C. Livieri

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.

Death during GH therapy in children with Prader-Willi syndrome: Description of two new cases

A few cases of death worldwide during GH treatment in pediatric patients with Prader-Willi syndrome (PWS) have been recently described. The evaluation of further cases is needed to better identify possible causal mechanism(s), as well as to suggest some additional guidelines for prevention. We report the death of 2 additional children with genetically confirmed PWS in the first months of GH therapy. Case 1: This 3.9-yr-old girl was born at 39 weeks gestation. Low GH response to two stimulation tests was observed. GH administration was started at the age of 3.5 yr (0.33 mg/kg per week), when the patient was at 130% of her ideal body weight (ibw). Hypertrophy of adenoids was previously demonstrated. Snoring and sleep apnea were present before GH treatment, and did not increase during therapy. Four months later she died at home suddenly in the morning. Case 2: This patient was a 6.3-yr-old boy. He was born at term after an uneventful pregnancy. At the age of 6 yr, his weight was at 144% of his ibw. He showed reduced GH secretion during provocation tests, and GH therapy was started (0.20 mg/kg per week). The previously reported nocturnal respiratory impairment had worsened after beginning GH administration. Tonsils and adenoids hypertrophy were noted. At the age of 6.3 yr he died at home in the morning following an acute crisis of apnea. These additional cases seem to confirm that some children with PWS may be at risk of sudden death at the beginning of GH therapy.

Auto-immunity in children with diabetes mellitus and in their relatives.

Islet cell antibodies (ICA-IgG and complement-fixing-ICA), parietal cell antibodies (PCA), intestinal epithelial cell antibodies (IECA), thyroglobulin (TgA) and thyroid microsomal antibodies (MsA), antinuclear (ANA) and reticulin antibodics (RA), were studied in 55 insulin-dependent diabetic patients (30 males and 25 females), aged 2–19 years with diabetes from a few days up to 14 years. In 58% of the diabetics one or more autoantibodies were found: ICA-IgG (31%), CF-ICA (16%), PCA (34%), TgA (9%), MsA (9%), ANA (13%), RA (2%). Autoantibodies were significantly more frequent in females (76%) than in males (43%) (P<0.025). ICA-IgG, CF-ICA, PCA, ANA were significantly more frequent in patients than in controls. The frequency of ICA-IgG and CF-ICA was significantly higher during the first 3 years of disease than afterwards (P<0.001); a similar pattern was observed for PCA, TgA, MsA. Of the 87 parents and 30 siblings screened for ICA-IgG, CF-ICA, PCA, IECA, TgA, MsA, ANA and RA, 42 (44%) had one or more autoantibodies, which were more frequent in females than in males. Seven relatives (6%) were ICA-IgG positive (four mothers, two fathers and one brother), and only one mother, ICA-IgG negative, was CF-ICA positive. Other autoantibodies were also more frequent in parents than in controls. Autoantibody-positive relatives have been asymptomatic up to now.

Alterations of in vitro interleukin 1 and 2 in diabetic children

We studied interleukin 1 (IL-1) and interleukin 2 (IL-2) production in unstimulated and stimulated cultures from 27 young diabetic patients and 21 age-matched healthy subjects. In unstimulated cultures monocytes from newly diagnosed patients produced significantly higher levels of IL-1 than controls. In lipopolysaccharide (LPS)-stimulated cultures, IL-1 production in patients with fresh and long-standing diabetes was no different from that of controls. IL-2 production was low or absent in unstimulated cultures from insulin-dependent diabetes mellitus (IDDM) patients and controls. In phytohaemagglutinin (PHA)-stimulated cultures both patient groups produced significantly less IL-2 than controls. No correlation was observed between IL-1, IL-2 production and HbA1 levels or the presence of HLA-DR3 or DR4. Our data on “spontaneous” IL-1 production support the hypothesis that monocytes from some newly diagnosed IDDM patients may circulate in a “preactivated” state. The low levels of IL-2 might be explained by an abnormal consumption or by the presence of increased soluble IL-2 receptor levels or by a serum factor which interferes with IL-2 production. Alternatively, it may be a genetically determined trait.

CYP21/C4 gene organisation in Italian 21-hydroxylase deficiency families

SummaryA total of 33 Italian 21-hydroxylase (21-OH) deficiency families were investigated using a combination of short and long range restriction mapping of the CYP21/C4 gene cluster. The analyses revealed that large-scale length polymorphism in this gene cluster strictly conformed to a compound variable number of tandem repeats (VNTR) plus insertion system with between one and four CYP21 + C4 units and seven BssHII restriction fragment length polymorphisms (RFLPs) (75kb, 80kb, 105kb, 110kb, 135kb, 140kb and 180kb). A total of 9/66 disease haplotypes, but only 1/61 nondisease haplotypes, showed evidence of gene addition by exhibiting three or more CYP21 + C4 repeat units. Of these, two were identified in one 21-OH deficiency patient who has a total of eight CYP21 + C4 units, being homozygous for the HLA haplotype DR2 DQ2 B5 A28. This haplotype carries four CYP21 + C4 units, three of which contain CYP21A-like genes and one of which contains a CYP21B-like gene that presumably carries a pathological point mutation. Of the other gene addition haplotypes associated with 21-OH deficiency, four show three CYP21 + C4 units flanked by HLA-DR1 and HLA-B14 markers. Although such haplotypes have commonly been associated with non-classical 21-OH deficiency, three examples in the present study are unexpectedly found in two salt-wasting patients, who are respectively homozygous or heterozygous for this haplotype. Only 7/66 disease haplotypes showed evidence of a CYP21B gene deletion.

A survey on prader-willi syndrome in the italian population: Prevalence of historical and clinical signs

Clinical criteria for the diagnosis of Prader-Willi Syndrome (PWS) were established by consensus in 1993 (Holm et al.). Specific molecular testing is now available and the purpose of diagnostic criteria has shifted to identify individuals to test, thus avoiding the expense of unnecessary analysis. The aim of this study was to find clinical indicators to select patients with suspected PWS for laboratory testing. We analyzed the prevalence of clinical signs and symptoms in 147 genetically diagnosed Italian patients with PWS (67 males and 80 females), aged from 9 months to 34.6 years (13.6 +/- 8.3 years), using the consensus diagnostic criteria, and according to age, sex and type of genetic abnormality. The prevalence of several clinical features changed significantly with age, but very few with sex. According to genetic subtypes (deletion vs UPD), only hypopigmentation and acromicria were more frequent in patients with deletion. Some criteria considered as minor or supportive by Holm et al. have higher prevalence than some major criteria. In conclusion, in order to identify patients with suspected PWS to submit to laboratory testing, we recommend a classification of clinical criteria according to age, giving more attention to those so-called minor or supportive criteria.

The influence of dietary education in diabetic children.

The aim of our study was to evaluate the efficacy of dietary education in inducing modification of the diet and to measure biochemical parameters in 36 children and adolescents with IDDM. At the beginning of the study, each patient was evaluated as follows: food intake (by the method of the 24-h recall for 3 days), auxological parameters, biochemical parameters. Thereafter a program of nutritional guidelines was provided. Subsequent meetings took place at 1-month-intervals. The study ended 3 months later, when all the parameters were completely revalued. We observed improved nutrition in our patients both in terms of total caloric intake and calorie distribution. In particular there was an increase in carbohydrates and a reduction in lipids, reaching the percentage levels recently recommended. With a reduction in lipid intake a significant decrease in LDL cholesterol and a significant increase in HDL cholesterol were noticed in our patients. These modifications are very important for the prevention of arteriosclerosis and thus macrovascular disease. We maintain that dietary education plays an important role in helping children and adolescents with IDDM to follow a suitable diet.

Ruvalcaba syndrome: a case report.

An 11-year-old child with mental retardation and short stature was examined and found to be affected with some skeletal malformations. The clinical and radiological pattern of limb alterations was particularly suggestive of the features of Ruvalcaba syndrome.A complete examination confirmed the diagnosis and showed ocular involvement. To the best of our knowledge this is first published confirmation of Ruvalcaba syndrome.

A Multicenter Italian Study on Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is a relatively common disorder with an incidence estimated at about 1:10,000 (Holm, 1981) which represents the most common dysmorphic/genetic form of human obesity. The primary features of this condition include infantile hypotonia, failure to thrive, hypogonadism and developmental delay followed by development of obesity, Short stature, mental retardation and behavior problems. Mild dysmorphism is part of the Syndrome. About 59% of patients with PWS have an interstitial of the proximal long arm of chromosome 15 (Ledbetter et al, 1987).