Luciano Beccaria

GH/IGF-I axis in Prader-Willi syndrome: Evaluation of IGF-I levels and of the somatotroph responsiveness to various provocative stimuli

Basal IGF-I levels and the GH response to at least two among provocative stimuli such as clonidine (CLO, Catapresan, 150 mcg/m2 po), GHRH (1 mcg/kg iv)+arginine (ARG, 0.5 g/kg iv infusion during 30 min) and GHRH+pyridostigmine (PD, Mestinon cpr 60 mg po) have been evaluated in 43 children with Prader-Willi syndrome (PWS, 17 males and 26 females, age 3–22 yr, 7 normal weight and 36 obese PWS), in 25 normal short children (NC, 17 males and 8 females, 7.7–18.5 yr) and in 24 children with simple obesity (OB, 14 males, 10 females, 7.7–21.5 yr). Both normal weight and obese PWS had mean IGF-I levels lower than those recorded in NC (p<0.001) and OB (p<0.001). The GH responses to GHRH+ARG and GHRH+PD in NC were similar and higher than that to CLO (p<0.001). In PWS the GH response to GHRH+ARG was higher than that to GHRH+PD (p<0.001) which, in turn, was higher than that to CLO (p<0.001); these responses in PWS were lower than those in normal children (p<0.02) and similar to those in OB. In normal weight PWS the GH responses to GHRH+ARG and to GHRH+PD were similar and higher than to CLO (p<0.05); however, each provocative stimulus elicited a GH rise lower than that in NC (p<0.05). In obese PWS as well as in OB the GH response to GHRH+ARG was higher than that to GHRH+PD (p<0.02) which, in turn, was higher than that to CLO (p<0.001); all GH responses in obese PWS and OB were lower than those in NC (p<0.001) but similar to those in normal weight PWS. In conclusion, patients with PWS show clear reduction of IGF-I levels as well as of the somatotroph responsiveness to provocative stimuli independently of body weight excess. These results strengthen the hypothesis that PWS syndrome is frequently connoted by GH insufficiency.

The Italian National Survey for Prader-Willi syndrome: an epidemiologic study.

Twenty‐five medical centers and the Prader–Willi Syndrome (PWS) Association collaborated on a study which attempted to identify all people with genetically confirmed diagnosis of PWS living in Italy. Investigators of the participating centers contacted PWS subjects and/or their family, filled in a specially developed form with the required data and forwarded this information by email. The study identified 425 subjects (209 males and 216 females, between the ages of 0.4–46.7). Two hundred thirty‐eight patients had del15, 104 had UPD15, 4 demonstrated a translocation affecting chromosome 15 and 79 showed a positive methylation test. There were fewer subjects found over the age of 35, probably due to the low rate of identification of older PWS patients as well as the high mortality rate. There were a greater number of male children and adolescents with PWS whilst, amongst adults, there were more females. As expected, the majority of subjects with PWS were obese, especially in adult life. Nevertheless, it is noteworthy that 26% of patients aged between 6 and 17 were normal weight. A total of 212 subjects had received GH treatment, of which 141 were still receiving therapy, while the remaining 71 had stopped. In children and adolescents (233 cases), 89 subjects had never undergone GH therapy. Eighteen PWS patients had died in the past 20 years. Obesity‐related cardiovascular and respiratory diseases were the cause of death, both during childhood and after 18 years of age. Three children died suddenly whilst undergoing GH therapy. Respiratory infection and cardiac illness were the causes of death in two cases. There was no definitive cause of death found in the third case. Overall, there was no increase in number of deaths during GH treatment, suggesting that GH administration in patients with PWS, as a group, does not increase the risk of death.

Assessment of central adrenal insufficiency in children and adolescents with Prader-Willi syndrome.

Objective  A recent study evidenced by metyrapone test a central adrenal insufficiency (CAI) in 60% of Prader–Willi syndrome (PWS) children. These results were not confirmed in investigations with low [Low‐Dose Tetracosactrin Stimulation Test (LDTST), 1 μg] or standard‐dose tetracosactrin stimulation tests. We extended the research by LDTST in paediatric patients with PWS.

Peripheral nerve abnormalities in newly-diagnosed diabetic children

SummaryThe prevalence of clinical and subclinical peripheral neuropathy was evaluated in 51 unselected children at the time of onset of type I diabetes. Twenty-eight patients were followed for one year in order to establish the influence of metabolic control on peripheral nerve function. Twenty-two % of the diabetic children showed nerve conduction abnormalities at the onset and 11.7% had clinical features of peripheral neuropathy. After one year of disease, these figures had changed to 14.3% and 7.1%. Five of 7 children with altered electrophysiological tests in the baseline assessment had had normalization of all parameters one year later. No correlations between insulin requirement and nerve conduction were found. The M value was significantly correlated only with median sensory conduction velocity (p<0.005). Significant correlations were demonstrated between HbA1 concentration and both peroneal motor conduction velocity (p<0.025) and median sensory conduction velocity (p<0.005); these correlations were still present after one year of disease. In the first period of diabetic disease there is functional rather than structural damage of the nerves. The pathogenetic role of hyperglycemia is confirmed; however individual susceptibility to nerve dysfunction may play an important role in the nerve impairment in diabetes.

Impairment of growth hormone responsiveness to growth hormone releasing hormone and pyridostigmine in patients affected by Prader-Labhardt-Willi syndrome

In order to evaluate the impairment of GH response in patients affected by Prader-Labhardt-Willi (PLW) syndrome, in 18 patients we studied GH response to clonidine and to GHRH + pyridostigmine, a cholinergic drug which enhances GHRH induced GH responsiveness in obese patients. After clonidine GH response was abnormal in 14/18 subjects (mean GH peak: 4.1±1.3 μg/l; area under curve: 208.1±74.2 μg/l·h) while all but 5 patients showed an inadequate GH response to GHRH + pyridostigmine (mean GH peak: 13.4±2.5 μg/l; area under curve: 903.4±171.0 μg/l·h). However, in the three patients with low adiposity index, GH response to GHRH + pyridostigmine was significantly higher than that observed in fatter subjects. In addition, GH response to GHRH + pyridostigmine was negatively correlated to age and adiposity index. In conclusion, our data are consistent with the hypothesis of the existence of a complex derangement of GH neuroendocrine regulation in these subjects.

Central adrenal insufficiency in young adults with Prader-Willi syndrome.

A high prevalence (60%) of central adrenal insufficiency (CAI) has been reported in Prader‐Willi syndrome (PWS) using the metyrapone test. We have assessed CAI in adults with PWS using the low‐dose short synacthen test (LDSST).

Prednisone Treatment in Newly Diagnosed Type I Diabetic Children: 1-Yr Follow-Up

Thirty-one children suffering from type I diabetes mellitus were arranged at onset of the disease in two different groups. Group 1 was treated with oral prednisone (60 mg · m−2 · day−1 for 14 days, 30 and 15 mg · m−2 · day−1 for 7 days). Group 2 matched the control group. All patients were treated with continuous subcutaneous insulin infusion for the first 15 days of treatment, and then with two daily injections of a mixture of intermediate- and fast-acting insulin. All subjects were followed for 1 yr. Group 1 required more insulin than group 2 after 30 days (1.5 ± 0.3 vs. 0.6 + 0.2 U · kg−1 · day−1, P < .001) and after 60 days (0.8 ± 0.1 vs. 0.5 ± 0.06 U · kg−1 · day−1, P < .001). After 3 mo, both groups reached the lowest mean stable HbA1 level (8.4 ± 0.4 and 8.3 ± 0.4% group 1 and 2 respectively). Between the 2nd and 9th mo of follow-up, mean postbreakfast C-peptide concentration increased in both groups. The highest levels of fasting C-peptide were reached by group 1 after 90 days (0.77 ± 0.32 nM) and group 2 after 60 days (0.34 ± 0.09 nM). The largest partial remission (C-peptide 0.3 nM, insulin requirement <0.5 U · kg−1 · day−1 and no glycosuria) was observed in group 1 after 180 days (5 of 16 patients) and in group 2 after 60 days (5 of 15 patients). We found no significant difference between the two groups in fasting and postbreakfast C-peptide levels, stable HbA1, and remission during 1-yr follow-up. Short-term prednisone therapy in newly diagnosed type I diabetic children does not considerably modify the natural history of the disease during the 1st yr.

Evaluation of central nervous conduction by visual evoked potentials in insulin-dependent diabetic children. metabolic and clinical correlations

SummaryPeripheral neuropathy is a well-known complication of diabetes, but few data are available on central lesions. Visual evoked potentials (VEPs) seem a reliable and feasible technique for detecting a conduction delay in the central nervous, system. Seventy-one insulin-dependent type 1 diabetic children (mean age 15±3 years) and 33 controls were investigated for central neuropathy. We used a pattern of reversal stimulation with television display of a checker board pattern (15 min and 30 min check size). The latencies of the positive peak (P100 wave) were significantly lengthened in 17 patients (27%) but no correlation was found between VEPs and age, duration of diabetes, insulin requirement and HbA1 level. A negative correlation was found between VEPs and peripheral nervous conduction velocity. VEPs measurement seems a simple and reliable technique for detecting early alterations in CNS function in diabetics. Our data suggest that central and peripheral nervous alterations progress simultaneously.

A Multicenter Retrospective Survey regarding Diabetic Ketoacidosis Management in Italian Children with Type 1 Diabetes

We conducted a retrospective survey in pediatric centers belonging to the Italian Society for Pediatric Diabetology and Endocrinology. The following data were collected for all new-onset diabetes patients aged 0–18 years: DKA (pH < 7.30), severe DKA (pH < 7.1), DKA in preschool children, DKA treatment according to ISPAD protocol, type of rehydrating solution used, bicarbonates use, and amount of insulin infused. Records (n = 2453) of children with newly diagnosed diabetes were collected from 68/77 centers (87%), 39 of which are tertiary referral centers, the majority of whom (n = 1536, 89.4%) were diagnosed in the tertiary referral centers. DKA was observed in 38.5% and severe DKA in 10.3%. Considering preschool children, DKA was observed in 72%, and severe DKA in 16.7%. Cerebral edema following DKA treatment was observed in 5 (0.5%). DKA treatment according to ISPAD guidelines was adopted in 68% of the centers. In the first 2 hours, rehydration was started with normal saline in all centers, but with different amount. Bicarbonate was quite never been used. Insulin was infused starting from third hour at the rate of 0.05–0.1 U/kg/h in 72% of centers. Despite prevention campaign, DKA is still observed in Italian children at onset, with significant variability in DKA treatment, underlying the need to share guidelines among centers.

Metabolic Control in Newly Diagnosed Type 1 Diabetic Children

15 insulin-dependent diabetic children at onset were randomly allocated to one of two different therapeutical protocols: continuous subcutaneous insulin infusion (CSII) and intensified conventional insulin treatment with three daily insulin injections (CIT). Both treatments were performed for 10 days; the initial insulin dose was 1.5 U/kg/day and thereafter the insulin dosage was modified in order to obtain a satisfactory control. Near-normal blood glucose levels were obtained after 24 h in the CSII group, and after 3 days in the CIT group. All subjects underwent 1 year of follow-up. HbA1 levels and insulin requirements decreased similarly in the two groups; C-peptide secretion did not increase significantly in both groups. A clear advantage of CSII cannot be assumed, and the usefulness of this therapeutical approach needs to be confirmed by further investigations.