Stimulated GH levels during the transition phase in Prader-Willi syndrome.

PURPOSE: Early institution of GH therapy in children with Prader-Willi syndrome (PWS) yields beneficial effects on their phenotype and is associated with a persistent improvement of body composition, both in the transition age and in adulthood. Reports from GH stimulation testing in PWS adults, however, suggest that GH deficiency (GHD) is not a universal feature of the syndrome, and the current Consensus Guidelines suggest to perform a reassessment of persistent GHD so as to continue GH therapy after reaching adult height. Few data about GH responsiveness to stimulation testing throughout the transitional period in PWS are available to date. Thus, we investigated the prevalence of GHD in a large cohort of patients with PWS during the transition phase. PATIENTS AND METHODS: One hundred forty-one PWS patients, 72 females and 69 males, aged 15.4-24.9 years, were evaluated by dynamic testing with growth hormone-releasing hormone (GHRH) plus arginine (GHRH + ARG). To define GHD, both BMI-dependent and BMI-independent diagnostic cut-off limits were considered. RESULTS: According to BMI-dependent criteria, 10.7% of normal weight (NW), 18.5% of overweight and 22.1% of obese PWS maintained a status of GHD. Similar results were obtained by adopting a cut-off limit specific for the adult age (26.2%), as well as criteria for the transition phase in NW subjects (25%). CONCLUSION: Our study shows that about 20% of patients with PWS fulfilled the criteria for GHD during the transitional age, suggesting the need of an integrated analysis of GH/IGF-I axis, in the context of the general clinical picture and other endocrine abnormalities, in all subjects after attainment of final stature.

Safety and effectiveness of a somatropin biosimilar in children requiring growth hormone treatment: second analysis of the PATRO Children study Italian cohort.

PURPOSE: To investigate the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the somatropin biosimilar Omnitrope®. METHODS: PATRO Children is an ongoing, multicenter, observational, post-marketing surveillance study. Children who received Omnitrope® for any indication were included. Adverse events (AEs) were evaluated in all study participants. Auxological data, including height standard deviation scores (HSDS) and height velocity standard deviation scores (HVSDS), were used to assess effectiveness. In this snapshot analysis, data from the Italian subpopulation up to August 2017 were reported. RESULTS: A total of 291 patients (mean age 10.0 years, 56.0% male) were enrolled at 19 sites in Italy. The mean duration of Omnitrope® treatment was 33.1 ± 21.7 months. There were 48 AEs with a suspected relationship to the study drug (as reported by the investigator) that occurred in 35 (12.0%) patients, most commonly headache, pyrexia, arthralgia, insulin-like growth factor above normal range, abdominal pain, pain in extremity and acute gastroenteritis. There were no confirmed cases of type 1 or type 2 diabetes; however, two patients (0.7%) had impaired glucose tolerance that was considered Omnitrope® related. The mean HSDS increased from - 2.41 ± 0.73 at baseline (n = 238) to - 0.91 ± 0.68 at 6.5 years (n = 10). The mean HVSDS increased from - 1.77 ± 1.38 at baseline (n = 136) to 0.96 ± 1.13 at 6.5 years (n = 10). CONCLUSIONS: In this sub-analysis of PATRO Children, Omnitrope® appeared to have acceptable safety and effectiveness in the treatment of in Italian children, which was consistent with the earlier findings from controlled clinical trials.

Disorders of glucose metabolism in Prader-Willi syndrome: Results of a multicenter Italian cohort study.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS) is characterized by a high incidence of altered glucose metabolism (AGM). However, epidemiological data on impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are still discordant. METHODS AND RESULTS: We performed a multicenter study based on 274 PWS patients [144 females, aged 20.3 ± 10.4 yrs (range: 8.1-50.1 years)] evaluating the prevalence for AGM in the entire group, and according to age (children <10 yrs; adolescents 10-18 yrs, and adults >18 yrs), Body Mass Index (BMI = kg/m(2)), gender, genotypes (deletion or uniparental disomy for chromosome 15), and GH therapy (GHT) (untreated, previously or currently treated). Altogether, AGM was detected in 67 (24.4%) of patients (0.7% IFG, 10.2% IGT, 13.5% T2DM). The prevalence of AGM was correlated to age (p = 0.001), BMI (p = 0.001) and HOMA-IR (p = 0.001). However, gender, genotype, and GHT did not influence AGM development in univariate analysis. These data were confirmed as positive predictors when inserted in a multivariate analysis model. CONCLUSION: This study is the first report on the prevalence of AGM in a large population of PWS. Overall, PWS subjects show a high prevalence of AGM that appears more common in obese and adult subjects. Our data confirm the main role of obesity on the individual metabolic risk clustering in PWS, and thus reinforce the concept that improvement in weight control remains the most important goal of any PWS treatment program.

Sentinel lymph node biopsy in head and neck melanoma*.

AIM: The purpose of this study is to evaluate prognosis and surgical management of head and neck melanoma (HNM) and the accuracy of sentinel lymph node biopsy (SLNB). PATIENTS AND METHODS: All patients with a primary cutaneous melanoma treated starting from 01/07/1994 to 31/12/2012 in the department of Plastic and Reconstructive Surgery of Bari are included in a electronic clinical medical registry. Within the 90th day from excision of the primary lesion all patients with adverse prognostic features underwent SLNB. All patients with positive findings underwent lymphadenectomy. RESULTS: out of 680 patients affected by melanoma, 84 (12.35%) had HNM. In the HNM cohort lymphoscintigraphy was performed in 57 patients, 15 of which (26.3%) were positive. The percentage of unfound sentinel lymph node was similar both to the HNM group (5,26%) and to patients with melanoma of different sites (OMS 4,92%). There was a recurrence of disease after negative SLNB (false negatives) only in 4 cases. Recurrence-free period and survival rate at 5 years were worse in HNM cohort. CONCLUSION: SLNB of HNM has been for a long time contested due to its complex lymphatic anatomy, but recent studies agreed with this technique. Our experience showed that identification of sentinel lymph node in HNM cohort was possible in 98.25% of cases. Frequency of interval nodes is significantly higher in HNM group. The prognosis of HNM cohort is significantly shorter than OMS one. Finally, this procedure requires a multidisciplinary team in referral centers.

Metabolic syndrome in adult patients with Prader-Willi syndrome.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS), the most common genetic cause of obesity, is characterized by elevated morbility and mortality in all ages. In this context, non-obese PWS children showed low frequency of metabolic syndrome (MetS), while a comparable prevalence was observed in obese PWS and obese controls. Aim of this study was to estimate the occurrence of MetS and its components in a large group of PWS adults, according to obesity status. METHODS AND RESULTS: A cross-sectional study was performed in 108 PWS aged 18.0-43.2 years (87 obese and 21 non-obese) and in 85 controls with nonsyndromic obesity matched for age, gender, and BMI with obese PWS. Non-obese PWS showed lower waist circumference, insulin, HOMA-index, triglycerides, diastolic blood pressure, and higher HDL-C than both obese PWS and obese controls (p < 0.017). Obese PWS showed higher glucose and systolic blood pressure than both non-obese PWS and obese controls (p < 0.017). MetS was found in 1/21 (4.8%) non-obese PWS, 36/87 (41.4%) obese PWS and 39/85 (45.9%) obese controls. Non-obese PWS showed lower frequency for each MetS component as compared with obese PWS and obese controls. PWS patients with deletion of the chromosome 15q11-13 showed a lower risk for low HDL-C (p < 0.01) and a trend towards a lower MetS risk (p < 0.06) compared to subjects without deletion. CONCLUSION: Our findings suggest the main role that obesity status plays on the individual metabolic risk clustering in PWS adults. Early identification of MetS could be helpful to improve morbidity and prevent mortality in such patients.

Metabolic syndrome in children with Prader-Willi syndrome: the effect of obesity.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS), the most frequent syndromic obesity, is associated with elevated morbidity and mortality in pediatric and adult ages. In PWS, the presence of metabolic syndrome (MS) has not yet been established. The aim of the study was to estimate the frequency of MS and its components in pediatric subjects according to obesity status. METHODS AND RESULTS: A cross-sectional study was performed in 109 PWS children aged 2-18 years (50 obese and 59 non-obese) and in 96 simple obese controls matched for age, gender, and also for BMI with obese PWS. Obesity was defined when SDS-BMI was >2. Non-obese PWS showed significantly lower frequency of hypertension (12%) than obese PWS (32%) and obese controls (35%)(p=0.003). The same was observed for low HDL-cholesterol (3% vs 18% and 24%, p=0.001) and high triglycerides (7% vs 23% and 16%, p=0.026). Frequency of altered glucose metabolism was not different among groups (2% vs 10% and 5%), but type 2 diabetes (four cases) was present only in obese PWS. Non-obese PWS showed lower insulin and HOMA-index respect to obese PWS and obese controls (p ≤ 0.017). Overall MS frequency in PWS was 7.3%. None of the non-obese PWS showed MS compared with 16% of obese PWS and controls (p<0.001). When obesity was excluded from the analysis, a significantly lower frequency for clustering of ≥ 2 factors was still found in non-obese PWS (p=0.035). CONCLUSION: Non-obese PWS showed low frequency of MS and its components, while that observed in obese PWS was very close to those of obese controls, suggesting the crucial role of obesity status. Prevention of obesity onset remains the most important goal of PWS treatment. Early identification of MS could be helpful to improve morbidity and mortality in such patients.

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.

Pituitary height and neuroradiological alterations in patients with Prader-Labhart-Willi syndrome.

Prader-Willi syndrome (PWS), a genetic disorder due to an alteration in the paternally derived long arm of chromosome 15, is characterized by a complex clinical picture (short stature, obesity, hypogonadism) that seems to be referable to as a central hypothalamic/pituitary dysfunction. To determine whether there is any diminution in the anterior pituitary gland or other neuroradiological alterations, we retrospectively analysed 91 patients with PWS (42 females, 49 males; age range: 0.7-16.8 years) by cerebral magnetic resonance imaging (MRI). Of these 91 patients, MRI analysis showed a reduction in pituitary height in 45 patients (49.4%), a complete absence of the posterior pituitary bright spot in six patients (6.6%) and other neuroradiological alterations in ten patients (11%). Altogether, neuroradiological alterations were present in 61 of the 91 (67%) patients. Our results indicate that neuroradiological alterations are more frequent in PWS patients than has been reported to date.

Impairment of GH responsiveness to combined GH-releasing hormone and arginine administration in adult patients with Prader-Willi syndrome.

OBJECTIVE: It is unclear if poor health outcomes of adult patients with Prader-Willi syndrome (PWS) are influenced by GH deficiency (GHD). Few studies have been focused on PWS adults, but further information on the concomitant role of obesity on GH/IGF-I axis function is needed. The aim of our study was to investigate the prevalence of GHD in a large group of adult subjects with genetically confirmed PWS. DESIGN AND SUBJECTS: We studied the GH response to a combined administration of GHRH (1 microg/kg i.v. at 0 minutes) and arginine (ARG) (30 g i.v., infused from 0 to 30 minutes) as well as the baseline IGF-I levels, in a group of 44 PWS adults (18 males, 26 females) aged 18-41.1 years. The same protocol was carried out in a control group of 17 obese subjects (7 males, 10 females) aged 21.8-45.8 years. MEASUREMENTS: Blood samples were taken at -15 and 0 minutes and then 30, 45, 60, 90 and 120 minutes after GHRH administration. Serum GH and total IGF-I concentrations were measured by chemioluminescence. Statistical analysis was performed by Student's t-test for unpaired data, and using analysis of variance for parametric and nonparametric (Mann-Whitney test) data, where appropriate. The relationship between pairs of variables was assessed by Pearson's correlation. Independent variables influencing GH secretion were tested by multiple linear regression analysis. RESULTS: The GH response to GHRH + ARG was significantly lower in PWS patients (GH peak (mean +/- SE) 8.4 +/- 1.2 microg/l; AUC: 471.4 +/- 77.8 microg/l/h) than obese subjects (GH peak 15.7 +/- 2.9 microg/l, P < 0.02; AUC 956 +/- 182.9 microg/l/h, P < 0.005). When considered individually, 17 of 44 PWS individuals (38.6%) were severely GHD, according to the cut-off limit of 4.1 microg/l for obese individuals, and low IGF-I-values were present in 33 PWS patients. Moreover, impaired GH response was combined with subnormal IGF-I levels in all PWS patients with GHD. CONCLUSIONS: Adult subjects with PWS had a reduced responsiveness to GHRH + ARG administration associated with reduced IGF-I levels. In addition, a severe GHD for age was demonstrated in a significant percentage of PWS subjects. These findings are in agreement with the hypothesis that a complex derangement of hypothalamus-pituitary axis occurred in PWS, and suggested that impaired GH secretion is not an artefact of obesity.

Distributed communication and psychosocial performance in simulated space dwelling groups.

The present report describes the development and application of a distributed interactive multi-person simulation in a computer-generated planetary environment as an experimental test bed for modeling the human performance effects of variations in the types of communication modes available, and in the types of stress and incentive conditions underlying the completion of mission goals. The results demonstrated a high degree of interchangeability between communication modes(audio, text) when one mode was not available. Additionally, the addition of time pressure stress to complete tasks resulted in a reduction in performance effectiveness, and these performance reductions were ameliorated via the introduction of positive incentives contingent upon improved performances. The results obtained confirmed that cooperative and productive psychosocial interactions can be maintained between individually isolated and dispersed members of simulated spaceflight crews communicating and problem-solving effectively over extended time intervals without the benefit of one another's physical presence.

GH/IGF-I axis in Prader-Willi syndrome: evaluation of IGF-I levels and of the somatotroph responsiveness to various provocative stimuli. Genetic Obesity Study Group of Italian Society of Pediatric Endocrinology and Diabetology.

Basal IGF-I levels and the GH response to at least two among provocative stimuli such as clonidine (CLO, Catapresan, 150 mcg/m2 p.o.), GHRH (1 mcg/kg i.v.)+arginine (ARG, 0.5 g/kg i.v. infusion during 30 min) and GHRH+pyridostigmine (PD, Mestinon cpr 60 mg p.o.) 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 connotated by GH insufficiency.

Serum leptin concentrations in obese women with Down syndrome and Prader-Willi syndrome.

We have evaluated serum leptin concentrations in two forms of genetic obesity. The subjects examined were eight women with Down syndrome and eight women with Prader-Willi syndrome. All patients were in the reproductive age range and were obese (body mass index > or = 27 kg/m2). Plasma leptin values, analyzed as a function of body mass index showed a statistically significant correlation in both Prader-Willi (r = 0.985; p < 0.001) and Down syndrome patients (r = 0.943; p < 0.001). Obese Down syndrome women exhibited significantly lower leptin values (10.8 +/- 1.1) as compared to patients with Prader-Willi syndrome (31 +/- 2.6; p < 0.01). The linear correlation between leptin and insulin in the two groups of patients was not statistically significant. The data suggested that obesity in Prader-Willi subjects could be caused by failure of leptin to reach its target in the brain, as a consequence of defects in the receptor or in postreceptor processing, whereas data on obese patients with Down syndrome could be due to a different pathogenetic origin.

[The biocompatibility of suture materials used in colon surgery. An experimental study in the rat]. / Biocompatibilità dei materiali di sutura in uso nella chirurgia del colon. Studio sperimentale nel ratto.

BACKGROUND: The aim of this experimental study was to compare the tissue behavior of biofragmentable anastomotic ring (BAR) with other synthetic materials used in colonic surgery. METHODS: Thirty-three rats were divided into four groups: group 1, sham-operated control animals without material implanted; group 2, with fragments of polypropylene monofilament implanted extraperitoneally in abdominal wound, between musculature and peritoneum; group 3, with metal clips implanted extraperitoneally in abdominal wound, between musculature and peritoneum and group 4, with fragments of biofragmentable anastomotic ring implanted extraperitoneally in abdominal wound, between musculature and peritoneum. Animals were sacrificed 30 days after the operation. Macroscopic and histological criteria were used to characterize the resistance of the wound and the tolerance of the host to the foreign material. RESULTS: The inflammatory cell reaction of host tissue was significantly greater in group 4 compared with other groups (p < 0.05). In three cases, in group 4, we observed the adhesion of implanted fragment to epiploa. The enumeration of giant cells and the degree of fibrotic reaction was similar in all groups with material implanted, but no significant difference between the groups was observed. Our findings showed the greater biocompatibility of polypropylene and metallic clips, compared to the biofragmentable ring anastomosis. The strong inflammatory reaction in the host tissue caused by biofragmentable anastomotic ring may explain partially clinical postoperative complications (anastomotic wound infection and/or dehiscence and/or stricture). CONCLUSIONS: In conclusion, the choice of suture materials should be based not only on the mechanical properties, but also on their biological interactions between host and suture materials and on the evaluation of their effective cost/benefit.

[Prader-Willi syndrome]. / La sindrome di Prader-Willi.

Prader-Willi syndrome (PWS) is the most frequent cause of secondary obesity, characterized by neonatal hypotonia, dysmorphic facies, acromicria, hypogonadism, stunted growth, obesity, behavioural disturbances and cognitive impairment. Clinical diagnosis is confirmed by alteration of imprinted genes on the proximal long arm of chromosome 15 (15q11-13) for deletion, translocation, uniparental disomy for maternal chromosome 15 or imprinting center defect. Methylation test is the most reliable test for diagnosis. This issue explains diagnostic tests, clinical, metabolic, endocrinological features, and the most frequent complications observed in this syndrome. Precocious diagnosis and multidisciplinary approach allow in these patients to prevent the severe obesity and linked complications.

IGF-I levels in prepubertal and pubertal children with Down syndrome.

BACKGROUND: Growth retardation is a main feature of Down syndrome but it is still unclear whether an alteration of the GH/IGF-I axis is present in this condition. Concerning IGF-I levels, they have been found reduced by some authors but normal by others. METHODS: On these bases, IGF-I levels have been assessed from prepubertal to late pubertal stages of gonadal maturation in a large group of children and adolescents with Down syndrome (DS, 68 M, 45 F, 12.5 +/- 0.6 yr; prepubertal n = 39, pubertal n = 74) with those in a group of normal children and adolescents (NS, 75 M, 87 F; 11.1 +/- 0.4 yr; prepubertal n = 94, pubertal n = 68). RESULTS: Within each group, IGF-I levels were gender-independent while showed age-related variations with positive association with pubertal stage--peaking up in pubertal stage IV--(DS: r = 0.6, NS: r = 0.4, both p < 0.0001) and testosterone (DS: r = 0.6, NS: r = 0.5, p < 0.001) or estradiol (DS: r = 0.6, NS: r = 0.5, p < 0.001) levels. Considering whole groups, mean IGF-I levels in DS were slightly but significantly lower than those in NS (257.9 +/- 12.5 vs 310.8 +/- 12.6 micrograms/l, p < 0.02). Analyzing individual IGF-I levels in DS with respect to normal ranges per pubertal stage, more than 85% of IGF-I levels resulted within the normal limits. These results demonstrate that IGF-I levels in DS patients are generally within the normal range--though a slight reduction of mean IGF-I levels is present--and follow normal age-related variations with clear cut increase at puberty and positive association with gonadal steroid levels. CONCLUSIONS: This evidence points toward the need to clarify the GH/IGF-I axis function and activity in DS patients.

Growth hormone administration normalizes the ovarian responsiveness to follicle-stimulating-hormone in the early stages of the follicular maturation in women with Down syndrome.

To investigate the sensitivity of ovary to follicle-stimulating hormone (FSH) during the early follicular phase of the human menstrual cycle in patients with Down Syndrome (DS) six postmenarchal patients with Down Syndrome and twelve normoovulatory women were studied. Randomly, DS patients were submitted in two consecutive cycles to a treatment with GH (0.1 IU/Kg i.m.) or saline for 3 days. Pure FSH (75 IU) was given i.v. at day 3 and plasma levels of LH, FSH, E2, Testosterone, DHEAS, Androstenedione, GH and IGF-I were assayed in samples collected for a period of 26 h after the injection. Data were compared with those obtained from controls receiving pure FSH or saline. In control patients FSH injection increased E2 stimulated area under curve (AUC). This value was significantly greater than that found in DS patients, who exhibited an E2-stimulated AUC superimposable to saline treated controls. In DS GH plasma concentrations were significantly lower than in control group (p < 0.05). The treatment with GH is able to normalize the ovarian response to FSH in DS patients at levels similar to those found in FSH treated controls. Moreover in GH treated cycles, both GH and IGF-I plasma concentrations were higher at time of FSH injection with respect to those found in the cycles where saline was given. These results indicate that the ovarian sensitivity to FSH in patients with DS is blunted. Lower GH plasma levels found in this group may in part account for this biological feature, since GH treatment is able to restore the ovarian response, probably via an increase of IGF-I plasma concentrations.

Ovarian sensitivity to follicle stimulating hormone is blunted in normo-ovulatory women with Down's syndrome.

Ovarian sensitivity to follicle stimulating hormone (FSH) during the early follicular phase of the human menstrual cycle was studied in six post-menarchal patients with Down's syndrome and 12 normo-ovulatory women. Pure FSH (75 IU) was given i.v. to six controls and six Down's syndrome patients, while saline was administered to the remaining six controls. Plasma concentrations of luteinizing hormone (LH), FSH, oestradiol, testosterone and growth hormone (GH) in samples collected for a period of 26 h after the injection were assayed. In control patients FSH injection increased oestradiol stimulated area under the curve (AUC). This value was significantly higher than that found in Down's syndrome patients (P < 0.02), who exhibited an oestradiol-stimulated AUC equivalent to saline-treated controls. In Down's syndrome, GH plasma concentrations were significantly lower than in the control group (P < 0.05). These results indicate that the ovarian sensitivity to FSH in patients with Down's syndrome is blunted. Lower GH plasma concentrations found in this group may in part account for this biological feature.

Bilateral non-communicating paraurethral meatus in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a complex multisystemic congenital disorder due to an interstitial deletion of chromosome 15q11-13 or to maternal uniparental disomy. Molecular genetic testing is complex, and often requires DNA from both parents, which is not always available. An accurate medical history and presenting clinical signs are frequently the only tools for the clinical diagnosis of this syndrome, therefore it is important to have complete and accurate criteria. The presence of a bilateral non-communicating paraurethral meatus in a 9-year-old female patient affected by PWS, previously unreported in the literature, should induce clinicians to look for this sign when examining such patients.

The enhancing effect of pyridostigmine on the GH response to GHRH undergoes an accelerated age-related reduction in Down syndrome.

Cholinergic agonists are known to potentiate GHRH-induced GH secretion, probably acting via inhibition of hypothalamic somatostatin release. Their effect is reduced in aging and in patients with Alzheimer's disease. This may be the consequence of age-related cholinergic impairment, which, in turn, could cause somatostatinergic hyperactivity leading to GH hyposecretion. As in Down syndrome (DS) neural alterations have been reported similar to those in aging, including cholinergic impairment, we verified the GH response to GHRH (1 microgram/kg i.v. at 0 min) alone or combined with pyridostigmine (PD), a cholinesterase inhibitor (60 and 120 mg, respectively, in children and adults, orally at -60 min) in 15 DS children (13.5 +/- 0.6 years) and in 11 DS young adults (24.0 +/- 1.2 years). Fifteen normal children (11.9 +/- 0.5 years), 15 normal adults (27.3 +/- 0.9 years) and 16 normal elderly (76.3 +/- 1.5 years) were studied as controls. IGF-I levels showed an age-related reduction both in DS (children vs. adults, mean +/- SEM:354.8 +/- 44.9 vs. 204.4 +/- 29.4 micrograms/l, p < 0.02) and in controls (normal children vs. normal adults vs. normal elderly:281.4 +/- 36.3 vs. 175.4 +/- 11.2 vs. 72.5 +/- 6.6 micrograms/l, p < 0.001). The GH response to GHRH in DS children was higher than in DS adults (areas under curve: 1,197.6 +/- 241.5 vs. 434.4 +/- 83.3 micrograms/l/h, p < 0.01). On the other hand, in normal subjects the GHRH-induced GH rise was similar in children and adults (1,056.2 +/- 128.4 vs. 800.8 +/- 124.5 micrograms/l/h) and both were higher than that in elderly subjects (296.0 +/- 61.0 micrograms/l/h, p < 0.001). PD enhanced the GH response to GHRH both in DS and in normal subjects (p < 0.005). The GH response to PD+GHRH was lower in DS adults than in DS children (1,068.1 +/- 145.7 vs. 1,897.4 +/- 198.8 micrograms/l/h, p < 0.001) as well as in normal elderly subjects with respect to that in normal children and normal adults (832.3 +/- 144.7 vs. 2,172.1 +/- 156.1 and 2,347.6 +/- 322.4 micrograms/l/h, respectively, p < 0.001). The GH response to GHRH alone or combined with PD in DS adults was lower (p < 0.01) than that in normal adults and similar to that in normal elderly subjects. In conclusion, the present data demonstrate that the stimulated GH secretion in DS undergoes an accelerated age-related reduction. They also suggest the existence of a precocious impairment of central cholinergic activity in DS, which, in turn, could cause somatostatinergic hyperactivity and reduced GH secretion.