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

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

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 considere

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

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. 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. 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. 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 practic

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 viv

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

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. 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. 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%). 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 testin

Maternale uniparentale disomie 14. In de differentiaaldiagnose bij Prader-Willi-syndroom

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. 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. 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 exclude

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

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