Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by haploinsufficiency of the SHANK3 gene and is characterized by global developmental delays and autism spectrum disorder (ASD). Based on several converging lines of preclinical and clinical evidence supporting the use of insulin-like growth factor-1 (IGF-1) in PMS, this study aims to follow-up a previous pilot study with IGF-1 to further evaluate this novel therapeutic for core symptoms of ASD in children with PMS. METHODS: Ten children aged 5-9 with PMS were enrolled. Participants were randomized to receive IGF-1 or placebo (saline) using a 12-week, double-blind, crossover design. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as secondary outcome measures reflecting core symptoms of ASD. To increase power and sample size, we jointly analyzed the effect of IGF-1 reported here together with results from our previous controlled trail of IGF-1 in children with PMS (combined N = 19). RESULTS: Results on the ABC-SW did not reach statistical significance, however significant improvements in sensory reactivity symptoms were observed. In our pooled analyses, IGF-1 treatment also led to significant improvements in repetitive behaviors and hyperactivity. There were no other statistically significant effects seen across other clinical outcome measures. IGF-1 was well tolerated and there were no serious adverse events. LIMITATIONS: The small sample size and expectancy bias due to relying on parent reported outcome measures may contribute to limitations in interpreting results. CONCLUSION: IGF-1 is efficacious in improving sensory reactivity symptoms, repetitive behaviors, and hyperactivity  in children with PMS. Trial registration NCT01525901.

A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS. METHODS: rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study. RESULTS: rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms. LIMITATIONS: Results should be interpreted with caution given the small sample size and lack of a placebo control. CONCLUSIONS: Overall, findings are promising and indicate the need for larger studies with rhGH in PMS. Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207 .

Demographics and anthropometrics impact benefits of health intervention: data from the Reduce Obesity and Diabetes Project.

OBJECTIVE: To determine the efficacy of a 4-month school-based health, nutrition and exercise intervention on body fatness and examine possible effects of demographic and anthropometric covariates. METHODS: Height, weight, waist circumference and body composition were measured in a diverse population of 644 NYC middle school students (mean ± SD age 12.7 ± 0.9 years; 46% male; 38% Hispanic, 17% East Asian, 15% South Asian, 13.5% African American, 8.5% Caucasian, 8% other) during the fall and spring semesters. Year 1 participants (n = 322) were controls. Experimental participants (year 2, n = 469) received a 12-session classroom-based health and nutrition educational programme with an optional exercise intervention. RESULTS: Groups were demographically and anthropometrically similar. The intervention resulted in significant reductions in indices of adiposity (ΔBMI z-scores [-0.035 ± 0.014; p = 0.01], Δ% body fat [-0.5 ± 0.2; p < 0.0001] and Δwaist circumference [-0.73 ± 0.30 cm; p < 0.0001]). Intervention effects were greater (p = 0.01) in men (ΔBMI z-score = -0.052 ± 0.015) versus women (0.022 ± 0.018), participants who were obese (ΔBMI z-score -0.083 ± 0.022 kg m-2) versus lean (-0.0097 ± 0.020 kg m-2) and South Asians (Δ% body fat -1.03 ± 0.35) versus total (-0.49 ± 0.20%) participants (p = 0.005). CONCLUSION: A 4-month school-based health intervention was effective in decreasing measures of adiposity in middle school students, particularly in men, participants who were obese and South Asians.

Plasma advanced glycation end products (AGEs), receptors for AGEs and their correlation with inflammatory markers in middle school-age children.

AIM: Advanced glycation end products (AGEs) and/or their receptors (RAGE) are significantly positively correlated with adiposity, inflammation, dyslipidemia, and insulin resistance in adults. However, the relationships between AGEs, RAGE, and adiposity-related comorbidites in children have not been well studied. METHODS: In a cross-sectional study of 88 children (age 11-15 years) from the New York area enrolled in the Reduce Obesity and Diabetes (ROAD) study, we examined the correlation of the AGE N(ε)-(carboxymethyl)lysine (CML), soluble RAGE (sRAGE), and endogenous secretory RAGE (esRAGE) with adiposity, inflammatory markers [interleukin-6 (IL-6), C-reactive protein, tumor necrosis factor-α], adiponectin, lipids, insulin sensitivity, and insulin secretory capacity. RESULTS: Pediatric CML levels were ~20% below average adult levels. CML was significantly (p < 0.05) positively correlated with age and insulin sensitivity and negatively with adiposity, dyslipidemia and IL-6. sRAGE correlated positively with esRAGE and negatively with adiposity and IL-6. Both sRAGE and esRAGE correlated negatively with insulin secretory capacity. CONCLUSION: Our findings suggest that unlike adults, CML is negatively associated with adiposity and adiposity-related comorbidity risk in children. As in adults, sRAGE and esRAGE were, to varying degrees, negatively correlated with body fatness and risk factors for adiposity-related comorbidities.

Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society.

OBJECTIVE: Low birth weight remains a major cause of morbidity and mortality in early infancy and childhood. It is associated with an increased risk of health problems later in life, particularly coronary heart disease and stroke. A meeting was convened to identify the key health issues facing a child born small for gestational age (SGA) and to propose management strategies. PARTICIPANTS: There were 42 participants chosen for their expertise in obstetrics, peri- and neonatal medicine, pediatrics, pediatric and adult endocrinology, epidemiology, and pharmacology. EVIDENCE: Written materials were exchanged, reviewed, revised, and then made available to all. This formed the basis for discussions at the meeting. Where published data were not available or adequate, discussion was based on expert clinical opinions. CONSENSUS PROCESS: Each set of questions was considered by all and then discussed in plenary sessions with consensus and unresolved issues identified. The consensus statement was prepared in plenary sessions and then edited by the group chairs and shared with all participants. CONCLUSIONS: The diagnosis of SGA should be based on accurate anthropometry at birth including weight, length, and head circumference. We recommend early surveillance in a growth clinic for those without catch-up. Early neurodevelopment evaluation and interventions are warranted in at-risk children. Endocrine and metabolic disturbances in the SGA child are recognized but infrequent. For the 10% who lack catch-up, GH treatment can increase linear growth. Early intervention with GH for those with severe growth retardation (height sd score, <-2.5; age, 2-4 yr) should be considered at a dose of 35-70 microg/kg x d. Long-term surveillance of treated patients is essential. The associations at a population level between low birth weight, including SGA, and coronary heart disease and stroke in later life are recognized, but there is inadequate evidence to recommend routine health surveillance of all adults born SGA outside of normal clinical practice.

Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis.

BACKGROUND: Recently, growth hormone (GH) therapy for children with short stature born small for gestational age (SGA) has been approved in the USA and Europe. There have been few reports examining adverse events during GH treatment of these children. AIMS: (i) To examine glucose tolerance and insulin sensitivity during GH treatment of children born SGA in a US trial. (ii) To determine and compare adverse events reported in children born SGA with those reported in children with idiopathic short stature (ISS) enrolled in KIGS - Pfizer International Growth Database. METHODS: In the US SGA trial, an oral glucose tolerance test was performed and fasting plasma glucose, insulin and glycosylated haemoglobin (HbA(1C)) concentrations were measured at baseline and after 12 months of GH therapy. Insulin sensitivity was calculated using the homeostasis model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI). In the KIGS analysis, a retrospective audit of spontaneously logged cumulative adverse events in children born SGA and those with ISS was undertaken. Adverse events are reported per 1,000 patients. Values are expressed as mean with 10th-90th percentiles. RESULTS: In the US trial, 84 patients had complete data sets for analysis. Median birth weight was 1.78 kg (SDS, -2.5) and birth length 43 cm (SDS, -2.2) at a median gestational age of 36.5 weeks; 79% were Caucasian. At entry, median age of the patients analysed was 6.6 years, and 65% were male. Median height was 104.3 cm (SDS, -2.97), median weight 15.95 kg (SDS, -2.21) and body mass index 14.66 kg/m(2) (SDS, -0.67). No patients developed impaired glucose tolerance or overt diabetes mellitus. The 0-min glucose concentration was 81 mg/dl at baseline and 86 mg/dl at 1 year, while the 120-min glucose concentration was 90 mg/dl at baseline and 96 mg/dl at 1 year. The 0-min insulin concentrations were 2.9 mU/l at baseline and 5.3 mU/l at 1 year, while the 120-min insulin levels were 7.7 mU/l at baseline and 11 mU/l at 1 year. The proportions of HbA(1C) were 5.2 and 5.4% at baseline and 1 year, respectively. HOMA and QUICKI values were 0.59 and 0.42, respectively, at baseline, and 1.13 and 0.38 at 1 year. In KIGS, there were 1909 children born SGA aged 9.1 (3.9-13.3) years with a birth weight SDS of -2.6 (-4.0 to -1.5), birth length SDS of -2.7 (-4.3 to -1.3) and height SDS of -2.71 (-3.9 to -1.8) prior to treatment. GH doses ranged from 0.032 to 0.037 in the USA and from 0.022 to 0.023 mg/kg/day in the remaining countries in KIGS. Neither total (187 vs. 183) nor serious (14 vs. 10) adverse events occurred more commonly in the SGA group than in the ISS group. Although respiratory adverse events occurred more commonly in children born SGA (34.3 vs. 16.8; p < 0.05), endocrine (12.0 vs. 2.7; p < 0.05) and hepatobiliary (6.2 vs. 1.1; p < 0.05) adverse events occurred more commonly in children with ISS. CONCLUSIONS: As expected, a reduction in insulin sensitivity occurred during GH treatment of children born SGA; however, glucose tolerance remained normal. No adverse events were reported more commonly in children born SGA than in those with ISS. Minor differences in adverse events reporting within organ systems between children born SGA and those with ISS are probably due to variable under-reporting of adverse events. GH appears to be a safe drug to use at current doses as a growth-promoting agent in short children born SGA.

Charge separation of dense two-dimensional electron-hole gases: mechanism for exciton ring pattern formation.

We report on new experiments and theory that unambiguously resolve the recent puzzling observation of large diameter exciton emission halos around a laser excitation spot in two dimensional systems. We find a novel separation of plasmas of opposite charge with emission from the sharp circular boundary between these two regions. This charge separation allows for cooling of initially hot optically generated carriers as they dwell in the charge reservoirs for very long times.

Negatively charged quantum well polaritons in a GaAs/AlAs microcavity: An analog of atoms in a cavity

The negatively charged exciton (X-) is observed to strongly couple with the microcavity- (MC-)confined photons in a GaAs quantum well containing a two-dimensional electron gas with 0

Long-term treatment with GHRH [1-44] amide in prepubertal children with classical growth hormone deficiency.

A cohort of 20 GH deficient prepubertal patients were treated with GHRH [1-44] 10 micrograms/kg or 20 micrograms/kg twice daily for up to four years (5 patients). GHRH treatment resulted in sustained improvement in height velocity. The mean prepubertal height velocity was 3.57 +/- 1.05 cm/yr pretreatment; 8.49 +/- 1.45 cm/yr at year 1; 6.86 +/- 1.45 cm/yr at year 2; 6.22 +/- 0.74 cm/yr at year 3; and 6.16 +/- 0.97 cm/yr at year 4. IGF-I levels increased and remained within normal range. The difference between the children's and the parents' Ht SD scores significantly diminished from a pretreatment difference of -2.43 to -0.48 after four years of treatment. No adverse effects were noted during treatment. We conclude that twice-daily GHRH [1-44] treatment in a small group of prepubertal GH deficient children resulted in sustained improvement in height and growth velocity, and achieved height SDS approaching closely those of their parents.

Modulating effect of human growth hormone on tumour necrosis factor-alpha and interleukin-1beta.

We measured serum tumour necrosis factor-alpha (TNF-alpha) as well as interleukin-1betta (IL-1beta) and GH concentrations in 15 children with isolated growth hormone deficiency (GHD), age range 5.1-13.9 years, before and 4 and 24h after the first GH injection (0.1 IU/kg s.c.). No differences were found in basal concentrations of serum TNF-alpha and IL-1beta between GHD children (10.01 +/- 1.55 pg/ml and 2.14 +/- .16 ng/ml respectively) and sex- and age-matched controls (11.57 +/- 2.16 pg/ml and 3.78 +/- 1.46 ng/ml respectively). In GHD children, serum TNF-alpha and IL-1beta values had significantly increased (P < 0.002) 4h (26.75 +/- 5.57 pg/ml and 2.99 +/- 0.21 ng/ml respectively) and decreased again 24 h after GH administration. Likewise, serum GH levels had significantly increased 4 h (from 1.29 +/- 0.69 to 48.71 +/- 13.35 ng/ml, P < 0.001) and decreased to basal values 24h after GH administration. A significant correlation was found between basal serum concentrations of GH and those of both TNF-alpha (P < 0.01) and IL-1beta (P < 0.05). However, no correlation was found between serum GH concentration and either TNF-alpha or IL-1beta levels 4 and 24h after GH administration. Our data suggest that GH plays a role in modulating TNF-alpha and IL-1beta release in humans.

Non-insulin dependent diabetes mellitus in a prepubertal child with Prader-Willi syndrome.

Diabetes mellitus has only rarely been reported in prepubertal children with Prader-Willi syndrome. All reported children have required insulin therapy. We report the development of a previously unrecognized association of non-insulin dependent diabetes mellitus in an obese 6 year-old child with Prader-Willi syndrome. She has never developed ketosis or acidosis, and she has been treated with oral hypoglycemic medication.

Role of B-cells in growth hormone-immune interactions.

Cells demonstrating cell surface markers for B-cells tend to be normal in growth hormone (GH)-deficient children. Treatment with pituitary-derived or recombinant human GH, however, produces a significant, albeit transient, decrease in the number of these cells both in vitro and in vivo. Receptors for GH have been detected on numerous cells of the immune system, notably B-cells and monocytes. Recent studies have shown that cells of the immune system are able to produce peptide hormones, such as GH, and studies in the rat (which have yet to be confirmed in humans) suggest that the B-cell is the cell type most involved in this production. These findings suggest that the B-cell has a significant role in the bi-directional communication network between the endocrine and immune systems.

Prediction of neonatal hyperthyroidism in infants born to mothers with Graves disease.

OBJECTIVE: To determine whether determinations of thyrotropin-receptor antibody (TRAb) levels in newborn infants of women with Graves disease would predict which infants will have hyperthyroidism. METHODS: The TRAb levels, assayed in the sera of 14 infants born to 14 women with Graves disease, were measured sequentially in the infants with hyperthyroidism during the course of antithyroid medication therapy. RESULTS: Seven infants had TRAb values less than 0.15 and remained euthyroid. In seven infants whose initial TRAb values were more than 0.25 (range, 0.48 to 0.88), clinical and biochemical signs of hyperthyroidism developed. The infants were treated with antithyroid medication until day 57 to day 123 of life. Therapy was discontinued when the infants were free of symptoms and when serum thyroxine and triiodothyronine and free thyroxine levels remained normal during therapy with decreasing doses of antithyroid medication. When the medication was discontinued, TRAb values were less than 0.20. CONCLUSIONS: Infants born to mothers with Graves disease with initial TRAb values less than 0.15 remained euthyroid. The TRAb values greater than 0.25 were associated with the development of neonatal hyperthyroidism. During treatment of neonatal hyperthyroidism, TRAb values less than 0.20 may be helpful in deciding when to withdraw antithyroid medication.