RESUMEN
BACKGROUND: The PedsQL™3.0 Diabetes Module is a widely used instrument to measure the disease-specific health-related quality of life summary measures in children and adolescents with type 1 diabetes. After cultural adaptation, we confirmed reliability and validity of PedsQL™3.0 Diabetes Module in its Italian version. METHODS: Participants were 169 Italian children and adolescents with type 1 diabetes aged 5-18 years and 100 parents. Reliability was determined by internal consistency using Cronbach's coefficient alpha, and test-retest reliability by intra-class correlation coefficient (ICC). Validity was assessed through factor validity examined by exploratory factor analysis, and discriminant validity examined through multitrait/multi-item scaling analysis. Discriminant validity with respect to dichotomous patients' characteristics at baseline was also examined through a multivariate analysis on the summary measures using the Wilks' Lambda test. RESULTS: Data completeness was optimal. Item internal consistency was satisfied at 89% for the child self-report scales and at 100% for the parents' proxy-report scales. Most diabetes module scales was acceptable for group comparisons. Discriminant validity was satisfied for 71% of children and adolescents and for 82% of parents. A ≥70% Cronbach's α coefficient was found for the summary measures of both reports. For the test-retest reliability, the ICC coefficients ranged from 0.66 (i.e., the Worry scale) to 0.82 for the other scales of the child self-report. The ICC coefficients were ≥0.87 for all the parents' proxy-report scales. Factor analysis showed that the PedsQL™3.0 Diabetes Module for child self-report could be summarized in 10 components, which explained the 62% of the variance. For the parent proxy-report the statistical analysis selected 9 factors, which explained about 68% of variance. The external discriminant validity of the PedsQL™3.0 Diabetes Module summary measures were compared across gender, age, time since diagnosis and HbA1c mean cut off values. Significant differences in the "Treatment adherence" scale and in the "Communication" scale were observed across age, and by time since diagnosis. CONCLUSIONS: The results show the reliability and validity of the Italian translation of the PedsQL™3.0 Diabetes Module, supporting therefore its use as an outcome measure for diabetes cross-national clinical trials and research.
Asunto(s)
Diabetes Mellitus Tipo 1/psicología , Padres/psicología , Calidad de Vida , Encuestas y Cuestionarios , Adolescente , Adulto , Niño , Características Culturales , Análisis Factorial , Femenino , Humanos , Italia , Masculino , Psicometría , Reproducibilidad de los Resultados , Autoinforme , TraduccionesRESUMEN
BACKGROUND: Type 1 diabetes mellitus (T1DM) may be associated with allergy. It was previously reported that >20% of children with T1DM had allergic rhinitis (AR), but none was asthmatic. This finding was surprising as allergic rhinitis is frequently associated with asthma and asthma prevalence is about 10% of the general paediatric population. Thus, it was hypothesized that T1DM could protect from asthma. OBJECTIVES: The aim of this preliminary study was to evaluate the pulmonary function and the response to bronchodilation testing in children, suffering from T1DM with associated AR, comparing them with a control group of children with AR alone. METHODS: Twenty children with T1DM and AR were compared with 59 children with AR alone; spirometry and bronchodilation testing were performed in all patients. RESULTS: There were no statistically significant differences in both "at baseline" and after bronchodilation testing about FVC, FEV1, and FEF25-75 values. However, changes in "post-bronchodilator" values of FEF25-75 (ΔFEF25-75) were significantly higher in children with AR alone than in children with T1DM and AR (p=0.04). CONCLUSIONS: This preliminary study could sustain the hypothesis that T1DM in children suffering also from AR might exert a protective effect of preventing the possible evolution in asthma.
Asunto(s)
Alérgenos/inmunología , Asma/prevención & control , Diabetes Mellitus Tipo 1/epidemiología , Rinitis Alérgica Perenne/epidemiología , Rinitis Alérgica Estacional/epidemiología , Adolescente , Asma/etiología , Pruebas de Provocación Bronquial , Niño , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/diagnóstico , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Prevalencia , Rinitis Alérgica Perenne/complicaciones , Rinitis Alérgica Perenne/diagnóstico , Rinitis Alérgica Estacional/complicaciones , Rinitis Alérgica Estacional/diagnóstico , Pruebas Cutáneas , EspirometríaRESUMEN
BACKGROUND: Early stages of glucose metabolism impairment are a period at risk in the long-term prognosis of cystic fibrosis (CF). Slow-release synthetic insulin glargine can be a therapeutic tool in this metabolic condition. METHODS: In this phase 3 multicenter, controlled, two-arm, randomized clinical study, glargine was administered up to a dosage of 0.15 U/kg/die for a period of 18 months. Primary endpoint was the improvement of nutritional status [body mass index (BMI) Z score], while glucose tolerance [hemoglobin A1c (HbA1C) and respiratory function (FEV1 predicted] improvement were the secondary endpoints. RESULTS: Thirty-four subjects (18 in the glargine arm and 16 in the control arm) were evaluated. Adherence to insulin treatment was excellent. No significant adverse events were reported. There were no significant differences in BMI, HbA1C and FEV1 values between the two groups nor within groups, except for HbA1C improvement in the glargine arm at month +18 (p = 0.04). CONCLUSIONS: Glargine treatment was well accepted and tolerated. No real efficacy in improving clinical and glycometabolic conditions was demonstrated. Further studies are necessary to test glargine at higher dosage and for a longer follow-up period.
Asunto(s)
Fibrosis Quística/tratamiento farmacológico , Intolerancia a la Glucosa/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina de Acción Prolongada/uso terapéutico , Adolescente , Adulto , Índice de Masa Corporal , Niño , Fibrosis Quística/fisiopatología , Femenino , Hemoglobina Glucada/análisis , Humanos , Insulina Glargina , Pulmón/efectos de los fármacos , Pulmón/fisiología , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Adulto JovenRESUMEN
We report on a case of Netherton syndrome showing a new SPINK5 mutation (c.957_960dupTGGT duplication in exon 11), associated with partial defect of biotinidase.
Asunto(s)
Eritrodermia Ictiosiforme Congénita/genética , Síndrome de Netherton/genética , Mutación Puntual , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Análisis Mutacional de ADN , Exones/genética , Facies , Humanos , Masculino , Inhibidor de Serinpeptidasas Tipo Kazal-5 , Adulto JovenRESUMEN
The Osteopontin (OPN) encoding gene, SPP1, can be considered as a candidate for genetic susceptibility to type 1 diabetes (T1D) because of its known function in immune response and inflammation. This work aimed to evaluate the role of SPP1 gene in susceptibility to T1D. Patients (238: 130 male, 108 female) and unaffected adult control individuals (137: 68 males and 69 females) have been genotyped for three variants in the SPP1 gene: -156 (G/GG) and -66 (T/G) in the promoter and a biallelic ins/del variant (TG/TGTG) at +245 in the first intron. The G allele at the -66 SNP had significantly higher frequency in controls than T1D patients. Interestingly, case-control comparison in males showed no significant association, whereas the association was confirmed in females. These results suggest that SPP1 can play a role as susceptibility gene, possibly by a sex-specific mechanism acting in the autoimmune process.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Osteopontina/genética , Adolescente , Alelos , Autoanticuerpos/sangre , Estudios de Casos y Controles , Niño , Preescolar , ADN/química , ADN/genética , Diabetes Mellitus Tipo 1/inmunología , Femenino , Predisposición Genética a la Enfermedad , Antígenos HLA-DQ/sangre , Cadenas alfa de HLA-DQ , Cadenas beta de HLA-DQ , Humanos , Lactante , Masculino , Glicoproteínas de Membrana/sangre , Osteopontina/inmunología , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
According to the 'Th(1)/Th(2) paradigm', children with type 1 diabetes mellitus (T1DM) should have a lower risk of developing allergic sensitization and, because of the involvement of insulin in modulating airway inflammation, different frequency or severity in allergy-related respiratory manifestations. This article aims at evaluating the frequency and type of allergic sensitization and its respiratory manifestation, asthma and/or rhinitis, in a group of pediatric patients with T1DM. Patients (112) with T1DM, 7.8-16.9 yr of age (63 males and 49 females) were evaluated. Skin prick test (SPT) reactivity to the most common classes of aeroallergens were performed and compared with data obtained in 709 school-aged children. The frequency of sensitization was not different in the T1DM and in the control subjects (43.7% and 40.8%, respectively; p = 0.55), with similar proportions of individuals sensitized to one allergen (32.7% and 38.1%, respectively; p = 0.47). In both groups, sensitization to house dust mite allergens was the most frequently detected (69.4% and 65.4%, respectively; p = 0.59), with a higher proportions of individuals sensitized to Graminae (+Cynodon dactylon; p < 0.0001) and a lower, but weakly significant, proportion sensitized to Parietaria (p = 0.03) in the T1DM group, as compared with controls. No differences were found between T1DM and control groups in the proportion of individuals reporting rhinitis (26.8% and 29.2%; p = 0.60). However, comparing separately sensitized and non-sensitized subjects, a lower proportion of rhinitis subjects was detected in the non-sensitized T1DM patients, when compared with the non-sensitized control subjects (p = 0.01). In addition, no differences were detected between T1DM and control groups in frequency of symptoms related to 'lifetime asthma', i.e., asthma episodes during life (14.3% and 16.5%, respectively: p = 0.55), also when sensitized and non-sensitized subjects were evaluated separately (p = 0.12 and p = 1.00, respectively). However, no T1DM patient had 'actual asthma', i.e., asthma episodes in the last year, vs. 5.8% of the individuals in the control group (p = 0.009), the difference being mostly ascribed to sensitized subjects (p = 0.012). Finally, out of the 16 T1DM patients with 'lifetime asthma', 15 had mild intermittent disease and only one mild persistent disease. T1DM does not seem to play a downregulating role on the development of allergic sensitization to aeroallergens, but may lower the frequency or the severity of its clinical manifestations at respiratory level.
Asunto(s)
Alérgenos/inmunología , Diabetes Mellitus Tipo 1/epidemiología , Hipersensibilidad/epidemiología , Adolescente , Niño , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Humanos , Hipersensibilidad/inmunología , Inhalación , Masculino , Pruebas Cutáneas , EspirometríaRESUMEN
Hyperglycemic status may be rarely complicated by Epilepsia partialis continua (EPC) that usually responds to metabolic normalization. Anti-glutamic acid decarboxylase antibodies (GAD-Ab) play a pivotal role in the autoimmune process that leads to clinical onset of type 1 diabetes mellitus (T1DM). GAD-Ab have been recently reported in association with rare forms of refractory epilepsy, with or without association to T1DM. Here we describe a young patient who developed EPC five months after T1DM onset; GAD-Ab were detected in his cerebrospinal fluid with evidence of oligoclonal bands. His epileptic disorder evolved over time into drug-resistant epilepsy with continuous spike-waves during slow sleep and severe behavioral impairment. The role of both metabolic imbalance and GAD autoimmunity is discussed.
Asunto(s)
Encéfalo/fisiopatología , Diabetes Mellitus Tipo 1/líquido cefalorraquídeo , Diabetes Mellitus Tipo 1/fisiopatología , Epilepsia Parcial Continua/líquido cefalorraquídeo , Epilepsia Parcial Continua/fisiopatología , Sueño/fisiología , Trastorno por Déficit de Atención con Hiperactividad/líquido cefalorraquídeo , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Autoanticuerpos/líquido cefalorraquídeo , Encéfalo/patología , Preescolar , Diabetes Mellitus Tipo 1/complicaciones , Progresión de la Enfermedad , Electroencefalografía , Electromiografía , Epilepsia Parcial Continua/complicaciones , Glutamato Descarboxilasa/inmunología , Humanos , Imagen por Resonancia Magnética , Masculino , Bandas Oligoclonales/líquido cefalorraquídeo , Factores de TiempoRESUMEN
BACKGROUND AND AIM: To establish normal values of insulin resistance, secretion and sensitivity using respectively HOMA-IR, HOMA-beta% and QUICKI indexes in healthy Italian children and adolescents, based on fasting samples. METHODS: We determined HOMA-IR, HOMA-beta% and QUICKI at baseline in 142 healthy subjects from Pediatric Centres, aged 2.7 to 19 years (10.6 +/- 3.8, Mean +/- SD), with different Tanner's pubertal Stages (TS). None had hypo/hyperglycemia (fasting plasma glucose ranging from 3.6 to 5.6 mmol/l), obesity (BMI (kg/m2) 17.9 +/- 2.4, M +/- SD), or family history for diabetes mellitus. RESULTS: The HOMA-IR index slightly increases with Tanner's stage. As regards HOMA-beta% and QUICKI, a weak variation throughout puberty was observed. No significant correlation was observed between HOMA-IR, HOM A-beta%, QUICKI and BMI-SDS or chronologic age. CONCLUSIONS: Normal values of HOMA-IR, HOMA-beta% and QUICKI are useful tools in the clinical and epidemiological practice for baseline screening and follow-up of subjects at risk for type 2 diabetes mellitus.
Asunto(s)
Glucemia/metabolismo , Resistencia a la Insulina/fisiología , Insulina/sangre , Adolescente , Factores de Edad , Niño , Preescolar , Estudios Transversales , Ayuno/metabolismo , Humanos , Resistencia a la Insulina/etnología , Células Secretoras de Insulina/fisiología , Italia , Pubertad/metabolismo , Valores de Referencia , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Patients with high-risk human leukocyte antigen (HLA)-DR-DQ genotypes for type 1 diabetes (T1D) were compared with HLA-matched controls to evaluate T1D risk for other HLA loci, including HLA-A, -B, -Cw, and DPB1. Patients (n = 133) with high-risk genotypes (DR3/DR3, DR3/DR4, DR4/DR4) were selected from the Lazio (Rome) region of Italy. Screening of more than 9000 patients from the Lazio region and northern Italy yielded 162 controls with high-T1D-risk haplotypes. Although the overall distributions did not differ significantly, allele frequency differences were discovered between the controls from Lazio and controls from northern Italy for some alleles previously determined to affect T1D risk, such as A*3002, DPB1*0301, and DPB1*0402. Therefore, Lazio patient data were compared both with the Lazio subset of controls (n = 53) and with the entire group of controls for association analyses. Significant allele frequency differences between patients and DR-DQ-matched controls existed for specific alleles at all loci. Data for the DR3/DR3 subset of patients and controls demonstrated an increase of Cw*0702 in patients. Compared with controls, reduced patient frequencies were seen for several alleles, including A*0101, B*0801, and Cw*0701, all on the highly conserved, extended DR3 haplotype known as 8.1 in DR3/DR3, but not DR3/DR4, subgroup. DPB1*0101, often reported on 8.1 haplotypes, was also less frequent in DR3/DR3 patients than controls. Analysis of family-based data from the HBDI repository was consistent with the observed results from the Italian patients, indicating the presence of a T1D-protective locus at or near A*0101 and a second T1D-protective locus at or near DPB1*0101. These data indicate that T1D risk conferred by the 8.1 haplotype is genotype dependent.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Antígenos HLA-A/genética , Antígenos HLA-DP/genética , Antígeno HLA-DR3/genética , Antígeno HLA-DR4/genética , Haplotipos , Estudios de Casos y Controles , Diabetes Mellitus Tipo 1/epidemiología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Antígeno HLA-A1 , Antígenos HLA-B/genética , Antígeno HLA-B8 , Cadenas beta de HLA-DP , Heterocigoto , Homocigoto , Humanos , Recién Nacido , Italia/epidemiologíaRESUMEN
Celiac disease (CD) is a T-cell-mediated enteropathy, triggered in genetically susceptible individuals by the ingestion of wheat gluten or related rye and barley proteins, whose clinical picture disease is considerably heterologous. Patients with CD are at high risk of autoimmune disorders; similarly, CD is frequent in patients with type 1 diabetes mellitus (T1DM), a disorder characterized by the immune-mediated beta-cell destruction, with the cooperation of environmental factors in genetically susceptible individuals. The immunological markers of beta-cell destruction are the autoantibodies to insulin, glutamic acid decarboxylase, and the protein tyrosine phosphatase. In absence of these markers, incidental hyperglycemia in children and adolescents appears unlikely to be associated with the progression to T1DM. We report a girl with CD and incidental hyperglycemia, without immunological markers of T1DM, with a family history for hyperglycemia, and diagnosed as maturity-onset diabetes of the young. We present this case as evidence that the possibility of monogenic forms of diabetes must be suspected in children with incidental hyperglycemia, a family history for mild hyperglycemia or diabetes, and absence of markers of beta-cell destruction, even if the patients are affected by an autoimmune disease.
Asunto(s)
Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/inmunología , Hiperglucemia/complicaciones , Hiperglucemia/inmunología , Autoanticuerpos , Enfermedades Autoinmunes , Biomarcadores , Glucemia/metabolismo , Enfermedad Celíaca/diagnóstico , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hiperglucemia/diagnóstico , Factores de RiesgoRESUMEN
CONTEXT: The current criteria for definition of partial GHD in young adults are still a subject of debate. OBJECTIVES: The objective of the study was to reinvestigate anterior pituitary function in young adults with congenital childhood-onset GHD associated with structural hypothalamic-pituitary abnormalities and normal GH response at the time of first reassessment of GH secretion. DESIGN AND SETTING: This was a prospective explorative study conducted in a university research hospital. PATIENTS AND METHODS: Thirteen subjects with a mean age of 17.2 +/- 0.7 yr and a peak GH after insulin tolerance test (ITT) higher than 5 microg/liter were recruited from a cohort of 42 patients with childhood-onset GHD and ectopic posterior pituitary at magnetic resonance imaging. GH secretion after ITT and GHRH plus arginine, IGF-I concentration, and body mass index, waist circumference, blood pressure, total cholesterol, and fibrinogen were evaluated at baseline and at 2-yr follow-up. RESULTS: At mean age of 19.2 +/- 0.7 yr, the mean peak GH response decreased significantly after ITT (P = 0.00001) and GHRH plus arginine (P = 0.0001). GH peak values after ITT and GHRH plus arginine were less than 5 and 9 microg/liter in 10 and eight patients, respectively. Additional pituitary defects were documented in eight patients. Significant changes were found in the values of IGF-I sd score (P = 0.0026), waist circumference (P = 0.00001), serum total cholesterol (P = 0.00001), and serum fibrinogen (P = 0.0004). CONCLUSIONS: The results of this study underline the importance of further reassessment of pituitary function in young adults with GHD of childhood-onset and poststimulation GH responses suggestive of partial GHD.
Asunto(s)
Coristoma/patología , Hormona de Crecimiento Humana/deficiencia , Hipopituitarismo/patología , Enfermedades de la Hipófisis/metabolismo , Enfermedades de la Hipófisis/patología , Adolescente , Edad de Inicio , Niño , Femenino , Estudios de Seguimiento , Hormona Liberadora de Hormona del Crecimiento/sangre , Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/sangre , Humanos , Hipopituitarismo/tratamiento farmacológico , Hipopituitarismo/metabolismo , Imagen por Resonancia Magnética , Masculino , Enfermedades de la Hipófisis/tratamiento farmacológico , Adenohipófisis/metabolismo , Adenohipófisis/patología , Estudios ProspectivosRESUMEN
Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive K(+) channel (K(ATP) channel), are a common cause of neonatal diabetes. We identified a novel KCNJ11 mutation, R50Q, that causes permanent neonatal diabetes (PNDM) without neurological problems. We investigated the functional effects this mutation and another at the same residue (R50P) that led to PNDM in association with developmental delay. Wild-type or mutant Kir6.2/SUR1 channels were examined by heterologous expression in Xenopus oocytes. Both mutations increased resting whole-cell currents through homomeric and heterozygous K(ATP) channels by reducing channel inhibition by ATP, an effect that was larger in the presence of Mg(2+). However the magnitude of the reduction in ATP sensitivity (and the increase in the whole-cell current) was substantially larger for the R50P mutation. This is consistent with the more severe phenotype. Single-R50P channel kinetics (in the absence of ATP) did not differ from wild type, indicating that the mutation primarily affects ATP binding and/or transduction. This supports the idea that R50 lies in the ATP-binding site of Kir6.2. The sulfonylurea tolbutamide blocked heterozygous R50Q (89%) and R50P (84%) channels only slightly less than wild-type channels (98%), suggesting that sulfonylurea therapy may be of benefit for patients with either mutation.
Asunto(s)
Arginina/genética , Diabetes Mellitus/genética , Mutación , Canales de Potasio de Rectificación Interna/fisiología , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/farmacología , Animales , Electrofisiología , Femenino , Heterocigoto , Humanos , Recién Nacido , Cinética , Magnesio/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Modelos Moleculares , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Oocitos/fisiología , Canales de Potasio de Rectificación Interna/química , Canales de Potasio de Rectificación Interna/genética , Estructura Secundaria de Proteína , Ratas , Compuestos de Sulfonilurea/farmacología , Xenopus laevisRESUMEN
OBJECTIVES: Evaluation of GH response to ghrelin in patients with GH deficiency (GHD) may help to elucidate the site and mechanism of action of ghrelin. We aimed to investigate the GH-releasing effect of ghrelin in children and young adults with childhood-onset GHD. DESIGN: All subjects underwent ghrelin testing and neuro-imaging examination. Magnetic resonance imaging evidenced the presence of a vascular pituitary stalk (VPS) or its complete absence (PSA). PATIENTS AND METHODS: Seventeen prepubertal children and nine adult patients with childhood-onset GHD were selected for the study. The children were enrolled at a median age of 5.8 years. The adult subjects were included at a median age of 23.3 years. The diagnosis of GHD in the adult patients had been established at a median age of 8.5 years. Ghrelin was administered at a dose of 1 microg/kg body weight, i.v. at time zero, and blood for GH determination was obtained at 0, 15, 30, 45, 60, 75, 90, 105 and 120 min. RESULTS: Median GH response after ghrelin was similar between children and adults. Median peak GH response to ghrelin (7.45 microg/l, IQR: 3.9-11.3 microg/l) was significantly higher in patients with VPS (10.9 microg/l, IQR: 2.4-15.1 mcirog/l) than in those with PSA (IQR: 2.3-6.7 microg/l; P=0.001). It was significantly higher in subjects with isolated GHD (12.5 microg/l, IQR: 10.8-15.5 microg/l) than in those with multiple pituitary hormone deficiencies (5.15 microg/l, IQR: 2.4-9.0 microg/l; P=0.003). No correlation was found between the GH peak after ghrelin and body mass index. CONCLUSION: The GH response to ghrelin in patients with congenital hypopituitarism depends on the degree of the anatomical abnormalities and lends further support to the assumption that the main action of the peptide is exerted at the hypothalamic level and requires the integrity of hypothalamic-pituitary connections.
Asunto(s)
Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/deficiencia , Sistema Hipotálamo-Hipofisario/anomalías , Sistema Hipotálamo-Hipofisario/fisiopatología , Hormonas Peptídicas/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Femenino , Ghrelina , Humanos , Hipopituitarismo/sangre , Hipopituitarismo/congénito , Hipopituitarismo/diagnóstico , Hipopituitarismo/tratamiento farmacológico , Hipopituitarismo/fisiopatología , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/fisiopatología , Concentración Osmolar , Hipófisis/anomalías , Hipófisis/irrigación sanguínea , Hipófisis/patología , Factores de TiempoAsunto(s)
Diabetes Mellitus Tipo 1/epidemiología , Obesidad/epidemiología , Hipersensibilidad Respiratoria/epidemiología , Adolescente , Contaminantes Atmosféricos/efectos adversos , Alérgenos/efectos adversos , Alérgenos/inmunología , Índice de Masa Corporal , Niño , Estudios Transversales , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Humanos , Inmunización , Masculino , Obesidad/fisiopatología , Prevalencia , Hipersensibilidad Respiratoria/fisiopatología , EspirometríaRESUMEN
Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disorder characterized by infantile onset and rapid progression of psychomotor regression and hypotonia evolving into spasticity. The neuroradiologic hallmark of the disease is represented by cerebellar atrophy and signal hyperintensity in the cerebellar cortex on MR T2-weighted images. We report a 2-year-old boy with psychomotor regression and hypotonia carrying a homozygous 5' splice site mutation in PLA2G6 gene, whose brain MRI revealed cerebellar atrophy with normal cerebellar cortex signal intensity. The absence of the signal hyperintensity of the cerebellar cortex does not rule out the diagnosis of INAD.
Asunto(s)
Cerebelo/patología , Mutación/genética , Distrofias Neuroaxonales/genética , Distrofias Neuroaxonales/patología , Fosfolipasas A/genética , Atrofia , Preescolar , Fosfolipasas A2 Grupo VI , Humanos , Imagen por Resonancia Magnética , Masculino , Sitios de Empalme de ARN/genéticaAsunto(s)
Diabetes Mellitus Tipo 1/complicaciones , Procesamiento Automatizado de Datos , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/enzimología , Niño , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Humanos , Insulina/administración & dosificaciónRESUMEN
CONTEXT: Hesx1 is one of the earliest homeodomain transcription factors expressed during pituitary development. Very few HESX1 mutations have been identified in humans; although in those cases the disease phenotype shows considerable variability, all but one of the patients display an ectopic posterior pituitary and/or optic nerve abnormalities. OBJECTIVE: The objectives of the study were to describe the complex phenotype associated with the panhypopituitarism of two unrelated Italian patients who, at birth, presented with hypoglycemic seizures and respiratory distress complicated by shock, in a familial context of neonatal death in one family and spontaneous miscarriage in both families and to identify the molecular basis of this unusual syndrome. MAIN OUTCOME MEASURES: Magnetic resonance imaging of the pituitary region, study of HESX1 gene and transcripts, and assessment of the ability of mutated HESX1 proteins to repress transcription were measured. RESULTS: Magnetic resonance imaging examination showed an anterior pituitary aplasia in a flat sella turcica and a normally located posterior pituitary in both patients. A constellation of extrapituitary developmental defects were found in the two patients, but without any optic nerve abnormalities. Sequencing of HESX1 exons and their flanking intronic regions revealed two different homozygous mutations. A frameshift (c.449_450delAC) was identified in one case, whereas the other patient carried a splice defect (c.357 + 2Tb > C) confirmed by the study of HESX1 transcripts. If translated, these mutations would lead to the synthesis of truncated proteins partly or entirely lacking the homeodomain, with no transcriptional repression, as shown by their inability to inhibit PROP1 activity. CONCLUSIONS: These observations reveal two novel HESX1 mutations in a so-far-undescribed disease phenotype characterized by a life-threatening neonatal condition associated with anterior pituitary aplasia, in the absence of ectopic posterior pituitary and optic nerve abnormalities, two features classically associated with HESX1 defects.
Asunto(s)
Proteínas de Homeodominio/genética , Nervio Óptico/anatomía & histología , Fenotipo , Enfermedades de la Hipófisis/genética , Neurohipófisis/anatomía & histología , Células Cultivadas , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Recién Nacido , Proteínas Mutantes/metabolismo , Mutación , Linaje , Procesamiento Postranscripcional del ARN , Factores de Transcripción/metabolismo , Transcripción Genética , TransfecciónRESUMEN
CONTEXT: It has been reported that patients with multiple pituitary hormone deficiencies (MPHDs) achieve a greater final height, compared with patients with isolated GH deficiency (IGHD). However, the outcome of patients with permanent GH deficiency (GHD) has not yet been reported. OBJECTIVES: The objectives of the study were to evaluate and compare adult height data and the effect of spontaneous or induced puberty after long-term treatment with GH in young adults with either permanent IGHD or MPHD. DESIGN AND SETTING: This was a retrospective multicenter study conducted in university research hospitals and a tertiary referral endocrine unit. PATIENTS AND METHODS: Thirty-nine patients with IGHD (26 males, 13 females) and 49 with MPHD (31 males, 18 females), diagnosed at a median age of 7.7 and 6.9 yr, respectively, were reevaluated for GH secretion after adult height achievement (median age 17.6 and 19.8 yr). The diagnosis of permanent GHD was based on peak GH levels less than 3 microg/liter after an insulin tolerance test or peak GH levels less than 5 microg/liter after two different tests. Fifteen subjects had idiopathic GHD and seventy-three had magnetic resonance imaging evidence of congenital hypothalamic-pituitary abnormalities. Height sd score (SDS) was analyzed at diagnosis, the onset of puberty (either spontaneous or induced), and the time of GH withdrawal. RESULTS: The subjects with IGHD entered puberty at a median age of 12.6 yr (females) and 13.4 yr (males). Puberty was induced at a median age of 13.5 and 14.0 yr, respectively, in males and females with MPHD. Median height SDS at the beginning of puberty was similar in the IGHD and MPHD subjects. Total pubertal height gain was similar between patients with IGHD or MPHD. Median adult height was also not significantly different between IGHD and MPHD patients (males, 168.5 vs. 170.3 cm; females, 160.0 vs. 157.3 cm). The adult height SDS of the IGHD subjects was positively correlated with height at the time of diagnosis and with total pubertal height gain. Conversely, the adult height SDS of the MPHD subjects was positively correlated with both the duration of GH treatment and height SDS at the time of GHD diagnosis. CONCLUSIONS: Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.
Asunto(s)
Estatura , Hormona de Crecimiento Humana/deficiencia , Hormonas Hipofisarias/deficiencia , Niño , Preescolar , Femenino , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Hipotálamo/anomalías , Insulina , Imagen por Resonancia Magnética , Masculino , Hipófisis/anomalías , Pubertad , Estudios RetrospectivosRESUMEN
Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K(ATP)) channel of the pancreatic beta-cell, were found in patients with PNDM. Closure of the K(ATP) channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), c.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes.