Luciano Tatò

Long-Term Effects of Childhood Obesity on Morbidity and Mortality

Obesity tracks from childhood into adulthood, and the persistence of obesity rises with age among obese children. Early onset obesity was suggested as a risk factor for morbidity and mortality later in life. In both sexes, rates of diabetes, coronary heart disease, atherosclerosis, hip fracture and gout were increased in those who were overweight as adolescents. Especially in females, obesity at late adolescence was associated with several and relevant psychosocial consequences in adulthood. Finally, a higher mortality risk for all causes of death, especially atherosclerotic cerebrovascular disease and colorectal cancer, was demonstrated in males but not in females who were overweight during high school years. Although the persistence of excess adiposity from childhood to adulthood is a morbidity risk factor, it is not known if total body fat or body fat distribution is the main factor responsible. In particular, a specific role for the intra-abdominal adipose tissue (IAAT) in childhood, independently from that of total body fat, on morbidity risk in adulthood was not demonstrated yet. The association between childhood obesity and adult morbidity and mortality strongly suggests that a more effective prevention and treatment of childhood obesity should be pursued.

Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease

Purpose: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease.Methods: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3–43 months old (median 13 months) with minimal acid α-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort.Results: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid α-glucosidase; no patients withdrew from the study because of safety concerns.Conclusions: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.

Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study.

In a randomized controlled study, we investigated the effect of treatment with intravenous neridronate in prepubertal children with OI. Our study suggests that quarterly intravenous infusions of the bisphosphonate significantly raise the rate of increase in BMD at both the spine and hip, the projected area of the lumbar vertebrae, and height. These results are associated with a significant decrease in the risk of clinical fractures.

Intravenous Neridronate in Adults With Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heritable disease of connective tissue, characterized by increased bone fragility. Bisphosphonates currently seems to be the most promising therapy, at least in children. We tested IV neridronate, an amino‐bisphosphonate structurally similar to alendronate and pamidronate in adults with OI. Twenty‐three men and 23 premenopausal women with OI were randomized to either iv neridronate (100 mg infused intravenously for 30 minutes every 3 months) or no treatment with a ratio of 2 to 1. Control patients were given the same bisphosphonate therapy at the end of the first year. Clinical evaluation included bone densitometry measurements using dual energy X‐ray absorptiometry (DXA), fasting serum and urinary biochemistry every 6 months, and radiographs of the spine taken at baseline and after 12 and 24 months of follow‐up. Spine and hip bone mineral density rose by 3.0 ± 4.6% (SD) and by 4.3 ± 3.9%, respectively, within the first 12 months of treatment, whereas small insignificant changes were observed in the control group. During the second year of follow‐up, additional 3.91% and 1.49% increases were observed at the spine and hip, respectively. Markers of skeletal turnover significantly fell during neridronate treatment. Fracture incidence during neridronate treatment was significantly lower than before therapy and compared with controls. Neridronate iv infusions, administered quarterly, significantly increase bone mineral density and lowered the risk of clinical fracture in adults with OI. Bisphosphonate therapy seems to provide clinical benefits, not only to children with OI, but also to adult patients.

Etiology and age incidence of precocious puberty in girls: a multicentric study.

We review the etiology and age incidence of precocious puberty in 438 girls examined between 1988-1998; 428 (97.7%) had central precocious puberty (CPP), the remaining 10 (2.3%) gonadotropin-independent precocious puberty (GIPP) of ovarian origin. The majority of CPP girls (59.6%) were aged between 7-7.9 yr, 22.4% were 6 year olds, and only 18% were under 6 years old. Cranial CT and/or MRI performed in 304/428 girls, showed neurogenic abnormalities in 56/304 (18.4%) CPP girls; 30 (9.9%) were due to previously diagnosed intracranial abnormalities and the remaining 26 (8.5%) were detected at the diagnosis of CPP. The frequency of neurogenic CPP tended to be higher in girls under 4 years of age while the frequency of idiopathic CPP tended to be higher in girls aged between 7-7.9 years, but no statistically significant differences were found. Interestingly, some CNS anomalies either of tumoral or congenital origin were detected at presentation in 7% of the girls aged over 7 years. Other related or coincidental clinical anomalies, mainly due to genetic diseases, were observed in 22/304 (7.2%) patients. History of precocious maternal menarche was found in 12/304 (4%) girls. In conclusion, idiopathic CPP was observed in 74% of the girls in this study. Neurogenic anomalies or other coincidental or related clinical findings were observed in the remaining 26%. The increased frequency of idiopathic CPP in girls aged over 7 years may suggest an early, but otherwise normal onset of puberty in many of these girls as a consequence of the trend towards earlier maturation. Nonetheless, the finding of CNS anomalies also in the older patients, raises the question of whether these patients should undergo a complete diagnostic work-up.

Growth hormone treatment in osteogenesis imperfecta with quantitative defect of type I collagen synthesis.

OBJECTIVES We studied growth rate, bone density, and bone metabolism in patients affected by type I osteogenesis imperfecta (OI) with quantitative defect in type I collagen synthesis during treatment with human growth hormone (hGH), being aware of its collagen-stimulating synthesis activity in vitro. STUDY DESIGN Fourteen patients (6 boys; ages 4.8 to 10.8 years) were studied. Any structural alteration in the collagen chains was excluded, and reduced production of structurally normal type I collagen (increase in type III/type I collagen; reduction in the messenger ribonucleic acid alpha 1 (I)/ alpha 2 (I) ratio) was demonstrated. The patients were divided into two groups comparable in sex, age, height, and clinical severity of OI; seven patients (three boys) were treated for 12 months with hGH at a dosage of 0.2 mg/kg per week (0.6 IU/kg per week), in six injections subcutaneously, and seven were followed as control subjects. Auxologic data were measured every 3 months, and bone age was determined at the start, after 1 year of treatment, and 1 year after its completion. Every 3 months, serum insulin-like growth factor type I, osteocalcin, carboxyterminal propeptide of type I procollagen, alkaline phosphatase, calcium, and phosphorus levels and urinary hydroxyproline and calcium levels were determined. Bone mass measurements were carried out at the start of the study in all patients and repeated after 12 months in treated patients at the lumbar spine by dual-energy x-ray absorptiometry and by anteroposterior (second, third, and fourth lumbar vertebrae) and lateral (third lumbar vertebra) scan. Results were expressed as areal (anteroposterior and lateral) bone density (in milligrams per square centimeter) and as calculated true density (in milligrams per cubic centimeter). RESULTS After 12 months, linear growth velocity in treated patients increased significantly in comparison with the pretreatment period (from 3.57 +/- 0.55 to 6.04 +/- 0.69 cm/yr; p < 0.05) and with the untreated group (p < 0.05). Bone age did not advance faster than chronologic age. The fracture index per year was low before treatment, and during therapy no patient had any fractures. Serum osteocalcin levels were statistically lower than in control subjects before treatment and increased significantly after 12 months (3.3 +/- 1.0 vs 2.1 +/- 0.9 nmol/L; p < 0.05). Serum levels of carboxyterminal propeptide of type I procollagen were significantly lower than normal values before treatment (164.6 +/- 46.7 vs 310.3 +/- 97.6 ng/ml; p < 0.05) and rose, but not significantly, during and after treatment. Before therapy, patients with OI had significantly lower lumbar anteroposterior, lateral, and calculated true bone density than the normal population of the same sex compared for both age and height. After hGH treatment, bone density increased significantly in the lumbar spine, in anteroposterior and lateral scans (+2.6 +/- 2.5% and +9.8% +/- 14.0%, respectively; p < 0.05). CONCLUSIONS From our results, we conclude that hGH treatment in moderate OI does not increase the fracture risk in treated patients in the short term, significantly increases the rate of linear growth velocity, and increases bone turnover and mineral content in trabecular bone at the lumber spine.

Distribution of food intake as a risk factor for childhood obesity.

OBJECTIVE: The purpose of our study was to assess the relationship between nutrient intake, partitioning of food intake, parents’ overweight and adiposity in a group of children.SUBJECTS: 530 7–11-year-old children: 278 males, 252 females.METHODS: Energy intake, nutrient intake and percentage distribution of the intake of energy among the different meals were assessed by means of diet history. Body composition was obtained by measuring skinfold thickness.RESULTS: We identified the relationship between the childrens adiposity and their parents’ body mass index (BMI) mother: r=0.12, P<0.01; father: r=0.13; P<0.01), carbohydrate (r=−0.15, P<0.001) and fat intake (r=0.14, P<0.002), and the proportion of energy taken at dinner (r=0.1, P<0.05). A multiple regression analysis was run with a stepwise procedure using relative adiposity as the dependent variable and parents’ BMI, dinner intake (percentage of energy intake), EI/BMR ratio (an index of energy intake validity), and sex (dummy variable) as independent variables. All the independent variables, except percentage of fat intake, were included in the final model. The equation was able to explain ≈19% (R=0.44, P<0.001) of inter-individual fat mass percentage variability.CONCLUSIONS: Diet composition did not contribute to explain the childrens adiposity when the parents’ overweight (BMI) was taken into account. However, the percentage distribution of the intake of energy among the different meals, particularly at dinner, contributed to explain inter-individual variance of fatness in children of both sexes.

Effects of two different regimens of recombinant human growth hormone therapy on the bone mineral density of patients with growth hormone deficiency

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Final height in girls with central precocious puberty: comparison of two different luteinizing hormone‐releasing hormone agonist treatments

In order to evaluate the effects of two long‐acting luteinizing hormone‐releasing hormone agonists on growth, bone maturation and final height in girls with central precocious puberty, we analyzed growth data from 40 girls (15 treated with buserelin intranasal spray (group A), 15 treated with triptorelin depot im every 28 days (group B) and 10 untreated (group C)). Patients in group A started treatment when chronological age (CA) was 7.7 ± 0.9 years, bone age (BA) was 10.2 ± 1.1 years and height was 131.9 ± 5.0 cm. Patients in group B started therapy when CA was 7.6 ± 0.5 years, BA 9.8 ± 1.0 years and height 133.2 ± 7.6 m. The diagnosis of untreated patients (group C) was made when CA was 7.2 ± 0.9 years, BA 9.6 ± 2.2 years and height 130.2 ± 8.6cm. Both luteinizing hormone‐releasing hormone agonists appeared to control precocious puberty. Final height in group B (160.6 ± 5.7 cm) was significantly higher than that of group A (153.2 ± 5.0 cm: p < 0.05) and group C (149.6 ± 6.3; p < 0.01), whereas the difference between groups A and C was not statistically significant. In group B a positive difference was observed between final height (160.6 ± 5.7 cm) and target height (157.6 ± 5.9 cm) (ns); on the contrary, in groups A and C, final height was lower than target height (155.5 ± 5.3 and 156.4 ± 1.3cm, respectively), but only in group C the difference was statistically significant (p < 0.01). The best results regarding final height obtained by slow‐release depot im therapy may be associated with more stable agonist blood levels during treatment.

Subclinical hypothyroidism in children and adolescents: a wide range of clinical, biochemical, and genetic factors involved.

OBJECTIVE The aim of the study was to examine clinical characteristics, biochemical parameters, and TSH-R gene variations in children and adolescents with subclinical hypothyroidism (SH) in order to evaluate their pattern of distribution in SH. PATIENTS We enrolled 88 patients, each having at least two TSH measurements above the upper limit of the reference range with normal free thyroid hormones and negative thyroid autoantibodies. MAIN OUTCOME MEASURES Clinical characteristics included height, weight, family history of thyroid diseases, thyroid volume, and echogenicity at ultrasonography. Biochemical parameters included TSH, free thyroid hormones, thyroid autoantibodies, and adjusted daily urinary iodine excretion (UIE). Genetic variations in the TSH-R gene were assessed. RESULTS The prevalence of overweight/obesity, positive family history of thyroid diseases, and thyroid hypoechogenicity was 28.4, 45.5, and 22.7%, respectively. Median TSH was higher in overweight/obese patients than in normal-weight ones (7.4 vs. 5.7 muIU/ml; P = 0.04) and in overweight/obese patients with hypoechogenicity than in those with normal ultrasound pattern (8.5 vs. 6.8 muIU/ml; P = 0.04). Adjusted daily UIE was lower in subjects without than in those with a positive family history of thyroid diseases (81 vs. 120 mug/d; P = 0.001). The prevalence of a positive family history of thyroid diseases was 1.9-fold higher in patients with nonsynonymous mutations in the TSH-R gene than in patients without any mutation (80 vs. 42%; P = 0.03). A novel mutation at position 1559 in exon 10 (W520X) was detected in one child. CONCLUSIONS Overweight/obesity, thyroid hypoechogenicity, and nonsynonymous mutations in the TSH-R gene are characterizing features of a large portion of SH children.