Lars Hagenäs

Dose-Dependent Effect of Growth Hormone on Final Height in Children with Short Stature without Growth Hormone Deficiency

CONTEXT The effect of GH therapy in short non-GH-deficient children, especially those with idiopathic short stature (ISS), has not been clearly established owing to the lack of controlled trials continuing until final height (FH). OBJECTIVE The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children, mainly with ISS, compared with untreated controls. DESIGN AND SETTING A randomized, controlled, long-term multicenter trial was conducted in Sweden. INTERVENTION Two doses of GH (Genotropin) were administered, 33 or 67 microg/kg.d; control subjects were untreated. SUBJECTS A total of 177 subjects with short stature were enrolled. Of these, 151 were included in the intent to treat (AllITT) population, and 108 in the per protocol (AllPP) population. Analysis of ISS subjects included 126 children in the ITT (ISSITT) population and 68 subjects in the PP (ISSPP) population. MAIN OUTCOME MEASURES We measured FH sd score (SDS), difference in SDS to midparenteral height (diff MPHSDS), and gain in heightSDS. RESULTS After 5.9+/-1.1 yr on GH therapy, the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 (33 microg/kg.d, -1.7+/-0.70; and 67 microg/kg.d, -1.4+/-0.86; P<0.032), vs. -2.4+/-0.85 (P<0.001); the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 (P<0.001); and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 (P<0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations. CONCLUSION GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls.

Growth hormone treatment of short children born small-for-gestational-age: the Nordic Multicentre Trial

The aims of this study were to evaluate the efficacy and safety of different doses of growth hormone (GH) treatment in prepubertal short children born small‐for‐gestational‐age (SGA). Forty‐eight children born SGA from Sweden, Finland, Denmark and Norway were randomly allocated to three groups: a control group of 12 children received no treatment for 2 y, one group was treated with GH at 0.1 IU/kg/d (n= 16), and one group was treated with GH at 0.2 IU/kg/d (n= 20). In total 42 children completed 2 y of follow‐up, and 24 children from the treated groups completed 3 y of treatment. Their mean (SD) age at the start of the study was 4.69 (1.61) y and their mean (SD) height was ‐3.16 (0.70) standard deviation scores (SDS). The children remained prepubertal during the course of the study. No catch‐up growth was observed in the untreated group, but a clear dose‐dependent growth response was found in the treated children. After the third year of treatment, the group receiving the higher dose of GH, achieved their target height. The major determinants of the growth response were the dose of GH used, the age at the start of treatment (the younger the child, the better the growth response) and the family‐corrected individual height deficit (the higher the deficit, the better the growth response). Concentration of insulin‐like growth factor‐I (IGF‐I) and IGF‐binding protein‐3 increased during treatment. An increase in insulin levels was found without negative effects on fasting glucose levels or glycosylated haemoglobin levels. GH treatment was well tolerated. In conclusion, short prepubertal children born SGA show a dose‐dependent growth response to GH therapy, and their target height SDS can be achieved within 3 y of treatment given GH at 0.2 IU/kg/d. However, the long‐term benefit of different regimens of GH treatment in children born SGA remains to be established.

Prevalence of coeliac disease in Turner syndrome.

This study was undertaken to investigate the prevalence of coeliac disease in children and adolescents with Turner syndrome. Eighty‐seven children and adolescents with Turner syndrome were screened for IgA‐antiendomysium antibodies (EMA) and IgA‐antigliadin antibodies (AGA), 5% (4/87) being found to be EMA‐positive, and 15% (13/87) to have AGA levels above normal. Of the 10 patients who were either AGA‐ or EMA‐positive and further investigated with intestinal biopsy, four manifested villous atrophy (i.e. all three of the EMA‐positive patients, but only one of the seven AGA‐positive patients). The results suggest EMA‐positivity to be a good immunological marker for use in screening for coeliac disease, and such screening to be justified in patients with Turner syndrome. □Coeliac disease, IgA‐antiendomysium antibodies, IgA‐antigliadin antibodies, Turner syndrome

Analysis of short stature homeobox-containing gene ( SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity

Abstract. Dyschondrosteosis (DCO; also called Léri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.

Growth hormone treatment in 35 prepubertal children with achondroplasia: a five-year dose-response trial

Background: Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature. Aim: In a 5‐y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia. Methods: Patients were randomized to either 0.1 IU/kg (n=18) or 0.2 IU/kg (n=17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch‐down growth. Mean height SDS (HSDS) at start was −5.6 and −5.2 for the low‐ and high‐dose groups, respectively, and mean age 7.3 and 6.6 y. Results: Mean growth velocity (baseline 4.5/4.6 cm/y for the groups) increased significantly by 1.9/3.6 cm/y during the first year and by 0.5/1.5 cm/y during the second year. During the third year, a decrease of growth velocity was observed at 1.9/1.3 cm/y below baseline values. HSDS increased significantly by 0.6/0.8 during the first year of treatment and in total by 1.3/1.6 during the 5 y of study. Sitting height SDS improved significantly from −2.1/−1.7 to −0.8/0.2 during the study. Body proportion (sitting height/total height) or arm span did not show any significant change.

Growth Hormone Treatment of Children with Prader-Willi Syndrome: Effects on Glucose and Insulin Homeostasis

Insulin and glucose homeostasis have been studied during growth hormone (GH) treatment in 19 prepubertal children with Prader-Willi syndrome (PWS) and compared with 11 healthy prepubertal obese children. Before treatment, insulin levels in children with PWS were lower (p < 0.01) than in healthy obese children. During GH treatment, fasting insulin levels increased in children with PWS (p < 0.001). Glucose levels were similar for PWS and obese children before treatment. Children with PWS showed a slow glucose disappearance rate (k = 1.7%) which deteriorated (k = 1.3%, p < 0.001) during GH treatment. HbA1c and fasting glucose levels remained normal. Thus, GH treatment of children with PWS resulted in increased insulin blood levels, unchanged fasting glucose and HbA1c but decreased glucose elimination rate after an intravenous glucose test. However, the observed dose-dependent increase in insulin levels during GH treatment, that reached supranormal concentrations in 6/19 patients, and the occurrence of NIDDM in 1 patient during follow-up suggest that close surveillance and low doses of GH should be applied, especially if the PWS patient is very obese.

Mutations in short stature homeobox containing gene ( SHOX ) in dyschondrosteosis but not in hypochondroplasia

Abstract. Dyschondrosteosis (DCO) and hypochondroplasia (HCH) are common skeletal dysplasias characterized by disproportionate short stature. The diagnosis of these conditions might be difficult to establish especially in early childhood. Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are found in 40–70% of HCH cases. In this study, we performed mutational analysis of the coding region of the SHOX gene in five DCO and 18 HCH patients, all of whom tested negative for the known HCH-associated FGFR3 mutations. The polymorphic CA-repeat analysis, direct sequencing and Southern blotting were used for detection of deletions and point mutations. The auxological and radiological phenotype of these patients was carefully determined. Three novel mutations in DCO patients were found: (1) a deletion of one base (del272G) (according to GenBank accession nos. Y11536, Y11535), resulting in a premature stop codon at position 75 of the amino acid sequence; (2) the transversion C485G resulting in the substitution Leu132Val; and (3) the transversion G549T causing an Arg153Leu substitution. These substitutions segregate with the DCO phenotype and affect evolutionarily conserved homeodomain residues, based on a comparison of homeobox containing proteins in 13 species. Moreover, these changes were not found in 80 unrelated, unaffected individuals. This strongly suggests that these mutations are pathogenic. The phenotype of our patients with DCO and HCH varied from mild to severe shortness and body disproportion. These results further support clinical and genetic heterogeneity of dyschondrosteosis and hypochondroplasia.

A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia

Hypochondroplasia and achondroplasia are skeletal dysplasias, characterised by autosomal dominant inheritance and disproportionate short stature, which occurs mainly due to growth failure of the extremities. Both dysplasias have been mapped to fibroblast growth factor receptor 3 (FGFR3) gene. For hypochondroplasia, two point mutations, both responsible for the Asn540Lys substitution in the region coding the tyrosine kinase domain have been reported.

Skeletal Dysplasia, Growth Hormone Treatment and Body Proportion: Comparison with Other Syndromic and Non-Syndromic Short Children

Skeletal dysplasias comprise a diverse group of conditions that usually compromise both linear growth and body proportions. It is of theoretical interest to evaluate the effect of GH treatment on linear growth, body proportion and final height in the different skeletal dysplasias. Reported experience of GH treatment in short children with skeletal dysplasia is sparse and often limited to short treatment periods and knowledge of its effects on final height and body proportion is generally lacking. Formal studies are almost all confined to achondroplasia as the most common entity. First-year response is typically a 2–3 cm increase in growth velocity in prepubertal children, or a gain of about 0.5 SDS or less in relative height from a baseline level of –4 to –5 SDS. GH treatment for up to 5 years in achondroplasia can produce a total height gain of about 1 SDS. Apart from achondroplasia, treatment of hypochondroplasia and dyschondrosteosis with GH has been reported in a small number of patients. Long-term data are, however, lacking. Of theoretical interest is that in many syndromic or non-syndromic short-statured children body proportion, i.e. trunk to leg length ratio, does not seem to be dependent on the degree of GH sufficiency and does not seem to be changed by GH treatment. GH treatment, at least in the prepubertal period, does seem to influence degree of disproportion.

Hunger behaviour contributes to early nutritional homeostasis

Objectives and methods: Our goal was to describe nutritional homeostasis in healthy exclusively breastfed infants (n= 175) during their first 5d, by cross‐sectional measurements of body weight, blood glucose, plasma insulin, insulin‐like growth factor‐I (IGF‐I), insulin‐like growth factor binding‐protein‐1 (IGFBP‐1), free fatty acids (FFA), glycerol, ketone (3‐OH‐butyric acid) and lactate. We also investigated whether nutrition affected feeding behaviour by timing the interval between feedings. Results: A progressive loss of body weight, as percentage of birthweight, occurred up to 2 d of age, with a maximal decrease of 5.8 ± 2.1% (mean ± SD); this was accompanied by inhibition of anabolic hormone and metabolic pathways and an increased mobilization of stored fat and ketogenesis. The interval between feedings decreased between d 1 and 2. Weight gain occurred at 3 d and the following re‐feeding phase returned fuel stores to their previous levels and established an anabolic hormonal and metabolic situation. Infants with weight loss exceeding 10% had a further accentuation in their peripheral picture of starvation and a further 7% shortening of the interval between feedings. Conclusions: breastfeeding on demand is accompanied by a balanced nutritional situation and an increased drive to eat when weight reduction is <6%. However, a weight loss of ≥10%, probably elicits hunger sensations in response to decreased fuel availability.