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BACKGROUND: The outlook for adolescents with Duchenne muscular dystrophy (DMD) has improved greatly as a result of corticosteroid use, but treatment will compromise growth and delay puberty. Whether exogenous testosterone can promote growth, development, and skeletal health is unclear. METHODS: We collected data retrospectively on growth and pubertal response in 14 adolescents with DMD who were treated with testosterone between 2008 and 2014. RESULTS: A total of 14 boys were treated at a median age of 14.5 years. Eight have finished treatment after a mean age of 3.1 years and the feedback from families was generally positive. The mean testicular volume pretreatment was 2.4 and 3.9 mL posttreatment. The mean baseline testosterone concentrations were < 1.0 and 5.4 nmol/L postintervention. Median height velocity increased from 0.45 cm/y before treatment to 3.6 cm/y after the treatment. The mean height gain was 14.2 cm. CONCLUSIONS: A broad range of testosterone preparations was used. Testosterone was generally well-liked, but side effects were experienced by some patients and the pubertal growth increment appears to be compromised. Few subjects had adult endogenous testosterone levels posttreatment. Controlled studies are required to determine the most appropriate treatment regimen and the precise impact of testosterone on key outcomes, such as muscle function and bone integrity. Clinicians will then be better placed to advise families about likely benefits and risks.
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Distrofia Muscular de Duchenne/tratamiento farmacológico , Pubertad Tardía/tratamiento farmacológico , Testosterona/uso terapéutico , Adolescente , Estatura/efectos de los fármacos , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Masculino , Distrofia Muscular de Duchenne/complicaciones , Pubertad Tardía/etiología , Estudios Retrospectivos , Testosterona/efectos adversosRESUMEN
Disorders of calcium homeostasis are uncommon but important because of the broad spectrum of potential underlying causes that lie on a spectrum from the benign to the life-threatening. Paediatricians may find them challenging because they do not arise often enough for the investigative approach to be second nature. We report a 4-year-old with acute onset profound hypercalcaemia. We focus on an approach to the clinical problem that is based on the potential organ systems affected, namely the gut, bone and kidney. Key biochemical parameters that may help the paediatric team to reach a diagnosis are discussed, as well as important components of acute management.
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Huesos/metabolismo , Calcio/sangre , Hipercalcemia/diagnóstico , Enfermedad Aguda , Preescolar , Diagnóstico Diferencial , Humanos , Hipercalcemia/etiología , Hipercalcemia/terapia , Absorción Intestinal , Riñón/metabolismo , Cálculos Renales/metabolismo , MasculinoRESUMEN
Vitamin D insufficiency and deficiency are widespread in many countries. We review the evidence pertaining to its prevention and treatment. Deficiency may be adequately treated with many different therapeutic regimens of either cholecalciferol or ergocalciferol, owing to the high therapeutic index of both compounds. Nevertheless, the current evidence suggests that regular dosing with oral cholecalciferol (e.g., 60,000 IU weekly) may have slight advantages over other regimens when replenishing vitamin D stores following deficiency. For long-term supplementation, smaller regular doses, such as cholecalciferol 1,000 IU daily, or 10,000 IU weekly, are suitable. Giving reliable and specific advice about appropriate sunlight exposure remains difficult because of differing interindividual skin pigmentation and variable sunlight UVB content at different latitudes, at different times of year, and in different terrestrial environments.
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Colecalciferol/uso terapéutico , Ergocalciferoles/uso terapéutico , Deficiencia de Vitamina D/prevención & control , Vitaminas/uso terapéutico , HumanosRESUMEN
INTRODUCTION: Copeptin concentrations are a useful component of the diagnostic workup of paediatric patients with polyuria and polydipsia, but the value of measuring copeptin in patients with hyponatraemia is less clear. CASE REPORTS: We report 5 children with hyponatraemia in the context of different underlying pathologies. Copeptin concentrations were elevated in 4 cases (13.7, 14.4, 26.1, and 233 pmol/L; reference range 2.4-8.6 pmol/L), suggesting that non-osmoregulated vasopressin release (syndrome of inappropriate antidiuretic hormone) was the underlying mechanism for low sodium levels. In one of the patients, there was an underlying diagnosis of Schaaf-Yang syndrome (MAGEL2 gene mutation) with a clinical picture suggestive of dysregulated vasopressin production with inappropriately high and then low copeptin release. In one hyponatraemic patient, low copeptin concentrations indicated that non-osmoregulated arginine vasopressin release was not the cause of hyponatraemia and oliguria. DISCUSSION: Copeptin measurement did not influence management acutely but helped to clarify the mechanism leading to hyponatraemia when the result was available. Relatively high and low copeptin concentrations in association with hypo- and hypernatraemia indicate dysregulated vasopressin production in Schaaf-Yang syndrome.
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Hiponatremia , Artrogriposis , Niño , Anomalías Craneofaciales , Femenino , Glicopéptidos , Humanos , Hiponatremia/diagnóstico , Hipopituitarismo , Discapacidad Intelectual , Masculino , Polidipsia/diagnóstico , Proteínas , VasopresinasRESUMEN
Whilst several studies have explored adolescent metabolic and cognitive function after preterm birth, few have explored muscle function and physical activity. We set out to examine the relationship between gestational age and muscle metabolism in a cohort of adolescents who were born preterm. Participants were recruited from the Newcastle preterm birth growth study cohort. They did not have severe neurological disease and were not on daily medication. Participants underwent an assessment of oxidative muscle function using phosphorus magnetic resonance spectroscopy that included the half-time for recovery of equilibrium of phosphocreatine, τ½PCr. In addition, we measured key variables that might affect muscle function including physical activity levels determined by 3-day accelerometry, body composition using air displacement plethysmography, insulin sensitivity using the homeostatic model assessment/Matsuda index and serum vitamin D concentrations. 60 adolescents (35F) median age 15.6 years (range 12.1−18.8) with a median gestation of 31 weeks (range 24 to 34 weeks) underwent a single assessment. Males were more active and spent less time in sedentary mode. Time spent in light activity was associated with insulin sensitivity (IS) (Matsuda Index; p < 0.05) but there were no strong correlations between activity levels and gestational age. Greater fat mass, waist circumference and body mass index were all associated with lower IS. Gestational age was negatively associated with adjusted measures of oxidative muscle function (τ½PCr). In a stepwise multivariate linear regression model, gestational age at birth was the most significant predictor of oxidative muscle function (p = 0.005). Higher serum vitamin D levels were also associated with faster phosphocreatine recovery time (p = 0.045). Oxidative function in the skeletal muscle of adolescents born preterm is associated with gestational age and vitamin D concentrations. Our study suggests that being born preterm may have a long-term impact on muscle metabolism.
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Resistencia a la Insulina , Nacimiento Prematuro , Adolescente , Masculino , Femenino , Recién Nacido , Humanos , Lactante , Vitamina D , Composición Corporal/fisiología , Ejercicio Físico , Fosfocreatina , Vitaminas , MúsculosRESUMEN
CONTEXT: Remission rates in young people with Graves hyperthyroidism are less than 25% after 2 years of thionamide antithyroid drug (ATD). OBJECTIVE: We explored whether rituximab (RTX), a B-lymphocyte-depleting agent, would increase remission rates when administered with a short course of ATD. METHODS: This was an open-label, multicenter, single-arm, phase 2 trial in young people (ages, 12-20 years) with Graves hyperthyroidism. An A'Hern design was used to distinguish an encouraging remission rate (40%) from an unacceptable rate (20%). Participants presenting with Graves hyperthyroidism received 500 mg RTX and 12 months of ATD titrated according to thyroid function. ATDs were stopped after 12 months and primary outcome assessed at 24 months. Participants had relapsed at 24 months if thyrotropin was suppressed and free 3,5,3'-triiodothyronine was raised; they had received ATD between months 12 and 24; or they had thyroid surgery/radioiodine. RESULTS: A total of 27 participants were recruited and completed the trial with no serious side effects linked to treatment. Daily carbimazole dose at 12 months was less than 5 mg in 21 of 27 participants. Thirteen of 27 participants were in remission at 24 months (48%, 90% one-sided CI, 35%-100%); this exceeded the critical value (9) for the A'Hern design and provided evidence of a promising remission rate. B-lymphocyte count at 28 weeks, expressed as a percentage of baseline, was related to likelihood of remission. CONCLUSION: Adjuvant RTX, administered with a 12-month course of ATD, may increase the likelihood of remission in young people with Graves hyperthyroidism. A randomized trial of adjuvant RTX in young people with Graves hyperthyroidism is warranted.
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Antitiroideos/uso terapéutico , Enfermedad de Graves/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Propiltiouracilo/uso terapéutico , Rituximab/uso terapéutico , Adolescente , Niño , Quimioterapia Combinada/métodos , Femenino , Enfermedad de Graves/sangre , Enfermedad de Graves/diagnóstico , Enfermedad de Graves/inmunología , Humanos , Inmunoglobulinas Estimulantes de la Tiroides/sangre , Inmunoglobulinas Estimulantes de la Tiroides/inmunología , Masculino , Recurrencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Previous studies of congenital hypothyroidism (CHT) have reported an increasing incidence which may suggest that environmental factors play an aetiological role. If so, then cases may exhibit space-time clustering, where cases occur at similar times and close proximities to other cases. In this study we investigated whether space-time clustering of elevated thyroid stimulating hormone (TSH) in newborns exists. All infants born in the Northern Region of England are screened by measuring levels of circulating TSH using a blood spot assay. Data on 207 cases of elevated TSH values, as a proxy for CHT, in newborns born from 1994 to 2006 inclusive were available and analysed using rigorous space-time clustering statistical methods. Analysis showed statistically significant evidence of space-time clustering. The strength of clustering was most marked for cases born within 0.1-0.7 year (1-8 months) of one another. This is the first study to find significant space-time clustering of cases of elevated TSH levels in newborns, a surrogate for space-time clustering of CHT. Whilst the reasons for the clustering are unclear, it would appear from this analysis that transient environmental exposures are likely to be involved, although environmental determinants of genetic mutations and epigenetic factors cannot be ruled out. Further research is required to a) validate these results in other populations and b) to assess in more detail the potential environmental determinants of increased CHT risk.
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Hipotiroidismo Congénito/sangre , Hipotiroidismo Congénito/epidemiología , Tirotropina/sangre , Hipotiroidismo Congénito/etiología , Inglaterra/epidemiología , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Incidencia , Recién Nacido , Masculino , Factores Sexuales , Agrupamiento Espacio-TemporalAsunto(s)
Suplementos Dietéticos/normas , Pediatría/normas , Guías de Práctica Clínica como Asunto , Deficiencia de Vitamina D/prevención & control , Vitamina D/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Reino Unido , Adulto JovenRESUMEN
Background: The etiology of most cases of congenital hypothyroidism (CHT) due to thyroid dysgenesis (DG) is unknown. If transient environmental factors can impact on thyroid gland development, then clustering of cases in time and/or space may occur, and this would be more likely in thyroid DG than dyshormonogenesis (DHG). Methods: The newborn screening program for CHT in Scotland is linked to a central database that includes case details such as postcode. The etiology of CHT is investigated in many cases of CHT using scintigraphy and/or ultrasonography. We looked for evidence of a change in CHT incidence with year of birth and according to season of the year. We then undertook space-time clustering analysis (using a method based on K-functions, with nearest neighbor thresholds) of CHT in Scotland between 1979 and 2015. We also looked for evidence of overall changes associated with sex and area-based birth density. Results: Of 531 cases with CHT during the study period, 290 cases had been categorized as DG (n = 229) or DHG (n = 61) following more detailed investigation. The incidence of CHT increased with year of birth and was in part linked to changing methodology, but there was no seasonality. There was no evidence of overall space-time clustering (p = 0.06), but there was evidence of clustering in babies with DG (p = 0.007). This picture appeared to be most closely linked to underlying thyroid gland hypoplasia rather than thyroid gland agenesis or ectopia. There was significant space-time clustering for both males and females, but clustering was restricted to lesser birth density areas. There was also evidence of clustering for unknown cases (p < 0.001). Clustering of these cases was restricted to females but was present for cases from both greater and lesser birth density areas. There was no evidence of clustering in cases of DHG. Conclusions: These data suggest that an unidentified environmental factor or factors may be involved in the etiology of thyroid DG in Scotland. The variation in CHT incidence observed internationally may reflect environmental as well as genetic factors.
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Hipotiroidismo Congénito/epidemiología , Exposición a Riesgos Ambientales/estadística & datos numéricos , Disgenesias Tiroideas/epidemiología , Hipotiroidismo Congénito/diagnóstico , Femenino , Humanos , Incidencia , Recién Nacido , Masculino , Tamizaje Neonatal , Cintigrafía , Factores de Riesgo , Escocia/epidemiología , Agrupamiento Espacio-Temporal , Disgenesias Tiroideas/diagnóstico , UltrasonografíaRESUMEN
CONTEXT: Although primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood. OBJECTIVE: We investigated genetic causes of PAI in children and young people over a 25 year period. DESIGN SETTING AND PARTICIPANTS: Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers. INTERVENTION AND OUTCOME MEASUREMENTS: Genetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018). RESULTS: A genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1/steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause. CONCLUSIONS: PAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved.
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Graves' hyperthyroidism is characterized by the presence of autoantibodies that stimulate the thyroid-stimulating hormone receptor (TSHR), resulting in uncontrolled secretion of excessive thyroid hormone. Conventional treatments, including antithyroid medication, radioiodine, or surgery have remained largely unchanged for the past 70 years and either lack efficacy for many patients, or result in lifelong thyroid hormone replacement therapy, in the case of the latter 2 options. The demand for new therapeutic options, combined with greater insight into basic immunobiology, has led to the emergence of novel approaches to treat Graves' hyperthyroidism. The current therapies under investigation include biologics, small molecules, and peptide immunomodulation. There is a growing focus on TSHR-specific treatment modalities, which carry the advantage of eliciting a specific, targeted approach, with the aim of avoiding disruption of the functioning immune system. These therapies present a new opportunity to supersede the inadequate treatments currently available for some Graves' patients, offering hope of successful restoration of euthyroidism without the need for ongoing therapy. Several of these therapeutic options have the potential to translate into clinical practice in the near future. This review provides a comprehensive summary of the recent advances and various stages of development of the novel therapeutic approaches to treat Graves' hyperthyroidism.
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Terapia Biológica , Enfermedad de Graves/terapia , Receptores de Tirotropina , Terapia Biológica/métodos , Humanos , Receptores de Tirotropina/efectos de los fármacosRESUMEN
BACKGROUND: We report monozygotic twin girls with a family history consistent with X-linked hypophosphataemic rickets (XLH). One twin had a skeletal and biochemical phenotype consistent with XLH, whilst the second twin appeared normal. Complete non-penetrance in XLH has not been previously reported and our aim was to explore potential reasons for this. METHODS: Serum and urine biochemistry were analysed at regular intervals. Microsatellite analysis was performed to confirm monozygosity and bi-parental inheritance of the X chromosome. The X chromosome inactivation pattern was studied in peripheral blood. Exons of the paternal PHEX and FGF23 genes were sequenced. RESULTS: Biochemistry was persistently abnormal in the slow-growing twin 1 and normal in twin 2 who has grown normally. Maximal tubular phosphate reabsorption was 0.68 mmol/l in twin 1 and 1.64 mmol/l in twin 2 at 10.8 years of age (normal 1.15-2.58 mmol/l). Microsatellite analysis confirmed monozygosity and the X chromosome inactivation pattern was random. These studies also excluded uniparental isodisomy. The exon sequence of paternal PHEX and FGF23 genes was normal. CONCLUSIONS: Discordant X inactivation is a well-recognised phenomenon in identical twins, and we suspect that non-random expression of the normal PHEX gene in critical tissues is the most likely explanation for non-penetrance.
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Raquitismo Hipofosfatémico Familiar/genética , Enfermedades Genéticas Ligadas al Cromosoma X , Gemelos Monocigóticos/genética , Adulto , Fosfatasa Alcalina/sangre , Niño , Preescolar , Enfermedades en Gemelos/genética , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Lactante , Masculino , Linaje , Penetrancia , Fosfatos/sangreRESUMEN
BACKGROUND: The aetiology of type 1 diabetes in children is uncertain. A number of recent studies have suggested an infectious aetiology. It has been postulated that an infectious agent may be involved. Support for this hypothesis may be provided by a finding of space-time clustering. The aims of this study were: (i) to determine whether there was space-time clustering in cases of childhood diabetes from north-east England; and to test for differences in space-time clustering: (ii) due to age at diagnosis; (iii) between the sexes and (iv) between levels of residential population density. METHODS: We studied incidence of type 1 diabetes diagnosed in children aged 0-14 years and diagnosed during the period 1990-2007. All cases were resident in a defined geographical region of north-east England (Northumberland, Newcastle upon Tyne and North Tyneside). We applied a second-order procedure based on K-functions to test for global clustering. Locations were residential addresses at time of diagnosis. Tests were repeated using nearest neighbour thresholds to allow for variable population density, providing the primary result for each analysis. Differences between sexes and between levels of population density were assessed. RESULTS: We analysed 457 cases of type 1 diabetes. Overall, there was marginally significant evidence of global space-time clustering (P = 0.089). There was statistically significant clustering amongst pairs of cases that contained at least one female (P = 0.017), but not amongst pairs of cases that contained at least one male (P = 0.190). Furthermore, there was significant clustering amongst pairs of cases that contained at least one from a more densely populated area (P = 0.044), but not amongst pairs of cases that contained at least one from a less densely populated area (P = 0.226). CONCLUSION: Although the analyses have only found marginally significant evidence of global space-time clustering for cases of type 1 diabetes diagnosed in north-east England, there were two notable findings. First, there was evidence of clustering amongst females and secondly clustering was confined to cases from more densely populated areas. These findings are consistent with a possible aetiological involvement of an infectious agent.
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Diabetes Mellitus Tipo 1/microbiología , Infecciones/complicaciones , Adolescente , Niño , Preescolar , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/virología , Inglaterra , Femenino , Geografía , Humanos , Lactante , Recién Nacido , Masculino , Densidad de Población , Factores Sexuales , Agrupamiento Espacio-Temporal , Virosis/complicacionesRESUMEN
OBJECTIVE: Hypoglycaemia may be a frequent occurrence in young GH deficient patients and so we studied the response to fasting in children and adolescents with GH and/or cortisol deficiency. METHODS: A total of 20 patients (2-18 years) fasted for 14 h (22.00-12.00 h) on two occasions as part of a randomized cross-over study. Fourteen had pituitary hormone deficiency (PHD) including GH deficiency (GHD). Of the 14 patients, seven were ACTH sufficient (PHDC+) and seven ACTH deficient (PHDC-). Six had primary adrenal failure (PAF). Subjects administered or omitted their normal dose of evening GH and/or morning hydrocortisone. Glucose, insulin, GH, cortisol, ketones and catecholamines were measured at 04.00 h and regularly from 07.00 to 12.00 h. Insulin sensitivity was assessed by HOMA and hypoglycaemia defined as a blood glucose (BG) = 3.3 mmol/l. RESULTS: BG was related to age and body mass index on treatment but no subject became hypoglycaemic on or off therapy prior to 07.00 h. Five children (aged 3, 4, 7, 8 and 11 years) were hypoglycaemic between 07.00 and 12.00 h off treatment. There was a positive relationship between GH AUC and minimum BG in patients with PHD on treatment (r(2) = 0.45, P = 0.012) with increased insulin sensitivity off treatment. Increased cortisol levels were seen in PHDC+ patients off GH (P < 0.001). A negative relationship was observed between minimum BG and adrenaline (r(2) = 0.37, P = 0.01), ketone bodies (r(2) = -0.20, P = 0.05) and NEFA (r(2) = -0.35, P = 0.02). Noradrenaline levels were reduced in patients with PHDC-. Low BMI (on treatment) and young age (off treatment) were determinants of low BG levels in a multiple regression model. CONCLUSIONS: Unrecognized overnight hypoglycaemia in children and adolescents on pituitary hormone replacement is uncommon but BG levels quickly become abnormal when treatment and meals are omitted. The insulin antagonistic actions of GH are important in preventing hypoglycaemia. Patients with PHD have altered sympathetic nerve activity.
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Insuficiencia Suprarrenal/sangre , Ayuno/fisiología , Trastornos del Crecimiento/sangre , Hormona de Crecimiento Humana/deficiencia , Hidrocortisona/deficiencia , Hipoglucemia/etiología , Cooperación del Paciente , Adolescente , Insuficiencia Suprarrenal/complicaciones , Insuficiencia Suprarrenal/tratamiento farmacológico , Glucemia/metabolismo , Índice de Masa Corporal , Niño , Preescolar , Estudios Cruzados , Susceptibilidad a Enfermedades , Femenino , Trastornos del Crecimiento/complicaciones , Trastornos del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/administración & dosificación , Humanos , Hidrocortisona/administración & dosificación , MasculinoRESUMEN
A 14-yr-old female presented with diabetes and Graves' disease. Eighteen months later, she was euthyroid on carbimazole, and her haemoglobin A1c (HbA1c) was normal (5.2%) on a small insulin dose (0.3-0.4 units/kg/day). An assessment of her pancreatic beta-cell reserve, determined by comparing HbA1c and insulin dose, suggested that this was greater than other patients with type 1 diabetes in our service 18 months postdiagnosis (n = 185). We suspect that excess thyroid hormone led to an insulin-resistant state and accelerated her presentation with hyperglycaemia. Insulin resistance fell once normal thyroid function was restored and helped to attenuate further beta-cell destruction when beta-cell mass was relatively well preserved.
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Diabetes Mellitus Tipo 1/fisiopatología , Enfermedad de Graves/fisiopatología , Tirotoxicosis/fisiopatología , Adolescente , Diabetes Mellitus Tipo 1/complicaciones , Femenino , Enfermedad de Graves/complicaciones , Humanos , Tirotoxicosis/complicacionesAsunto(s)
Hipotiroidismo/diagnóstico , Discapacidades para el Aprendizaje/epidemiología , Tirotropina/análisis , Tiroxina/análisis , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/etiología , Inteligencia , Masculino , Tamizaje Masivo , Nigeria/epidemiología , Prevalencia , Pruebas de Función de la TiroidesRESUMEN
Regulatory T lymphocytes play a crucial role in modulating potentially self-reactive clones, and dysfunction of this cell type contributes to autoimmune disease. FOXP3 is a critical determinant of CD(4+)CD(25+)T regulatory (T(reg)) cell development and function. The aim of this study was to investigate whether genetic polymorphisms at the FOXP3 locus predispose to autoimmune endocrinopathies. Five single nucleotide polymorphisms (SNPs) and two microsatellite polymorphisms were genotyped in our Caucasian cohorts of 633 unrelated Graves' disease (GD) subjects, 104 autoimmune Addison's disease (AAD) subjects and 528 healthy controls. SNP genotyping was performed by either restriction enzyme digestion or by primer-extension-MALDI-TOF (matrix-assisted laser desorption/ionisation time-of-flight) assay. Microsatellites were analysed using fluorescent PCR. Case-control analysis was performed using chi(2) testing on contingency tables for allele frequency. Haplotype analysis was performed using the UNPHASED package. No evidence for disease association was found with any of the seven polymorphisms in either of the GD or AAD subjects as compared with controls (P = 0.26-0.94). Haplotype analysis found a weak evidence for the association of a minor haplotype with GD; this was not significant when corrected for multiple testing. This study has found no robust evidence that FOXP3 gene polymorphism contributes to the susceptibility to GD or AAD in the UK population.
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Enfermedad de Addison/genética , Factores de Transcripción Forkhead/genética , Predisposición Genética a la Enfermedad , Enfermedad de Graves/genética , Polimorfismo Genético , Enfermedad de Addison/inmunología , Análisis Mutacional de ADN , Femenino , Genotipo , Haplotipos , Humanos , Repeticiones de Microsatélite , Estadística como Asunto , Reino UnidoRESUMEN
X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.