Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes.

OBJECTIVE: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM). RESEARCH DESIGN AND METHODS: The 11 coding exons and the polyadenylation region of FOXP3 were sequenced in 26 male subjects with diabetes diagnosed before 6 months of age in whom common genetic causes of PNDM had been excluded. Ten subjects had at least one additional immune-related disorder, and the remaining 16 had isolated diabetes. RESULTS: We identified four hemizygous FOXP3 mutations in 6 of 10 patients with associated immune-related disorders and in 0 of 16 patients with isolated diabetes (P = 0.002). Three patients with two novel mutations (R337Q and P339A) and the previously reported L76QfsX53 developed classic IPEX syndrome and died within the first 13 months. The novel mutation V408M was found in three patients from two unrelated families and had a mild phenotype with hypothyroidism and autoimmune enteropathy (n = 2) or nephrotic syndrome (n = 1) and survival to 12-15 years. CONCLUSIONS: FOXP3 mutations result in approximately 4% of cases of male patients with permanent diabetes diagnosed before 6 months. Patients not only have classic IPEX syndrome but, unexpectedly, may have a more benign phenotype. FOXP3 sequencing should be performed in any male patient with the diagnosis of diabetes in the first 6 months who develops other possible autoimmune-associated conditions, even in the absence of full IPEX syndrome.

Use of atorvastatin in hyperlipidemic hypertensive renal transplant recipients.

The aim of the present short-term study was to evaluate the use of a new HMG-CoA reductase inhibitor, atorvastatin, in the treatment of hyperlipidemia and the effect on blood pressure in a group of hypertensive stable renal transplant recipients with hypercholesterolemia who received kidney grafts before 18 years of age. Eight patients (aged 10.8-30.1 years) with inadequately controlled total cholesterol (TC) levels by a lipid-lowering diet (8 weeks) were treated daily for 12 weeks with atorvastatin at an initial dose of 2.5 mg. The dose was increased monthly by 2.5 mg in order to lower TC levels to less than 200 mg/dl. Serum lipoprotein profile, cyclosporin A (CsA), serum creatinine (SCr), and liver and muscle enzyme levels were measured before starting the lipid-lowering diet, at the start of treatment (baseline), and during treatment. Ambulatory blood pressure monitoring (ABPM) (24-h) was carried out in each patient at both baseline and the end of the follow-up. During the lipid-lowering diet, no significant changes in lipoprotein parameters were observed. Atorvastatin was tolerated well and no clinical side effects were noted during the follow-up. The final dose of atorvastatin ranged from 2.5 to 7.5 mg/day. At the end of the study, TC was reduced by 32.2% ( P<0.05), low-density lipoprotein cholesterol (LDL-C) by 41.8% ( P<0.05), and apo B by 29.5% ( P<0.05). No significant changes in HDL-C, VLDL-C, apolipoprotein AI, and lipoprotein(a) were observed. SCr and CsA levels were unaffected. Overall, no significant changes in mean 24-h, daytime, and nighttime ABPM values between the first and the second recordings were observed. However, both daytime and nighttime systolic and diastolic ABPM values dropped in four patients. In conclusion, low-dose atorvastatin appears to be safe, well tolerated, and effective in the treatment of post-transplant hyperlipidemia. In addition, the capacity of atorvastatin to reduce blood pressure, whether or not related to its lipid-lowering action, deserves further investigation.

La acidosis láctica en la presentación de la leucemia linfoblástica aguda / Lactic acidosis as an initial event in a case of acute lymphoblastic leukemia

Diferentes neoplasis han sido relacionadas causalmente con acidosis metabólica láctica,aunque ésta es rara como evento de presentación.El aumento del lactato plasmático en las enfermedades tumorales se asocia a pobre pronóstico.El manejo sintomático es objeto de múltiples controversias y la resolución definitiva está relacionada con el tratamiento de la enfermedad de base.Presentamos un paciente pediátrico con severa acidosis láctica a juzgar por el grado de acidemia,hipobicarbonatemia y lactatemia, como forma de presentación de una leucemia linfoblástica aguda.Se discuten los posibles mecanismos de generación y perpetuación de la acidosis láctica que resultan de un imbalance entre la producción y eliminación de lactato y su respuesta a diversas modalidades terapéuticas.Como en la literatura,no hubo respuesta a la infusión de grandes dosis de bicarbonato,en cambio se observó mejoría,con disminución de la concentración de lactato en un 50 por ciento y corrección de la acidosis metabólica,con la adecuación de aporte de glucosa y la administración de dicloracetato por vía oral

La acidosis láctica en la presentación de la leucemia linfoblástica aguda / Lactic acidosis as an initial event in a case of acute lymphoblastic leukemia

Diferentes neoplasis han sido relacionadas causalmente con acidosis metabólica láctica,aunque ésta es rara como evento de presentación.El aumento del lactato plasmático en las enfermedades tumorales se asocia a pobre pronóstico.El manejo sintomático es objeto de múltiples controversias y la resolución definitiva está relacionada con el tratamiento de la enfermedad de base.Presentamos un paciente pediátrico con severa acidosis láctica a juzgar por el grado de acidemia,hipobicarbonatemia y lactatemia, como forma de presentación de una leucemia linfoblástica aguda.Se discuten los posibles mecanismos de generación y perpetuación de la acidosis láctica que resultan de un imbalance entre la producción y eliminación de lactato y su respuesta a diversas modalidades terapéuticas.Como en la literatura,no hubo respuesta a la infusión de grandes dosis de bicarbonato,en cambio se observó mejoría,con disminución de la concentración de lactato en un 50 por ciento y corrección de la acidosis metabólica,con la adecuación de aporte de glucosa y la administración de dicloracetato por vía oral