Marco Cappa

Reduced growth hormone response to growth hormone-releasing hormone in children with simple obesity: evidence for somatomedin-C mediated inhibition.

We have evaluated the plasma GH response to a single injection of 1μg/kg of GH‐releasing hormone (GHRH)‐40 in 15 obese children and 15 age‐matched control children. Most of the obese children showed a subnormal plasma GH response to GHRH and the mean plasma GH integrated area (IC‐GH) following stimulation was significantly smaller in obese than control children. Plasma somatomedin‐C (SM‐C) levels were significantly higher in obese than control children, and were negatively correlated with the peak plasma GH levels (r=−0.616, P<001) and the IC‐GH (r=−0.554, P<0.02) after GHRH. Non‐esterified fatty acids (NEFA) and fasting plasma insulin levels were also elevated in obese children, but did not correlate with the extent of plasma GH response to GHRH. These data confirm previous observations on the refractoriness of obese children to release GH after GHRH, and imply that it may be due to the feedback inhibition operated by the elevated plasma levels of SM‐C.

Final height after growth hormone therapy in non-growth-hormone-deficient children with short stature

We report the effect of growth hormone (GH) treatment for 4 to 10 years in 15 prepubertal non-GH-deficient short children (10 boys, 5 girls, aged 7.4 to 13.2 years). In 7 patients, GH was administered at a dosage of 0.5 U/kg per week (group 1: 4 boys, 3 girls) and in 8 patients (group 2: 6 boys, 2 girls) at a dosage of 1.0 U/kg per week. After the first year, mean linear growth velocity had significantly increased in both groups. The increase in growth velocity was sustained during the first 4 years and then declined to pretreatment values in the majority of subjects. Treatment with GH did not induce an earlier onset of puberty, but there was a tendency toward faster skeletal maturation. The mean final height standard deviation score (SDS) was similar in the two groups and was significantly higher than the height SDS for chronologic age before treatment, but it did not differ from mean pretreatment predicted adult height SDS nor from mean target height SDS in both groups. Final height was significantly correlated with target height in both groups. These preliminary observations indicate that GH treatment does not generally increase final height over target height in short non-GH-deficient children.

No protective effect of calcitriol on β-cell function in recent-onset type 1 diabetes the IMDIAB XIII trial.

OBJECTIVE We investigated whether supplementation of the active form of vitamin D (calcitriol) in recent-onset type 1 diabetes can protect β-cell function evaluated by C-peptide and improve glycemic control assessed by A1C and insulin requirement. RESEARCH DESIGN AND METHODS Thirty-four subjects (aged 11–35 years, median 18 years) with recent-onset type 1 diabetes and high basal C-peptide >0.25 nmol/l were randomized in a double-blind trial to 0.25 μg/day calcitriol or placebo and followed-up for 2 years. RESULTS At 6, 12, and 24 months follow-up, A1C and insulin requirement in the calcitriol group did not differ from the placebo group. C-peptide dropped significantly (P < 0.001) but similarly in both groups, with no significant differences at each time point. CONCLUSIONS At the doses used, calcitriol is ineffective in protecting β-cell function in subjects (including children) with recent-onset type 1 diabetes and high C-peptide at diagnosis.

Altered Bone Mineral Density in Patients with Complete Androgen Insensitivity Syndrome

Androgens have major influences on the regulation of bone mineralization. Because of their unique peripheral metabolism androgens may act on bone via activation of the androgen and/or estrogen receptor. Patients with complete androgen insensitivity syndrome (cAIS) are natural models to assess androgen actions on bone. We studied bone mineral density (BMD) in 10 patients with cAIS (mean age 13.70, range 4.7–19.8 years); 3 patients were studied before gonadectomy; the others were castrated and 6 were on hormonal replacement therapy. The BMD area (aBMD) was measured by dual energy X-ray; lumbar ‘apparent’ volumetric density (vBMD) was calculated using the formula vBMD = aBMD × [4/(π × width)]. In the patients, aBMD (0.72 ± 0.16 g/cm2) and vBMD (0.23 ± 0.04 g/cm3) were significantly (p < 0.001) reduced in comparison with those of a control group (n = 15, age 5.0–20.5 years: aBMD 1.028 ± 0.20 g/cm2; vBMD 0.35 ± 0.04 g/cm3). Both aBMD and vBMD were also reduced in comparison with normal values for males (aBMD –2.66 ± 0.99 SDS, p < 0.001; vBMD –3.08 ± 1.53 SDS, p < 0.0005) and females (aBMD –2.88 ± 1.05 SDS, p < 0.001; vBMD –2.84 ± 1.18 SDS, p < 0.0007). Real lumbar bone density, assessed by computed tomography in 1 patient, was also reduced (–6.2 SDS and –3.5 SDS for male and female normal values, respectively). Biochemical markers of bone metabolism were normal and not significantly different in patients and controls. Girls with cAIS did not have more fractures than controls. In conclusion, both aBMD and vBMD are reduced in cAIS patients, while bone turnover and the fracture risk seem not to be increased. Our data indicate that both androgens and estrogens may be required for acquisition of bone density during childhood.

Clinical effects of early treatment with insulin glargine in patients with cystic fibrosis and impaired glucose tolerance

Diabetes mellitus is an increasing complication of cystic fibrosis (CF), as a result of the improved life expectancy. There is clear association between diabetes and increased morbidity and mortality. Lung function and clinical status deteriorate up to 2–4 yr before the diagnosis of cystic fibrosis-related diabetes (CFRD). The aim of our study was to evaluate the effects, on glucose homeostasis and clinical status, of the early treatment with insulin glargine in CF patients with impaired glucose tolerance (IGT). We selected six subjects with IGT diagnosed at oral glucose tolerance test (OGTT). Median age was 18.12 yr (range 9.2–27.8). Insulin glargine was administered at the median dosage of 0.3 U/kg/day (range 0.2–0.5). After the initial adjustment of the dosage, no patient manifested hypoglycemia during treatment. Median glycosylated hemoglobin (HbAIc) did not show any significant variation during treatment: it was 5.9% at baseline (range 5.5–6.2) and 6.1% (range 5.0–6.7) at the end of follow-up (p = 0.496). Median body mass index (BMI) z-score significantly increased during treatment, from −0.95 (range −3.2–+0.6) at baseline to −0.5. (range −3.0–+0.9) at the end of follow-up (p = 0.026). Lung function, measured by median forced expiratory volume in the first second (FEV1%), showed a mild but significant improvement during insulin treatment. It was 72.7% at baseline (range 41.5–98.4) and 76.7% (range 42.0–106.8) at the end of follow-up (p = 0.027). No significant variation was found between the number of hospitalizations for clinical exacerbation (no./patient/yr) in the last 2 yr before treatment and during follow-up. Median number at baseline was 1.95/patient/yr (range 1–3) and 2.0/patient/yr (range 1–3) at follow-up (p = 0.715). Our data seem to indicate that early insulin therapy can be safe, no patient manifested hypoglycemia or other adverse effects during treatment. Insulin is an anabolic hormone implicated in both lipid and protein metabolism. The appearance of IGT out of infections can indicate an early insulin deficiency, with a potential impact on the nutritional and clinical status of the patient, even before the appearance of overt diabetes. Larger controlled trials are necessary to verify if early insulin therapy is able to reduce the deterioration of nutritional status and lung function associated with the onset of IGT. (J. Endocrinol. Invest. 29: RC1-RC4, 2006)

The natural history of the normal/mild elevated TSH serum levels in children and adolescents with Hashimoto’s thyroiditis and isolated hyperthyrotropinaemia: a 3‐year follow‐up

Objective  The natural history of Hashimoto’s thyroiditis (HT) and isolated hyperthyrotropinaemia (IH) is not well defined. We therefore studied the natural course of patients with HT and IH and looked for possible prognostic factors.

Simpson-golabi-behmel syndrome: An X-linked encephalo-tropho-schisis syndrome

The following paper by Professor Giovanni Neri and colleagues was originally published in 1988, American Journal of Medical Genetics 30:287–299. This paper represented a seminal work at the time of publication as it not only reported a new family with a disorder that had been called the “gigantism‐dysplasia syndrome”, but also suggested naming the condition the Simpson‐Golabi‐Behmel syndrome. This eponym has clearly stood “the test of time”, and that designation is now widely accepted. This paper is graciously republished by Wiley‐Blackwell in the Special Festschrift issue honoring Professor Neri.

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.

McCune-Albright syndrome: A longitudinal clinical study of 32 patients

We report the diagnostic clinical features and their long term evolution in 32 patients with McCune-Albright syndrome. Patient data are made up of two periods: the first, classified as personal history, is from birth until the time when the diagnosis of McCune-Albright syndrome was made; the second, classified as clinical observation, is from the first observation until the end of follow up. The total duration of these two periods was 9.6+/-2.9 yr; mean age at first observation was 5.7 yr (range 0.7-11 yr). The probability of manifesting main clinical signs according to age was calculated: almost all had skin dysplasia at birth, 50% probability of peripheral precocious puberty in females at 4 years and 50% of bone dysplasia at 8 years of age were found. Other clinical signs had diagnostic relevance when preceding the main signs leading to diagnosis of McCune-Albright syndrome even without specific genetic investigation. The most important clinical manifestations have different evolutions: skin lesions increase in dimensions according to body growth; precocious puberty in females evolves rapidly but periods of regression can be seen in some patients; bone dysplasia in most patients evolves with an increase both in the number of affected bones and in the severity of lesions.

Molecular Analysis of the GNAS1 Gene for the Correct Diagnosis of Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH resistance and classified as types Ia, Ib, Ic, and II, according to its different pathogenesis and phenotype. PHP-Ia patients show Gsα protein deficiency, PTH resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous mutations in the GNAS1 gene encoding the Gsα protein have been identified both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP in the same family when inherited from the maternal and the paternal allele, respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether molecular diagnosis is a useful tool to characterize AHO and PHP when testing for Gsα activity and PTH resistance is not available, we have performed GNAS1 mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP patients, eight of which have not been reported previously. Inheritance was ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were inherited from the mothers, who had AHO (PPHP), consistent with the proposed imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia and PPHP in the mutated patients. Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia.