Jacques Beltrand

Metabolic Correction Induced by Leptin Replacement Treatment in Young Children With Berardinelli-Seip Congenital Lipoatrophy

OBJECTIVE. Berardinelli-Seip syndrome is a rare congenital lipoatrophy with a severe prognosis and no efficient therapy. Children present with low leptin levels and severe metabolic complications (insulin resistance, elevated triglyceride levels, and hepatic steatosis). The objective of this study was to test safety and efficacy of recombinant-methionyl-human leptin replacement in children with Berardinelli-Seip syndrome before development of severe metabolic disease METHODS. As part of an open trial, recombinant-methionyl-human leptin was given daily for 4 months to children who did not have diabetes and had Berardinelli-Seip congenital lipoatrophy and metabolic complications at a dosage that was meant to achieve physiologic levels. Six boys and 1 girl (age: 2.4–13.6 years), with a mean fasting insulin level of >15 mIU/L and hypertriglyceridemia, were included. RESULTS. At the end of the recombinant-methionyl-human leptin treatment, a 63% reduction of fasting triglycerides level was achieved. A simultaneous 30% increase in insulin sensitivity was seen, and liver volume was reduced by 20.3%. More remarkable, values of insulin sensitivity and triglyceride level were in the reference range in 4 patients. CONCLUSIONS. Leptin replacement is able to reverse metabolic complications in the majority of children with Berardinelli-Seip congenital lipoatrophy and with insulin resistance or dyslipidemia before the development of overt diabetes.

Childhood Craniopharyngioma: Hypothalamus-Sparing Surgery Decreases the Risk of Obesity

CONTEXT Craniopharyngioma is a brain tumor whose high local recurrence rate has for a long time led to a preference for extensive surgery. Limited surgery minimizing hypothalamic damage may decrease the severe obesity rate at the expense of the need for radiotherapy to complete the treatment. OBJECTIVE We compared weight gain and local recurrence rates after extensive resection surgery (ERS) and hypothalamus-sparing surgery (HSS). DESIGN Our observational study compared a historical cohort managed with ERS between 1985 and 2002 to a prospective cohort managed with HSS between 2002 and 2010. SETTING The patients were treated in a pediatric teaching hospital in Paris, France. PATIENTS Thirty-seven boys and 23 girls were managed with ERS (median age, 8 years); 38 boys and 27 girls were managed with HSS (median age, 9.3 years). MAIN OUTCOME MEASURES Data were collected before and 6 months to 7 years after surgery. Body mass index (BMI) Z-score was used to assess obesity and the number of surgical procedures to assess local recurrence rate. RESULTS Mean BMI Z-score before surgery was comparable in the 2 cohorts (0.756 after ERS vs 0.747 after HSS; P = .528). At any time after surgery, mean BMI Z-score was significantly lower after HSS (eg, 1.889 SD vs 2.915 SD, P = .004 at 1 year). At last follow-up, the HSS cohort had a significantly lower prevalence of severe obesity (28% vs 54%, P < .05) and higher prevalence of normal BMI (38% vs 17%, P < .01). Mean number of surgical procedures was not significantly different in the 2 cohorts. CONCLUSIONS Hypothalamus-sparing surgery decreases the occurrence of severe obesity without increasing the local recurrence rate.

Impact of fetal growth restriction on body composition and hormonal status at birth in infants of small and appropriate weight for gestational age.

BACKGROUND Fetal growth restriction (FGR) has been related to several health risks, which have been generally identified in small-for-gestational age (SGA) individuals. OBJECTIVE To evaluate the impact of FGR on body composition and hormonal status in infants born either small- or appropriate-for-gestational age (AGA). METHODS Fetal growth was assessed by ultrasound every 4 weeks from mid-gestation to birth in 248 high-risk pregnancies for SGA. Fetal growth velocity was calculated as change in the estimated fetal weight percentiles and FGR defined as its reduction by more than 20 percentiles from 22 gestational weeks to birth. Impact of FGR on body composition, cord insulin, IGF-I, IGF binding protein-3 (IGFBP-3), and cortisol concentrations was assessed in SGA and AGA newborns. RESULTS Growth-retarded AGA infants showed significantly reduced birth weight, ponderal index, percentage of fat mass, and bone mineral density when compared with AGA newborns with stable intrauterine growth. Cord IGF-I and IGFBP-3 concentrations were significantly decreased in growth-retarded infants in both SGA and AGA groups. Cord insulin concentration was significantly lower and cord cortisol significantly higher in AGA infants with FGR versus AGA newborns with stable intrauterine growth. After adjustment for gestational age and gender, birth weight was directly related to fetal growth velocity and cord IGF-I concentration. The variation in infants adiposity was best explained by fetal growth velocity and cord insulin concentration. CONCLUSIONS FGR affects body composition and hormonal parameters in newborns with birth weight within the normal range, suggesting these individuals could be at similar metabolic risks as SGA. .

Glucose Metabolism in 105 Children and Adolescents After Pancreatectomy for Congenital Hyperinsulinism

OBJECTIVE To describe the long-term metabolic outcome of children with congenital hyperinsulinism after near-total or partial elective pancreatectomy. RESEARCH DESIGN AND METHODS Patients (n = 105: 58 diffuse and 47 focal congenital hyperinsulinism) received operations between 1984 and 2006. Follow-up consisted of periodic measurements of pre- and postprandial plasma glucose over 24 h, OGTT, and IVGTT. Cumulative incidence of hypo- or hyperglycemia/insulin treatment was estimated by Kaplan-Meier analysis. RESULTS After near-total pancreatectomy, 59% of children with diffuse congenital hyperinsulinism still presented mild or asymptomatic hypoglycemia that responded to medical treatments and disappeared within 5 years. One-third of the patients had both preprandial hypoglycemia and postprandial hyperglycemia. Hyperglycemia was found in 53% of the patients immediately after surgery; its incidence increased regularly to 100% at 13 years. The cumulative incidence of insulin-treated patients was 42% at 8 years and reached 91% at 14 years, but the progression to insulin dependence was very variable among the patients. Plasma insulin responses to IVGTT and OGTT correlated well with glycemic alterations. In focal congenital hyperinsulinism, hypoglycemia or hyperglycemia were rare, mild, and transient. CONCLUSIONS Patients with focal congenital hyperinsulinism are cured of hypoglycemia after limited surgery, while the outcome of diffuse congenital hyperinsulinism is very variable after near-total pancreatectomy. The incidence of insulin-dependent diabetes is very high in early adolescence.

Resistance to leptin-replacement therapy in Berardinelli-Seip congenital lipodystrophy: an immunological origin.

CONTEXT Recently, in a 4-month proof-of-concept trial, beneficial metabolic effects were reported in non-diabetic children with Berardinelli-Seip congenital lipodystrophy (BSCL); this information prompted us to hypothesize that long-term leptin-replacement therapy might improve or reverse the early complications of the disease in these patients. PATIENTS AND METHODS A 28-month trial was implemented in eight patients. Efficacy assessment was based on a decrease in serum triglyceride concentrations, and/or a decrease in liver volume and/or an increase in insulin sensitivity of at least 30% respectively. The response was defined as follows: total (3/3 positive criteria), partial (1 or 2/3), or negative (0/3). Anti-leptin antibodies were measured with a radiobinding assay, and a neutralizing effect was assessed in primary cultures of embryonic neurons incubated with an apoptotic agent (N-methyl-D-aspartate) and the patient serum, with or without leptin. RESULTS A negative or partial response to treatment was observed in five of eight patients even when leptin dosages were increased. A displaceable leptin binding was detectable in all patients after 2 months of treatment. At 28 months, binding was higher in the patients with a negative response than in the total responders, and it paralleled both the increase in leptin dosage and serum leptin concentrations. Co-incubation of embryonic neurons with serum from two patients with a negative response inhibited the neuroprotective effect of leptin. CONCLUSION Under leptin therapy, patients with BSCL may develop a resistance to leptin, which could be partly of immunological origin, blunting the previously reported beneficial effects.

ZnT8 Is a Major CD8+ T Cell–Recognized Autoantigen in Pediatric Type 1 Diabetes

Type 1 diabetes results from the destruction of β-cells by an autoimmune T-cell response assisted by antigen-presenting B cells producing autoantibodies. CD8+ T-cell responses against islet cell antigens, thought to play a central role in diabetes pathogenesis, can be monitored using enzyme-linked immunosorbent spot (ELISpot) assays. However, such assays have been applied to monitoring of adult patients only, leaving aside the large and increasing pediatric patient population. The objective of this study was twofold: 1) to develop a CD8+ T-cell interferon-γ ELISpot assay for pediatric patients and 2) to determine whether zinc transporter 8 (ZnT8), a recently described target of autoantibodies in a majority of patients, is also recognized by autoreactive CD8+ T cells. Using DNA immunization of humanized mice, we identified nine HLA-A2–restricted ZnT8 epitopes. Among 36 HLA-A2+ children with diabetes, 29 responded to ZnT8 epitopes, whereas only 3 of 16 HLA-A2+ control patients and 0 of 17 HLA-A2− control patients responded. Some single ZnT8 epitopes performed as well as the group of epitopes in discriminating between patients and control individuals. Thus, ZnT8 is a major CD8+ T-cell autoantigen, and ELISpot assays display similar performance in adult and pediatric type 1 diabetes.

Bone mineral content at birth is determined both by birth weight and fetal growth pattern.

Adult peak bone mass is related to birth weight, suggesting it could be affected by fetal growth pattern. Small-for-gestational-age (SGA) newborns have lower bone mineral content (BMC), but what about adapted-for-gestational-age (AGA) newborns with fetal growth restriction? The purpose of the study was to determine the respective role of birth weight and fetal growth pattern on BMC. Full-term newborns from SGA high-risk pregnancies were included (n = 185). Estimated fetal weight percentiles were measured monthly from mid-gestation to birth, and restricted fetal growth (FGR) was defined as a loss by more than 20 percentiles. BMC was measured at birth, using dual x-ray absorptiometry. Newborns were SGA (n = 56) or AGA (n = 129). Newborns with FGR (n = 111) were AGA (n = 71) or SGA (n = 41). BMC was significantly lower in SGA than AGA (1.48 ± 0.02 vs. 1.87 ± 0.04 g/cm) and lower when FGR irrespective of birth weight (1.66 g/cm ± 0.03 vs. 1.89 g ± 0.05). In multivariate analysis, FGR and SGA were significant and independent predictors of low BMC. In conclusion, fetal growth pattern affects BMC not only in SGA infants but also when birth weight is maintained in the normal range.

Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

OBJECTIVE Neonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin. RESEARCH DESIGN AND METHODS We conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1–18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing. RESULTS At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change −1.55% [range −3.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin. CONCLUSIONS SU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.

CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism

Primary aldosteronism (PA) is the most common form of secondary hypertension. Mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D are found in aldosterone producing adenoma (APA) and familial hyperaldosteronism (FH). A recurrent mutation in CACNA1H (coding for Cav3.2) was identified in a familial form of early onset PA. Here we performed whole exome sequencing (WES) in patients with different types of PA to identify new susceptibility genes. Four different heterozygous germline CACNA1H variants were identified. A de novo Cav3.2 p.Met1549Ile variant was found in early onset PA and multiplex developmental disorder. Cav3.2 p.Ser196Leu and p.Pro2083Leu were found in two patients with FH, and p.Val1951Glu was identified in one patient with APA. Electrophysiological analysis of mutant Cav3.2 channels revealed significant changes in the Ca2 + current properties for all mutants, suggesting a gain of function phenotype. Transfections of mutant Cav3.2 in H295R-S2 cells led to increased aldosterone production and/or expression of genes coding for steroidogenic enzymes after K+ stimulation. Identification of CACNA1H mutations associated with early onset PA, FH, and APA suggests that CACNA1H might be a susceptibility gene predisposing to PA with different phenotypic presentations, opening new perspectives for genetic diagnosis and management of patients with PA.

Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of pancreatic β-cells by the immune system that involves innate and adaptive immune cells. Mucosal-associated invariant T cells (MAIT cells) are innate-like T-cells that recognize derivatives of precursors of bacterial riboflavin presented by the major histocompatibility complex (MHC) class I–related molecule MR1. Since T1D is associated with modification of the gut microbiota, we investigated MAIT cells in this pathology. In patients with T1D and mice of the non-obese diabetic (NOD) strain, we detected alterations in MAIT cells, including increased production of granzyme B, which occurred before the onset of diabetes. Analysis of NOD mice that were deficient in MR1, and therefore lacked MAIT cells, revealed a loss of gut integrity and increased anti-islet responses associated with exacerbated diabetes. Together our data highlight the role of MAIT cells in the maintenance of gut integrity and the control of anti-islet autoimmune responses. Monitoring of MAIT cells might represent a new biomarker of T1D, while manipulation of these cells might open new therapeutic strategies.