The shape of the plasma glucose curve during an oral glucose tolerance test as an indicator of Beta cell function and insulin sensitivity in end-pubertal obese girls.

It is hypothesized that the shape of the glucose curve during an oral glucose tolerance test is an early indicator of the risk for developing type 2 diabetes mellitus. In this study, we aimed to examine the shape of plasma glucose response curves and study their relationship with insulin sensitivity, insulin secretion and components of the metabolic syndrome in end-pubertal obese girls. Eighty-one end-pubertal obese girls [median (range) age: 14.4 (11.2-18.0) years; BMI: 34.6 (25.4-50.8) kg/m(²)] who underwent a 2-h oral glucose tolerance test were classified according to the shape of the glucose curve. Four shape types of the plasma glucose response curve were observed: 28 (34.6%) monophasic, 30 (37.0%) biphasic, 14 (17.3%) triphasic, and 9 (11.1%) unclassified. Patients with a monophasic shape had a higher area under the curve for glucose (p = 0.008), a lower early-phase insulin secretion (p = 0.005), and a poorer beta cell function relative to insulin sensitivity as reflected by the oral disposition index (p = 0.022) compared to the bi- and triphasic shape types. In addition, the triglyceride level and TG/HDL-C ratio was higher in patients with a monophasic shape compared to those with a biphasic shape (p = 0.040 and p = 0.048, respectively). In conclusion, end-pubertal obese girls with a monophasic plasma glucose curve are at increased risk for insulin resistance, which can contribute to the development of type 2 diabetes mellitus and cardiovascular diseases.

Mutation screen of the SIM1 gene in pediatric patients with early-onset obesity.

BACKGROUND: The transcription factor SIM1 (Single-minded 1) is involved in the control of food intake and in the pathogenesis of obesity. In mice, Sim1 is involved in the development of the paraventricular nucleus, and Sim1 deficiency leads to severe obesity and hyperphagia. In humans, chromosomal abnormalities in the SIM1 gene region have been reported in obese individuals. Furthermore, recent data also suggest that loss-of-function point mutations in SIM1 are responsible for SIM1 haplo-insufficiency that is involved in causing human obesity. In this study, we therefore wanted to expand the evidence regarding the involvement of SIM1 mutations in the pathogenesis of severe early-onset obesity. METHODS: We screened 561 severely overweight and obese children and adolescents and 453 lean adults for mutations in the coding region of the SIM1 gene. Mutation screening in all patients and lean individuals was performed by high-resolution melting curve analysis combined with direct sequencing. To evaluate the effect of the mutations on SIM1 transcriptional activity, luciferase reporter assays were performed. RESULTS: Mutation analysis identified four novel nonsynonymous coding variants in SIM1 in four unrelated obese individuals: p.L242V, p.T481K, p.A517V and p.D590E. Five synonymous variants, p.P57P, p.F93F, p.I183I, p.V208V and p.T653T, were also identified. Screening of the lean control population revealed the occurrence of four other rare SIM1 variants: p.G408R, p.R471P, p.S492P and p.S622F. For variants p.T481K and p.A517V, which were found in obese individuals, a decrease in SIM1 transcriptional activity was observed, whereas the transcriptional activity of all variants found in lean individuals resembled wild type. CONCLUSIONS: In this study, we have demonstrated the presence of rare SIM1 variants in both an obese pediatric population and a population of lean adult controls. Further, we have shown that functional in vitro analysis of SIM1 variants may help in distinguishing benign variants of no pathogenic significance from variants which contribute to the obesity phenotype.

Defining priorities in the transition from paediatric to adult healthcare for rare bone disease patients: a dialogic approach.

The Italian patient association for Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome, Associazione Conto Alla Rovescia-ACAR Aps, conducted a mixed-methods study at its 2023 annual conference. The study included the Open Dialogue Approach and a feedback survey to identify the main priorities in the transitioning process from paediatric to adult healthcare for patients with Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome. The common needs identified by patients, families, caregivers, and healthcare professionals were coordination and continuity of care, patient empowerment and communication, social and practical support, and transition planning and support. This experience fostered a sense of collaboration and cooperation among stakeholders, helping to build trust and create a shared vision for improving the quality of care for these patients. Furthermore, it could be considered a starting point for other patient associations interested in using different approaches to identify the needs of their members and actively involve all stakeholders.

Care delivery and outcomes among Belgian children and adolescents with type 1 diabetes.

UNLABELLED: We aimed to investigate care processes and outcomes among children and adolescents with type 1 diabetes treated in hospital-based multidisciplinary paediatric diabetes centres. Our retrospective cross-sectional study among 12 Belgian centres included data from 974 patients with type 1 diabetes, aged 0-18 years. Questionnaires were used to collect data on demographic and clinical characteristics, as well as process of care completion and outcomes of care in 2008. Most patients lived with both biological or adoption parents (77 %) and had at least one parent of Belgian origin (78 %). Nearly all patients (≥95 %) underwent determination of HbA(1c) and BMI. Screening for retinopathy (55 %) and microalbuminuria (73 %) was less frequent, but rates increased with age and diabetes duration. Median HbA(1c) was 61 mmol/mol (7.7 %) [interquartile range 54-68 mmol/mol (7.1-8.4 %)] and increased with age and insulin dose. HbA(1c) was higher among patients on insulin pump therapy. Median HbA(1c) significantly differed between centres [from 56 mmol/mol (7.3 %) to 66 mmol/mol (8.2 %)]. Incidence of severe hypoglycaemia was 30 per 100 patient-years. Admissions for ketoacidosis had a rate of 3.2 per 100 patient-years. Patients not living with both biological or adoption parents had higher HbA(1c) and more admissions for ketoacidosis. Parents' country of origin was not associated with processes and outcomes of care. CONCLUSION: Outcomes of care ranked well compared to other European countries, while complication screening rates were intermediate. The observed centre variation in HbA(1c) remained unexplained. Outcomes were associated with family structure, highlighting the continuing need for strategies to cope with this emerging challenge.

Humanization of care in pediatric wards: differences between perceptions of users and staff according to department type.

BACKGROUND: As the quality and quantity of patient-centered care may be perceived differently by recipients and independent observers, assessment of humanization of pediatric care remains an elusive issue. Herein we aim to analyze differences between the degrees of verified existing vs. perceived humanization issues of a pediatric ward. Furthermore, we examine whether there is concurrence between the degrees of humanization perceived by users (parents/visitors) vs. staff members. METHODS: The study was conducted in the pediatric wards of seven medical centers of the Campania region (Italy) categorized as general (n = 4), children's (n = 1), and university (n = 2) hospitals. The degree of existing humanization was assessed by a multidisciplinary focus group for each hospital through a pediatric care-oriented checklist specifically developed to individuate the most critical areas (i.e., those with scores < 2.5). The degree of perceived humanization was assessed through four indicators: well-being, social aspects, safety and security, and health promotion. RESULTS: The focus groups showed that critical areas common to all centers were mainly concerned with welfare, mediation, translation, and interpretation services. Specific critical issues were care and organizational processes oriented to the respect and specificity of the person and care of the relationship with the patient. Perceived humanization questionnaires revealed a lack of recreational facilities and mediation and translation services. As for specific features investigated by both tools, it was found that mediation and interpretation services were lacking in all facilities while patient perceptions and observer ratings for space, comfort, and orientation concurred only in the general hospital evaluations. CONCLUSIONS: Future humanization interventions to ensure child- and family-friendly hospital care call for careful preliminary assessments, tailored to each pediatric ward category, which should consider possible differences between perceived and verified characteristics.

Concerns, expectations and perception regarding stature, physical appearance and psychosocial functioning before and during high-dose growth hormone treatment of short pre-pubertal children born small for gestational age.

BACKGROUND/AIMS: Few data are available about parental concerns and psychosocial functioning of young children born small for gestational age (SGA) treated with growth hormone (GH). The present study focused on the perception of short stature and the concerns and expectations of the parents regarding GH treatment. METHODS: Forty prepubertal short SGA children, randomized into a GH-treated and a GH-untreated group, and their parents were evaluated by a questionnaire and a semi-structured interview at start and after 2 years of follow-up. RESULTS: Before start, 85% of the parents were concerned about short stature, 76% expected an increase in adult height of > or =10 cm and 81% expected a positive impact on well-being. Half of the parents expressed fears regarding GH treatment. After 2 years, more parents of treated children reported obvious growth and physical changes, and fewer parents reported teasing because of short stature. An improvement of well-being was reported by half of the parents of treated and untreated children. Fears about GH treatment disappeared almost completely. CONCLUSION: The perspective of GH treatment induced major adult height expectations. In treated children, the physical effects of GH treatment became obvious, teasing because of short stature decreased and initial concerns about short stature and GH therapy decreased.

A strategic approach for investigating light recipes for 'Outredgeous' red romaine lettuce using white and monochromatic LEDs.

To optimize crop production/quality in space, we studied various "light recipes" that could be used in the Advanced Plant Habitat currently aboard the International Space Station (ISS). Lettuce (Lactuca sativa cv. 'Outredgeous') plants were grown for 28 days under seven treatments of white (W) LEDs (control), red (635 nm) and blue (460 nm) (RB) LEDs, W + blue (B) LEDs, W + green (520 nm) (G) LEDs, W + red (R) LEDs, W + far red (745 nm) (FR) LEDs, and RGB + FR LEDs with ratios similar to natural sunlight. Total PAR was maintained near 180 µmol m-2 s-1 with an 18 h photoperiod. Lettuce grown under RGB + FR produced the greatest leaf expansion and overall shoot biomass, while leaves from WB and RB showed the highest levels of pigmentation, secondary metabolites, and elemental nutrients. All other supplemental treatments had varying impacts on morphology that were dependent on crop age. The WG treatment increased fresh mass early in the cycle, while WR increased biomass later in the cycle. The plants grown under WFR exhibited elongation of petioles, lower nutrient content, and similar shoot biomass to the W control. The findings suggest that supplementing a broad spectrum, white light background with discrete wavelengths can be used to manipulate total yield, morphology, and levels of phytonutrients in lettuce at various times during the crop cycle.

Adult Height after Growth Hormone Treatment at Pubertal Onset in Short Adolescents Born Small for Gestational Age: Results from a Belgian Registry-Based Study.

OBJECTIVES: Information on the efficacy of GH treatment in short SGA children starting their treatment in adolescence is limited. Therefore, adult height (AH), total height gain, and pubertal height gain were evaluated in short SGA children who started GH treatment at pubertal onset. PATIENT AND METHODS: Growth data of 47 short SGA adolescents (22 boys) who started GH treatment at pubertal onset (PUB group) were compared with results from 27 short SGA patients (11 boys) who started GH therapy at least 1 year before pubertal onset (PrePUB group). RESULTS: The PUB group achieved a mean (±SD) total height gain of 0.8 ± 0.7 SDS and an AH of -2.5 ± 0.7 SDS after 4.1 ± 1.1 years of GH treatment with a dosage of 41.8 ± 8.4 µg/kg/day. These results were comparable with those in the PrePUB group, which was treated for a longer duration (5.8 ± 2.1 years), resulting in a total height gain of 1.1 ± 0.7 SDS and an AH of -2.1 ± 1.0 SDS. Multiple regression analysis showed a significantly lower height gain in pubertal patients, females, and patients weighing less at start of GH treatment. An AH above -2 SDS and above the parent-specific lower limit of height was, respectively, reached in 28% and 70% of PUB and 44% and 67% of PrePUB patients (NS). AH SDS was positively correlated with the height SDS at start of GH. CONCLUSIONS: Short SGA adolescents starting GH therapy at an early pubertal stage have a modest and variable height gain. A normal AH can be expected in one third of the patients, especially in those with a smaller height deficit at onset of GH treatment.

Effect of 2 years of high-dose growth hormone therapy on cognitive and psychosocial development in short children born small for gestational age.

OBJECTIVE AND DESIGN: Children born small for gestational age (SGA) are not only at risk for short stature, but also for neurodevelopmental and behavioral problems. In this study, we analyzed the effects of high-dose GH therapy on cognitive development and psychosocial functioning in 34 prepubertal (3-8 years) short SGA children, equally randomized into a GH-treated group (TRG) and an untreated group (UTRG). METHODS: At start and after 2 years, children underwent standardized tests measuring the intellectual abilities (Wechsler Preschool and Primary Scale of Intelligence-Revised, or Wechsler Intelligence Scale for Children-Revised); their parents completed a standardized questionnaire evaluating psychosocial functioning (Child Behavior Checklist; CBCL). RESULTS: At start, total IQ scores were significantly (P < 0.05) lower in the SGA group than in the general population: 32% of the SGA patients had scores below 85. After 2 years, IQ scores remained unchanged in the TRG, but increased significantly (P < 0.05) in the UTRG. After exclusion of children with developmental problems, however, no significant changes in IQ scores occurred in the UTRG as well as the TRG. At baseline, 24% (8/34) children had problematic CBCL total problems scores, equally distributed among the two groups; no significant changes in the different subscale scores occurred after 2 years. CONCLUSION: No beneficial effect of 2 years of GH therapy on cognitive and behavioral profile could be observed in a cohort of rather young short SGA children presenting a variable degree of developmental delay and behavioral problems. Subsequent follow-up could reveal potential long-term effects of GH therapy on development and behavior.

[Childhood obesity as a risk factor for diabetes mellitus type I: the accelerator hypothesis]. / Overgewicht bij kinderen als risicofactor voor diabetes mellitus type I: de acceleratorhypothese.

Diabetes mellitus (DM) type I was diagnosed in two children, a girl aged 10.9 years and a boy aged 10.3 years, who suffered from overweight. Both were treated with subcutaneous insulin injections and dietary adjustments. Some of the data in the literature suggest that overweight or obesity during childhood increases the risk of type-I DM. Important in this connection is the so-called 'accelerator hypothesis', which postulates a common basis for both type-I and type-2 DM with genetic predisposition, insulin resistance (caused by rapid weight gain) and autoimmunity, leading to beta-cell insufficiency, as 'accelerators'. It is important to consider a diagnosis of type-I DM in children with overweight or obesity, especially in case of abnormal weight loss associated with polydipsia and polyuria.

Multiple gut-liver axis abnormalities in children with obesity with and without hepatic involvement.

BACKGROUND: Gut-liver axis (GLA) dysfunction appears to play a role in obesity and obesity-related hepatic complications. OBJECTIVES: This study sought to concurrently explore several GLA components in a paediatric obese population with/without liver disease. METHODS: Thirty-two children (mean age 11.2 years) were enrolled: nine controls with normal weight and 23 patients with obesity (OB+). Of the 23 patients OB(+), 12 had not steatosis (ST-), and 11 had steatosis (ST+) (associated [n = 8] or not [n = 3] with hypertransaminasaemia [ALT +/-]). Subjects were characterized by using auxologic, ultrasonographic and laboratory parameters. A glucose hydrogen breath test was performed to test for small intestinal bacterial overgrowth, a urinary lactulose/mannitol ratio (LMR) was obtained to assess intestinal permeability, and tests for transaminases, blood endogenous ethanol, endotoxin and faecal calprotectin were also conducted. RESULTS: Eleven out of 23 patients OB(+) (p < 0.05) exhibited pathological (>90th percentile of the control group values) LMR, with values paralleling the grade of liver involvement (normal weight < OB[+] < OB[+]ST[+]ALT[-] < OB[+)]ST[+]ALT[+] [p < 0.05]). LMR significantly correlated with ethanolaemia (r = 0.38, p = 0.05) and endotoxaemia (r = 0.48, p = 0.015) concentrations. Increased permeability was a risk factor for the development of steatosis (p < 0.002). SIBO was present only in patients with obesity. Faecal calprotectin concentrations were within normal limits in all subjects. CONCLUSIONS: Increased permeability, endogenous ethanol and systemic endotoxin concentrations reflect some GLA dysfunction in obesity and its hepatic complications. Pending further results to establish their potential causative roles, the modulation of the GLA appears to represent a possible target for the prevention and treatment of these conditions.

Hematopoietic precursor cells in mice treated with 4-demethoxydaunorubicin and doxorubicin.

The hematologic toxicity of 4-demethoxydaunorubicin (4-dmDNR), a new anthracycline more potent and less cardiotoxic than doxorubicin (Dx), was studied. Dose-survival curves of bone marrow hematopoietic precursor cells (HPC) in situ were determined with the use of (C57BL X C3H)F1 mice and with assays of colony-forming units--spleen, culture, and erythroid--by in vivo and in vitro methods. Time response of HPC was followed in mice treated at days 0, 2, and 5 with 0.75 mg 4-dmDNR/kg of 4.5 mg Dx/kg and in mice receiving 2.23 mg 4-dmDNR/kg or 3.96 mg Dx/kg twice a week for 4 weeks. The dose-survival curves of HPC for 4-dmDNR were exponential. Slight differences in sensitivity among assayed populations were seen. Although the doses of 4-dmDNR required to reduce the survival of HPC to 37% were similar or lower than those of Dx, following intermittent treatment with doses of 4-dmDNR with the same optimal antitumor activity as with Dx, 4-dmDNR seemed to have a lesser effect on hematopoietic progenitors and a greater effect on peripheral blood cells than did Dx. However, during prolonged administration 4-dmDNR appeared to be toxic at every hematopoietic level.

Effects of high-dose methotrexate and leucovorin on murine hemopoietic stem cells.

This study compares the effects of a high dose of methotrexate (HDMTX) to that of a high dose of methotrexate plus leucovorin protection on the hemopoietic stem cells in a murine model. C57BL X C3H F1 mice were treated with a single large bolus (500 mg/kg body weight) of methotrexate or with the same dose of the drug plus leucovorin administered in fractionated doses during the following 24 hr. At 1 to 2 days after the administration of HDMTX, there was a large bone marrow and spleen depopulation of pluripotent stem cells and of committed and recognizable progenitors. At 2 to 3 days, a severe fall of white blood cells and reticulocytes ensued. The recovery process of hemopoietic precursors followed alternate phases of overshooting and secondary falls. Leucovorin administration appeared to protect all stages of hemopoiesis and prevented the severe drops of bone marrow cellularity and stem cell content which followed the HDMTX bolus. However, the effect of leucovorin on peripheral blood cell reduction was less significant. After treatment with HDMTX, the recovery of bone marrow cells and the burst of splenic hemopoietic activity followed a pattern similar in both leucovorin-protected and unprotected animals, but in the former, the increase in stem cells and hemopoietic progenitors appeared to reach higher values and to last longer. In particular, the overshooting of colony-forming units, culture and erythroid, reached a higher peak in leucovorin-treated mice and was more prolonged. Our results indicate that, in HDMTX-treated mice, leucovorin protection involves the earliest stages of hemopoiesis, assuring the maintenance of a satisfactory endowment of stem and progenitor cells.

[Treatment of central precocious puberty with Gonadotropin-Releasing Hormone agonist (triptorelin) in girls: breast development, skeletal maturation, height and weight evolution during and after treatment]. / Traitement de la puberté précoce par un agoniste du GnRH (triptoréline) chez les filles: évolution des caractères sexuels secondaires, de la maturation osseuse, de la taille et du poids pendant et après traitement.

Central precocious puberty (CPP) is treated with GnRH analogues to stabilize secondary sexual characteristics and to prevent loss of final height (FH) due to accelerated bone maturation. However, some studies suggest that FH is not always improved and that treatment may induce excessive weight gain. We analysed data from 19 girls treated for CPP with monthly injections of 3.75 mg triptorelin. Pubertal development, bone age, height, weight and body mass index (BMI) were evaluated at start (chronological age: 7.8 +/- 1.8 yrs, mean +/- SD), at the end of treatment (10.6 +/- 1.1 yrs) and at FH (14.9 +/- 2.5 yrs). At start of treatment, breast (B) development was B3 (from 2 to 4), bone age 10.6 +/- 1.7 yrs, height 2.1 +/- 1.1 SDS and BMI 1.3 +/- 0.8 SDS. Treatment stabilized or reduced breast development and decreased bone maturation. Final height was 162.3 +/- 6.6 cm (0.0 +/- 1.1 SDS) and was comparable to predicted adult height at the start of treatment and to corrected mid-parental height. BMI SDS at the start, the end of treatment and at final evaluation were 1.3 +/- 0.8, 1.6 +/- 0.8 and 1.4 +/- 0.9 SDS. In conclusion, in our girls with central precocious puberty, treatment with GnRH agonist stabilized or decreased breast development and stabilized bone maturation, but did not increase neither final height nor weight. Aspects other than height should also be taken into account when considering treatment of children with precocious puberty.

Initial characterization and sexual dimorphism of serum growth hormone-binding protein in adult rats.

The in vitro binding of 125I-bovine growth hormone (bGH) to adult rat serum was studied using Ultrogel AcA34 filtration. When analytical chromatography on a 1.6 x 100 cm column was performed, four peaks of radioactivity were revealed: the first two peaks with Mr +/- 220,000 and +/- 110,000 corresponded to bound 125I-bGH (abolished by excess of unlabeled bGH), the third corresponded to free 125I-bGH and the fourth to free Na125I (Vt). On a short (1 x 40 cm) column, bound 125I-bGH eluted as a single peak between the void volume (Vo) and the peak of free 125I-bGH. Serum 125I-bGH binding was specific, saturable, and time-dependent. Specific serum 125I-bGH binding (bound/total radioactivity x 100), calculated as the difference of binding in the absence and the presence of an excess unlabeled bGH, was higher in female than in male rats (26 +/- 2% vs. 11 +/- 1%, respectively; mean +/- SE; n = 6; P less than 0.01). Scatchard analysis revealed a binding affinity of 2 x 10(8) M-1 for both sexes, and a binding capacity of 6.4 x 10(-8) mol/liter for the female rats and 1.6 x 10(-8) mol/liter for the male rats (mean of three serum pools of three animals each). Specific binding of 125I-bGH to serum correlated significantly with 125I-bGH binding to liver homogenates (r = 0.83; n = 12; P less than 0.01). These results suggest the presence of a specific GH-binding protein in rat serum and provide further evidence for a close relationship between serum GH-binding protein and hepatic GH receptors.

Serum growth hormone (GH)-binding protein and insulin-like growth factor-I levels in Turner's syndrome before and during treatment with recombinant human GH and ethinyl estradiol.

Serum levels of GH-binding protein (GH-BP) and insulin-like growth factor-I (IGF-I) were measured in 14 adolescent girls with Turner's syndrome (TS) before and during treatment with recombinant human GH (rhGH) and oral ethinyl estradiol (EE2). Before treatment, the mean +/- SE GH-BP level in TS patients was 33.2 +/- 2.0%; this was higher (P < 0.05) than that in bone age-matched (27.9 +/- 1.1%; n = 13) or chronological age-matched (28.1 +/- 0.8%; n = 17) control girls. The mean +/- SE IGF-I level in TS girls (283 +/- 26 micrograms/L) was comparable to that in bone age-matched controls (255 +/- 17 micrograms/L), but lower (P < 0.005) than that in chronological age-matched pubertal controls (568 +/- 35 micrograms/L). In 7 TS girls treated with daily sc injections of rhGH in a dose of 0.8 U/kg.week for 18 months, serum levels of IGF-I increased from 330 +/- 39 to 707 +/- 48 micrograms/L after 3 months of treatment and remained elevated for the entire observation period (P < 0.002). In contrast, GH-BP levels did not change significantly. In 7 other TS girls, puberty was induced after 2 yr of daily sc injections with rhGH (1 U/kg.week) by adding 100 ng/kg.day EE2, orally, during ongoing rhGH therapy. During 18 months of pubertal induction, serum GH-BP levels increased gradually from 31.4 +/- 2.7% at the start of EE2 treatment to a maximum of 49.2 +/- 0.8% after 1 yr (P < 0.001). Serum IGF-I levels, in contrast, did not change significantly. These results show that in adolescent TS patients 1) pretreatment serum GH-BP levels are higher than in bone age-matched or chronological age-matched control girls, and IGF-I levels are similar to those in bone age-matched but lower than those in chronological age-matched controls; 2) during rhGH treatment GH-BP levels do not change, whereas IGF-I levels increase significantly; and 3) oral EE2 treatment during ongoing rhGH treatment increases GH-BP levels markedly, but does not modify IGF-I levels.

Growth-promoting effect of growth hormone and low dose ethinyl estradiol in girls with Turner's syndrome.

Forty patients with Turner's syndrome, aged 5.0-16.6 yr, were randomly allocated to receive daily sc injections of recombinant human GH (hGH) at a dose of 1 IU/kg.week alone (group I) or in combination with 25 ng/kg.day ethinyl estradiol (E2; group II). The mean pretreatment height velocity was 3.8 cm/yr for both groups. During the first year of treatment height velocity increased significantly (P less than 0.001) in both groups, to 7.5 +/- 1.3 and 8.1 +/- 1.6 cm/yr, respectively. The difference between the two groups was not significant. The mean (+/- SD) height velocity expressed as the SD score for chronological age (Turner references) was 0.0 +/- 1.2 for group I and 0.2 +/- 1.4 for group II and increased significantly (P less than 0.001) during the first year of treatment to +4.3 +/- 1.1 in group I and +5.4 +/- 1.2 in group II. The difference between both groups was statistically significant (P less than 0.01). Height SD score for chronological age (Turner references) increased from -0.2 +/- 0.9 to +0.6 +/- 1.0 in group I and from -0.2 +/- 1.0 to +0.7 +/- 1.1 in group II. Mean bone age progressed similarly in both treatment groups (1.1 +/- 0.6 yr during 1 yr of treatment). However, bone age maturation accelerated more rapidly in younger patients. Twelve girls (three in group I and nine in group II) had minor breast development. No major adverse effects were reported. We conclude that daily sc therapy with hGH stimulates height velocity in Turner's syndrome. The beneficial effect on height velocity increment of E2 addition was small. Furthermore, even very low doses of E2 may induce breast development at an early age and accelerate bone maturation. For these reasons, the addition of E2 to hGH is not warranted in young patients with Turner's syndrome.

Growth hormone therapy in Turner's syndrome: one versus two daily injections.

In 44 girls with Turner's syndrome, aged 4.0-15.3 yr, the effects of biosynthetic GH (25 U/m2.week) given as once daily or twice daily injections were compared. During 1 yr of treatment, the growth rate increased similarly by 3.5 +/- 1.3 cm/yr in the once daily group and 2.7 +/- 1.8 cm/yr in the twice daily group. Although pretreatment height velocity was negatively related to age, the increase in height velocity during therapy was not. The mean progression in bone age (TW2-RUS method), during therapy was 1.3 yr in both groups. No significant change in the median insulin secretory response to an oral glucose tolerance test was found. Serum cholesterol and triglyceride concentrations did not change significantly throughout the study in either treatment group. Thyroid hormone concentrations remained within normal limits. Normal increments in left ventricular wall thickness and left ventricular mass for age and body surface were observed after 1 yr of GH treatment. We conclude that division of the daily GH dose given to Turner's syndrome patients into two injections does not result in either a significantly different growth response or different side-effects from once daily treatment during the first year of therapy.

Late or delayed induced or spontaneous puberty in girls with Turner syndrome treated with growth hormone does not affect final height.

Although it has been well established that GH treatment increases final height (FH) in girls with Turner syndrome (TS), the optimal ages to start GH therapy and introduce estrogens for pubertal induction have not been defined. We evaluated retrospectively the influence of the age at onset of GH treatment and age at onset of puberty on FH of 186 adult TS women treated during childhood with GH. Puberty started spontaneously in 38 patients, and it was induced in 148 girls with ethinyl estradiol (mean +/- SD starting dose, 66 +/- 32 ng/kg.d). Patients with spontaneous or induced puberty were divided into quartiles on the basis of age at initiation of GH treatment (3-10, 10-12, 12-14, and 14-19 yr). FH was 151.7 +/- 6.0 cm; there were no FH differences between patients with induced or spontaneous puberty, nor were there differences between the age quartiles. Puberty started earlier in the girls with spontaneous puberty than in those with induced puberty (12.4 +/- 1.3 yr vs. 14.5 +/- 1.9 yr; P < 0.0001). The age at onset of puberty was not related to FH. Pubertal growth was 15.4 +/- 4.6 cm in the girls with spontaneous puberty and 8.6 +/- 4.3 cm in the girls with induced puberty (P < 0.0001). We conclude that GH treatment results in a significant increase in FH in most TS girls. Under the conditions of GH treatment and induction of puberty that we have used, the age at start of GH treatment was not related to FH; in addition, late or delayed induced or spontaneous puberty did not affect FH.

Isolated GH deficiency with dominant inheritance: new mutations, new insights.

Autosomal dominantly inherited isolated GH deficiency is caused by mutations of GH-1 that alter the normal structure of GH. We studied 16 familial cases and 1 sporadic case with isolated GH deficiency type II from 1 Dutch and 4 German families by direct sequencing of PCR-amplified genomic DNA and ectopic transcript analysis of lymphocyte mRNA. In addition, the clinical data of the affected individuals were analyzed. Two previously reported mutations and 1 novel splice site mutation in intron III of GH-1 (+1G to C and +1G to A; new, +2T to C) were detected that cause exon 3 skipping. We also discovered a novel G6191 to T missense mutation in exon 4 of GH-1 that changes valine 110, which is highly conserved in mammalian and several nonmammalian GH, to phenylalanine. Splicing of the primary RNA transcript was not affected by this mutation, which is very likely to alter the normal GH structure at the protein level. The onset of growth failure was earlier, and the degree was more severe in affected children with GH-1 splice site mutations compared with those in children with the GH-1 missense mutation. In addition, the severity of the phenotype was variable, even within the same family. The age at diagnosis was between 0.8-9.6 yr (median, 5.1 yr); height at diagnosis was between -2.5 and -8.1 SD score (median, -4.0). Most of the children were lean at diagnosis, with a body mass index ranging from -1.7 to +3.3 SD score (median, -0.5). The 5 affected adults had final heights between -1.8 and -4.5 SD score (median, -3.6), centripetal obesity, and muscular hypotrophy. Before therapy, IGF-I and IGF-binding protein-3 serum levels of all affected children were severely diminished (<<5th percentiles for age). The maximum GH peak in a total of 25 stimulation tests was between 0.1-5.0 microg/liter (median, 0.9), indicating severe GH deficiency. The height of the adenohypophysis studied by magnetic resonance imaging was normal in 2 affected children and mildly decreased in 2 others. Substitution with GH resulted in good catch-up growth in all treated children. Children with severe GH and IGF-I deficiencies, but normal size of the adenohypophysis should be examined for GH-1 splice site and missense mutations. The observed discrepancy between the very homogeneous hormone data proving severe GH and IGF-I deficiencies and the high variability of growth failure even within the same family suggests that the onset and predominance of GH-dependent growth during infancy are individually different and modified by as yet unknown factors.