[Effect of Psychosocial Factors on Growth]. / Einfluss von psychosozialen Belastungsfaktoren auf das Längenwachstum.

BACKGROUND: Genes, hormones and factors such as nutrition and psychosocial environment affect growth. OBJECTIVE: What is the significance of various psychosocial factors on growth? METHODS: Evaluation of results of a working meeting of paediatric endocrinologist with current literature research. RESULTS: Psychosocial deprivation in children can be associated with growth hormone deficiency (GHD) and short stature. GHD can be reversed by a change of environment and psychosocial support. War and migration are often associated with underweight, growth disturbances and poor health care. These factors can improve after the end of conflicts, but children often remain too short. Consumption of alcohol or opiates during pregnancy are associated with lower birth weight and increased risk of early and small for gestational age (SGA) childbirth. Children with attention deficit hyperactivity disorder show a slight slowdown in growth after they started stimulant therapy. However, they reach normal adult height. CONCLUSIONS: In children with idiopathic short stature, psychosocial causes should be taken into account in the differential diagnosis. Notably there is an increased risk of growth disturbances in children from conflict regions or after prenatal drug exposure.

Psychometric properties of the quality of life in short statured youth (QoLISSY) questionnaire within the course of growth hormone treatment.

BACKGROUND: The Quality of Life of Short Stature Youth (QoLISSY) questionnaire is a patient- and parent-reported outcome measure assessing health-related quality of life (HRQOL) in short stature youth. This study evaluates the psychometric properties of the QoLISSY questionnaire within a German prospective trial of short statured children treated with human growth hormone (hGH). METHOD: The instrument was administered to children with idiopathic growth hormone Deficiency (IGHD) and small for gestational age (SGA) before and after 12 month of hGH treatment. Children with idiopathic short stature (ISS) served as a reference group receiving no treatment. Psychometric testing included scale distribution characteristics, reliability (internal consistency), criterion-and convergent validity (correlations with the generic KIDSCREEN-Index, inter-correlations among QOLISSY subscales), known-group validity (treatment status, height SDS), and responsiveness analysis (ability to detect change). RESULTS: One hundred fifty-two parents and 66 children/adolescents completed both HRQOL assessments. The QoLISSY demonstrated good reliability with Cronbach's alpha > .70. Moderate significant correlations between QoLISSY domains and the KIDSCREEN-10 Index supported criterion validity. Statistically significant differences in HRQOL were observed between treatment groups at baseline with children who were about to start treatment reporting a significantly lower HRQOL compared to the children who will not receive treatment. No significant differences were found between the level of short stature based on height SDS scores (≤ - 2 SDS, > - 2 SDS). Furthermore, the instrument detected significant changes in HRQOL between the treated and the untreated group in patient-reports. CONCLUSIONS: In conclusion, the scales showed satisfactory reliability, adequate validity and ability to detect change in self-reported HRQOL within GH treatment. Findings support QoLISSY's further use in clinical trials, offering the opportunity to adequately assess HRQOL from the patients' and caregivers' perspective to improve patient-centered care.

Adrenarche and pubarche in girls with turner syndrome during growth-promoting therapy with human growth hormone.

BACKGROUND: Data on adrenarche and pubarche in girls with Turner syndrome (TS) are inconsistent in the literature. METHODS: The cohort consisted of 94 girls and young women with TS born between 1971 and 2001 (age range: 3.1-23.2 yrs.), who were treated with human growth hormone and regularly presented at our outpatient clinic every 4 to 6 months.The longitudinal data of all patients were ascertained retrospectively from patient charts. The data collection ended in January 2016. Adrenarche was assessed by serum DHEAS levels and pubertal status by Tanner stages. Pubarche was defined as the appearance of pubic hair (PH2), whereas spontaneous puberty was defined as Tanner stage B2. The patients were retrospectively subdivided in two groups with regard to pubertal development: group 1 (n = 21) with spontaneous puberty and group 2 (n = 70) with induced puberty. Since blood samples were not taken at every visit, we generated seven groups according to the age of the children at which the blood samples were taken: 3-5, 5-7, 7-9, 9-11, 11-13, 13-15, and 15-17 yrs. Serum DHEAS and follicle-stimulating hormone (FSH) levels were measured by chemiluminescence immunoassay and compared with those of a control group of healthy girls. RESULTS: Adrenarche started in TS girls between 5 and 7 years. TS girls had higher DHEAS levels than the control group, with statistically significant differences in the age groups 7 to 17 years. No differences were determined between the TS girls with spontaneous puberty and those with POI. TS girls in group 2 reached the Tanner stages PH2 (p < 0.04), PH3 (p < 0.01), PH4 and PH5 (p < 0.001) markedly later than TS girls in group 1. CONCLUSIONS: The onset of adrenarche in girls with TS undergoing GH therapy does not differ from that in healthy girls. However, adrenarche is more pronounced in girls with TS. There is no difference in DHEAS levels between the TS girls with spontaneous puberty and the TS girls with primary ovarian insufficiency (POI), while the tempo of pubarche is markedly slower in the girls with POI.

Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature.

PurposeShort stature is a common condition of great concern to patients and their families. Mostly genetic in origin, the underlying cause often remains elusive due to clinical and genetic heterogeneity.MethodsWe systematically phenotyped 565 patients where common nongenetic causes of short stature were excluded, selected 200 representative patients for whole-exome sequencing, and analyzed the identified variants for pathogenicity and the affected genes regarding their functional relevance for growth.ResultsBy standard targeted diagnostic and phenotype assessment, we identified a known disease cause in only 13.6% of the 565 patients. Whole-exome sequencing in 200 patients identified additional mutations in known short-stature genes in 16.5% of these patients who manifested only part of the symptomatology. In 15.5% of the 200 patients our findings were of significant clinical relevance. Heterozygous carriers of recessive skeletal dysplasia alleles represented 3.5% of the cases.ConclusionA combined approach of systematic phenotyping, targeted genetic testing, and whole-exome sequencing allows the identification of the underlying cause of short stature in at least 33% of cases, enabling physicians to improve diagnosis, treatment, and genetic counseling. Exome sequencing significantly increases the diagnostic yield and consequently care in patients with short stature.

Mortality in children with classic congenital adrenal hyperplasia and 21-hydroxylase deficiency (CAH) in Germany.

BACKGROUND: Adrenal crises in children with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) are life-threatening and have the potential to death. METHODS: A survey was performed among Paediatric Endocrinologists in Germany to report on deceased children with CAH. Our survey covered the whole of Germany. RESULTS: The participating centres reported 14 cases of death (9 female, 5 male) from 1973 until 2004, but no deaths thereafter. 11 children had the SW form and 3 the simple virilizing (SV) form. All patients were on glucocorticoid replacement, and the SW forms additionally on mineralocorticoid replacement. The age at death varied between 6 weeks and 16.5 years. Seven children died before introduction of general neonatal screening, and 7 children thereafter. Before death, the clinical signs of impending crisis were nonspecific. Five patients developed hypoglycaemia and convulsions with cerebral oedema. Half of the deceased patients died at home. The hydrocortisone dosage was only doubled in two of the 14 cases. CONCLUSIONS: According to the assessments by the attending centres, almost all deaths could be related to an inadequate administration of stress doses of hydrocortisone. Since no deceased CAH children were reported in Germany from 2005 on, we assume the effectiveness of educational programs over the past years.

Miscarriages in families with an offspring that have classic congenital adrenal hyperplasia and 21-hydroxylase deficiency.

BACKGROUND: The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (CAH). Both men and women with classic CAH have lower fertility rates than the general population, and an increased rate of miscarriages has been reported in affected women. There are no data on the incidence rate of miscarriages in families with an offspring that have classic CAH. METHODS: We studied families with a history of classic CAH. The families came from different parts of Germany and attended the annual meeting of the German CAH support group for parents and patients which was held in Hamburg in September 2014. The data was collected anonymously by a paper-based questionnaire which was completed by the families at home. The families also accepted the responsibility to address this question to their siblings. In all, the data of 50 families with at least one child with classic CAH, and the data of 164 parental siblings were available for evaluation. Miscarriage rates were calculated in relation to the reported pregnancies. RESULTS: Twenty-two miscarriages were reported from 19 families. At least one miscarriage occurred in 38% of the families, three families experienced two miscarriages and 16 families had one miscarriage each. The mean miscarriage rate was 15.8%. The heterozygous mothers had a total of 90 siblings (41 m, 49 f), while 74 siblings (33 m, 41 f) were reported from the heterozygous fathers. The miscarriage rate was 10.1% in the families of the mothers` siblings, and 11.4% in the families of the fathers` siblings. The genotype was known in all parents that have an offspring with classic CAH, but not defined in 82% of the maternal siblings, and in 86% of the paternal siblings. No child with classic CAH has been diagnosed in any of the sibling's families to date. CONCLUSION: Our data show that the miscarriage rate in German families with a child with classic CAH is not elevated.

Intrauterine Growth Restriction (IUGR) Induces Signs of Subclinical Atherosclerosis in 6-Year-Old Infants Despite Absence Of Excessive Growth.

Background Postnatal catch-up growth and rapid weight gain after intrauterine growth restriction (IUGR) seem to increase the risk for later disease. This study aimed to compare features of the metabolic syndrome early in life between IUGR and appropriate for gestational age (AGA) infants. Patients Data for 9 infants with IUGR defined by a birth weight<10th percentile and ultrasound-proven placental insufficiency and 11 AGA children were available. Method Postnatal growth, auxological, cardiovascular, and metabolic parameters up to a chronological age of 6 years were assessed: Fasting serum concentrations of LDL-cholesterol, insulin, leptin, IGF-I, DHEAS, skinfold thicknesses, blood pressure, and mean carotid intima-media thickness (cIMT). Results All IUGR infants showed catch-up growth, although mean BMI SDS and total subcutaneous fat mass at the age of 6 years were still slightly lower compared to the AGA cohort. Reduced serum leptin concentrations were observed in IUGR infants (p=0.02), whereas no significant difference was found for IGF-I, insulin, LDL-cholesterol and DHEAS concentrations. Mean cIMT was significantly higher in IUGR infants (p<0.05). Mean arterial pressure did no differ. Discussion and Conclusion In 6-year-old IUGR infants with catch-up growth, who still had a slightly reduced BMI SDS compared to the AGA group, signs of subclinical atherosclerosis were detectable suggesting that cardiovascular risk in IUGR may be present even in the absence of excessive growth.

MAP4-dependent regulation of microtubule formation affects centrosome, cilia, and Golgi architecture as a central mechanism in growth regulation.

Numerous genes are involved in human growth regulation. Recently, autosomal-recessive inherited variants in centrosomal proteins have been identified in Seckel syndrome, primary microcephaly, or microcephalic osteodysplastic primary dwarfism. Common hallmarks of these syndromic forms are severe short stature and microcephaly. In a consanguineous family with two affected children with severe growth retardation and normocephaly, we used homozygosity mapping and next-generation sequencing to identify a homozygous MAP4 variant. MAP4 is a major protein for microtubule assembly during mitosis. High-expression levels in the somite boundaries of zebrafish suggested a role in growth and body segment patterning. The identified variant affects binding sites of kinases necessary for dynamic instability of microtubule formation. We found centrosome amplifications in mitotic fibroblast cells in vivo and in vitro. These numeric centrosomal aberrations were also present during interphase resulting in aberrant ciliogenesis. Furthermore, affected cells showed a dysfunction of the microtubule-dependent assembly of the Golgi apparatus, indicated by a significant lack of compactness of Golgi membranes. These observations demonstrated that MAP4 mutations contribute to the clinical spectrum of centrosomal defects and confirmed the complex role of a centrosomal protein in centrosomal, ciliary, and Golgi regulation associated with severe short stature.

Differential effects of low birthweight and intrauterine growth restriction on umbilical cord blood insulin-like growth factor concentrations.

OBJECTIVE: Alterations in the growth hormone-insulin-like growth factor (IGF) axis have been considered as a causal factor for intrauterine growth restriction (IUGR) and for the increased risk of metabolic disease in later life. We compared members of the IGF axis in umbilical cord blood between IUGR neonates, small for gestational age without foetal restriction (SGA) and appropriate for gestational age (AGA) neonates. DESIGN: Prospective controlled multicenter study. PATIENTS: Sixteen ultrasound-proven IUGR, 8 SGA and 40 AGA neonates. MEASUREMENTS: Concentrations of total IGF-I and total IGF-II by immunoassays, bioactive IGF by cell-based bioassay and IGFBP-I in mixed venous and arterial umbilical cord blood samples at birth. Auxological parameters at birth. RESULTS: IGF-I concentrations in IUGR [17·7 µg/l (CI 13·8;21·6)] were clearly below those in AGA [48·3 µg/l (CI 43·7;52·9)] and SGA neonates [36·0 µg/l (CI 26·6;45·4)]. IGF-II levels were significantly reduced in IUGR [201·4 µg/l (CI 190·2;212·6)] compared to AGA neonates [231·2 µg/l (CI 220·6;241·9)]. A trend for lower IGF-II concentrations was observed in IUGR when compared to SGA neonates [232·0 µg/l (CI 207·2;256·8)]. These differences could not be explained by confounding. For IGFBP-1, a trend towards higher values in IUGR was observed. CONCLUSIONS: Low IGF-I cord blood concentrations in hypotrophic neonates after IUGR might not only result from low birthweight per se, but also reflect prenatal placental environment. Alterations of the IGF axis could be in the causal pathway of IUGR and thus constitute a potential surrogate marker for IUGR in the assessment of foetal programming.

Spontaneous postnatal growth is reduced in children with CHARGE syndrome.

AIM: There is a scarcity of data on postnatal growth in children with CHARGE syndrome, a genetic disorder. This study analysed spontaneous growth and weight in German children with CHARGE from birth to the age of 6 years. METHODS: This was a retrospective analysis of 19 children, nine females and 10 males, using data from child health records. Standard deviation scores (SDS) were calculated based on Swiss references. RESULTS: The median birthweight was 2950 g (-0.78 SDS), and the birth length was 49 cm (-0.5 SDS). There was a significant loss of median body length, at around 4 weeks of age from -0.5 to -2.3 SDS (p < 0.05). At 1 year, the median length was -2.6 SDS and it remained low until 5 years of age when the lowest value was found to be -2.8 SDS. There was a significant increase in median body mass index (BMI) from -1.15 SDS at 1 year to -0.15 SDS at 5 years (p < 0.01). CONCLUSION: Children with CHARGE syndrome displayed almost normal length and weight data at birth, with just one of the 19 infants having below average length for gestational age. However, postnatal growth was retarded during infancy and childhood, and the increase in BMI-SDS did not correlate with growth.

Graves' disease in children with Down syndrome.

While subclinical or overt hypothyroidism are common in Down syndrome (DS); Graves' disease (GD) is rare (ranges 0.6-3%). We aimed to evaluate the clinical features, course, and treatment of GD in children with DS and compare them with those without DS. Among 161 children with GD, 13 (8 female, 5 male) had DS (8%). Data were collected retrospectively from patients' medical records. The mean age at diagnosis was 10.6 ± 4.5 years, with a female-to-male ratio 1.6:1. The main symptoms were weight loss (n = 6), increased irritability (n = 3), and increased sweating (n = 3). None had orbitopathy. Seven of 11 patients with a thyroid ultrasound at diagnosis had a goitre. On admission, all had thyroid-stimulating hormone (TSH) <0.01 mU/L (normal range (NR): 0.51-4.30), free triiodothyronine, free thyroxine (mean ± s.d .), and thyrotrophin receptor antibodies (median, range) were 22.2 ± 10.2 pmol/L (NR: 3.5-8.1), 50.2 ± 18.7 pmol/L (NR 12.6-20.9), and 17.0 (2.89-159.0) U/L (NR <1), respectively. Patients were treated either with methimazole (n = 10) or carbimazole (n = 3), a dose of 0.54 ± 0.36 mg/kg/day. The treatment was 'block and replace' in ten patients and 'dose titration' in three patients, with a mean duration of 43.4 ± 11.0 months. Of 13 patients, four are still receiving primary treatment, three are in remission, one patient had two medically treated recurrences, three underwent surgery without complications, and two patients were lost to follow-up. Our data show that the clinical course of GD in patients with DS was similar to those without DS and suggest that a prolonged medical therapy should be the preferred option.

Growth hormone treatment in children with short stature: impact of the diagnosis on parents.

OBJECTIVES: This prospective multicenter study aimed (1) to examine changes in parent-reported health-related quality of life (HRQOL) of children with short stature and the effects of the children's condition on parents themselves within the first year of human growth hormone (hGH) treatment and (2) to predict effects on parents based on main and interaction effects of children's HRQOL and increase in height. METHODS: A total of 110 parents of children aged 4-18 years, diagnosed with idiopathic growth hormone deficiency, small for gestational age, or idiopathic short stature, were recruited from 11 participating German pediatric endocrinologists and asked to fill out the short stature-specific Quality of Life in Short Stature Youth (QoLISSY) Questionnaire before hGH treatment was initiated and one year later. RESULTS: Negative effects of the children's short stature on the parents decrease over time, independent of diagnosis and treatment status. Furthermore, treatment status and height increase moderated the links between children's improved HRQOL as perceived by their parents and decreased caregiving burden. CONCLUSIONS: Based on the children's improved HRQOL and the parent's decrease in caregiving burden, patient-reported outcomes that consider parental and child's perspectives should be considered when deciding on hGH treatment for children.

Neutropenia Occurs More Often Under Carbimazole than Under Methimazole Treatment in Pediatric Graves' Disease Patients.

Background: Agranulocytosis is a rare antithyroid drug treatment (ATD) side effect seen in children suffering from Graves' disease (GD). Neutropenia is a recognized adverse event associated with ATD but has also been reported as pre-treatment neutropenia in GD. Methods: We performed a retrospective cohort study to analyze the longitudinal clinical and biochemical data of 161 pediatric patients with GD who received either methimazole (MMI) or carbimazole (CBZ) as ATD. The inclusion criteria were elevated free thyroxine (fT4 >25 pmol/L), suppressed thyrotropin (TSH <0.05 mlU/mL), and elevated thyrotropin receptor antibodies (TSHRAbs >2.5 IU/L). Absolute neutrophil count (ANC) was used to define neutropenia (ANC <1800/µL) and agranulocytosis (ANC <500/µL). Results: Nine of the 161 patients had neutropenia at diagnosis (ANC: 1348/µL ± 250) without further deterioration under ATD. In this subgroup, we found higher levels of free triiodothyronine (fT3: 31.45 pmol/L ± 3.99) at diagnosis in comparison with those who developed neutropenia (26.29 pmol/L ± 12.96; p = 0.07) and those without neutropenia before and during therapy (23.12 pmol/L ± 13.7; p = 0.003). Thirty-eight patients (23.6%) became neutropenic (ANC: 1479/µL ± 262) while receiving ATD. Neutropenia occurred after a mean of 551.8 (range: 10-1376) days, mostly without further deterioration. Two of these 38 patients developed agranulocytosis and underwent emergency thyroidectomy. The patients with neutropenia were significantly younger (p = 0.031). Neutropenia occurred significantly more often in patients receiving CBZ (50%; n = 20/40) than in those receiving MMI (16.5%; n = 18/110; p = 0.001). The minimum ANC was significantly lower in the CBZ (1971/µL ± 1008) than in the MMI group (2546 ± 959); p = 0.004. Conclusions: Neutropenia occurred significantly more often under CBZ than MMI. As this is potentially due to higher immunogenicity, we suggest that children with GD should be treated with MMI. Frequent measurements of ANC may be needed to detect severe agranulocytosis, although low pre-treatment ANC may not necessarily be a contraindication to ATD treatment. Young age may be potentially associated with an increased risk of reduced ANC. Further investigation is necessary to fully understand risk factors for neutropenia in children with GD.

Impact of Newborn Screening on Adult Height in Patients With Congenital Adrenal Hyperplasia (CAH).

CONTEXT: Treatment of children with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is challenging. Linear growth and adult height are compromised according to recent publications. However, most of these data were obtained in the era before CAH newborn screening. DESIGN: Body height of patients with classical CAH diagnosed before and after the establishment of newborn screening were analyzed retrospectively. PATIENTS AND METHODS: We identified 600 patients with classical CAH (227 male) with data on near-adult height (NAH), target height (TH), and information on newborn screening from the electronic German CAH registry (German Society for Paediatric Endocrinology and Diabetology). Newborn screening was performed in 101 (16.8%) patients. All patients received hydrocortisone with or without fludrocortisone.To assess the effects of newborn screening, a linear regression model adjusted/stratified for sex and phenotype was used (SAS 9.4). RESULTS: TH corrected NAH (mean; 95% confidence interval) was closer to 0 in patients with CAH and newborn screening [-0.25 standard deviation score (SDS); -0.44 to -0.06] than in patients without newborn screening (-0.44 SDS; -0.52 to -0.36) (P = .069). Screening had no effect on NAH in female patients. In male patients, NAH was significantly better (P = .033) with screening than without screening. After stratifying for CAH phenotype, screening did not affect the NAH of patients with salt-wasting CAH. Patients with simple-virilizing CAH had a significantly better cNAH (P = .034) with screening (0.15 SDS; -0.28-0.59) than without screening (-0.35 SDS; -0.52 to -0.18). CONCLUSIONS: Our data suggest that newborn screening might be associated with improved NAH in male CAH patients and in patients with simple-virilizing CAH.

Caring for a Child with Congenital Adrenal Hyperplasia Diagnosed by Newborn Screening: Parental Health-Related Quality of Life, Coping Patterns, and Needs.

Diagnosing a child by newborn screening with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) causes multiple challenges for the affected parents and the whole family. We aimed to examine the health-related Quality of Life (HrQoL), coping, and needs of parents caring for a child with CAH to develop demand-responsive interventions for improving the psychosocial situation of affected families. In a retrospective cross-sectional design, we assessed HrQoL, coping patterns, and the needs of parents caring for a CAH-diagnosed child using specific questionnaires. Data of 59 families with at least one child diagnosed with CAH were analyzed. The results show that mothers and fathers in this study reached significantly higher HrQoL scores compared to reference cohorts. Decisive for the above-average parental HrQoL were effective coping behaviors and the parental needs being met. These findings verify the importance of helpful coping patterns and rapid fulfillment of parental needs for maintaining a good and stable HrQoL of parents with a child diagnosed with CAH. It is crucial to strengthen the parental HrQoL to build a reasonable basis for a healthy upbringing and improve the medical care of CAH-diagnosed children.

Is there sufficient evidence to consider the use of 11ß-hydroxysteroid dehydrogenase type 1 inhibition in children?

Manifestations of the metabolic syndrome [obesity, dyslipidaemia, hypertension, blood glucose derangements including prediabetes or type 2 diabetes mellitus (T2DM)] in juvenile populations are becoming increasingly prevalent throughout the world and are at the point of being a global public health concern. Derangements in cortisol regeneration seem to be involved in the pathophysiology. Treatment with selective 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) inhibitors could be a therapeutic strategy in paediatric patients with manifestations of the metabolic syndrome. Based on preclinical and clinical data regarding development of the 11ß-HSD1 enzyme, it appears that maturation occurs within the first year of life. Different changes in biomarkers for assessing the efficacy and safety of 11ß-HSD1 inhibitors are to be expected in paediatric patients compared to adults, reflecting differences in metabolism. The effect of 11ß-HSD1 treatment in children on bone differentiation and development as well as adrenocorticotropic hormone (ACTH), circulating and local cortisol tissue concentrations, androgens and respective stress response is not yet known. Based on current literature, the concept of inhibition of 11ß-HSD1 is considered a potentially effective mean to regulate local cortisol levels in the paediatric population, and 11ß-HSD1 inhibitors may provide a valuable target and treatment option for the metabolic syndrome in paediatric patients. However, the uncertainty over effects on the developing skeleton combined with mild increases in adrenal androgen levels raises potential concerns regarding growth as well as onset of puberty as to their future use in children. Future clinical studies are needed to thoroughly assess the risks and benefits of this new class of drugs in the paediatric population.

Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort.

CONTEXT: The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. OBJECTIVE: This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. METHODS: Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (≥ 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. RESULTS: The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. CONCLUSION: Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.

Different relationships between the first 2 years on growth hormone treatment and the d3-growth hormone receptor polymorphism in short small-for-gestational-age (SGA) children.

BACKGROUND: There has been controversy in recent years on whether the d3 polymorphism of the GH receptor is associated with a better growth response to GH in idiopathic short children born small for gestational age (SGA). METHODS: In this prospective study, we evaluated exon 3-GHR polymorphisms in 142 (62 f, 80 m) short prepubertal children born SGA (birth length and/or weight of ≤-2 SD for GA) and treated with rhGH (mean dose of 0·30 mg/kg/week) in 24 centres in Germany. A growth prediction for the first year of therapy was calculated for each child according to Ranke and co-workers. The index of responsiveness (IOR) was calculated by dividing the response (observed growth minus predicted growth) by the standard error of the prediction. All analyses were performed in one centre on samples collected and shipped on filter paper. The DNA fragment containing or missing exon 3 of the GHR was amplified by multiplex PCR. RESULTS: The fl-GHR isoform was most common with a frequency of 47·8%, followed by the d3/fl isoform with 38% and the d3-GHR isoform with 14·2%. There were no significant differences regarding gestational age, birth weight and birth length, mid parental height-SDS, chronological age at start of therapy, height-SDS, BMI-SDS, height velocity and GH dose between the different subgroups according to the genotype. After the first treatment year, height (H)-SDS (P < 0·05), height velocity (HV) (P < 0·01), HV-SDS (P < 0·001) and delta-H-SDS (P < 0·05) were significantly higher in patients with d3-GHR than in those with fl-GHR. The mean IOR was above 0 in children with at least one d3 allele, and highest, with 0·54, in those with the d3-GHR isoform. After the second year on GH, no differences between the different GHR-isoforms were found. CONCLUSIONS: According to our results, the exon 3-deleted GHR explains the better growth response to GH only for the first and not for the second year.

Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey.

OBJECTIVE: Autosomal dominant hypocalcaemia or hypoparathyroidism is caused by activating mutations of the calcium-sensing receptor (CaSR). Treatment with calcium and vitamin D often worsens hypercalciuria and nephrocalcinosis, and renal impairment can result. Our aim was to describe the phenotypic variance of this rare disorder in a large series and to evaluate the outcome after long-term treatment. DESIGN: Nationwide retrospective collaborative study. PATIENTS: We describe 25 patients (14 men and 11 women), 20 belonging to 11 families and five single cases. MEASUREMENTS: Activating CaSR mutations and clinical and biochemical findings were evaluated. RESULTS: Nine different missense mutations of the CaSR, including one novel variant (M734T), were found. Twelve patients (50%) were symptomatic, 9 (36%) had basal ganglia calcifications and 3 (12%) had nephrocalcinosis. Serum calcium was decreased (1·87 ± 0·13 mm), and PTH was decreased (n = 19) or inappropriately low (n = 4). The occurrence of hypocalcaemic symptoms at diagnosis was related to the degree of hypocalcaemia. The occurrence of features like calcification of basal ganglia or kidney calcification did not correlate with the severity of hypocalcaemia or the age at diagnosis. The most common treatment was calcitriol (median dosage 0·6 µg/day), and the mean duration of therapy was 7·1 years (max. 26 years). Hypercalcaemic episodes rarely occurred, and the rate of kidney calcifications was remarkably low (12%). CONCLUSION: This series increases the limited knowledge of mutations and phenotypes of this rare disorder. Mutation analysis of the CaSR gene facilitates patient and family management. Low dosages of calcitriol resulted in less frequent renal calcifications.

Intrauterine growth restriction (IUGR) is associated with increased leptin synthesis and binding capability in neonates.

OBJECTIVE: Animal studies suggest pathological foetal programming of hypothalamic circuits regulating food intake in the setting of leptin deficiency and intrauterine growth restriction (IUGR). We aimed to compare placental leptin synthesis and leptin-binding capability in venous cord blood between IUGR newborns and neonates born appropriate for gestational age (AGA). DESIGN: Prospective controlled multicentre study. PATIENTS: Twenty-one ultrasound-proven IUGR and 33 AGA neonates. MEASUREMENTS: The concentration of leptin and soluble leptin receptor (sOB-R) in venous cord blood at birth was determined. Moreover, placental gene and protein expression of leptin and placental mRNA expression of functional and total leptin receptor isoforms were measured. RESULTS: Whereas log-leptin concentration in venous cord blood did not differ between IUGR and AGA newborns, the concentration of log-sOB-R was elevated in IUGR neonates (p(confounder adjusted)=0·009). Placental leptin protein synthesis as well as leptin mRNA was significantly higher in IUGR than in AGA infants (log-transformed, relative gene expression, p(confounder adjusted)=0·004). Analysis of gene expression of functional and total leptin receptor isoforms did not show any difference between both groups. CONCLUSIONS: Leptin-binding capability in venous cord blood is increased in IUGR newborns. Thus, via foetal programming, reduced biologically active leptin levels might contribute to a perturbed regulation of appetite.