Growth Patterns of Children With Short Stature in Adulthood According to Auxological Status and Maturity at Birth.

CONTEXT: Prematurity carries a risk for impaired postnatal growth and long-term growth restriction. Especially children born SGA seem vulnerable for poor growth, as a persistent short stature can be observed in app 10-15% of these children. OBJECTIVE: In this study we aimed to recognize differences in growth patterns of children according to sex, maturity, and auxological status at birth facilitating earlier identification of small-for-gestational-age (SGA) children with adult short stature. METHODS: The growth data of 44 791 infants born between January 1, 1980, and December 30, 2012, among 2 pediatric cohorts with follow-up through December 31, 2020, were analyzed. A total of 5698 children with birth data had measurements at near final height (nfh) and at least 2 further points. RESULTS: Preterm children (gestational age < 37 weeks) had a significantly lower mean nfh SDS than term children (preterm, -0.61; term, -0.18) and a higher likelihood of nfh < third percentile (preterm, 20.5%; term, 12.2%). SGA born children also had a lower mean nfh SD score (SDS) than children born appropriate for gestational age (AGA) (SGA, -1.06; AGA, -0.15) and a higher likelihood of nfh < third percentile (SGA, 28.2%; AGA 10.1%). Of 1204 SGA children, 672 (56%) showed successful catch-up growth (CUG) to nfh greater than or equal to the 10th percentile (SGA-CU), and 532 children (44%) did not (SGA-S). The difference in their mean nfh SDS (SGA-CU, -0.12; SGA-S -2.26) can only partly be explained by the differences in mean mid-parental height SDS (SGA-CU, -0.3; SGA-S, -1.19). During the first year, SGA-CU showed higher CUG (SGA-CU, +1.2 SDS; SGA-S, +0.45 SDS), which helps to discriminate between groups earlier. CONCLUSION: Final growth outcome was influenced by prematurity and auxological status at birth, but not by sex. Height/length SDS increments during year 1 are instrumental to discern SGA children with later normal or short stature. While observing CUG until year 2 and 3 can add specificity, discrimination thereafter becomes difficult.

A Novel Method for Adult Height Prediction in Children With Idiopathic Short Stature Derived From a German-Dutch Cohort.

Context: Prediction of adult height (AH) is important in clinical management of short children. The conventional methods of Bayley-Pinneau (BP) or Roche-Wainer-Thissen (RWT) have limitations. Objective: We aimed to develop a set of algorithms for AH prediction in patients with idiopathic short stature (ISS) which are specific for combinations of predicting variables. Methods: Demographic and auxologic data were collected in childhood (1980s) and at AH (1990s). Data were collected by Dutch and German referral centers for pediatric endocrinology. A total of 292 subjects with ISS (219 male, 73 female) were enrolled. The population was randomly split into modeling (n = 235) and validation (n = 57) cohorts. Linear multi-regression analysis was performed with predicted AH (PAH) as response variable and combinations of chronological age (CA), baseline height, parental heights, relative bone age (BA/CA), birth weight, and sex as exploratory variables. Results: Ten models including different exploratory variables were selected with adjusted R² ranging from 0.84 to 0.78 and prediction errors from 3.16 to 3.68 cm. Applied to the validation cohort, mean residuals (PAH minus observed AH) ranged from -0.29 to -0.82 cm, while the conventional methods showed some overprediction (BP: +0.53 cm; RWT: +1.33 cm; projected AH: +3.81 cm). There was no significant trend of residuals with PAH or any exploratory variables, in contrast to BP and projected AH. Conclusion: This set of 10 multi-regression algorithms, developed specifically for children with ISS, provides a flexible tool for AH prediction with better accuracy than the conventional methods.

Age- and weight group-specific weight gain patterns in children and adolescents during the 15 years before and during the COVID-19 pandemic.

BACKGROUND/OBJECTIVES: There is a concern that measures aiming to limit a further spread of COVID-19, e.g., school closures and social distancing, cause an aggravation of the childhood obesity epidemic. Therefore, we compared BMI trends during the 15 years before and during the COVID-19 pandemic. SUBJECTS/METHODS: To assess the change in weight dynamics during the first months of COVID-19, we compared the trends of 3-month change in BMI-SDS (ΔBMI-SDS) and the proportions of children showing a high positive (HPC) or high negative (HNC) weight change between 2005 and 2019 and the respective changes from 2019 (pre-pandemic) to 2020 (after the onset of anti-pandemic measures) in more than 150,000 children (9689 during the pandemic period). The period of 3 months corresponds approximately to the first lockdown period in Germany. RESULTS: During the COVID-19 pandemic, we found a substantial weight gain across all weight and age groups, reflected by an increase in the 3-month change in BMI-SDS (ß = 0.05, p < 0.001), an increase in the proportion of children showing HPC (OR = 1.4, p < 0.001), and a decrease in the proportion of children showing HNC (OR = 0.7, p < 0.001). Besides, we found the same trends since 2005 on a low but stable level with a yearly increase of ΔBMI-SDS by ß = 0.001 (p < 0.001), the odds of HPC increased by ORhigh_pos = 1.01 (p < 0.001), and the odds of HNC decreased by ORhigh_neg = 0.99 (p < 0.001). These rather small effects accumulated to ß = 0.02, ORhigh_pos = 1.14, and ORhigh_pos = 0.85 over the whole period 2005-2019. Alarmingly, both the long-term and the short-term effects were most pronounced in the obese subgroup. CONCLUSIONS: There are positive dynamics in different measures of weight change, indicating a positive trend in weight gain patterns, especially within the group of children with obesity. These dynamics are likely to be escalated by COVID-19-related measures. Thus, they may lead to a significant further aggravation of the childhood obesity pandemic.

Acceleration of BMI in Early Childhood and Risk of Sustained Obesity.

BACKGROUND: The dynamics of body-mass index (BMI) in children from birth to adolescence are unclear, and whether susceptibility for the development of sustained obesity occurs at a specific age in children is important to determine. METHODS: To assess the age at onset of obesity, we performed prospective and retrospective analyses of the course of BMI over time in a population-based sample of 51,505 children for whom sequential anthropometric data were available during childhood (0 to 14 years of age) and adolescence (15 to 18 years of age). In addition, we assessed the dynamics of annual BMI increments, defined as the change in BMI standard-deviation score per year, during childhood in 34,196 children. RESULTS: In retrospective analyses, we found that most of the adolescents with normal weight had always had a normal weight throughout childhood. Approximately half (53%) of the obese adolescents had been overweight or obese from 5 years of age onward, and the BMI standard-deviation score further increased with age. In prospective analyses, we found that almost 90% of the children who were obese at 3 years of age were overweight or obese in adolescence. Among the adolescents who were obese, the greatest acceleration in annual BMI increments had occurred between 2 and 6 years of age, with a further rise in BMI percentile thereafter. High acceleration in annual BMI increments during the preschool years (but not during the school years) was associated with a risk of overweight or obesity in adolescence that was 1.4 times as high as the risk among children who had had stable BMI. The rate of overweight or obesity in adolescence was higher among children who had been large for gestational age at birth (43.7%) than among those who had been at an appropriate weight for gestational age (28.4%) or small for gestational age (27.2%), which corresponded to a risk of adolescent obesity that was 1.55 times as high among those who had been large for gestational age as among the other groups. CONCLUSIONS: Among obese adolescents, the most rapid weight gain had occurred between 2 and 6 years of age; most children who were obese at that age were obese in adolescence. (Funded by the German Research Council for the Clinical Research Center "Obesity Mechanisms" and others; ClinicalTrials.gov number, NCT03072537 .).

Children and adolescents with type 1 diabetes in Germany are more overweight than healthy controls: results comparing DPV database and CrescNet database.

AIMS: To describe the development of weight in children and adolescents with type 1 diabetes in Germany. METHODS: We analyzed the body mass index (BMI) of the most recent treatment year of each patient with diabetes in the Pediatric Quality Initiative (DPV) database. BMI SD score (SDS) was calculated based on pooled historical German normative data (AGA) and based on healthy children from the CrescNet database. Thus, 25,762 children and adolescents with diabetes were compared with more than 75,000 healthy controls. RESULTS: BMI-SDS was 0.49±0.88 and 0.26±0.79 when children and adolescents, respectively, with diabetes were compared with AGA reference or with CrescNet controls from the same year. In both analyses, female patients (0.57±0.89 and 0.30±0.79) had significantly higher BMI-SDS than male patients (0.41±0.86 and 0.22±0.78; p<0.0001). Analysis of different age groups showed highest BMI-SDS in patients below 6 years (0.61 and 0.56, respectively). After adjustment for metabolic control, center, and insulin treatment, BMI-SDS was significantly influenced by diabetes duration, age, and female gender. CONCLUSIONS: BMI of children and adolescents with type 1 diabetes is higher compared with healthy children measured in the same year. Especially, very young children and adolescent girls are at risk for overweight independent of annual trends.

Early detection of growth disorders with the CrescNet system at the Leipzig treatment center.

BACKGROUND: Growth hormone replacement therapy is more effective the earlier it is begun. This article adresses the question whether children with growth hormone deficiency (GHD) were able to begin treatment earlier through the use of the CrescNet system in the Department of Pediatrics at the Leipzig University Hospital. CrescNet is a network of pediatricians and endocrinological treatment centers, established in Leipzig in 1998, whose aim is to improve the early detection of growth disorders. METHODS: Pediatricians participating in CrescNet provided anonymized data on their patients' height and weight to the CrescNet database. Each participating pediatrician received a quarterly screening report with recommendations for the work-up of children with abnormal growth. Some patients with GHD who were treated in the Leipzig treatment center were referred in response to these recommendations, while others came spontaneously from the practices of pediatricians participating or not participating in CrescNet. We determined the age at the onset of treatment for the 139 patients treated for GHD in the University Children's Hospital Leipzig from 1999 to 2005 and compared the findings with data from other treatment centers in Germany. RESULTS: Patients from CrescNet practices began treatment at a younger age than those from non-CrescNet practices (8.77 ± 3.40 versus 9.50 ± 3.78 years, p = 0.26). Patients from CrescNet practices whose GHD was detected by screening began treatment earlier than those for whom no data had been sent (7.67 ± 3.21 versus 9.28 ± 3.39 years, p = 0.031). In the center in Leipzig, but not in other German GHD treatment centers, the age at onset of treatment dropped significantly over the period of the study and then remained steady till 2009 in the range of 7.61 ± 3.0 years. CONCLUSION: These descriptive results imply that the linking of pediatricians' practices with the CrescNet system resulted in earlier treatment of children with GHD.

Age-specific stabilization in obesity prevalence in German children: a cross-sectional study from 1999 to 2008.

OBJECTIVE: Trends of overweight (ov)/obesity (ob) prevalence among German children aged 4-16 years were studied between 1999 and 2008. SUBJECTS: Body mass index (BMI) data (>P90 [ov] and >P97 [ob]) from the national CrescNet database were analysed in three age groups: 4-7.99, 8-11.99, and 12-16 years. RESULTS: Trend analyses. Data from 272 826 children were analyzed. a) Whole study population aged 4-16 years old. A significant upward trend for ov/ob prevalence was found between 1999 and 2003, and a significant downward trend between 2004 and 2008. b) Subgroup analyses. Ov/Ob prevalence increased in most subgroups studied until 2004. Between 2004 and 2008, a downward trend for ov/ob prevalence was found in children, aged 4-7.99 years, whereas it stabilized in most other subgroups studied. Cross-sectional analyses. Data from 93 028 children were analyzed. Ov/ob prevalence was significantly higher in 2004 compared with 2000 in girls aged 12-16 years and in boys aged 8-16 years. Ov/ob obesity prevalence was significantly lower in 2008 compared with 2004 in children aged 4-7.99 years. CONCLUSION: Ov/ob prevalence increased between 1999 and 2003 in German children. Since 2004, this trend has been stabilizing or turning into a downward trend. Our data confirm the global trend of stabilizing prevalence rates of childhood obesity at a high level and add important information for individual age groups. Intervention programs targeted to prevent childhood obesity may have had beneficial effects, and a new balance between factors favouring obesity and those favouring leanness may have been reached recently. Age- and gender-specific differences found in trends of ov/ob prevalence may help optimise preventive and therapeutic measures.

Impact of weight status on the onset and parameters of puberty: analysis of three representative cohorts from central Europe.

It is controversial whether obesity in children is associated with earlier onset of puberty and advanced appearance of distinct parameters of pubertal development. To investigate the impact of obesity on markers of the onset and parameters representing stages of puberty, we analyzed auxological parameters and secondary sex characteristics in three representative cohorts of Caucasian children. Body weight, height, peak height velocity and pubertal stages were evaluated in two recent German cohorts (CrescNet and Leipzig Schoolchildren), and a historical Swiss cohort. According to body mass index (BMI), children were classified into three weight groups of lean, overweight, or normal weight with limits defined below -1.28 and above +1.28 BMI SDS. Peak height velocity (PHV) occurred significantly later in lean compared to normal weight children in the CrescNet and Swiss cohort, while there was no difference between obese and normal weight children. There was a trend towards acceleration of parameters of puberty onset and progression in obese children in all three cohorts. Height SDS was significantly higher in obese children compared to normal weight peers, but after completion of pubertal development it was similar in adolescents. The impact of overweight on the acceleration of puberty seems to be slightly stronger in boys. Once girls have reached a critical weight for entering the process of maturation, further increase in body weight does not seem to advance the onset of puberty.

Secular trends in body mass index in German children and adolescents: a cross-sectional data analysis via CrescNet between 1999 and 2006.

To assess secular trends in alterations in body mass index (BMI) in German children and adolescents between 1999 and 2006, we performed an analysis using data from a computerized database (CrescNet) and focusing on the data ranges above the 97th percentile (P97) and below the median (P50). This cross-sectional assessment of BMI data used a total of 143 495 single values (73 290 males and 70 205 females aged 0.5-17.5 years) from screening and/or consulting visits at 1 of the 294 participating German pediatricians. Body mass index data were calculated from standardized measurements of body weight and height entered into the CrescNet database. Individual percentiles were estimated according to German reference data sets. Across all age groups, the respective mean value of children with BMI above P97 increased from 5.32% to 7.02% in boys and from 5.70% to 7.18% in girls between 1999 and 2006, whereas those below P50 decreased from 48.52% to 43.71% in boys and from 47.48% to 42.57% in girls. The proportions of obese children (above the 97th percentile) were significantly higher than estimated by German reference values throughout the study period. The significant increase in childhood obesity between 1999 and 2006 was more pronounced in boys compared to girls. In conclusion, the cross-sectional study performed at a large cohort of German children and adolescents reveals an alarming increase in the number of obese children and adolescents and an accompanied shift toward higher BMI values. As the number of children below the 50th centile decreases accordingly, the shift in the distribution panel of the German reference percentile curves affecting the whole population can be observed.

Patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency can achieve their target height: the Leipzig experience.

BACKGROUND: Despite treatment, the mean final height (FH) of patients with classic congenital adrenal hyperplasia (CAH) is below the mean height of a normal population. AIMS: To show that CAH patients can achieve their target height (TH), 39 adult subjects, whose therapy had started in infancy, were studied in a retrospective analysis. All height SDS were corrected so that they related to TH SDS. PATIENTS: Group 1: patients born before 1975 (n = 13) had received prednisolone, at doses equivalent to hydrocortisone 39.4 +/- 15.6 mg/m2 BSA daily, together with DOCA in the first 2 years of life. Group 2: patients born from 1975 to 1986 (n = 26) received at this age lower hydrocortisone doses (16.4 +/- 6.9 mg/m2 BSA daily, divided 8 hourly; p < 0.001) combined with fludrocortisone, had outpatient visits every 3 months and bone age (BA) estimation every 6 months. RESULTS: Patients of group 1 (FH SDS -1.2 +/- 1.0) had a poor outcome, whereas patients of group 2 (FH SDS 0.1 +/- 0.9; p = 0.01) achieved their TH. CONCLUSION: Combined corticoid administration adjusted quarterly to keep height, BMI, blood pressure and BA within normal limits resulted in FH close to TH in patients with classic CAH.

Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration.

OBJECTIVE: Pharmacokinetic and pharmacodynamic data after recombinant human GH (rhGH) administration in adults are scarce, but necessary to optimize replacement therapy and to detect doping. We examined pharmacokinetics, pharmacodynamics, and 20 kDa GH after injection of rhGH at different doses and routes of administration. DESIGN: Open-label crossover study with single boluses of rhGH. METHODS: Healthy trained subjects (10 males, 10 females) received bolus injections of rhGH on three occasions: 0.033 mg/kg s.c., 0.083 mg/kg s.c., and 0.033 mg/kg i.m. Concentrations of 22 and 20 kDa GH, IGF-I, and IGF-binding proteins (IGFBP)-3 were measured repeatedly before and up to 36 h after injection. RESULTS: Serum GH maximal concentration (Cmax) and area under the time-concentration curve (AUC) were higher after i.m. than s.c. administration of 0.033 mg/kg (Cmax 35.5 and 12.0 microg/l; AUC 196.2 and 123.8). Cmax and AUC were higher in males than in females (P < 0.01) and pharmacodynamic changes were more pronounced. IGFBP-3 concentrations showed no dose dependency. In response to rhGH administration, 20 kDa GH decreased in females and remained suppressed for 14-18 h (low dose) and 30 h (high dose). In males, 20 kDa GH was undetectable at baseline and throughout the study. CONCLUSIONS: After rhGH administration, pharmacokinetic parameters are mainly influenced by route of administration, whereas pharmacodynamic variables and 20 kDa GH concentrations are determined mainly by gender. These differences need to be considered for therapeutic use and for detection of rhGH doping.

HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism.

CONTEXT: Mutations in the transcription factor HESX1 have previously been described in association with septooptic dysplasia (SOD) as well as isolated defects of the hypothalamic-pituitary axis. OBJECTIVE: Given that previous screening was carried out by SSCP detection alone and limited to coding regions, we performed an in-depth genetic analysis of HESX1 to establish the true contribution of HESX1 genetic defects to the etiology of hypopituitarism. DESIGN: Nonfamilial patients (724) with either SOD (n = 314) or isolated pituitary dysfunction, optic nerve hypoplasia, or midline neurological abnormalities (n = 410) originally screened by SSCP were rescreened by heteroduplex detection for mutations in the coding and regulatory regions of HESX1. In addition, direct sequencing of HESX1 was performed in 126 patients with familial hypopituitarism from 66 unrelated families and in 11 patients born to consanguineous parents. PATIENTS: All patients studied had at least one of the three classical features associated with SOD (optic nerve hypoplasia, hypopituitarism, midline forebrain defects). RESULTS: Novel sequence changes identified included a functionally significant heterozygous mutation at a highly conserved residue (E149K) in a patient with isolated GH deficiency and digital abnormalities. The overall incidence of coding region mutations within the cohort was less than 1%. CONCLUSIONS: Mutations within HESX1 are a rare cause of SOD and hypopituitarism. However, the large number of familial patients with SOD in whom no mutations were identified is suggestive of an etiological role for other genetic factors. Furthermore, we have found that within our cohort SOD is associated with a reduced maternal age compared with isolated defects of the hypothalamopituitary axis.

Blood pressure in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: In patients with congenital adrenal hyperplasia (CAH) recording of blood pressure (BP) must be included in monitoring treatment to detect hypertension. AIM: To investigate the BP patterns in patients with CAH. METHODS: Twenty-three children and adolescents (age 6-17 years) and 11 adult patients (age 18-26 years) were studied (21 females, 13 males; 28 salt-wasting patients). In the whole group BP in the outpatient clinic was compared with BP under hospitalisation and in 11 of the children and adolescents also with 24-hour ambulatory blood pressure monitoring (ABPM). RESULTS: BP in the ward in children and adolescents but not in adults was significantly higher than BP in the outpatient clinic, where BP was in the upper normal range. There was also a significant difference between BP in the outpatient clinic and the lower ABPM in the 11 patients tested. Atrial natriuretic peptide (ANP) in blood serum showed normal values. CONCLUSIONS: BP measured in outpatients in a relaxed and calm atmosphere meets the requirements for monitoring of treatment. Measurement of BP on the ward leads to falsely high results. ABPM is not necessary. Estimation of ANP provides no additional information.

Comparison of adrenal function tests in children--the glucagon stimulation test allows the simultaneous assessment of adrenal function and growth hormone response in children.

The accurate assessment of adrenal function is necessary in many children with suspicion of pituitary insufficiency. The objective of this study was to evaluate the adrenal response during the glucagon stimulation test (GST) and its diagnostic utility in children. A total of 290 children, aged 10.1 +/- 5.0 years, were evaluated for adrenal function using the corticotrophin releasing hormone (CRH) test, the GST, and/or the insulin tolerance test (ITT). Glucagon stimulation provoked a substantial rise in cortisol and adrenocorticotropin (ACTH) that was independent of gender, age, or underlying growth hormone deficiency. There were no differences in peak cortisol levels in the GST compared to the CRH test in pair-wise intra-individual analyses in children with both tests performed within one year (615.4 +/- 30.5 vs 602.8 +/- 22.4 nmol/l, n=52). Similarly, there were no differences in the cortisol response between the ITT and CRH test. Peak cortisol levels in the CRH test correlated with the GST and the ITT. The magnitude of ACTH response, in contrast, was highest in the ITT with a 9.8-fold increase over baseline, while the increase in the GST (3.1-fold) and CRH test (1.6-fold) were more subtle. Since there is controversy concerning reliable cut-off values for adrenal function tests in children, we analyzed cut off levels in 186 children, including 26 children with adrenal insufficiency, using the CRH test. A peak cortisol level of 450 nmol/l provided the best balance of sensitivity (88.5%) and specificity (86.8%), while higher cut-off levels did not increase sensitivity but lost in specificity. In summary, the GST constitutes an1 equally sensitive test for the assessment of adrenal function in children that is not confounded by anthropometric parameters and is generally not accompanied by major side effects. It allows the simultaneous assessment of corticotroph and somatotroph function and may thus constitute a valuable alternative to the ITT.

PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis.

Mutations in the PROP1 gene are the most frequent genetic defects in patients with combined pituitary hormone insufficiency. However, controversy exists about the timing and extent of pituitary insufficiency, and it remains unclear whether adrenal failure is a typical feature of this condition. We performed a retrospective longitudinal analysis of nine patients with PROP1 mutations who were under medical supervision at our clinic for 15.7 +/- 3.4 yr. All patients initially presented with growth failure (height sd score, -3.7 +/- 0.3) at a mean age of 4.9 +/- 0.8 yr. They were first diagnosed with GH and TSH deficiency, and replacement therapy was instituted at 6.1 +/- 1.1 and 6.8 +/- 1.2 yr, respectively. All seven patients who reached pubertal age required sex hormone substitution at 15.0 +/- 0.7 yr. Repeated functional testing of the anterior pituitary axes revealed a progressive decline with age in peak levels of GH, TSH, prolactin, and LH/FSH. All patients developed at least partial adrenal insufficiency, with a gradual decline of the function of the pituitary adrenal axis and eventually required substitution with hydrocortisone at a mean age of 18.4 +/- 3.5 yr. It is concluded that anterior pituitary function in patients with PROP1 mutations deteriorates progressively and includes adrenal insufficiency as a feature of this condition, which has important clinical relevance in childhood and adolescence.

Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels.

Adiponectin is an adipocytokine with profound antidiabetic and antiatherogenic effects that is decreased in obesity. With the increasing prevalence of obesity and the emergence of related disorders, including type 2 diabetes in children, the regulation of adiponectin and its relationship to childhood obesity is of great interest. In this study we aimed to elucidate the impact of gender, pubertal development, and obesity on adiponectin levels in children. We investigated two phenotypically characterized cohorts of 200 normal weight and 135 obese children and adolescents covering a wide range of age (3.4-17.9 yr) and body mass index (-2.1 to +4.8 sd score). In healthy lean boys, adiponectin levels significantly declined in parallel with physical and pubertal development, subsequently leading to significantly reduced adiponectin levels in adolescent boys compared with girls (5.6 +/- 0.5 vs. 7.1 +/- 0.5 mg/liter; P = 0.03). This decline was inversely related to testosterone (r = -0.42; P < 0.0001) and dehydroepiandrosterone sulfate (r = -0.20; P = 0.0068) serum concentrations and may account for the gender differences seen in adults. Using a stepwise forward multiple regression model, pubertal stage was the strongest independent predictor of adiponectin (r(2) = 0.206; P < 0.0001), with additional influences of body mass index sd score and testosterone. Adiponectin levels were decreased in obese children and adolescents compared with lean peers of corresponding age and pubertal stage (5.18 vs. 7.13 mg/liter; P = 0.015). In obese children, adiponectin levels were closely associated with parameters related to the metabolic syndrome, such as insulin resistance, hyperinsulinemia, blood pressure, and uric acid, in univariate and multivariate analyses, with the insulin sensitivity index being the strongest independent parameter identified by stepwise forward multiple regression (r(2) = 0.226; P < 0.0001). Hence, there is a strong association of adiponectin serum concentrations with obesity, pubertal development, and metabolic parameters in children indicating epidemiological and pathophysiological relevance already in childhood.

Pregnancies in patients with congenital adrenal hyperplasia with complete or almost complete impairment of 21-hydroxylase activity.

OBJECTIVE: To show that, with appropriate therapy, women with classic congenital adrenal hyperplasia (CAH) can become pregnant. DESIGN: Observational clinical study. SETTING: University hospital. PATIENT(S): Adult young women with CAH: three with the salt-wasting form and four patients with simple virilizing CAH due to severe homozygous or compound heterozygous mutations of the CYP21B gene (deletions, I172N in exon 4 and nt656A/C-->G in intron 2) who wished to become pregnant. INTERVENTION(S): After confirmation in the first patient of the beneficial effect of additional treatment with fludrocortisone in lowering 17alpha-hydroxyprogesterone (17-OHP) levels, five other patients were treated with hydrocortisone as three daily doses at 8-hour intervals and fludrocortisone 0.1-0.2 mg daily divided into two to three doses. One patient received glucocorticoid alone. MAIN OUTCOME MEASURE(S): Treatment was controlled on the basis of morning salivary 17-OHP estimates and plasma renin concentrations. RESULT(S): Nine pregnancies occurred in six women. The course of the pregnancies (except one spontaneous abortion) was normal without any other modification of therapy. Only the women treated with hydrocortisone alone did not become pregnant. CONCLUSION(S): When treated with a combination of glucocorticoids and mineralocorticoids, sexually active patients with the classic phenotype of CAH can become pregnant.

IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation.

BACKGROUND: Approximately 10 percent of infants with intrauterine growth retardation remain small, and the causes of their growth deficits are often unclear. We postulated that mutations in the gene for the insulin-like growth factor I receptor (IGF-IR) might underlie some cases of prenatal and postnatal growth failure. METHODS: We screened two groups of children for abnormalities in the IGF-IR gene. In one group of 42 patients with unexplained intrauterine growth retardation and subsequent short stature, we used single-strand conformation polymorphism analysis, followed by direct DNA sequencing of any abnormalities found. A second cohort consisted of 50 children with short stature who had elevated circulating IGF-I concentrations. Complete sequencing of the IGF-IR gene was performed with DNA from nine children. We also studied a control group of 43 children with normal birth weights. RESULTS: In the first cohort, we identified one girl who was a compound heterozygote for point mutations in exon 2 of the IGF-IR gene that altered the amino acid sequence to Arg108Gln in one allele and Lys115Asn in the other. Fibroblasts cultured from the patient had decreased IGF-I-receptor function, as compared with that in control fibroblasts. No such mutations were found in the 43 controls. In the second group, we identified one boy with a nonsense mutation (Arg59stop) that reduced the number of IGF-I receptors on fibroblasts. Both children had intrauterine growth retardation and poor postnatal growth. CONCLUSIONS: Mutations in the IGF-IR gene that lead to abnormalities in the function or number of IGF-I receptors may also retard intrauterine and subsequent growth in humans.

Effect of growth hormone (GH) treatment on bone in postpubertal GH-deficient patients: a 2-year randomized, controlled, dose-ranging study.

GH treatment in children with GH deficiency is frequently terminated at final height. However, in healthy individuals bone mass continues to accrue until peak bone mass is achieved. Because no prospective data specifically prove the role of GH in attainment of peak bone mass, we performed a multinational, controlled, 2-yr study in patients who had terminated pediatric GH at final height. Patients were randomized to: GH at 25.0 microg/kg x day (pediatric dose, n = 58) or 12.5 microg/kg x day (adult dose, n = 59), or no GH treatment (control, n = 32). Bone mineral content (BMC) and density were measured by dual-energy x-ray absorptiometry and evaluated centrally. Laboratory measurements were also performed centrally. After 2 yr, significant increases were seen with both GH treatments, compared with control in bone-specific alkaline phosphatase (P = 0.004) and type I collagen C-terminal telopeptide:creatinine ratio (P < 0.001), but there were no significant dose effects. Total BMC increased by 9.5 +/- 8.4% in the adult dose group, 8.1 +/- 7.6% in the pediatric dose group, and 5.6 +/- 8.4% in controls (analysis of covariance, P = 0.008), with no significant GH dose effect. BMC increased predominantly at the lumbar spine (11.0 +/- 10.6%, P = 0.015) rather than at the femoral neck or hip. In contrast, a significant dose-dependent increase was seen in IGF-I concentrations (adult dose: 114.5 +/- 119.4 microg/liter; pediatric dose: 178.5 +/- 143.7 microg/liter; P = 0.023). There were no gender-related differences in BMC changes with either dose, whereas the IGF-I increase was significantly higher with the pediatric than with the adult dose in females (P < 0.001) but not males (P = 0.606). In summary, reinstitution of GH replacement after final height in severely GH-deficient patients induced significant progression toward peak bone mass. Although there was a by-gender dose effect on IGF-I concentration, the treatment effect on bone was obtained in both males and females with the adult GH dose regimen.