M. Martín-Frías

LEOPARD syndrome (PTPN11, T468M) in three boys fulfilling neurofibromatosis type 1 clinical criteria.

Noonan syndrome (NS) and neurofibromatosis type 1 (NF1) are well-defined entities. The association of both disorders is called neurofibromatosis–Noonan syndrome (NFNS), a disorder that has been related to mutations in the NF1 gene. Both NS and NFNS display phenotypic overlapping with LEOPARD syndrome (LS), and differential diagnosis between these two entities often represents a challenge for clinicians. We report on three patients (two brothers and a not-related patient) diagnosed as having NFNS. They fulfilled NF1 diagnostic criteria and had some features of NS. The three of them had hypertophic cardiomyopathy while neurofibromas, Lisch nodules, and unidentified bright objects on MRI were absent. PTPN11 gene assays revealed a T468M mutation, typical of LS. Thorough clinical examinations of the patients revealed multiple lentigines, which were considered to be freckling in the initial evaluation. We conclude that NF1 clinical criteria should be used with caution in patients with features of NS. Patients with hyperpigmented cutaneous spots associated with cardiac anomalies, even if fulfilling the minimal NF1 criteria for diagnosis, should be strongly considered for LS diagnosis.

Impact of insulin pump therapy on long-term glycemic control in a pediatric Spanish cohort

AIMS To evaluate the efficacy and safety of Continuous Subcutaneous Insulin Infusion (CSII) in a pediatric cohort and to determine if the ISPAD/IDF/ADA criteria for good metabolic control are achieved during long periods of time. METHODS Retrospective longitudinal study including ninety patients [10.5 (6.5-13.9) years of age, 58% males]. Age at debut, type 1 diabetes mellitus duration, pubertal stage, HbA1c, insulin dose, mean number of glycemic controls, number of basal rates, % basal/total insulin, severe hypoglycemia and diabetic ketoacidosis events were analyzed. Subgroup analysis based on age and pubertal stage was performed. RESULTS HbA1c decreased from 6.9% [52 mmol/mol] to 6.7% [50 mmol/mol] after one year of CSII. Afterwards, it remained less than 7% during the follow-up period (median 3.5 ± 1.8 years (range 1-8). Prior to CSII, 76% of the subjects met ISPAD/ADA criteria. One year after initiating CSII, 96% of children had HbA1c<7.5%. Improvement in glycohemoglobin levels was most prominent in those patients with the highest HbA1c initial levels. Total insulin dose decreased from 0.89 to 0.73 UI/kg/day (p<0.001). Proportion of basal/total insulin changed significantly (47 to 42% (p<0.05)). Number of fractions of the basal rate increased from 5.6 ± 1.8 at one year of CSII to 6.7 ± 2.1 five years later. Incidence of severe hypoglycemic events decreased from 19 to 6.9 episodes/100 patient-year. Only 2 episodes of diabetic ketoacidosis occurred. CONCLUSIONS CSII allows reaching ISPAD/IDF/ADA goals safely during an extended follow-up period in a diabetic pediatric cohort.

LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic Cardiomyopathy

INTRODUCTION AND OBJECTIVES LEOPARD syndrome is an autosomal dominant condition related to Noonan syndrome, although it occurs less frequently. The aim of this study was to characterize the clinical and molecular features of a large series of LEOPARD syndrome patients. METHODS We collected clinical data from 19 patients in 10 hospitals. Bidirectional sequencing analysis of PTPN11, RAF1, and BRAF focused on exons carrying recurrent mutations. RESULTS After facial dysmorphism, structural heart defects (88%) were the most common feature described. Hypertrophic cardiomyopathy (71%) was diagnosed more often than pulmonary valve stenosis (35%). Multiple lentigines or café au lait spots were found in 84% of the series, and deafness was diagnosed in 3 patients. Mutations in PTPN11 were identified in 16 (84%) patients (10 patients had the recurrent LEOPARD syndrome mutation, p.Thr468Met) (NP_002825.3T468M). Two other patients had a mutation in RAF, and 1 patient had a mutation in BRAF. When compared with other neurocardiofaciocutaneous syndromes, LEOPARD syndrome patients showed a higher prevalence of hypertrophic cardiomyopathy and cutaneous abnormalities, and a lower prevalence of pulmonary valve stenosis and short stature. CONCLUSIONS LEOPARD syndrome patients display distinctive features apart from multiple lentigines, such as a higher prevalence of hypertrophic cardiomyopathy and lower prevalence of short stature. Given its clinical implications, active search for hypertrophic cardiomyopathy is warranted in Noonan syndrome spectrum patients, especially in LEOPARD syndrome patients.

Monitorización continua de glucosa para cribado de alteraciones hidrocarbonadas en fibrosis quística

BACKGROUND Diabetes mellitus (DM) is an increasing complication of cystic fibrosis (CF). It is associated with enhance morbidity. Continuous glucose monitoring system (CGMS) could detect glucose disorders earlier than other screening tests usually used. AIMS To compare oral glucose tolerance test (OGTT), HbA(1c) and CGMS in patients with CF and recent disorders of glucose homeostasis and to analyse changes in nutritional status and/or pulmonary function. PATIENTS AND METHODS Thirteen patients with CF (11-22 years, 7 males) were studied using OGTT, HbA(1c) and CGMS. All of them had newly diagnosed glucose disturbances. They were not receiving steroid therapy or had an underlying illness. In all subjects we compared: HbA(1c) levels (%), fasting and 2-hours glucose OGTT (mg/dl) and glucose CGMS values (overall, fasting, 2-hours post mean-meals and excursions >140mg/dl at any time). Furthermore, body mass index, forced expiratory volume in the first second (%) and forced vital capacity (%) were evaluated in the previous year and at the time of the study. We also analysed exocrine pancreatic function and CF-mutation. RESULTS Mean age at diagnosis of glucose disturbance was 16.4 years. All patients had insufficient exocrine pancreatic function and 11/13 presented DeltaF508 CF-mutation. Only one patient was diagnosed with DM using OGGT and 7/13 (53.8%) with CGMS. A total 77% of patients had poor nutritional status and/or pulmonary function at time of diagnosing the glucose disorder. Only 4 patients had abnormal HbA(1c) levels. CONCLUSIONS CGMS allows a better detection of glucose disorders than OGTT. Glucose homeostasis abnormalities are associated with a decrease in nutritional status and/or pulmonary function. HbA(1c) does not aid in the early diagnose of glucose disorders.

Alteraciones hidrocarbonadas en pacientes impúberes con fibrosis quística

INTRODUCTION Annual screening for abnormal glucose tolerance (AGT) with oral glucose test should begin by age 10 years in cystic fibrosis (CF) patients (Consensus-2010). AIMS To examine the frequency of AGT and its outcome in prepubertal CF patients and the changes in glycemic and nutritional status and lung function over the preceding year. PATIENTS AND METHODS Retrospective study of 19 prepubertal CF patients (68% males). All subjects underwent an oral glucose tolerance test (OGTT). Results were classified as: normal glucose tolerance (NGT) or AGT (impaired glucose tolerance [IGT], CF related diabetes [CFRD] or indeterminate glucose tolerance [INDET]). We analyzed: OGTT (glucose and insulin levels), nutritional status (BMI-SD) and lung function (forced spirometry). Statistical analysis was performed with SPSS program-version-15.0, non parametric tests. RESULTS Mean age at first OGGT: 8.5 years (5.8-9.8). Mean follow-up: 2 years (2-3). Initially, 47% patients had AGT and 53% NGT. In follow-up: 4/10 NGT patients developed AGT (3 IGT, 1 CFRD). Among initial AGT patients, of 4 INDET: 2 developed IGT, 1 CFRD. Mean age of AGT onset: 8.6 years (6.4-11.1). In 69% AGT patients a declining BMI-DS and/or lung function was found in the preceding year. In OGTTs performed, fasting and 2h AUC insulin levels were comparable between NGT and AGT; however, insulinogenic index was lower in AGT patients (p=.006). Insulin secretion was delayed in all patients. CONCLUSIONS The high frequency of AGT in prepubertal CF patients and their negative clinical impact supports the usefulness of an earlier glycemic screening.

Pulmonary function in children with type 1 diabetes mellitus

Abstract Aim: To assess lung function in children and adolescents with type 1 diabetes mellitus (T1DM). Patients and methods: We conducted a case-control study of 100 patients with T1DM [median age 13 (10.6–14.7), 44% men, 23% prepubertal, and all nonsmokers] and 77 controls. None had evidence of lung disease or any other comorbidity. We performed pulmonary function tests, including spirometry [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC ratio], plethysmography [total lung capacity (TLC), residual volume (RV), RV/TLC ratio, and airway resistance (Raw)], and diffusing capacity of carbon monoxide in the lung (TLCO), alveolar volume (AV), and TLCO/AV ratio. The duration of diabetes, degree of metabolic control, insulin dose, and presence of diabetic complications were registered. The χ2-test and analysis of variance were used to compare categorical and quantitative variables, respectively. Results: The duration of diabetes was 6.2±3.8 years with a median HbA1c of 7.08±0.4%. FEV1/FVC ratio was found to be significantly higher in patients with TIDM than in controls. Patients with diabetes also had a nonsignificant trend towards lower FVC, FEV1, Raw, and TLCO, and higher RV, TLC, and RV/TLC than controls. There were no differences in pulmonary function based on duration of disease or metabolic control. We found differences in pulmonary evaluation when pubertal stage was analyzed. Conclusions: The lung is functionally involved in children with T1DM. Pubertal development stage influences the evaluation of lung function.

Efecto beneficioso y prolongado del buen control metabólico de la diabetes relacionada con fibrosis quística sobre la función pulmonar y el estado nutricional

Cystic fibrosis related diabetes (CFRD) is a strong determinant for lung function decline and increased mortality. Insulin treatment of CFRD is reportedly beneficial for this situation. We report on the long-term impact of insulin treatment of CFRD on pulmonary function and nutritional status in a CF male patient since diagnosis of diabetes. We report the case of a patient diagnosed with CF at the age of 16. Two years later, he experienced a rapidly evolving decrease in pulmonary function, some months later criteria were met warranting lung transplantation. Concomitantly, he was diagnosed with CFRD and insulin therapy was started. Lung function (spirometry), nutritional status (body mass index) and metabolic control (HbA(1c)) were determined every 3 months. After the introduction of insulin treatment, pulmonary function and nutritional status progressively improved and good glycemic control was achieved. The significant and sustained improvement in pulmonary function allowed for the patients withdrawal from the lung transplantation program within 4 months, a situation which has been maintained until now, 8 years later. The long follow-up of our patient documents the rapid and prolonged beneficial effect of proper metabolic control of CFRD on the respiratory deterioration in CF.

Factores de riesgo cardiovascular en niños y adolescentes españoles con diabetes mellitus tipo 1: evolución a lo largo de 9 años

OBJECTIVES To analyse the prevalence, evolution of cardiovascular risk factors (CVRF) and their relationship with follow-up of metabolic control in pediatric patients with Type 1 Diabetes (T1DM). PATIENTS AND METHODS Longitudinal ambispective study including 75 children and adolescents with T1DM diagnosed from 1996 to 2003 and followed-up for nine years. Family history of CVRF was registered. Data from the second, sixth and ninth year after diagnosis were analysed. RESULTS Family history of CVRF was found in 46.6% of the patients. The prevalence of HbA1c>7.5% in the second, sixth and ninth year after diagnosis was 45.3%, 53.3% y 56%, respectively. The prevalence of obesity (BMI>2SDS) in the three visits was 5.3%, 5.3% y 6.7%, respectively. Hypertension (BP>p90) was found in 14.6%, 8% and 13.3% of the patients in the three visits, respectively. Total cholesterol>200mg/dl: 25.3%, 13.3% and 16%; high density cholesterol lipoprotein< 40 mg/dl: 1.3%, 1.3% and 4%; low density cholesterol lipoprotein>100mg/dl: 38.6%, 34.6% and 38.6%; triglyceride>150 mg/dl: 0%, 1.3% and 2.6%, respectively. There was a significant increase in the prevalence of TG/HDL-C ≥ 2 between the sixth and the ninth year after diagnosis (1.3% and 9.3%, P<.05). A persistent HbA1c ≥ 7.5% showed a statistically significant relationship to a 0.94 decrease in HDL-C z-score between the second and the sixth year, and a persistent HbA1c<7.5% was significantly associated with a 0.55 increase in HDL-C z-score (P=.015) in the same period. CONCLUSIONS A non-optimal metabolic control in first years of DM1 is associated with a decrease in HDL-C z-score. TG/HDL-C ratio could be an early marker of cardiovascular risk.

La respuesta monofásica a la sobrecarga oral de glucosa como factor predictivo del riesgo de diabetes tipo 2 en pacientes pediátricos con obesidad

INTRODUCTION The onset of obesity at young ages is strongly associated with the early development of type 2diabetes (T2D). The shape of the curves of glucose and insulin curves during an oral glucose tolerance test (OGTT) could predict the risk of developing T2D. OBJECTIVE To analyse the morphology of the OGTT and determine T2D risk factors in a mainly Caucasian population of children and adolescents. METHODS Observational retrospective study including 588 patients (309 males, 279 females) with a mean age of 11.1±2years, and of whom 90.3% were Caucasian. Risk factors for T2D were compared in patients with a monophasic or biphasic pattern during the performance of an OGTT, as well as anthropometric and biochemical variables, insulin resistance, and beta-cell function. RESULTS The shape of the glucose curve was monophasic in 50.2% of patients (50.8% male), biphasic in 48.5% (47.6% males), and indeterminate in 1.3%. The monophasic pattern showed lower insulin-sensitivity and worse beta-cell function. Patients with a biphasic pattern had a higher BMI, waist circumference, and blood pressure, although the results were not significant. Latin-American patients had significantly lower serum glucose levels with higher insulin levels during the OGTT. CONCLUSIONS The pattern of response to an OGTT reflects different metabolic phenotypes. Paediatric patients with a biphasic pattern have lower risk-profiling for T2D. The performing of an OGTT could be useful to implement early intervention strategies in children and adolescents with obesity, in order to prevent the development of pre-diabetes or T2D.

Carta al EditorInfundíbulo-neurohipofisitis: evolución a 10 años de un caso en la edad pediátricaInfundibulo-hypophysitis in a girl: 10 years follow-up

las series más numerosas (26 y 35 casos, respectivamente) de infección probable/probada por B. capitatus en pacientes oncohematológicos. La taxonomía del género ha sido revisada atendiendo a la formación de aneloconidias y artroconidias, crecimiento a 45◦C, resistencia a cicloheximida y carencia de ureasa. Las vías de acceso habituales son piel y tractos digestivo y respiratorio. Sus manifestaciones clínicas son variadas, frecuentemente similares a una candidiasis invasora de inicio febril refractario al tratamiento en el contexto de neutropenia grave, fungemia y diagnóstico por hemocultivos positivos en más del 70% de los casos. No obstante, dada la reactividad cruzada con el antígeno galactomanano de Aspergillus, Bonini et al proponen una alternativa diagnóstica y de manejo terapéutico interesante que obviaría la demora de un crecimiento detectable mediante hemocultivos y respondería a aquellos casos sin fungemia o cuando su aislamiento de mucosas dificulta su discriminación como colonización o infección. Así un galactomanano positivo, no siendo un marcador diagnóstico específico de infección por B. capitatus, sí orientaría precozmente un antifúngico eficaz frente a Aspergillus spp. y B. capitatus. La terapia óptima es aún incierta. Frente a los limitados estudios de sensibilidad in vitro, la experiencia clínica sugiere elevada actividad de la anfotericina B y reducida sensibilidad a fluorcitosina, fluconazol e itraconazol. Problemas farmacocinéticos, de dosificación o absorción, junto a fenómenos de resistencia, pueden explicar los fracasos terapéuticos con cepas de B. capitatus sensibles a los antifúngicos habituales. Respecto a las nuevas equinocandinas, su utilidad en la asociación con un azol o anfotericina B requiere de evidencia clínica. En nuestro estudio, micafungina más voriconazol no tuvo efecto terapéutico. La variabilidad de respuesta in vivo a los antifúngicos disponibles y el papel esencial de la neutropenia ha planteado una posible terapia combinada con citoquinas, con experiencia clínica aún limitada.