Positive effect of growth hormone treatment in maternal uniparental disomy chromosome 14.

OBJECTIVE: Maternal uniparental disomy of chromosome 14 (matUPD(14)) resembles Prader-Willi syndrome (PWS). As positive effects of growth hormone (GH) are observed in individuals with PWS, treatment with GH may be useful in individuals with matUPD(14) as well. The aim of this study was to investigate the effect of GH treatment on growth and body composition in children with matUPD(14). DESIGN: This is a prospective observational study of GH treatment in two girls with matUPD(14) during 2 years, and spontaneous growth in another matUPD(14) girl of similar age. PATIENTS: Three girls (patient A, B and C, aged 8·9, 11·4 and 12·7 years, respectively) with matUPD(14) were included in this study. MEASUREMENTS: Patients A and B were treated with GH during 2 years. Patient C was not treated with GH, as she was diagnosed at an age at which she attained near-final height. Main outcome measures included height, weight, body proportions, IGF-1, bone age, and DXA scan for body composition. RESULTS: In both treated girls, a considerable increase in height (from -2·3SD and -1·2SD to -1·2SD and -0·6SD, respectively) and IGF-1 levels (from +0·1SD and -1·4SD to +1·3SD and +0·9SD, respectively) and, in patient A, a decrease in weight (+1·2 SD to -0·7SD), and improved body composition (fat percentage from 51·5% to 45·4%) were found. Both experienced improved muscle strength. CONCLUSIONS: GH treatment in matUPD(14) cases can show beneficial effects on growth and body composition if started in time. Larger, international studies to determine detailed effectivity and side effects are suggested.

[Diaper dermatitis is not always a harmless condition]. / Luierdermatitis is niet altijd onschuldig.

BACKGROUND: Diaper dermatitis in children is common and usually harmless. Often the cause is irritation, a secondary candida infection or eczema, for which treatment is simple and effective. In this paper we show that a therapy resistant diaper dermatitis can be the diagnostic clue to the rare but important diagnosis Langerhans cell histiocytosis (LCH). CASE DESCRIPTION: We saw a 14 months old girl with therapy resistant diaper dermatitis, skin abnormalities on the hairy scalp, fever, otorrhea and extensive lymphadenopathy. After a long period of doctor visits, skin biopsies confirmed the diagnosis of LCH. CONCLUSION: LCH is a rare condition that often manifests in the skin. LCH can manifest in different organs. Although skin involvement is sometimes considered as less relevant, cutaneous manifestations can be an important diagnostic clue. In this paper we show that diaper dermatitis is not always harmless: it can be a symptom of LCH.

[Not to be missed signs of primary amenorrhea]. / Niet te missen signalen van primaire amenorroe.

Primary amenorrhea is defined as the absence of the menarche by the age of 16. Knowledge of the new arrangement of all causes into four pathofysiologic compartments by the NVOG and NVK guideline contributed the diagnostic process. This article present the alarm symptoms of primary amenorrhea in the anamnesis, physical examination and supplementary tests including the interpretation of stages of puberty in relation with length and vaginal examination. In this article, we propose the optimal diagnostic traject for general practitioner, pediatrician and gynaecologist. We describe four cases, one of each compartment, to illustrate the importance of this process.

[The diagnostic evaluation of tall stature in children]. / Diagnostiek van grote lengte bij kinderen.

In this case series, we describe four children and adolescents with tall stature or growth acceleration to illustrate the diagnostic evaluation of tall stature according to the new Paediatric Association of the Netherlands (NVK) Guideline on growth disorders. A 14-year-old girl with tall stature and a relatively late onset of puberty was diagnosed with idiopathic familial tall stature, and the patient decided not to opt for epiphysiodesis. A 14-year-old boy with prepubertal growth acceleration and a history of behavioural problems was diagnosed with Klinefelter syndrome. A 7-year-old boy with tall stature, arachnodactyly, pectus excavatum and lumbar scoliosis was diagnosed with Marfan syndrome. Finally, a 16-year-old girl with isolated progressive tall stature was diagnosed with growth hormone excess caused by a pituitary somatotroph adenoma. The most clinically relevant conditions associated with tall stature are Klinefelter and Marfan syndrome, and secondary growth disorders such as precocious puberty and growth hormone excess.

Towards a Rational and Efficient Diagnostic Approach in Children Referred for Growth Failure to the General Paediatrician.

Based on a recent Dutch national guideline, we propose a structured stepwise diagnostic approach for children with growth failure (short stature and/or growth faltering), aiming at high sensitivity for pathologic causes at acceptable specificity. The first step is a detailed clinical assessment, aiming at obtaining relevant clinical clues from the medical history (including family history), physical examination (emphasising head circumference, body proportions and dysmorphic features) and assessment of the growth curve. The second step consists of screening: a radiograph of the hand and wrist (for bone age and assessment of anatomical abnormalities suggestive for a skeletal dysplasia) and laboratory tests aiming at detecting disorders that can present as isolated short stature (anaemia, growth hormone deficiency, hypothyroidism, coeliac disease, renal failure, metabolic bone diseases, renal tubular acidosis, inflammatory bowel disease, Turner syndrome [TS]). We advise molecular array analysis rather than conventional karyotyping for short girls because this detects not only TS but also copy number variants and uniparental isodisomy, increasing diagnostic yield at a lower cost. Third, in case of diagnostic clues for primary growth disorders, further specific testing for candidate genes or a hypothesis-free approach is indicated; suspicion of a secondary growth disorder warrants adequate further targeted testing.

Towards a Rational and Efficient Diagnostic Approach in Children Referred for Tall Stature and/or Accelerated Growth to the General Paediatrician.

Tall stature and/or accelerated growth (TS/AG) in a child can be the result of a primary or secondary growth disorder, but more frequently no cause can be found (idiopathic TS). The conditions with the most important therapeutic implications are Klinefelter syndrome, Marfan syndrome and secondary growth disorders such as precocious puberty, hyperthyroidism and growth hormone excess. We propose a diagnostic flow chart offering a systematic approach to evaluate children referred for TS/AG to the general paediatrician. Based on the incidence, prevalence and clinical features of medical conditions associated with TS/AG, we identified relevant clues for primary and secondary growth disorders that may be obtained from the medical history, physical evaluation, growth analysis and additional laboratory and genetic testing. In addition to obtaining a diagnosis, a further goal is to predict adult height based on growth pattern, pubertal development and skeletal maturation. We speculate that an improved diagnostic approach in addition to expanding use of genetic testing may increase the diagnostic yield and lower the age at diagnosis of children with a pathologic cause of TS/AG.

Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects.

INTRODUCTION: Short stature homeobox-containing gene (SHOX) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on patients with intragenic variants or deletions. However, recent discoveries showed that deletions of the enhancer elements are quite common. The majority of these patients show less body disproportion and respond better to recombinant human growth hormone treatment. We redefined clinical criteria for genetic analysis to facilitate detection of the full spectrum of SHOX haploinsufficiency. METHODS: We analyzed 51 children with SHOX variants or deletions and 25 children with a deletion in its enhancer region. Data were compared to 277 children referred for suspicion of growth failure without endocrine or genetic pathology. RESULTS: Only half of the patients with an enhancer region deletion fulfilled any of the current screening criteria. We propose new clinical criteria based on sitting height to height ratio >1 SDS or arm span ≥3 cm below height, with a sensitivity of 99%. When these criteria are combined with obligatory short stature, the sensitivity to detect SHOX haploinsufficiency is 68.1%, the specificity 80.6%, and the number needed to screen 21 patients. CONCLUSION: Novel clinical criteria for screening for SHOX haploinsufficiency allow the detection of patients within the full genetic spectrum, that is, intragenic variants and enhancer region deletions.

Genetic Analyses in Small-for-Gestational-Age Newborns.

Context: Small for gestational age (SGA) can be the result of fetal growth restriction, which is associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood. Objective: The aim of the current study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA newborns. We hypothesized that one or more copy number variations (CNVs) and disturbed methylation and sequence variants may be present in genes associated with fetal growth. Design: A prospective cohort study of subjects with a low birth weight for gestational age. Setting: The study was conducted at an academic pediatric research institute. Patients: A total of 21 SGA newborns with a mean birth weight below the first centile and a control cohort of 24 appropriate-for-gestational-age newborns were studied. Interventions: Array comparative genomic hybridization, genome-wide methylation studies, and exome sequencing were performed. Main Outcome Measures: The numbers of CNVs, methylation disturbances, and sequence variants. Results: The genetic analyses demonstrated three CNVs, one systematically disturbed methylation pattern, and one sequence variant explaining SGA. Additional methylation disturbances and sequence variants were present in 20 patients. In 19 patients, multiple abnormalities were found. Conclusion: Our results confirm the influence of a large number of mechanisms explaining dysregulation of fetal growth. We concluded that CNVs, methylation disturbances, and sequence variants all contribute to prenatal growth failure. These genetic workups can be an effective diagnostic approach in SGA newborns.

Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty.

OBJECTIVE: Our objective was to assess final height (FH) and adverse effects of combined GH and GnRH agonist (GnRHa) treatment in short adolescents born small for gestational age or with normal birth size (idiopathic short stature). DESIGN AND PATIENTS: Thirty-two adolescents with Tanner stage 2-3, age and bone age (BA) less than 12 yr for girls or less than 13 yr for boys, height sd score (SDS) less than -2.0 SDS or between -1.0 and -2.0 SDS plus a predicted adult height (PAH0) less than -2.0 SDS were randomly allocated to receive GH plus GnRHa (n=17) or no treatment (n=15) for 3 yr. FH was assessed at the age of 18 yr or older in girls or 19 yr or older in boys. RESULTS: FH was not different between treatment and control groups. Treated children had a larger height gain (FH-PAH0) than controls: 4.4 (4.9) and -0.5 (6.4) cm, respectively (P<0.05). FH was higher than PAH0 in 76 and 60% of treated and control subjects, respectively. During follow-up, 50% of the predicted height gain at treatment withdrawal was lost, resulting in a mean gain of 4.9 cm (range, -4.0 to 12.3 cm) compared with controls. Treatment did not affect body mass index or hip bone mineral density. Mean lumbar spine bone mineral density and bone mineral apparent density tended to be lower in treated boys, albeit statistically not significant. CONCLUSION: Given the expensive and intensive treatment regimen, its modest height gain results, and the possible adverse effect on peak bone mineralization in males, GH plus GnRHa cannot be considered routine treatment for children with idiopathic short stature or persistent short stature after being born small for gestational age.

Growth failure in adolescents: etiology, the role of pubertal timing and most useful criteria for diagnostic workup.

BACKGROUND: The aim of the study was to evaluate the etiology, the role of pubertal timing and most useful criteria for diagnostic workup in adolescents with growth failure. METHODS: Adolescents (n=182) aged 10.0-18.0 years underwent a standardized diagnostic protocol. Constitutional delay of growth and puberty (CDGP) was defined as late pubertal onset or a Tanner stage less than -2 SDS. Dutch and Finnish criteria for growth monitoring were retrospectively assessed. RESULTS: In 13 children (7.1%) a specific diagnosis could be established. CDGP was diagnosed in 10% of patients aged ≥13 (girls) or ≥14 years (boys). Sensitivity to detect pathologic causes was 85% and 62% for, respectively Dutch and Finnish criteria for growth monitoring as used in younger children, but specificity was low (55%-59%). CONCLUSIONS: In adolescents, pathological causes for growth failure and pubertal delay are common, and we recommend a combination of height SDS, distance to THSDS and growth deflection for deciding on further diagnostic testing.

Motives for choosing growth-enhancing hormone treatment in adolescents with idiopathic short stature: a questionnaire and structured interview study.

BACKGROUND: Growth-enhancing hormone treatment is considered a possible intervention in short but otherwise healthy adolescents. Although height gain is an obvious measure for evaluating hormone treatment, this may not be the ultimate goal for the person, but rather a means to reach other goals such as the amelioration of current height-related psychosocial problems or the enhancement of future prospects in life and society. The aim of our study was to clarify the motives of adolescents and their parents when choosing to participate in a growth-enhancing trial combining growth hormone and puberty-delaying hormone treatment. METHODS: Participants were early pubertal adolescents (25 girls, 13 boys) aged from 11 to 13 years (mean age 11.5 years) with a height standard deviation score (SDS) ranging from -1.03 to -3.43. All had been classified as idiopathic short stature or persistent short stature born small for the gestational age (intrauterine growth retardation) on the basis of a height SDS below -2, or had a height SDS between -1 and -2 and a predicted adult height SDS below -2. The adolescents and their parents completed questionnaires and a structured interview on the presence of height-related stressors, parental worries about their child's behavior and future prospects, problems in psychosocial functioning, and treatment expectations. Questionnaire scores were compared to norms of the general Dutch population. RESULTS: The adolescents reported normal psychosocial functioning and highly positive expectations of the treatment in terms of height gain, whereas the parents reported that their children encountered some behavioral problems (being anxious/depressed, and social and attention problems) and height-related stressors (being teased and juvenilized). About 40% of the parents were worried about their children's future prospects for finding a spouse or job. The motives of the adolescents and their parents exhibited rather different profiles. The most prevalent parental worries related to the current or future functioning of their children, while a few cases were characterized by no observed motives or by psychosocial problems only reported by the adolescents themselves. CONCLUSION: The motives for participating in a growth-enhancing hormone trial are more obvious in the parents than in the adolescents themselves. Two out of three parents report worries about the future opportunities or observe modest current psychosocial problems in their children. The adolescents want to gain height, but the motivation underlying this remains unclear. Few of the adolescents experience psychosocial problems. Our analyses revealed differences among individuals in terms of motives, which implies that in an evaluation of hormone treatment, the importance of divergent outcome variables will also differ among individuals. Effectiveness evaluations of hormone treatment to increase height and the consequential fulfillment of other goals must be awaited.

Diagnostic Work-up and Follow-up in Children with Tall Stature: A Simplified Algorithm for Clinical Practice.

OBJECTIVE: No evidence-based guideline has been published about optimal referral criteria and diagnostic work-up for tall stature in children. The aim of our study was to describe auxological and clinical characteristics of a cohort of children referred for tall stature, to identify potential candidates for adult height reduction, and to use these observations for developing a simple algorithm for diagnostic work-up and follow-up in clinical practice. METHODS: Data regarding family and medical history, auxological measurements, bone age development, physical examination, additional diagnostic work-up, and final diagnosis were collected from all children referred for tall stature, irrespective of their actual height standard deviation score (HSDS). Predicted adult height (PAH) was calculated in children above 10 years. Characteristics of patients with an indication for adult height reduction were determined. RESULTS: Hundred thirty-two children (43 boys) with a mean ± SD age of 10.9±3.2 (range 0.5-16.9) years were included in the study. Fifty percent of the referred children had an HSDS ≤2.0 (n=66). Two pathological cases (1.5%) were found (HSDS 2.3 and 0.9). Tall children without pathology were diagnosed as idiopathic tall, further classified as familial tall stature (80%), constitutional advancement of growth (5%), or unexplained non-familial tall stature (15%). Of the 74 children in whom PAH was calculated, epiphysiodesis was considered in six (8%) and performed in four (5%) patients. CONCLUSION: The incidence of pathology was very low in children referred for tall stature, and few children were potential candidates for adult height reduction. We propose a simple diagnostic algorithm for clinical practice.

[Maternal uniparental disomy 14; differential diagnosis with Prader-Willi syndrome]. / Maternale uniparentale disomie 14. In de differentiaaldiagnose bij Prader-Willi-syndroom.

BACKGROUND: Maternal uniparental disomy 14 is a rare genetic disorder in which both chromosomes 14 are maternally inherited. The disorder is characterised by neonatal hypotonia and feeding difficulties, intrauterine or later growth retardation, truncal obesity and precocious puberty. During the neonatal period its clinical phenotype shows great similarities with that of Prader-Willi syndrome. CASE DESCRIPTION: We describe two patients with dysmaturity, neonatal hypotonia and feeding difficulties who initially showed clinical signs of Prader-Willi syndrome. However, molecular testing for this disorder was normal. Some years later, additional molecular testing confirmed the diagnosis of maternal uniparental disomy 14. CONCLUSION: Maternal uniparental disomy 14 shows many phenotypic similarities with Prader-Willi syndrome. In a hypotonic neonate, molecular testing for maternal uniparental disomy 14 should therefore be considered if Prader-Willi syndrome has been excluded.

Application of the Dutch, Finnish and British Screening Guidelines in a Cohort of Children with Growth Failure.

AIMS: To evaluate three guidelines for selecting short children for diagnostic workup in a general pediatric clinic. METHODS: All patients (n = 131) aged 3.00-9.99 years who were referred for growth failure to a general pediatric clinic were evaluated for their medical history and growth and examined. All of them underwent the same standardized diagnostic workup. Retrospectively, the criteria for the diagnostic workup from three guidelines (proposed in the Netherlands, Finland and the UK) were applied, and their sensitivity was assessed. A Dutch reference sample (n = 958) was used for calculating population specificity. RESULTS: In 23 patients (17.6%), a pathological cause of their growth failure was found. The sensitivity of the original Dutch, Finnish and British guidelines was 73.9, 78.3 and 56.5% and their specificity 98.5, 83.7 and 95.8%, respectively. When adding recent growth deflection to the Dutch guideline, sensitivity increased to 87%, but specificity decreased markedly (to 87%). CONCLUSION: The proposed cutoff values for height standard deviation score and distance to target height/mid-parental height, as used in the Netherlands and Finland, are effective for population growth monitoring, and superior to the monitoring algorithm in the UK. Growth deflection irrespective of height is an important sign of acquired growth disorders, but its specificity is too low for population screening.

[A practical algorithm for polydipsia in children]. / Een praktisch algoritme voor polydipsie bij kinderen.

There is a lack of consent on a clinical diagnostic work-up for children with polydipsia. This can result in a delay in diagnosis in some children and unnecessary investigations in others. We describe three children who presented with polydipsia. Two of them were diagnosed with psychogenic polydipsia and one with central diabetes insipidus. We discuss the differential diagnosis and relevant clinical signs before going on to propose a clinical diagnostic algorithm that can be used in children with polydipsia. A systematic diagnostic work up for children with polydipsia helps to differentiate between those in whom polydipsia is unlikely to have a somatic cause and those where a water deprivation-test is indicated. A water deprivation test in children is an invasive procedure and should be performed by a paediatric endocrinologist or nephrologist.

[Children with hyperthyroidism due to elevated hCG levels]. / Kinderen met hyperthyreoïdie door verhoogd hCG.

We describe two children with hyperthyroidism secondary to elevated hCG levels: one patient with gestational trophoblastic disease and one patient with choriocarcinoma. hCG resembles other glycoproteins that can lead to hyperthyroidism through TSH receptor activation. Also, through its LH-mimicking effect, hCG can induce high oestradiol levels, resulting in stormy pubertal development. False negative hCG tests due to the high-dose hook effect may complicate the diagnostic process. In patients with antibody-negative thyrotoxicosis, the diagnosis of hCG-induced hyperthyroidism must be considered.

[Premature pubarche is not always an innocent phenomenon]. / Premature pubarche is niet altijd onschuldig.

Premature pubarche is defined as growth of pubic hair before the age of 8 years in girls and 9 years in boys. In most cases, it is caused by premature adrenarche, which is a premature increased synthesis of androgens in the adrenal gland and is considered to be relatively harmless. Premature pubarche can also result from severe pathology, which makes it necessary to find the cause of premature exposition to androgens. We present 3 girls, aged 5-8 years, with premature pubarche. They were eventually diagnosed with 'premature adrenarche', 'non-classical congenital adrenal hyperplasia' and 'adrenal adenoma', respectively. No treatment is indicated for premature adrenarche. The patient with non-classical congenital adrenal hyperplasia was treated with hydrocortisone; in the patient with an adrenal adenoma - a rare but severe condition - the adenoma was resected. The diagnoses were established based on progression of growth, bone age and serum levels of dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone and 17-hydroxyprogesterone. Fast progression of pubarche, accelerated growth velocity and advanced bone age should be considered alarm symptoms in patients with premature pubarche.

Long-term psychosocial consequences of hormone treatment for short stature.

AIM: To examine psychosocial functioning of young adults with idiopathic short stature or short stature born small for gestational age after growth hormone (GH) and gonadotropin-releasing hormone agonist (GnRHa) treatment in early adolescence or no intervention. METHODS: Thirty young adults (18 treated, 12 untreated; age 17-23 years; on average 5.5 years after the end of treatment) completed questionnaires regarding perceived competence and psychological distress. They and their parents were interviewed on social circumstances, height-related psychosocial stressors and parental worries about prospects in society. RESULTS: Height gain was on average 2.3 cm more for the treated than for the untreated group. On none of the psychosocial variables differences were found between treated and untreated participants. Compared to Dutch population norms, psychological and social functioning was normal. CONCLUSION: GH/GnRHa treatment, with arrest of pubertal development and lower than expected effects on final height, is not observed to lead to long-term negative or positive effects. Both treated and untreated participants go well through the psychosocial transition period of young adulthood. This suggests that, in the long term and independent of hormone treatment, adequate psychosocial adjustment is expected in case of short stature.

Psychosocial functioning of adolescents with idiopathic short stature or persistent short stature born small for gestational age during three years of combined growth hormone and gonadotropin-releasing hormone agonist treatment.

AIM: To examine psychosocial functioning of medically referred adolescents with idiopathic short stature (ISS) or persistent short stature born small for gestational age (SGA) during 3 years of combined growth hormone (GH) and gonadotropin-releasing hormone agonist (GnRHa) treatment. METHODS: Thirty-eight adolescents participated in a controlled trial with GH/GnRHa treatment or no intervention. Each year the adolescents and their parents completed questionnaires and structured interviews. Multilevel analysis was used to analyze data. RESULTS: The adolescents of the treatment group showed a worse outcome than the adolescents of the control group on 3 of 16 variables: perceived competence of scholastic (p < 0.01) and athletic ability (p < 0.05) and trait anxiety (p < 0.05). Adolescents in both the treatment and control groups perceived improved current height (p < 0.001) and self-appraisal of physical appearance (p < 0.05). The parents did not report changes in their children during treatment. CONCLUSION: The observation of some adverse psychological consequences as experienced by the adolescents indicates that it is useful to monitor psychosocial functioning during a combined GH/GnRHa treatment in adolescents with ISS or SGA. It is uncertain whether the hypothesized positive effects of the expected gain in final height by adulthood can sufficiently counterbalance possible short-term negative effects.

Skin fibroblasts of children with idiopathic short stature show an increased mitogenic response to IGF-I and secrete more IGFBP-3.

OBJECTIVE AND PATIENTS: To study differences in cellular parameters of GH and IGF-I responsiveness in skin fibroblasts of 14 children with idiopathic short stature (ISS) treated with recombinant human GH and 13 children with normal height. Secondly, to investigate whether these cellular parameters can predict the growth response to GH treatment in children with ISS. DESIGN AND MEASUREMENTS: The mitogenic responsiveness to GH and IGF-I was investigated by 3H-Thymidine incorporation. Insulin-like growth factor binding protein-3 (IGFBP-3) levels in the media were measured by radioimmunoassay (RIA). RESULTS: No significant mitogenic responses were observed to various doses of GH (1000, 5000 or 50.000 ng/ml) in children with ISS or controls. ISS fibroblasts showed an increased mitogenic response to IGF-I (10 ng/ml) compared to controls (mean +/- SD 5.9 +/- 2.4- vs. 4.2 +/- 1.5-fold stimulation, P < 0.05), and GH enhanced this effect in both groups. IGFBP-3 secretion was increased in ISS fibroblasts when compared to controls under all conditions examined (basal, 200 and 5000 ng/ml GH, 10 ng/ml IGF-I for 24 and 48 h). High IGFBP-3 levels were related to low mitogenic responses to IGF-I or to GH + IGF-I in children with ISS (r = -0.7, P < 0.05), but not in controls. Within the ISS group, an enhanced mitogenic response to IGF-I in vitro was related to more extreme short stature before GH treatment (r = -0.70, P < 0.05) and to a relatively impaired response to high dose GH treatment in vivo (r = -0.52, P < 0.05). CONCLUSION: The demonstration of high IGFBP-3 levels and enhanced mitogenic response to IGF-I shows that ISS fibroblasts have different cellular characteristics compared to controls of normal height. It is hypothesized that in ISS an alteration of the signal transduction pathway between the GH receptor and IGFBP-3 synthesis results in a local imbalance with high IGFBP-3 levels and lower IGF-I availability for the IGF-I receptor. This may be reflected by an increased IGF-I responsiveness in vitro which is associated with an impaired capacity to grow in vivo.