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Eczema in children is a chronic disabling condition. The impact of this condition on the lives of families is often underestimated by conventional physicians. As a consequence parents may investigate complementary treatment options. Close monitoring by a paediatrician is essential, considering that a variety of adverse effects can occur during the use of complementary treatment. We present a 5-year-old girl with eczema. She visited a Chinese herbalist who prescribed an ointment. The parents noticed that the eczema resolved fast, itching decreased and she was finally sleeping well. However, her behaviour changed and appetite increased. Undetectable levels of serum cortisol were found, which was indicative of exogenous Cushing's syndrome. Analysis of the ointment revealed the presence of dexamethasone. Hydrocortisone substitution and subsequently a reduction schedule were implemented, after which endogenous cortisol production recovered after 4 months. Physicians should be aware that unregistered herbal medicine can contain potent drugs such as glucocorticoids., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.

Background: The work-up of patients with clinical and/or biochemical features of growth hormone insensitivity (GHI) usually contains genetic analysis of the growth hormone receptor (GHR) gene, and if negative, of STAT5B, IGFALS and IGF1. In a previous report we described 2 siblings presenting with short stature, low IGF-1 levels, elevated GH secretion and no increase of IGF-1 after 1 week of GH administration. Repeated analysis of the GHR showed no abnormalities; however, further testing revealed a heterozygous STAT5B defect in both siblings., Subjects and Methods: Two boys of Surinam-Hindustan origin showed growth failure up to the age of 6-7 years, followed by partial catch-up growth associated with increasing body mass index. Reanalysis of GHR including published intronic sequences was performed on the patients' DNA collected 7 years earlier., Results: The heterozygous STAT5B variant proved to be functionally benign. A homozygous intronic mutation of the GHR, c.618+792A>G (IVS6+792A>G), was subsequently found, resulting in the activation of pseudoexon 6ψ, and explaining the GHI phenotype of the patients., Conclusion: An intronic GHR mutation should be considered in all patients with signs of GHI and no coding exon mutations, even if the phenotype is mild and even if other genetic variants have been found., (© 2013 S. Karger AG, Basel.)

Molecular defects of the insulin-like growth factor 1 gene (IGF1) are rare in the human. Only three homozygous and two families with heterozygous mutations of the IGF1 gene have been described, resulting in a variable degree of intrauterine and postnatal growth retardation, microcephaly, developmental delay and deafness. Detailed genetic analysis and functional experiments have shown that IGF-1 plays a key role in pre- and postnatal growth and development in human. Eleven patients with heterozygous and 2 patients with compound heterozygous mutations in the type 1 IGF1 receptor gene (IGF1R) have been reported. Intrauterine and postnatal growth retardation, microcephaly and IGF-1 levels above the mean of age references are consistent findings in these patients, although IGF-1 levels can be low initially because of feeding problems. The first reported patients showed the most severe phenotype, but with the identification of additional patients the phenotype appears to be more variable. The functional effect of the defects has been studied by in vitro experiments. From these studies, receptor haploinsufficiency, decreased IGF1R biosynthesis, interference with ligand binding and transmembrane signaling, and disruption of the intrinsic tyrosine kinase activity have been suggested as possible mechanisms with a variable pathogenetic spectrum. Data on GH treatment in these children are limited, showing a poor to modest growth response., (Copyright © 2013 S. Karger AG, Basel.)

Information about the role of insulin-like growth factors (IGFs) is mainly derived from knockout (KO) and transgenic mice, human mutations in IGF1, IGF1R and IGFALS, and association studies with IGF1 SNPs. Igf1 KO mice show severely impaired pre- and postnatal growth and brain development and sensorineural hearing loss. Both local and endocrine IGF-1 are needed for normal growth. Igfals KO mice show a modest postnatal growth attenuation. Homozygous igf1r KO mice are severely growth impaired, while heterozygous mutations only show mild growth retardation. Two patients with a complete absence of biologically active IGF-1 showed severe pre- and postnatal growth, extreme microcephaly, sensorineural deafness and failure to thrive. A patient with a mutation that led to a partially functional protein had a less severe growth phenotype and no deafness, similarly to two siblings with a heterozygous IGF1 mutation. Heterozygosity for a dysfunctional IGF1 mutation leads to a mild effect on birth weight, adult height and head circumference. Patients with heterozygous mutations or deletions of IGF1R have a moderate pre- and postnatal growth failure, microcephaly and a history of feeding problems. Children with homozygous mutations of IGFALS have a low or normal birth weight, a mild growth failure, a head circumference in the lower normal range, and no failure to thrive. Association studies of IGF1 polymorphisms in large populations have shown variable results with respect to height, but a more consistent association with head circumference. In conclusion, a normal IGF-I bioactivity (normal local and endocrine IGF-1 availability, normal IGF1R function, normal signaling) is needed for a normal pre- and postnatal longitudinal and cranial growth. IGF-1 dysfunction causes severe growth failure, while heterozygous defects of IGF1R and homozygous defects of IGFALS are associated with a milder phenotype. Feeding disturbances in infants with IGF1 and IGF1R mutations suggest a role of IGF-1 signaling in regulatory brain centers., (Copyright © 2013 S. Karger AG, Basel.)

Growth hormone (GH) is widely prescribed for children with short stature across a range of growth disorders. Recombinant human (rh) insulin-like growth factor-1 (rhIGF-1) therapy is approved for severe primary IGF-I deficiency - a state of severe GH resistance. Evidence is increasing for an unacceptably high rate of poor or unsatisfactory response to growth-promoting therapy (i.e. not leading to significant catch up growth) in terms of change in height standard deviation score (SDS) and height velocity (HV) in many approved indications. Consequently, there is a need to define poor response and to prevent or correct it by optimizing treatment regimens within accepted guidelines. Recognition of a poor response is an indication for action by the treating physician, either to modify the therapy or to review the primary diagnosis leading either to discontinuation or change of therapy. This review discusses the optimal investigation of the child who is a candidate for GH or IGF-1 therapy so that a diagnosis-based choice of therapy and dosage can be made. The relevant parameters in the evaluation of growth response are described together with the definitions of poor response. Prevention of poor response is addressed by discussion of strategy for first-year management with GH and IGF-1. Adherence to therapy is reviewed as is the recommended action following the identification of the poorly responding patient. The awareness, recognition and management of poor response to growth-promoting therapy will lead to better patient care, greater cost-effectiveness and increased opportunities for clinical benefit., (© 2012 Blackwell Publishing Ltd.)

Background/aims: In short children, a low IGF-I and normal GH secretion may be associated with various monogenic causes, but their prevalence is unknown. We aimed at testing GH1, GHR, STAT5B, IGF1, and IGFALS in children with GH insensitivity., Subjects and Methods: Patients were divided into three groups: group 1 (height SDS <-2.5, IGF-I <-2 SDS, n = 9), group 2 (height SDS -2.5 to -1.9, IGF-I <-2 SDS, n = 6) and group 3 (height SDS <-1.9, IGF-I -2 to 0 SDS, n = 21). An IGF-I generation test was performed in 11 patients. Genomic DNA was used for direct sequencing, multiplex ligation-dependent probe amplification and whole-genome SNP array analysis., Results: Three patients in group 1 had two novel heterozygous STAT5B mutations, in two combined with novel IGFALS variants. In groups 2 and 3 the association between genetic variants and short stature was uncertain. The IGF-I generation test was not predictive for the growth response to GH treatment., Conclusion: In severely short children with IGF-I deficiency, genetic assessment is advised. Heterozygous STAT5B mutations, with or without heterozygous IGFALS defects, may be associated with GH insensitivity. In children with less severe short stature or IGF-I deficiency, functional variants are rare., (Copyright © 2012 S. Karger AG, Basel.)

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.)

Background/aims: It is not exactly known how many children develop the triphasic response (diabetes insipidus (DI)/hyponatremia/DI) immediately after surgery for childhood craniopharyngioma; neither is it known which factors predict this. We studied the occurrence of the triphasic response after primary surgery for craniopharyngioma in children, and aimed to identify possible predictors., Methods: Patients <18 years old who had undergone a primary craniopharyngioma resection between January 1990 and February 2010 in either of the 2 academic centers in Amsterdam were studied retrospectively., Results: Twenty-one patients (5 males) fulfilled the inclusion criteria. Median age at surgery was 9.1 (range: 4.0-15.1) years. Six patients developed a triphasic response (29%). Of all factors, only the duration of surgery was found to be a predictor of a triphasic response: 8.5 (6.0-11.0) versus 4.6 (3.5-11.5) h in patients who did not develop a triphasic response (p = 0.03)., Conclusion: After primary surgery for a craniopharyngioma, a considerable number of patients develop a triphasic response in the regulation of the sodium and water balance. This is predicted by (factors associated with) a longer duration of surgery. Other predictors could not be identified, which may be due to the small sample size., (Copyright © 2011 S. Karger AG, Basel.)

Context: Homozygous IGF1 deletions or mutations lead to severe short stature, deafness, microcephaly, and mental retardation. Heterozygosity for an IGF-I defect may modestly decrease height and head circumference., Objective: The objective of the study was to investigate the clinical features of heterozygous carriers of a novel mutation in the IGF1 gene in comparison with noncarriers in a short family and to establish the effect of human GH treatment., Subjects: Two children, their mother, and their maternal grandfather carried the mutation and were compared with two relatives who were noncarriers., Results: The two index cases had severe short stature (height sd score -4.1 and -4.6), microcephaly, and low IGF-I levels. Sequencing of IGF1 revealed a heterozygous duplication of four nucleotides, resulting in a frame shift and a premature termination codon. The mother and maternal grandfather had the same IGF1 mutation. Adult height (corrected for shrinking and secular trend) and head circumference sd score of carriers of the paternally transmitted mutation was -2.5 and -1.8, in comparison with -1.6 and 0.3 in noncarriers, respectively. After 2 yr of GH treatment, both index cases exhibited increased growth., Conclusions: Heterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation, presumably in combination with other genetic factors for short stature, leads to severe short stature, which can be successfully treated with GH.

Context: NF-kappaB is a family of transcription factors involved in cell proliferation, differentiation, and apoptosis., Objective: We have recently demonstrated that NF-kappaB is expressed in the growth plate and it mediates the growth-promoting effects of IGF-I on chondrogenesis and longitudinal bone growth. Humans with defects of the NF-kappaB pathway exhibit growth failure, which suggests a possible regulatory role for NF-kappaB in statural growth. We have previously reported a child with ectodermal dysplasia, immunodeficiency, and growth retardation, harboring a heterozygous mutation of IkappaBalpha, an essential component of the NF-kappaB pathway. Since he was found with low IGF-l and IGFBP-3, and elevated GH secretion, an IGF-l generation test was carried out: baseline IGF-l was low and only responded to a high dose of GH. Thus, the diagnosis of GH resistance was made., Results: To assess the underlying mechanisms of his GH resistance, we cultured the patient's skin fibroblasts with GH and/or IGF-I. While both GH and IGF-l induced cell proliferation and NF-kappaB activity in controls' fibroblasts, they had no effect on the patient's fibroblasts. In the fibroblasts of the patient's father (who displays mosaicism for the IkappaBalpha mutation), GH and IGF-l elicited an attenuated stimulatory effect. In addition, GH stimulated STAT5 phosphorylation and IGF-l mRNA expression in controls ' and the father's fibroblasts, while IGF-l induced PI3K activity and mRNA and protein expression of TDAG51, a target gene for IGF-I. In contrast, none of these effects was elicited by GH or IGF-l in the patient's fibroblasts., Conclusion: Our findings suggest that this patient's IkappaBalpha mutation caused GH and IGF-l resistance which, in turn, contributed to his growth failure.

Background: Premature thelarche is defined as breast development before 8 years of age. This is most often caused by central hormone disregulation and is accompanied by concurrent bone maturation. However, we present a case of premature thelarche with concurrent bone maturation without central hormone disregulation. Genes within the estrogen signaling pathway were examined for genetic changes which might be responsible for the clinical phenotype., Patient Report: A girl presented with breast development from 18 months of age with undetectable serum estrogens, prepubertal serum gonadotropins, advanced growth and skeletal maturation, but no increase of uterine size, thus presenting a premature thelarche variant. Serum estrogens remained below detectable limits until she entered into an unremarkable puberty at 12.1 years of age. No abnormalities or SNPs were found in the genes tested., Conclusion: We describe a case of premature thelarche which cannot be attributed to a central cause of abnormal hormone levels or to alterations in genes suspected for this phenotype. We conclude that other yet to be identified factors are involved in this unique case of premature thelarche.

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.

Context: Microscopically visible heterozygous terminal 15q deletions encompassing the IGF1R gene are rare and usually associated with intrauterine growth retardation and short stature. The incidence of submicroscopic deletions is unknown, as is the effect of GH therapy in this condition., Objective: The objective of the study was to describe the use of a novel genetic technique [multiplex ligation probe amplification (MLPA)] to detect haploinsufficiency of the IGF1R gene in a patient suspected of an IGF1R gene defect and evaluate the effect of long-term GH therapy., Patient: A 15-yr-old adolescent, born small for gestational age, showed persistent postnatal growth retardation, microcephaly, and elevated IGF-I levels. She had been treated with GH since the age of 5 yr., Methods: MLPA and array comparative genomic hybridization (aCGH) were performed to examine gene copy number changes. Dermal fibroblast cultures were used for functional analysis., Results: With MLPA, a deletion of one copy of the IGF1R gene was detected, defined by aCGH as a loss of 15q26.2->qter. IGF1R mRNA expression was decreased in fibroblasts. IGF-I binding and type 1 IGF receptor protein expression as well as activation of type 1 IGF receptor autophosphorylation and protein kinase B/Akt by IGF-I tended to be lower, but this did not reach statistical significance. GH treatment resulted in a good growth response and a normal adult height., Conclusions: MLPA and aCGH are useful tools to detect submicroscopic deletions of the IGF1R gene in patients born small for gestational age with persistent growth failure. The phenotype resembles that of a heterozygous inactivating IGF1R mutation. Long-term GH therapy causes growth acceleration in childhood and a normal adult height.

Context: Patients with GHRH receptor (GHRH-R) mutations present with familial isolated GH deficiency, which untreated leads to a severely compromised adult height. Few data are available about the efficacy of treatment with GH in combination with a GnRH analog (GnRHa) in adolescence., Objective: The objective of the study was to describe the evolution of growth and skeletal age of a brother and sister of Moroccan descent with a homozygous GHRH-R mutation who presented at an advanced age (16 and 14.9 yr, respectively) and pubertal stage (Tanner stage G4 and B3, respectively) with a height of -5.1 sd score and -7.3 sd score on treatment with a combination of GH and GnRHa for 2.5 and 3 yr followed by GH alone., Methods: GH was given in a dosage of 0.7 mg/m2.d (25 microg/kg.d) sc and triptorelin in a dosage of 3.75 mg per 4 wk im. Height and pubertal stage were measured three-monthly, bone age yearly., Results: Combined GH and GnRHa treatment resulted in a height gain of 24 and 28.2 cm, respectively, compared with the initial predicted adult height by the method of Bayley and Pinneau. Adult height was within the population range and well within the target range., Conclusions: Our patients demonstrate that, in case of isolated GH deficiency caused by a GHRH-R mutation, combined treatment of GH and GnRHa can be very effective in increasing final height, even at an advanced bone age and pubertal stage.

Animal knockout experiments have offered the opportunity to study genes that play a role in growth and development. In the last few years, reports of patients with genetic defects in GH-IGF-I axis have greatly increased our knowledge of genetically determined causes of short stature. We will present the animal data and human reports of genetic disorders in the GH-IGF-I axis in order to describe the role of the GH-IGF-I axis in intrauterine and postnatal growth. In addition, the effects of the GH-IGF-I axis on the development and function of different organ systems such as brain, inner ear, eye, skeleton, glucose homeostasis, gonadal function, and immune system will be discussed. The number of patients with genetic defects in the GH-IGF-I axis is small, and a systematic diagnostic approach and selective genetic analysis in a patient with short stature are essential to identify more patients. Finally, the implications of a genetic defect in the GH-IGF-I axis for the patient and the therapeutic options will be discussed.

Objective: STAT5b is a component of the GH signaling pathway. Recently, we described a 31-year-old male patient (height, -5.9 SDS) with a novel homozygous inactivating mutation in the STAT5b gene. The purpose of this study is to describe the phenotype in detail, including GH secretion and immunological function. In addition, we report four family members of this patient, all heterozygous carriers of the mutation., Design and Methods: Twenty-four hour GH and prolactin secretion characteristics were assessed by blood sampling at 10-min intervals. An IGF-I generation test was performed. Monocyte function was tested by stimulation of whole blood with lipopolysaccharide (LPS) in the presence or absence of Interferon-gamma (IFN-gamma). In addition, T cell function was determined by measuring proliferative responses of peripheral blood mononuclear cells (PBMC) after stimulation by various polyclonal activators and Interleukin-2 (IL-2). Clinical and biochemical characteristics were determined in the carriers of the mutation., Results: GH secretory parameters were comparable with that of healthy male controls (mean fat percentage 25), but likely increased in relation to the patient's 40% body fat. The regularity of GH secretion was diminished. Prolactin secretion was increased by sixfold. The IGF-I generation test showed a small increase in IGF-I and IGF-binding protein-3 on lower GH doses and an increase in IGF-I to -2.4 SDS on the highest dose of GH. In vitro, IL-12p40, IL 10, and tumour necrosis factor-alpha (TNF-alpha) production rates by PBMC increased to values within the normal range upon stimulation of LPS. Heterozygous carriers of the mutation did not show abnormalities, although the height of the males was below the normal range., Conclusions: This report shows that GH and prolactin secretion were increased in this patient homozygous for a new STAT5b mutation. Although STAT5b plays a role in signaling within immune cells, clinical immunodeficiency is not an obligatory phenomenon of STAT5b deficiency per se. Heterozygous carriers of a STAT5b mutation show no signs of GH insensitivity.

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.

Context: GH insensitivity can be caused by defects in the GH receptor (GHR) or in the postreceptor signaling pathway. Recently, two female patients with severe growth retardation and pulmonary and immunological problems were described with a defect in STAT5b, a critical intermediary of downstream GHR signaling., Objective: The objective was to determine the functional characteristics of a novel STAT5b mutation and describe the phenotype., Patient: We describe an adult male patient with short stature [-5.9 sd score (SDS)], delayed puberty, and no history of pulmonary or immunological problems. GH-binding protein level as well as GH secretion characteristics were normal. Plasma prolactin level was elevated. Extremely low levels of IGF-I (-6.9 SDS), IGF-binding protein-3 (-12 SDS), and acid-labile subunit (-7.5 SDS) were found., Results: We found a homozygous frameshift mutation in the STAT5b gene (nucleotide 1102-3insC, Q368fsX376), resulting in an inactive truncated protein, lacking most of the DNA binding domain and the SH2-domain., Conclusions: This report confirms the essential role of STAT5b in GH signaling in the human. We show for the first time that immunological or pulmonary problems or elevated GH secretion are not obligatory signs of STAT5b deficiency, whereas hyperprolactinemia appears to be part of the syndrome. Therefore, in patients with severe short stature, signs of GH insensitivity, and a normal GHR, analysis of the STAT5b gene is recommended.

Context: The type 1 IGF-I receptor (IGF1R) mediates the biological functions of IGF-I. Binding of IGF-I to the IGF1R results in autophosphorylation of the intracellular beta-subunit and activation of intracellular signaling., Objective: The objective of this study was to evaluate the functional characteristics of a novel IGF1R mutation and describe the phenotypic features of two patients with this mutation., Design: The study was performed in a university hospital., Patients: We describe a 35-yr-old female with mild intrauterine growth failure, progressive postnatal growth retardation, severe failure to thrive, and microcephaly. Her daughter was born with severe intrauterine growth retardation and also showed postnatal failure to thrive and microcephaly., Results: We found a heterozygous G3148-->A nucleotide substitution in the IGF1R gene, changing a negatively charged glutamic acid at position 1050 into a positively charged lysine residue (E1050K). E1050 is a conserved residue in the intracellular kinase domain. Dermal fibroblasts of the mother showed normal binding of iodinated IGF-I, but autophosphorylation and activation of downstream signaling cascades upon challenging with IGF-I was markedly reduced. Consequently, the maximal [(3)H]thymidine incorporation upon challenge with a dose range of IGF-I was reduced compared with a panel of control cells (3.65 +/- 1.79-fold vs. 6.75 +/- 4.7-fold stimulation; P < 0.01). These data suggest that the mutation results in the inactivation of one copy of the IGF1R gene., Conclusions: These two patients support the key role for IGF-I in intrauterine and postnatal growth. The different phenotypes of these and earlier described patients may be associated with variability in IGF-I signaling. The degree of intrauterine growth retardation may be partially determined by the presence or absence of maternal IGF-I resistance.

In the last few years, our knowledge of genetically determined causes of short stature has greatly increased by reports of challenging patients, who offered the opportunity to study genes that play a role in growth. Since the first paper that showed the etiology of Laron syndrome [Godowski PJ, et al: Proc Natl Acad Sci USA 1989;86:8083-8087], many mutations in the growth hormone (GH) receptor have been identified. Recently, new mutations or deletions have been found in several components of the GH-insulin-like growth factor-I (IGF-I) axis: a homozygous mutation of the GH1 gene, resulting in a bio-inactive GH; mutations in the STAT5b gene, which plays a major role in the GH signal transduction; a homozygous missense mutation in the IGF-I gene; heterozygous mutations in the IGF-I receptor gene and a homozygous deletion of the acid-labile subunit gene. In this mini review, we describe the clinical and biochemical features of these genetic defects. Genetic analysis has become essential in the diagnostic workup of a patient with short stature. However, regarding the time consuming nature of molecular analysis, it is important to carefully select the patient for specific genetic evaluation. To help in this selection process, we developed flowcharts, based on the recently described patients, that can be used as guidelines in the diagnostic process of patients with severe short stature of unknown origin.

IGF-I is a key factor in intrauterine development and postnatal growth and metabolism. The secretion of IGF-I in utero is not dependent on GH, whereas in childhood and adult life, IGF-I secretion seems to be mainly controlled by GH, as revealed from studies on patients with GHRH receptor and GH receptor mutations. In a 55-yr-old male, the first child of consanguineous parents, presenting with severe intrauterine and postnatal growth retardation, microcephaly, and sensorineural deafness, we found a homozygous G to A nucleotide substitution in the IGF-I gene changing valine 44 into methione. The inactivating nature of the mutation was proven by functional analysis demonstrating a 90-fold reduced affinity of recombinantly produced for the IGF-I receptor. Additional investigations revealed osteoporosis, a partial gonadal dysfunction, and a relatively well-preserved cardiac function. Nine of the 24 relatives studied carried the mutation. They had a significantly lower birth weight, final height, and head circumference than noncarriers. In conclusion, the phenotype of our patient consists of severe intrauterine growth retardation, deafness, and mental retardation, reflecting the GH-independent secretion of IGF-I in utero. The postnatal growth pattern, similar to growth of untreated GH-deficient or GH-insensitive children, is in agreement with the hypothesis that IGF-I secretion in childhood is mainly GH dependent. Remarkably, IGF-I deficiency is relatively well tolerated during the subsequent four decades of adulthood. IGF-I haploinsufficiency results in subtle inhibition of intrauterine and postnatal growth.

We have previously described the phenotype resulting from a missense mutation in the IGF-I gene, which leads to expression of IGF-I with a methionine instead of a valine at position 44 (Val44Met IGF-I). This mutation caused severe growth and mental retardation as well as deafness evident at birth and growth retardation in childhood, but is relatively well tolerated in adulthood. We have conducted a biochemical and structural analysis of Val44Met IGF-I to provide a molecular basis for the phenotype observed. Val44Met IGF-I exhibits a 90-fold decrease in type 1 IGF receptor (IGF-1R) binding compared with wild-type human IGF-I and only poorly stimulates autophosphorylation of the IGF-1R. The ability of Val44Met IGF-I to signal via the extracellular signal-regulated kinase 1/2 and Akt/protein kinase B pathways and to stimulate DNA synthesis is correspondingly poorer. Binding or activation of both insulin receptor isoforms is not detectable even at micromolar concentrations. However, Val44Met IGF-I binds IGF-binding protein-2 (IGFBP-2), IGFBP-3, and IGFBP-6 with equal affinity to IGF-I, suggesting the maintenance of overall structure, particularly in the IGFBP binding domain. Structural analysis by nuclear magnetic resonance confirms retention of near-native structure with only local side-chain disruptions despite the significant loss of function. To our knowledge, our results provide the first structural study of a naturally occurring mutant human IGF-I associated with growth and developmental abnormalities and identifies Val44 as an essential residue involved in the IGF-IGF-1R interaction.

It is generally assumed that busulphan/cyclophoshamide (Bu/Cy)-based conditioning regimens for haematopoietic stem cell transplantation (SCT) do not affect growth. We evaluated growth and endocrine function after Bu/Cy-based conditioning in 64 children without a history of irradiation. Mean height standard deviation scores remained stable, but unexplained disturbances of growth after SCT were found in 17/48 (35%) of the children without growth-limiting disorders (10/23 in patients treated for haematological malignancies). In 10 patients, growth hormone (GH) secretion status was evaluated, and insufficient GH secretion was diagnosed in four patients. Thyroid function was evaluable in 52 patients. Two developed antibody-mediated thyroid disorders and 10 (19%) compensated primary hypothyroidism. Gonadal function was evaluable in 21 patients and was normal in all seven patients treated with low-dose Bu (8 mg/kg), whereas seven of the 14 children receiving high-dose Bu (16-20 mg/kg) developed gonadal failure; the majority of these patients had not been exposed to gonadotoxic therapy prior to Bu/Cy. Of the 49 evaluable patients, 16 developed subclinical hyperparathyroidism. We conclude that, besides gonadal and thyroid dysfunction, impaired growth and hyperparathyroidism often occur after Bu/Cy conditioning for SCT and that growth impairment may be the result of insufficient GH secretion.

Background: If in growth studies on adults of different ages and generations height standard deviation scores (SDS) is to be calculated, individual heights should be compared with the average height for that generation (corrected for secular trend) at that age (corrected for shrinking)., Aim: To generate mathematical formulas for calculating adult height SDS corrected for shrinking and secular trend., Subjects and Methods: Decline of height by age was modelled based on data derived from the Baltimore Longitudinal Study of Aging. Based on mean height of Dutch conscripts in 1917 and data from four consecutive nationwide growth studies (1955, 1965, 1980 and 1997), and assuming a constant male-female difference of 13 cm, the secular trend was modelled over 80 years. The average coefficient of variation was calculated from the last three Dutch nationwide growth studies., Results: Height at 21 years of age can be estimated as current height t 0.042*(age - 21) -0.0015*(age - 21)2 for males, and current height + 0.039*(age - 21) + 0.0019*(age - 21)2 for females. Mean height of 21-year-olds between 1917 and 1997 is characterized by linear regression. The coefficient of variation was close to 3.8%. Adult height SDS is calculated by the equation (A - B)/(0.038B), where A is the estimated individual height at 21 years and B is the average height of 21-year-olds in that generation., Conclusion: For studies on adult height at various ages and in various generations, these equations can be used to reduce experimental noise.

Two children with a syndrome of pulmonary hemorrhage and immune complex nephritis are reported. Clinical history suggests that pulmonary lesions precede renal abnormalities. Necrotizing glomerulonephritis with granular immune deposits along the glomerular basement membrane was found. Although the etiology of this disease complex is still unknown, the clinical and pathological findings in these patients suggest that immune complex glomerulonephritis is an unusual complication of idiopathic pulmonary hemosiderosis.

Four out of 10 children in two unrelated families presented with a total pituitary growth hormone (GH) and prolactin deficiency and a partial thyrotropin (TSH) deficiency. The GH gene was intact in family I. The pituitaries, visualized by magnetic resonance imaging, were normal. All children responded well to GH and L-thyroxine therapy. Baseline plasma somatostatin and its peak response to arginine infusion were elevated in family I and they had a milder TSH deficiency than family II. Plasma insulin showed a poor response to arginine infusion. This hereditary combination of pituitary deficiencies suggests a deficiency of a common positive transcription factor.