting in childhood is autoimmune type 1. Increasingly type 2 diabetes, maturity onset diabetes of the young, iatrogenic diabetes, and rare syndromic forms of diabetes such as Wolfram's syndrome have been identified in children. This review is aimed at the general paediatrician looking after children with diabetes, and aims to provide an algorithm for assessment, investigation, and suggested management for the newly diagnosed child with suspected non-type 1 diabetes. This article will also be relevant to the child with atypical diabetes-that is, on low insulin doses outside the honeymoon period.
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Diabetes Mellitus/diagnóstico , Niño , Complicaciones de la Diabetes/diagnóstico , Diabetes Mellitus/terapia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/diagnóstico , Diagnóstico Diferencial , Humanos , Resistencia a la InsulinaRESUMEN
BACKGROUND: Wolcott-Rallison syndrome is a rare autosomal recessive condition characterized by early infancy onset diabetes mellitus and multiple epiphyseal dysplasia. So far, 17 children have been described in the world literature. Recently, mutations in the gene encoding EIF2AK3 have been shown to segregate with the syndrome in three affected families. AIMS: We aimed to describe the clinical characterization and mutation analysis of a further child, and full clinical and follow-up details on our first family including the longest surviving child. METHODS: Retrospective case notes review of three children presenting to the diabetic unit at our institution; mutation analysis of the EIF2AK3 gene in our most recent patient; and review of the literature on Wolcott-Rallison syndrome. RESULTS: Previously unreported phenotypic features in our patients included developmental regression after episodes of hepatic failure, and pachygyria on brain imaging. We have identified a novel 4-base pair deletion (nt 3021-3024 del GAGA) in exon 13, which results in a frameshift and premature stop codon (R908 F/S +22X), causing premature truncation of the protein and abolition of the carboxy-segment of the catalytic domain. CONCLUSIONS: Wolcott-Rallison syndrome causes early-onset diabetes and acute hepatic failure, before epiphyseal dysplasia is manifest. We have identified a novel mutation in EIF2AK3, and prenatal diagnosis may now be offered to affected families.
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Codón sin Sentido/genética , Diabetes Mellitus Tipo 1/genética , Osteocondrodisplasias/genética , eIF-2 Quinasa/genética , Adolescente , Preescolar , Discapacidades del Desarrollo/etiología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/patología , Femenino , Trastornos del Crecimiento/etiología , Humanos , Lactante , Hepatopatías/etiología , Masculino , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/patología , SíndromeRESUMEN
AIMS: To estimate the UK prevalence of childhood type 2 diabetes and maturity onset diabetes of the young (MODY), and distinguish them from each other and from type 1 diabetes. METHODS: The British Society for Paediatric Endocrinology and Diabetes Clinical Trials/Audit Group undertook a cross-sectional questionnaire survey of all paediatric diabetes centres during 2000, collecting data on all children with non-type 1 diabetes. RESULTS: Of 112 children reported to the survey, 25 had type 2 diabetes and 20 had MODY. In contrast to type 1, type 2 patients presented later (12.8 v 9.3 years), were usually female, overweight, or obese (92% v 28%), and a greater proportion were of ethnic minority origin (56% v 22%). In contrast to type 2, MODY patients were younger (10.8 years), less likely to be overweight or obese (50% v 92%), and none were from ethnic minority groups. The crude minimum UK prevalence of type 2 diabetes under 16 years is 0.21/100 000, and of MODY is 0.17/100 000. South Asian children have a relative risk of type 2 diabetes of 13.7 compared to white UK children. CONCLUSIONS: UK children still have a low prevalence of type 2 diabetes. Children from ethnic minorities are at significantly higher risk, but in white UK children with non-type 1 diabetes a diagnosis of MODY is as likely as type 2 diabetes. Childhood type 2 diabetes is characterised by insulin resistance, and is distinct from both type 1 and MODY.
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Diabetes Mellitus Tipo 2/epidemiología , Adolescente , Niño , Estudios Transversales , Recolección de Datos , Diabetes Mellitus/epidemiología , Etnicidad , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Obesidad , Factores de Riesgo , Encuestas y Cuestionarios , Reino Unido/epidemiologíaAsunto(s)
Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus/etiología , Adolescente , Factores de Edad , Asia/etnología , Pueblo Asiatico , Índice de Masa Corporal , Peso Corporal/etnología , Peso Corporal/fisiología , Niño , Preescolar , Diabetes Mellitus/etnología , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/etnología , Femenino , Humanos , Resistencia a la Insulina , Masculino , Reino Unido , Población BlancaRESUMEN
Inherited diabetes syndromes are individually rare but collectively make up a significant proportion of patients attending diabetes clinics, some of whom have multiple handicaps. This chapter focuses on syndromes in which major advances have been made in our understanding of the underlying molecular genetics. These conditions demonstrate novel genetic mechanisms such as maternal inheritance and genetic imprinting. They are also fascinating as they aid our understanding of insulin metabolism, both normal and abnormal. As the causative genes are identified, future issues will be the availability of genetic testing, their contribution to the genetic heterogeneity of the more common types of diabetes, and functional studies of the relevant proteins. It is probable that other subtypes of diabetes will be identified as the relevant metabolic pathways are characterized. This is an exciting time to be a diabetes physician as diabetology returns to being a diagnostic rather than a mainly management-based speciality.