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Besides four well-documented genetic causes of GH insensitivity (GHI) (GHR, STAT5B, IGF1, IGFALS defects), several other congenital and acquired conditions are associated with GHI. With respect to its anabolic actions, GH induces transcription of IGF1, IGFBP3 and IGFALS through a complex regulatory cascade including GH binding to its receptor (GHR), activation of JAK2 and phosphorylation of STAT5b, which then trafficks to the nucleus. GH also activates the MAPK and PI3K pathways. The synthesis of GHR can be reduced by estrogen deficiency or corticosteroid excess, and is possibly decreased in African pygmies. An increased degradation of GHRs because of overexpression of cytokine-inducible SH2-containing protein (CIS) was suggested for some children with idiopathic short stature. Effects on several downstream components of GH signaling were observed for FGF21, cytokines, sepsis, fever and chronic renal failure. In Noonan syndrome and other "rasopathies" the activation of the RAS-RAF-MAPK-ERK pathway leads to inhibition of the JAK/STAT pathway. In contrast, fibroblasts from tall patients with Sotos syndrome showed a downregulation of this axis. Experimental and clinical evidence suggests that the NF-κB pathway plays a role in GH signaling. In a patient with an IκBα mutation presenting with short stature, GHI, severe immune deficiency and other features, NF-κB nuclear transportation and STAT5 and PI3K expression and activity were reduced. A patient with a mosaic de novo duplication of 17q21-25 presented with several congenital anomalies, GHI and mild immunodeficiency. Studies in blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-κB and related proteins. Functional studies on skin fibroblasts revealed that NF-κB activation, PI3K activity and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. The expression of one of the duplicated genes, PRKCA, was significantly higher than in control cells, which might be the cause of this clinical syndrome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Besides growth hormone, several pharmaceutical products have been investigated for efficacy and safety in increasing short term growth or adult height. Short-term treatment with testosterone esters in boys with constitutional delay of growth and puberty is efficacious in generating secondary sex characteristics and growth acceleration. The addition of oxandrolone to growth hormone (GH) in Turner syndrome has an additive effect on adult height gain. Treatment with GnRH analogs is the established treatment of central precocious puberty, and its addition to GH therapy appears effective in increasing adult height in GH deficient children, and possibly short children born SGA or with SHOX deficiency, who are still short at pubertal onset. Aromatase inhibitors appear effective in several rare disorders, but their value in increasing adult height in early pubertal boys with GH deficiency or idiopathic short stature is uncertain. A trial with a C-natriuretic peptide analog offers hope for children with achondroplasia., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Decreased insulin-like growth factor-I (IGF-I) levels in adults have been associated with an increased risk of ischemic heart disease and heart failure. It is currently unknown whether patients with low circulating IGF-I levels due to a homozygous acid-labile subunit (IGFALS) gene mutation also have increased risk of cardiovascular disease. Therefore, we evaluated atherosclerotic burden in a 27 year old male patient who was diagnosed with a homozygous IGFALS mutation and consequently had extremely low circulating IGF-I levels., Methods: Ten year's cardiovascular risk was calculated using the Framingham risk score. Presence of (subclinical) atherosclerosis was assessed using a 64-slice CT scan of the coronary arteries. Cardiac performance was measured by conventional echocardiographic measurements, three dimensional (3D)-echocardiography, and tissue deformation imaging., Results: Despite his extremely low circulating IGF-I levels due to Acid-Labile Subunit (ALS) deficiency, our patient had a low Framingham risk score and no signs of coronary atherosclerosis. Adjusted for physical height, cardiac performance was not impaired compared with healthy subjects., Conclusion: The present case report does not lend support to routine cardiovascular screening in patients with extremely low circulating IGF-I levels due to a homozygous IGFALS mutation, when cardiovascular risk is low., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Growth hormone (GH) regulates insulin-like growth factor (IGF)-I production primarily through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5b signaling cascade. One of four STAT proteins (STAT1, -3, -5a and -5b) activated by the GH-GHR system, the critical importance of STAT5b in IGF-I production became evident with the identification of homozygous, autosomal recessive STAT5b mutations in patients who presented with severe postnatal growth failure, growth hormone insensitivity syndrome (GHIS) and marked IGF-I deficiency. Unlike GHIS due to GHR mutations, patients carrying STAT5b mutations also presented with chronic pulmonary disease and evidence of perturbations of T-cell homeostasis. At present, no single treatment(s) is available to improve both poor statural growth and immune deficiency. Continued clinical evaluations of patients with STAT5b mutations and elucidating the impact of the mutation on STAT5b structure and function, are important to understanding the pathophysiology of this rare, complex, disease (MIM 245590)., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

After a proper medical history, growth analysis and physical examination of a short child, followed by radiological and laboratory screening, the clinician may decide to perform genetic testing. We propose several clinical algorithms that can be used to establish the diagnosis. GH1 and GHRHR should be tested in children with severe isolated growth hormone deficiency and a positive family history. A multiple pituitary dysfunction can be caused by defects in several genes, of which PROP1 and POU1F1 are most common. GH resistance can be caused by genetic defects in GHR, STAT5B, IGF1, IGFALS, which all have their specific clinical and biochemical characteristics. IGF-I resistance is seen in heterozygous defects of the IGF1R. If besides short stature additional abnormalities are present, these should be matched with known dysmorphic syndromes. If no obvious candidate gene can be determined, a whole genome approach can be taken to check for deletions, duplications and/or uniparental disomies., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: While in previous studies heterozygosity for an Insulin-Like Growth Factor 1 (IGF1) defect only modestly decreased height and head circumference, we recently reported on two siblings with severe short stature with a maternally transmitted heterozygous duplication of 4 nucleotides, resulting in a frame shift and a premature termination codon in the IGF1 gene. In this paper we describe the structural and functional characteristics of the putative truncated IGF-I protein., Design: Two children, their mother and maternal grandfather carried the mutation. In addition, two family members who were not affected were included in the study. Mutant (MT) IGF-I was synthesized in oxidized and reduced form using two methods. Neutral gel filtration studies were carried out with wild-type (WT) and synthetic MT IGF-I. Binding analysis of synthetic MT IGF-I to the IGF1R and insulin receptors were performed with EBNA-293 cells, stably transfected with the IGF-I receptor, and IM9 cells. L6 cells were used to examine the mitogenic potency and the potential antagonizing effect of synthetic MT IGF-I by [(3)H]-thymidine incorporation assays., Results: In the sera of both the carriers and non-carriers the proportion of (125)I-IGF-I that was associated with the 150 kDa complex was somewhat less (varying between ~37 and ~52%) than in normal pooled serum (~53-~63%) and, instead, slightly increased amounts of radioactivity were eluted in the 40-50 kDa fraction (consisting of binary IGF-IGFBP complexes) or remained unbound. Synthetic MT IGF-I did not bind to the IGF-I receptor, nor antagonize the growth-promoting effect of IGF-I. It did bind to IGFBPs, but was barely incorporated into 150 kDa complexes. Because in all cases WT IGF-I immunoreactivity was recovered in one peak, corresponding to the MW of WT IGF-I, i.e. ~7.6 kDa, an interaction of circulating truncated mutant peptide with WT IGF-I is very unlikely., Conclusions: There is no evidence that the severe short stature associated with heterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation is caused by a dominant negative effect of the truncated protein. We speculate that the growth failure is caused by a combination of partial IGF-I deficiency, placental IGF-I insufficiency, and other genetic factors., (Copyright © 2010 Growth Hormone Research Society. Published by Elsevier Ltd. All rights reserved.)

Objective: To construct new Dutch reference curves for birthweight by parity, sex and ethnic background., Design: Retrospective nationwide study., Material and Methods: Reference curves for birthweight were constructed using the LMS model and were based on 176,000 singleton births in the Netherlands in the year 2001 (approximately 95% of all births in that year)., Results: Separate birthweight curves were constructed for male and female babies born from primiparous and multiparous women from 25 to 43 weeks gestational age. The reference curves are similar to the Swedish references. Birthweight at early gestation was lower than in the previous Dutch reference curves and higher from term onwards. Infants of Hindustani women had a significantly lower birthweight, so that a separate reference curve was constructed., Conclusion: The new Dutch reference curves show a different pattern than the Dutch reference curves collected more than 50 years ago, reflecting changes in prenatal conditions and care.

The growth hormone-insulin-like growth factor-I (GH-IGF-I) axis plays a key role in intra-uterine growth and development. This review will describe the consequences of genetic defects in various components of the GH-IGF-I axis on intra-uterine growth and development. Animal knockout experiments have provided evidence for the GH-independent secretion of IGF-I and its effect in utero. Reports of patients with a deletion or mutation of the IGF-I and IGF1R genes have provided insight into the role of intra-uterine IGF-I in the human. Homozygous defects of the IGF-I gene have dramatic effects on intra-uterine growth and development, whereas heterozygous defects of the IGF1R gene have a more variable clinical presentation. The phenotype in relation to the genotype of the different disorders will be reviewed in this chapter.

In the management of ISS auxological, biochemical, psychosocial and ethical elements have to be considered. In boys with constitutional delay of growth and puberty androgens are effective in increasing height and sexual characteristics, but adult height is unchanged. GH therapy is efficacious in increasing height velocity and adult height, but the inter-individual variation is considerable. The effect on psychosocial status is uncertain. Factors affecting final height gain include GH dose, height deficit in comparison to midparental height, age and first year height velocity. In case of a low predicted adult height at the onset of puberty, addition of a GnRH analogue can be considered. Although GH therapy appears safe, long-term monitoring is recommended.

Idiopathic short stature is a condition in which the height of the individual is more than 2 SD below the corresponding mean height for a given age, sex and population, in whom no identifiable disorder is present. It can be subcategorized into familial and non-familial ISS, and according to pubertal delay. It should be differentiated from dysmorphic syndromes, skeletal dysplasias, short stature secondary to a small birth size (small for gestational age, SGA), and systemic and endocrine diseases. ISS is the diagnostic group that remains after excluding known conditions in short children.

Objectives: Reliability studies are frequently organized within the context of a large (multicenter) study, with only a small sample of subjects measured by the observers of the large study. To estimate interobserver reliability, data from the large study are not frequently used. In this article, the advantages of combining data from the reliability study and the large study to improve the estimation of intra-class correlation coefficients (ICCs) are highlighted., Study Design and Setting: This was done within the scope of estimating fat percentages in the Project On Preterm and Small-for-gestational-age infants-19 (POPS-19) study and with simulations. To calculate ICCs, three approaches were used: (1) the classical approach using data from a reliability study only, (2) the combined variances approach using inter-subject variances from the POPS-19 study, and (3) the maximum likelihood approach using all data., Results: The ICCs (95% confidence interval [CI]) for fat percentage calculated by the three approaches were 0.84 (0.57, 0.99), 0.94 (0.90, 0.97), and 0.94 (0.88, 0.97), respectively., Conclusion: The efficient use of data by combining data from a small reliability study with the data from the large study itself for the calculation of ICCs will lead to more precise ICCs.

Objective: To describe growth in infants <32 weeks GA. To assess the relationship between growth and perinatal factors (like intrauterine growth retardation and the postnatal use of dexamethasone) and neurodevelopmental outcome., Design: Regional, prospective study in two health regions in the Netherlands. Part of the Leiden Follow-Up Project on Prematurity (LFUPP)., Patients: 196 live born infants with GA <32 weeks., Methods: At two years corrected age length, weight and head circumference of 160 of 196 surviving infants (82%) were evaluated. Standard Deviation Scores were calculated and means were compared to Dutch growth references. Mean SDS for length was corrected for the mean SDS for target height. Birth weight (BW)-SDS for gestational age (GA) was calculated according to Swedish references., Results: Length, weight and weight-for-length were equally impaired in both sexes at two years in premature infants compared to Dutch growth charts. Catch-up in length and weight occurred mostly in the first year of life. Intrauterine growth retardation was associated with impairment of all growth parameters. The use of postnatal dexamethasone was associated with shorter length, lower weight, lower weight for length and smaller head circumference; this effect remained after correction for GA, BW and BW-SDS. Growth retardation (length and weight) was associated with an abnormal neurologic examination; smaller head circumference also with mental and psychomotor delay., Conclusion: Growth at two years corrected age in children born <32 weeks is impaired. Postnatal dexamethasone is associated with impairment of all growth parameters including head circumference, which may be a significant contributing factor for abnormal neurodevelopmental outcome.

The effect of a short-term intervention with parents in the Neonatal Intensive Care Unit (NICU) on their knowledge of infant behavioral cues and confidence in caregiving was examined. Ten sets of parents with a total of 22 premature infants born <32 weeks gestational age admitted to a NICU were enrolled in a time-lag control trial over an 8-month period. The intervention group was given 4 sessions of instructions on preterm infant behavior for a period of 2 weeks. The control group did not receive the instructions. All parents completed two subscales of the Mother and Baby Scale (MABS) at weeks 1 and 3 and a short questionnaire concerning nursing support at week 3. Intervention parents completed a pre- and post-test on knowledge of preterm infant behavioral cues at weeks 1 and 3. There was a significant improvement in the post-test scores concerning knowledge of preterm infant behavioral cues and a higher nursing support score for mothers in the intervention group. Intervention mothers showed no significant improvement in confidence in caregiving. Only half of the intervention group fathers participated in the sessions and there were no significant differences in fathers' scores. While the intervention significantly increased maternal knowledge of infant behavioral cues, there was no significant effect on mothers' confidence in caregiving. Very few fathers participated in the entire intervention. A longer, more intensive program with a larger sample size and finding ways of incorporating more participation from fathers is recommended.

This study explored the opinions of (para)medical and nursing staff in two Dutch Neonatal Intensive Care Units (NICU's). A questionnaire was used that measured: a) the perceived impact of NIDCAP on several NICU conditions, b) attitudes, subjective norm, perceived behavioral control, knowledge and abilities of using the NIDCAP method (based on the Theory of Planned Behavior) and c) training interest, requirements, information sources and the relevance of the NIDCAP method for different groups of NICU patients. Respondents were positive about NIDCAP and felt that using NIDCAP is fulfilling and leads to improvement of the infant's development, health and well-being. However, NIDCAP was also thought to be time-consuming and might worsen job conditions. The nursing staff, compared to the medical staff, had a more positive attitude (p=.004), higher perceived behavioral control (p=.004) and perceived a more positive impact of NIDCAP on NICU conditions (p=.008).

Trisomy of 15q26-qter is frequently associated with tall stature and mental retardation. Here we describe a patient with such trisomy, without a partial monosomy of another chromosome. The tall stature in this patient is most probably caused by duplication of the IGF1R gene. A duplication of the IGF1R gene is not a frequent finding in patients with tall stature. In 38 patients with features of Sotos syndrome without NSD1 alterations, a duplication was found only once. This patient was already known to have an unbalanced 2;15 translocation. Looking for a duplication of the 15qter region is still worth consideration in patients with tall stature and features of Sotos syndrome without an NSD1 alteration, especially when there is craniosynostosis or marked speech delay.

Background: Increasing evidence indicates that adult body composition is associated with prenatal and infancy weight gain, but the relative importance of different time periods has not been elucidated., Objective: The objective was to study the association between prenatal, early postnatal, and late infancy weight gain and body mass index (BMI), fat mass, and fat distribution in young adulthood., Design: We included 403 men and women aged 19 y from a Dutch national prospective follow-up study who were born at <32 wk of gestation. BMI, waist circumference, and waist-to-hip ratio SD scores and subscapular-to-triceps ratio, percentage body fat, fat mass, and fat-free mass at age 19 y were studied in relation to birth weight SD scores, weight gain from preterm birth until 3 mo postterm (early postnatal weight gain), and weight gain from 3 mo until 1 y postterm (late infancy weight gain)., Results: Birth weight SD scores were positively associated with weight, height, BMI SD scores, and fat-free mass at age 19 y but not with fat mass, percentage body fat, or fat distribution. Early postnatal and late infancy weight gain were positively associated with adult height, weight, BMI, waist circumference SD scores, fat mass, fat-free mass, and percentage body fat but not with waist-to-hip ratio SD scores or subscapular-to-triceps ratio., Conclusions: In infants born very preterm, weight gain before 32 wk of gestation is positively associated with adult body size but not with body composition and fat distribution. More early postnatal and, to a lesser extent, late infancy weight gain are associated with higher BMI SD scores and percentage body fat and more abdominal fat at age 19 y.

Objective: To investigate the influence of perinatal risk factors, especially hypotension, on neuromotor status at term in surviving preterm infants born before 32 weeks of gestation., Methods: This study is part of the Leiden Follow-Up Project on Prematurity: a prospective, regional study of 266 live born infants with a gestational age (GA) < 32 weeks born in 1996-1997. Twenty-eight infants died before term age. Two hundred and eleven infants were examined neurologically at term according to Prechtl. The findings were classified as normal (N), mildly abnormal (MA) or definitely abnormal (DA). Hypotension was defined as a mean arterial blood pressure (MABP) < 30 mm Hg on at least two occasions., Results: One hundred and six (50%) infants were classified as neurologically N, 92 (44%) infants were classified as MA and 13 (6%) infants as DA. Hypotension, bronchopulmonary dysplasia (BPD), flaring and cystic periventricular leucomalacia (PVL) were risk factors for neurological morbidity. Of the 68 infants with hypotension, 33 (49%) were classified as MA and 7 (10%) as DA. Of the 141 infants without hypotension, 58 (41%) were MA, and 5 (4%) were DA. The odds ratio of hypotension for neurological morbidity was 1.9 (95% CI 1.06-3.40), adjusted for gestational age, birth weight, small for gestational age (SGA) and gender, it was 1.96 (95% CI 1.02-3.77). The adjusted odds ratio of PVL was 18.6 (4.4-78.5), of flaring was 2.37 (1.18-4.74) and of BPD was 2.44 (1.08-5.5)., Conclusions: Apart from gestational age, periventricular leucomalacia, and bronchopulmonary dysplasia, hypotension in preterm infants is a major risk factor for neurological morbidity at term.

Objective: To determine the effect of prematurity (gestational age (GA) < 32 weeks) on developmental outcome at the corrected age of 18 and 24 months in a regionally defined, prospective cohort study., Study Design: The Leiden Follow-Up Project on Prematurity (LFUPP) includes all live-born infants < 32 weeks GA, born in 1996/1997 in three Dutch health regions (n=266). Mental and psychomotor developmental indices (MDI, PDI) were determined with the Bayley Scales of Infant Development I: > or = -1 S.D.: normal, -2 to -1 S.D.: moderate delay and < -2 S.D.: severe delay., Results: At 18 months 168 (71%) and at 24 months, 151 children (64%) of 235 survivors were assessed. Moderate to severely delayed mental and/or psychomotor development occurred in 40% of the children at both ages. Children lost to follow-up were of lower socioeconomic status and more frequently of non-Dutch origin. Since non-Dutch origin negatively affected the outcome at both test ages, availability of the data of these children would probably have worsened the outcome. Postnatal treatment with dexamethasone was associated with an increased risk of delayed development. Other independent predictors of delayed development were bronchopulmonary dysplasia at 18 months and ethnicity, maternal age at birth, birthweight and gender at 24 months. After adjustment for these other predictors of delayed development, the mean PDI of dexamethasone-treated infants was 16.1 points lower than of non-treated infants at 18 months (p=0.03) and 12.7 points lower at 24 months (p=0.04)., Conclusions: At 18 and 24 months corrected age, 40% of the very prematurely born children had both delayed mental and/or psychomotor development. Treatment with dexamethasone postnatally was a major risk factor for delayed (psychomotor) development.

Since 1958 growth hormone (GH) has been used as substitution treatment for children with GH deficiency. At present, it is clear that a dose of 0.23 mg/kg/week can lead to a final height close to target height, but in view of the wide inter-individual variation, alternative regimens based on invidualizing the dosage with the help of prediction models are being investigated. The best strategy during puberty (increase the dosage, delay puberty) is still uncertain. The value of GH in idiopathic short stature is still heavily debated, although the average final height gain on 0.33 mg/kg/week is 5-7 cm. GH is efficacious in short stature due to chronic renal failure and Prader-Willi syndrome. In other conditions insufficient data are available. There are few side-effects.

Stunted growth is a serious problem for children with chronic renal failure (CRF) despite normal endogenous growth hormone secretion and normal or elevated plasma concentrations of insulin-like growth factors (IGF) I and II. Biosynthetic growth hormone (GH) was given to 20 prepubertal children (eleven boys, nine girls; mean age 9.5 years, range 4-16) with CRF and severe growth retardation in a placebo-controlled, double-blind, cross-over trial. 6 months of subcutaneous injection of GH (4 IU/m2 per day) was either preceded or followed by 6 months of placebo injection. The patients had a full examination every 3 months. Sixteen children completed the study. Height velocity improved significantly with GH therapy (p less than 0.0001) and placebo (p less than 0.04), but the GH-induced height-velocity increase exceeded that of placebo by 2.9 cm per 6 months. There was a positive relationship between prestudy height velocity and height-velocity increase. Bone maturation was not affected. GH caused a significant increase in IGF-I and a moderate increase in IGF-II plasma concentrations. The pretreatment elevation of IGF-binding protein-1 decreased by almost 50% during GH therapy, while IGF-binding protein-3 increased significantly in concentration, although this increase was significantly smaller than the GH-induced increase in IGF-I. Fructosamine, lipid, and parathyroid concentrations remained constant. Renal function deterioration did not accelerate. Impressive height-velocity increase can be achieved with GH therapy in children with CRF and growth retardation without changes in renal function. Bone maturation appears unaffected suggesting improved final height. Treatment is best started before growth retardation becomes considerable.