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A proportion of children with growth hormone deficiency (GHD) have persistence of GHD as young adults. To date, no markers have been shown in childhood to have predictive value in determining persistence of GHD into adult life. We examined the hypothesis in 31 patients that variables present at the time of diagnosis of childhood-onset GHD, or those related to the early response to growth hormone (GH) therapy, are associated with the likelihood of persistence of GHD. The results show that, as previously demonstrated, children with GHD are more likely to have persistent severe GHD in adult life when the diagnosis is associated with other pituitary hormone deficiencies (p = 0.02), abnormal pituitary neuroimaging (p = 0.003), induced puberty (p = 0.001), early age of diagnosis (p = 0.03) and lower peak GH response at the first dynamic GH test in childhood (p = 0.02). However, there are no associations of persistent severe GHD with the pattern of pretreatment growth or growth response to GH treatment in the initial phase.

The pituitary-expressed GH1 gene was screened for mutation in a group of 74 children with familial short stature. Two novel mutations were identified: an Ile179Met substitution and a -360A-->G promoter variant. The Ile179Met variant was shown to exhibit a similar degree of resistance to proteolysis as wild-type GH, indicating that the introduction of Met does not cause significant misfolding. Secretion of Ile179Met GH from rat pituitary cells was also similar to that of wild type. Although receptor binding studies failed to show any difference in binding characteristics, molecular modeling studies suggested that the Ile179Met substitution might nevertheless perturb interactions between GH and the GH receptor loop containing the hotspot residue Trp169, thereby affecting signal transduction. The ability of the Ile179Met variant to activate a signal transducer and activator of transcription (STAT) 5-responsive luciferase reporter gene and induce phosphorylation of STAT 5 and ERK was therefore studied. In contrast to its ability to activate STAT 5 normally, activation of ERK by the Ile179Met variant was reduced to half that observed with wild type. Although differential effects on the activation of distinct signaling pathways by a mutant receptor agonist are unprecedented, these findings also suggest that the ERK pathway could play a role in mediating the action of GH.

Aim: To survey the investigation of short stature in Wales and suggest guidelines to improve practice., Methods: Questionnaires were circulated to paediatricians and consultant clinical biochemists or consultant chemical pathologists at 13 Welsh hospitals where children with short stature are investigated., Results: A 100% response was obtained from laboratory and clinical staff. Clinicians screened 1-50 patients each year (median, 10). Growth hormone (GH) deficiency was subsequently diagnosed in 0-30% (median, 10%) and GH treatment started in 30-100% (median, 100%) of patients. Five paediatricians and eight laboratories had written investigative protocols. Investigation of GH secretion was initiated in some centres before a complete clinical evaluation was carried out. Various screening tests for GH deficiency, including insulin-like growth factor 1 (IGF-1), random GH, and exercise tests were used. The clonidine stimulation test was used to assess the GH axis in most centres but eight different protocols were described. GH was measured in four Welsh laboratories using two automated immunoassay methods. However, nine different ranges of cutoff values for defining abnormal GH responses were quoted, and in three centres laboratories and paediatricians quoted different cutoffs., Conclusion: This survey demonstrates the need for practical guidelines for the investigation and management of short stature in children, agreed by paediatricians and their laboratory colleagues. The guidelines should encompass the initial clinical investigation, assessment of the GH-IGF-1 axis (using standardised protocols), and provision for the transition to adult management. This article presents practical guidelines based on published points for good practice.

Subtle mutations in the growth hormone 1 (GH1) gene have been regarded as a comparatively rare cause of short stature. Such lesions were sought in a group of 41 individuals selected for short stature, reduced height velocity, and bone age delay; a group of 11 individuals with short stature and idiopathic growth hormone deficiency (IGHD); and a group of 154 controls. Heterozygous mutations were identified in all three groups but disproportionately in the individuals with short stature, both with (odds ratio 25.2; 95% CI, 5.1-132.2) and without (odds ratio 3.6; 95% CI, 1.0-12.9) IGHD. Twenty-four novel GH1 gene lesions were found. Thirteen novel missense mutations were characterized by assaying the signal transduction activity of in vitro expressed variants; six (T27I, K41R, N47D, S71F, S108R, and T175A) exhibited a reduced ability to activate the JAK/STAT pathway. Molecular modeling suggested that both K41R and T175A might compromise GH receptor binding. Seven GH variants (R16C, K41R, S71F, E74K, Q91L, S108C, and a functional polymorphism, V110I) manifested reduced secretion in rat pituitary cells after allowance had been made for the level of expression attributable to the associated GH1 proximal promoter haplotype. A further leader peptide variant (L-11P) was not secreted. Eleven novel mutations in the GH1 gene promoter were assessed by reporter gene assay but only two, including a GH2 gene-templated gene conversion, were found to be associated with a significantly reduced level of expression. Finally, a novel intron 2 acceptor splice-site mutation, detected in a family with autosomal dominant type II IGHD, was shown to lead to the skipping of exon 3 from the GH1 transcript. A total of 15 novel GH1 gene mutations were thus considered to be of probable phenotypic significance. Such lesions are more prevalent than previously recognized and although most may be insufficient on their own to account for the observed clinical phenotype, they are nevertheless likely to play a contributory role in the etiology of short stature., (Copyright 2003 Wiley-Liss, Inc.)

Introduction: The effects of an intensive training programme involving screening of children for disorders of growth and puberty for community based nursing and medical staff employed by Cardiff Community Healthcare NHS Trust were audited to assess the impact of this training on referrals to the local hospital based growth clinic., Method: Referrals from community based staff to the growth clinic of patients living in the geographical area in which staff underwent training were compared with those from general practitioners in the 18 months prior to and following the training programme. Hospital notes were available for 209 of 254 (82.2%) patients identified. We excluded 112 referrals as they did not have a problem relating to growth or puberty or were inter-hospital referrals. Hence 97 referrals were included in the final audit., Results: Forty referrals occurred prior to compared with 57 following the training programme. The number of referrals from community based staff increased threefold during the six months immediately following the training programme but then returned to the previous level. There were no differences in age or height standard deviation scores at referral between groups at any time. The proportion of children referred from the community with significant abnormalities of growth or puberty (for example, hypothyroidism or precocious puberty) increased from two of 15 referrals to six of 30 referrals following the training programme., Conclusions: Intensive training in screening for disorders of growth and puberty can increase the number of referrals of children with significant pathology but at the cost of increased total number of referrals. The increase in referrals is not sustained with time, suggesting continued training is necessary.

Aims: To evaluate the effects of discontinuing growth hormone (GH) treatment on energy expenditure and body composition, which might help predict those most likely to benefit from early reintroduction of GH treatment in young adult life., Methods: Body composition was calculated from skinfold thicknesses and dual energy x ray absorptometry (DXA). Resting metabolic rate (RMR) and whole body bone mineral content (BMC) were also measured. Measurements were made before stopping treatment, at discontinuation of GH treatment, and two weeks, six months, and one year later in 11 adolescents with growth hormone deficiency (GHD) and five adolescents without GHD who were treated with GH. Measurements were compared with 10 healthy controls, in whom measurements were repeated one year later., Results: During the nine months before discontinuation of GH there were no changes in body composition, RMR, or BMC of patients with GHD, nor differences when compared with controls. RMR was reduced by 11.3 kJ/kg fat free mass two weeks after stopping GH in GHD patients and remained suppressed thereafter compared with controls. Percentage body fat increased by 4.3%/year in patients with GHD after discontinuing GH, whereas no changes were noted in control or non-GHD patients at one year. The patients experiencing the greatest reductions in RMR/kg fat free mass at six months showed the largest increases in body fat at one year. No change in BMC was noted in patients one year after stopping treatment., Conclusion: Important metabolic changes occur early after discontinuing GH treatment. In patients whose growth is complete, these changes might be used to predict those most likely to benefit from continuation of GH treatment into adult life.

In the majority of cases, short stature is due to normal physiological variations in growth and maturation. However, there are a significant number of other causes, some of which are amenable to treatment. This article reviews the clinical assessment and investigation of the short child in order to identify those children who might benefit from treatment.

Fourteen children receiving one year of recombinant human growth hormone (rhGH) treatment underwent measurement of serial changes in body composition (measured by skinfold thickness, bioelectrical impedance, and H2(18)O dilution), resting energy expenditure (REE, estimated by ventilated hood indirect calorimetry), and total free living daily energy expenditure (TEE, measured by the doubly labelled water technique). Mean height velocity increased from 4.9 to 8.6 cm/year after six months of treatment. Fat free mass (FFM) increased more during the first six weeks (24.4 g/day) than from six to 26 weeks of treatment (6.8 g/day); fat mass decreased by 7.2 g/day and 1.1 g/day respectively. The six week increase in REE (kJ/day) was maintained after six months of treatment, though expressed per kilogram FFM (kJ/kgFFM/day), returned to pretreatment values by three months. Height velocity increases at six months correlated with six week changes in fat mass measured by skinfold thickness and REE, though use of this relationship to predict growth response in individuals is limited by the wide 95% prediction intervals. No significant changes in growth, body composition, or energy expenditure were observed between six and 12 months of treatment, in either patients who had initially responded well to treatment or those who were poor initial responders to treatment and who had their dose of rhGH doubled after six months.

Total body water was estimated as part of the assessment of body composition in children with growth disorders, using the newly commercially available method of bioelectrical impedance. This was undertaken to compare the precision and accuracy of the results with those derived from skinfold thickness against measurement of stable isotopically labelled water (H2(18)O) dilution as a standard. The comparisons were carried out to see to what extent the impedance method could be applied with confidence to assessment of children with growth disorders. Total body water was derived from impedance (I) using an association with height (Ht2/I). Impedance and skinfold thickness estimates of total body water were equally precise when compared with values obtained from H2(18)O dilution (limits of agreement -1.9 to +1.3 and -1.7 to +2.0 kg respectively). The mean intraobserver coefficient of variation for repeat measurements of impedance was 0.9% compared with 4.6% for skinfold thickness with an interobserver coefficient of variation for impedance of 2.8%. Bioelectrical impedance estimation of body composition is likely to be of value in the growth clinic when expertise in measurement of skinfold thickness is limited or repeated measurements are to be undertaken by different observers.