RESUMEN
OBJECTIVE: To study the optimal cut-off value for anti-tissue transglutaminase type 2 IgA antibodies (TG2A) in serum to select for diagnostic small bowel biopsies for celiac disease in children with type 1 diabetes mellitus. STUDY DESIGN: Children with type 1 diabetes mellitus with elevated TG2A titers and duodenal biopsies performed during the course of their diabetes treatment were included. Anti-endomysial antibodies were recorded if present. The optimal TG2A cut-off value, expressed as the ratio between obtained value and upper limit of normal (ULN), was determined using receiver operating characteristic curve analysis and compared with the cut-off value used in the European Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines in terms of sensitivity, specificity, positive and negative predictive value. RESULTS: We included 63 children. The optimal cut-off value for performing biopsies is demonstrated to be 11 times the ULN. Raising the cut-off value from 3 times the ULN to 11 times the ULN changed sensitivity from 96% to 87% and increased specificity from 36% to 73%, increased the positive predictive value from 88% to 94% and lowered negative predictive value from 67% to 53%. The percentage of normal histology was decreased from 12% to 6%. CONCLUSIONS: Increasing the TG2A cut-off value for performing duodenal biopsies in children with type 1 diabetes mellitus and suspected celiac disease leads to a substantial reduction of unnecessary biopsies. We advocate to adapt the European Society for Pediatric Gastroenterology, Hepatology and Nutrition 2012 guidelines for this group of children, including monitoring patients with TG2A levels of less than 11 times the ULN over time.
Asunto(s)
Enfermedad Celíaca/diagnóstico , Diabetes Mellitus Tipo 1/complicaciones , Proteínas de Unión al GTP/sangre , Transglutaminasas/sangre , Adolescente , Anticuerpos , Biopsia/efectos adversos , Enfermedad Celíaca/sangre , Enfermedad Celíaca/etiología , Niño , Preescolar , Femenino , Humanos , Intestino Delgado/inmunología , Masculino , Proteína Glutamina Gamma Glutamiltransferasa 2 , Curva ROC , Estudios Retrospectivos , Sensibilidad y Especificidad , Procedimientos InnecesariosRESUMEN
OBJECTIVE: Some features of subjects with Prader-Willi syndrome (PWS) resemble those seen in growth hormone deficiency (GHD). Children with PWS are treated with growth hormone (GH), which has substantially changed their phenotype. Currently, young adults with PWS must discontinue GH after attainment of adult height when they do not fulfil the criteria of adult GHD. Limited information is available about the prevalence of GHD in adults with PWS. This study aimed to investigate the GH/insulin-like growth factor (IGF-I) axis and the prevalence of GHD in previously GH-treated young adults with PWS. DESIGN: Cross-sectional study in 60 young adults with PWS. MEASUREMENTS: Serum IGF-I and IGFBP-3 levels, GH peak during combined growth hormone-releasing hormone (GHRH)-arginine stimulation test. RESULTS: Serum IGF-I was <-2 standard deviation scores (SDS) in 2 (3%) patients, and IGFBP-3 was within the normal range in all but one patient. Median (IQR) GH peak was 17.8 µg/L (12.2; 29.7) [~53.4 mU/L] and below 9 µg/L in 9 (15%) patients. Not one patient fulfilled the criteria for adult GHD (GH peak < 9 µg/L and IGF-I < -2 SDS), also when BMI-dependent criteria were used. A higher BMI and a higher fat mass percentage were significantly associated with a lower GH peak. There was no significant difference in GH peak between patients with a deletion or a maternal uniparental disomy (mUPD). CONCLUSIONS: In a large group of previously GH-treated young adults with PWS, approximately 1 in 7 exhibited a GH peak <9 µg/L during a GHRH-arginine test. However, none of the patients fulfilled the consensus criteria for adult GHD.
Asunto(s)
Enanismo Hipofisario/sangre , Enanismo Hipofisario/epidemiología , Hormona del Crecimiento/uso terapéutico , Síndrome de Prader-Willi/sangre , Síndrome de Prader-Willi/tratamiento farmacológico , Adulto , Índice de Masa Corporal , Estudios Transversales , Enanismo Hipofisario/etiología , Femenino , Hormona del Crecimiento/efectos adversos , Hormona de Crecimiento Humana/sangre , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Prevalencia , Adulto JovenRESUMEN
BACKGROUND: In 2002, a nationwide screening for congenital adrenal hyperplasia (CAH) was introduced in the Netherlands. The aim of our study is to evaluate the validity of the neonatal screening for CAH and to assess how many newborns with salt-wasting (SW) CAH have already been clinically diagnosed before the screening result was known. METHODS: Retrospective, descriptive study. The following data of patients with positive screening results since implementation of the screening programme were collected (1 January 2002 up until 31 December 2013): gestational age, sex, diagnosis, clinical presentation and contribution of screening to the diagnosis. RESULTS: In the evaluated period, 2 235 931 newborns were screened. 479 children had an abnormal screening result, 133 children were diagnosed with CAH (114 SW, 14 simple virilizing (SV)), five non-classic CAH. During this period, no patients with SW CAH were missed by neonatal screening (sensitivity was 100%). After exclusion of 17 cases with missing information on diagnosis, specificity was 99.98% and positive predictive value was 24.7%. Most false positives (30%) were attributable to prematurity. Of patients with SW CAH, 68% (71/104) patients were detected by neonatal screening and 33 (33/104) were clinically diagnosed. Of girls with SW CAH, 38% (14/37) were detected by neonatal screening and 62% (23/37) were clinically diagnosed. CONCLUSION: The Dutch neonatal screening has an excellent sensitivity and high specificity. Both boys and girls can benefit from neonatal screening.
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Hiperplasia Suprarrenal Congénita/epidemiología , Tamizaje Neonatal/normas , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/patología , Femenino , Humanos , Incidencia , Recién Nacido , Masculino , Países Bajos/epidemiología , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. METHODS: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. RESULTS: We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion. IRS4 mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary Tshb mRNA levels but had unchanged serum thyroid hormone concentrations. CONCLUSIONS: Mutations in IRS4 are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling.
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Hipotiroidismo/genética , Proteínas Sustrato del Receptor de Insulina/genética , Leptina/metabolismo , Transducción de Señal , Tiroxina/sangre , Adolescente , Adulto , Animales , Niño , Preescolar , Femenino , Heterocigoto , Humanos , Hipotálamo/metabolismo , Lactante , Masculino , Ratones , Persona de Mediana Edad , Mutación , Linaje , Hipófisis/metabolismo , Adulto JovenRESUMEN
Growth hormone deficiency (GHD), mostly after cranial radiotherapy (CRT), may lead to several negative effects. Young adult survivors of acute lymphoblastic leukemia (ALL) could benefit from GH therapy in different ways. Twenty ALL survivors (17.1 ± 4.3 y after diagnosis) with low bone mineral densities and/or low insulin-like growth factor-1 were included. Two of the 3 patients who only received chemotherapy had GHD. Of the 20 patients, 17 started with GH therapy and 14 completed the 2-year study period. At several time points, bone mineral density (BMD) was measured. Psychological functioning was assessed. At the start of the study, standard deviation scores of height, insulin-like growth factor-1, lumbar spine, and femoral neck BMD were all below -1. After 2 years of GH therapy, total body BMD and lean mass were significantly higher (P < 0.01 and P < 0.001, respectively), whereas the percentage fat was significantly lower (P < 0.02). Several psychological measures improved significantly after 2 years. In conclusion, GH therapy during 2 years in young adult survivors of childhood ALL did have a number of benefits, such as improvement of total body bone density and body composition. Results also suggest improvement of psychological well being. Furthermore, it also became clear that patients after chemotherapy alone should be tested for GHD.