New insights into factors influencing adult height in short SGA children: Results of a large multicentre growth hormone trial.

BACKGROUND: Growth hormone (GH) treatment is effective in improving adult height (AH) in short children born SGA. However, there is a wide variation in height gain, even after adjustment for predictive variables. It is therefore important to investigate new factors which can influence the response to GH. OBJECTIVE: To investigate the efficacy of GH treatment (1 mg/m(2/) day) in short SGA children on AH. To assess the relation between spontaneous catch-up growth after birth and growth during puberty on the total height gain SDS to AH. PATIENTS: Longitudinal GH trial in 170 children. RESULTS: Median age at start of GH was 7·1 years and height -3·0 SDS. AH was -1·8 SDS (TH-corrected AH -1·1 SDS) in boys and -1·9 SDS (TH-corrected AH -1·3 SDS) in girls. Spontaneous catch-up growth after birth was ≥0·5 SDS in 42% of children. In contrast to expectation, spontaneous catch-up growth was negatively correlated with total height gain SDS during GH (P = 0·009). During puberty, height SDS declined (-0·4 SDS in boys and -0·5 SDS in girls) resulting in a lower total height gain SDS than expected. Pubertal height gain was 25·5 cm in boys and 15·3 cm in girls, significantly lower compared to AGA children (P < 0·001). At onset of puberty, BA for boys and girls was moderately advanced (P = 0·02 and P < 0·001, respectively). Growth velocity was comparable to AGA children during the first two years of puberty, but thereafter significantly lower until reaching AH (P < 0·001). CONCLUSION: In contrast to our hypothesis, children with greater spontaneous catch-up growth after birth show a lower total height gain SDS during GH. Height SDS declines from mid-puberty, due to a marked early deceleration of growth velocity.

Successful treatment of severe subcutaneous insulin resistance with inhaled insulin therapy.

The potential of inhaled insulin therapy for severe resistance to subcutaneous insulin was tested in a 7-yr old boy with type 1 diabetes mellitus. The efficiency of 1 mg inhaled insulin (Exubera) was examined by a 4-h euglycemic clamp study. During the clamp, the glucose infusion rate started to increase 25 min after inhalation and peaked 120 min after inhalation. Subsequently, a trial of inhaled insulin monotherapy was initiated consisting of pre-meal inhalations and one inhalation during the night. Since glycemic control remained fair (HbA1c approximately 8.5%), this therapy was continued. Over the ensuing 18 months, mild keto-acidosis occurred twice during gastro-enteritis. Inhaled insulin was well tolerated and pulmonary function did not deteriorate. We conclude that severe resistance to subcutaneous insulin does not preclude sufficient absorption of insulin delivered by pulmonary.

Slow baseline growth and a good response to growth hormone (GH) therapy are related to elevated spontaneous GH pulse frequency in girls with Turner's syndrome.

Spontaneous growth and growth responses to GH therapy vary considerably among girls with Turner's syndrome. In an attempt to clarify this variability, we assessed growth parameters, 24-h GH profiles, arginine-stimulated serum GH levels, and plasma insulin-like growth factor-I (IGF-I) concentrations in a group of 41 girls with Turner's syndrome with a mean (+/- SD) age of 13 +/- 3 yr (range, 6.7-18.9). We subsequently treated all girls with biosynthetic GH (24 IU/m2 x week) and documented the growth response after 1 yr of therapy. GH profiles were analyzed according to Pulsar and Cluster, and GH secretion rates were calculated by waveform-independent deconvolution (Pulse). Factor analysis selected the mean 24-h GH secretion rate and number of GH peaks according to Cluster and Pulse as the principal GH profile variables to be used for further analysis. The mean (+/- SD) daily pituitary GH secretion rate was 127 +/- 47 micrograms/L.24 h (range, 37-232). The GH secretion rate correlated inversely with body mass index (r = -0.45; P < 0.01; n = 41). There was no relationship between the GH secretion rate and the growth parameters before or after GH therapy. However, the number of GH peaks (Pulse) correlated negatively with baseline height velocity (r = -0.53; P = 0.03) and was a positive predictor for height velocity increment during the first year of GH therapy (r = 0.71, P = 0.001). The mean (+/- SD) IGF-I level was 217 +/- 91 ng/mL (range, 87-413). There was no relationship between GH secretion rate or growth parameters and IGF-I. However, the number of GH peaks correlated negatively with IGF-I (r = -0.49; P = 0.04; n = 17). We conclude that an elevated spontaneous GH pulse frequency pattern is associated with relatively low IGF-I levels and slow baseline growth in girls with Turner's syndrome and that girls with such a pulse pattern may benefit most from exogenous GH therapy.

Yearly stepwise increments of the growth hormone dose results in a better growth response after four years in girls with Turner syndrome. Dutch Working Group on Growth Hormone.

To optimize the growth promoting effect of growth hormone (GH), 65 previously untreated girls with Turner syndrome (TS), chronological age (CA) 2-11 yr, were randomized into 3 dosage regimen groups: A, B, and C, with a daily recombinant-human GH dose during 4 study years of 4-4-4-4, 4-6-6-6, and 4-6-8-8 IU/m2 b.s. The first GH dosage increase in groups B and C resulted in a significantly higher mean height velocity (HV) compared with constant dose group A. During the third year, when the dose was raised again only in group C, mean HV was significantly higher in groups B and C than in group A, and in group C compared with group B. In year 4 only group C mean HV remained significantly higher than group A. The pattern of change in HSDSCA (Dutch-Swedish-Danish Turner references) was identical; however, in year 4 mean delta HSDSCA in group B also remained significantly higher than group A. After 4 yr GH treatment, the following was determined. 1) The mean delta HSDSCA was significantly higher for groups B and C compared with group A, but not significantly different between groups B and C. 2) Although significantly higher compared with estimated values for untreated Dutch girls with TS, bone maturation of the GH treated girls was not significantly different between groups. 3) It was positively related with the degree of bone age (BA) retardation at start of study and negatively with baseline CA. 4) Both the modified Index of Potential Height (mIPHRUS) and a recently developed Turner-specific final height (FH) prediction method (PTSRUS), based on regression coefficients for H, CA, and bone age, showed significant increases in mean FH prediction, without significant differences between groups. PTSRUS values were markedly higher than the mIPHRUS values. Dose dependency could be shown for the area under the curve (AUC) for GH, but delta HSDSCA was not linearly related with AUC. Baseline GH binding protein (BP) levels were in 84% of the cases within the normal age range; the decrease in mean levels after 6 months GH was not significant. Mean insulin-like growth factor I (IGF-I) and IGFBP-3 plasma levels increased significantly, without significant differences between groups. delta HSDSCA during GH was dependent on IGF-I plasma levels at baseline and during the study period, beta-0.002 and beta-0.0004. Thus, a stepwise GH-dosing approach reduced the "waning" effect of the growth response after 4 yr treatment without undue bone maturation. FH prediction was not significantly different between treatment groups. Irrespective of the GH dose used, initiation of GH treatment at a younger age was beneficial after 4 yr GH when expressed as actual cm gained or as gain in FH prediction, but was not statistically significant when expressed as delta HSDSCA over the study period.

Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial.

Short stature and ovarian failure are the main features in Turner syndrome (TS). To optimize GH and estrogen treatment, we studied 68 previously untreated girls with TS, age 2-11 yr, who were randomly assigned to one of three GH dosage groups: group A, 4 IU/m2 day (approximately 0.045 mg/kg x day); group B, first yr 4, thereafter 6 IU/m2 x day (approximately 0.0675 mg/kg/day); group C, first yr 4, second yr 6, thereafter 8 IU/m2 x day (approximately 0.090 mg/kg x day). In the first 4 yr of GH treatment, no estrogens for pubertal induction were given to the girls. Thereafter, girls started with 17beta-estradiol (5 microg/kg bw x day, orally) when they had reached the age of 12 yr. Subjects were followed up until attainment of adult height or until cessation of treatment because of satisfaction with the height achieved. Seven-year data of all girls were evaluated to compare the growth-promoting effects of three GH dosages during childhood. After 7 yr, 85% of the girls had reached a height within the normal range for healthy Dutch girls. The 7-yr increment in height SD-score was significantly higher in groups B and C than in group A. In addition, we evaluated the data of 32 of the 68 girls who had completed the trial after a mean duration of treatment of 7.3 yr (range, 5.0 - 8.75). Mean (SD) height was 158.8 cm (7.1), 161.0 cm (6.8), and 162.3 cm (6.1) in groups A, B, and C, respectively. The mean (SD) difference between predicted adult height before treatment and achieved height was 12.5 cm (2.1), 14.5 cm (4.0), and 16.0 cm (4.1) for groups A, B, and C, respectively, being significantly different between group A and group C. GH treatment was well tolerated in all three GH dosage groups. In conclusion, GH treatment starting in relatively young girls with TS results in normalization of height during childhood, as well as of adult height, in most of the individuals. With this GH and estrogen treatment regimen, most girls with TS can grow and develop much more in conformity with their healthy peers.

[Transposition of the great vessels, results of 2 surgical technics]. / Transpositie van de grote vaten, resultaten van twee operatietechnieken.

Venous switch operations for simple transposition of the great arteries are being carried out in increasingly younger patients. To guarantee sufficient growth of the reconstructed atria into adulthood it is advantageous to use as little prosthetic material as possible. We therefore compared the results in 36 patients who underwent the Mustard operation in which a large amount of foreign material is used with the results in 36 patients who underwent the Senning operation in which a small amount, if any, foreign material is used. The Senning operation resulted in a lower hospital mortality and a lower incidence of dysrhythmias.

[Turner syndrome: a virtually certain indication for growth hormone treatment]. / Turner-syndroom: een vrijwel vaststaande indicatie voor groeihormoonbehandeling.

Short stature is a feature in almost all cases with Turner syndrome. The etiology is unknown, but GH secretion appears to be normal. The treatment with anabolic steroids does not seem to increase final height. Oestrogens are needed for secondary sex characteristics, but should be given in a low dosage and at approximately 12-13 years of age, in order not to compromise final height. Growth hormone increases growth velocity and leads to an average gain of 5 cm in terms of final height. The addition of oxandrolone leads to an even higher growth rate, but final height is probably similar to that reached by growth hormone alone. The dosage, injection frequency, age and bone age at the start of therapy have influence on the efficacy. GH in the dosages given appears safe.

[Hyperthyroxinemia without hyperthyroidism]. / Hyperthyroxinemie zonder hyperthyreoïdie.

The various causes of persisting hyperthyroxinemia without hyperthyroidism are discussed after short case histories of an infant with hyperthyroxinemia due to TBG excess, discovered by newborn screening for congenital hypothyroidism and a girl with peripheral resistance to thyroid hormones disclosed by investigation of a small goiter. The differentiation of these various causes by thyroid function-tests is indicated. Though the anomalies leading to euthyroid hyperthyroxinemia are usually harmless their timely recognition, also in other members of the family, will prevent erroneous diagnosis and treatment of hyperthyroidism.

Primary adrenocortical insufficiency in childhood.

Seven patients with primary glucocorticoid or glucocorticoid and mineralocorticoid deficiency are described with emphasis on the clinical presentation and laboratory investigations. Two patients presented with irreversible shock and at autopsy adrenal tissue was recognized only microscopically. In 3 patients adrenal antibodies were present. One girl had the polyglandular autoimmune disorder type I and one boy had glucocorticoid deficiency only. The histories of the patients illustrate that the presenting symptoms of primary adrenocortical insufficiency are very insidious and that it may take several years before the correct diagnosis is made and hydrocortisone substitution therapy is instituted.

Body weight in children with Turner syndrome treated with growth hormone.

OBJECTIVE: As overweight is a major concern in many children with Turner syndrome, we studied the effect of growth-promoting treatment with human growth hormone (hGH) on body weight indices. DESIGN: Longitudinal study of the effect of hGH on weight indices over time in a cohort of Turner girls of different ages. SUBJECTS: An index group of 199 hGH treated girls and a reference group of 569 untreated girls. METHODS: Turner-specific weight-for-age, weight-for-height and body mass index-for-age (BMI) values were computed. In order to take account of regression to the mean, we studied spontaneous changes of these variables in the reference group. References for spontaneous changes over 3, 6, 12 or 24 months were constructed. Observed changes in the index group were corrected by subtracting the expected spontaneous change. Corrected changes were compared between overweight, normal and underweight children. RESULTS: Treatment with hGH leads to a temporary decrease of weight indices during the first six months. This decreasing effect was not seen in overweight children. Treatment increases BMI in overweight children over 24 months, but not in normal or underweight children. BMI at start of hGH treatment did not modify long-term growth response. CONCLUSION: hGH treatment does not help to improve BMI in Turner syndrome children with a tendency to overweight.

Long-term effect of human growth hormone therapy on the prevalence of autoantibodies in Turner syndrome. The Dutch Growth Hormone Working Group.

Abnormalities of immune status, particularly a high prevalence (about 50%) of thyroid autoantibodies, have been reported before in Turner syndrome. Results are conflicting as regards other abnormalities of immune function. Growth hormone (GH) has immunomodulatory effects, but results of its effects on GH-deficient children are inconsistent. In this study, 42 girls with Turner syndrome, aged 7.3-19 years, are investigated before, during and after 4 years of human GH therapy. Girls over 12 years old also received ethinyl oestradiol. The prevalence of antithyroid antibodies was 16.7% initially, 35.3% after 24-45 months and 48% after 4 years of therapy though, as there was no control group, it was difficult to conclude that GH was enhancing their appearance. Hypothyroidism was extremely uncommon, and the growth response was no different in those who had the antibodies from those who had not. There were no dramatic increases in prevalence of any of the other antibodies investigated, though the prevalence of parietal cell antibodies was higher than expected.

Immunologic studies in Turner syndrome before and during treatment with growth hormone. The Dutch Growth Hormone Working Group.

Immunologic studies of 14 girls with Turner syndrome were done before and during treatment with biosynthetic growth hormone (GH). Compared with control subjects, the patients before treatment had a decreased CD4/CD8 ratio and an increased number of cells bearing the natural killer cell marker CD16; serum immunoglobulin levels were within the normal range. During GH treatment some of the girls had a slight reduction in the percentage of CD20+ B cells, but we observed no impairment of B lymphocyte function as demonstrated by the normal in vivo antibody response to the primary antigen Helix Pomatia hemocyanin, administered 6 months after the start of GH treatment. The number of CD16+ natural killer cells returned to normal. Although the number of children with thyroid antibodies increased from two before treatment to five after 1 year, no conclusion about an adverse effect of GH is warranted, because the phenomenon might be part of the natural course of the disease. We conclude that girls with Turner syndrome have minor changes in some immunologic measurements and that GH treatment resulted in some alterations that have no effect on immune function.

Reference values for height, height velocity and weight in Turner's syndrome. Swedish Study Group for GH treatment.

As Northern Europeans are currently the tallest people in the world, specific growth charts for girls with Turner's Syndrome from this area are needed. Based on height and weight measurements from 598 girls with Turner's Syndrome (372 from the Netherlands, 108 from Denmark, 118 from Sweden) not treated with growth-promoting substances and without signs of spontaneous puberty, we constructed growth charts for height-for-age, height-velocity-for-age, weight-for-age, weight-for-height and Body Mass Index for age. Reference tables and regression equations for mean and standard deviation are provided allowing calculation of Standard Deviation Scores. The height and height velocity curves show a low birth length, gradual deviation from the normal percentile curves without pubertal growth spurt, and a prolonged growth until the early 20s. Mean adult height was 146.9 +/- 7.8 cm. Mean weight-for-age was lower than in normal reference children but height-adjusted weight was higher, except in infancy and early childhood. Further studies are required on the factors influencing the weight-height relationship in Turner's Syndrome.

A regression method including chronological and bone age for predicting final height in Turner's syndrome, with a comparison of existing methods.

A total of 235 measurement points of 57 Dutch women with Turner's syndrome (TS), including women with spontaneous menarche and oestrogen treatment, served to develop a new Turner-specific final height (FH) prediction method (PTS). Analogous to the Tanner and Whitehouse mark 2 method (TW) for normal children, smoothed regression coefficients are tabulated for PTS for height (H), chronological age (CA) and bone age (BA), both TW RUS and Greulich and Pyle (GP). Comparison between all methods on 40 measurement points of 21 Danish TS women showed small mean prediction errors (predicted minus observed FH) and corresponding standard deviation (ESD) of both PTSRUS and PTSGP, in particular at the "younger" ages. Comparison between existing methods on the Dutch data indicated a tendency to overpredict FH. Before the CA of 9 years the mean prediction errors of the Bayley and Pinneau and TW methods were markedly higher compared with the other methods. Overall, the simplest methods--projected height (PAH) and its modification (mPAH)--were remarkably good at most ages. Although the validity of PTSRUS and PTSGP remains to be tested below the age of 6 years, both gave small mean prediction errors and a high accuracy. FH prediction in TS is important in the consideration of growth-promoting therapy or in the evaluation of its effects.

Shape of the craniofacial complex in children with Turner syndrome.

The shape of the craniofacial complex was established in 69 children with Turner syndrome aged between 3.5 and 16.6 years. The children had not been treated with growth hormone (GH) or anabolic steroids. On a standardized lateral roentgenencephalogram 13 linear and 7 angular variables were measured. Data of all variables were available from normal Dutch children for comparison. The main abnormalities were located in the cranial base and in the mandible and consisted of a short posterior cranial base, all increased cranial base angle and a short, retrognathic and posteriorly rotated mandible. The maxilla was smaller than normal and also slightly posteriorly rotated. The abnormalities were already present in young children with Turner syndrome. Indications were found that in Turner syndrome interstitially as well as appositionally growing cartilage is affected. The changes in the maxilla can be explained in various ways. They may be due to defective growth of the nasal cartilage or to a disorder in the intramembranous ossification of the maxilla or they may be adaptive to the changes in the cranial base and the mandible. From this study it can be concluded that patients with Turner syndrome exhibit several craniofacial abnormalities, probably due to a cartilage disorder.

Growth hormone treatment in Turner syndrome accelerates growth and skeletal maturation. Dutch Growth Hormone Working Group.

Sixteen girls with Turner syndrome (TS) were treated for 4 years with biosynthetic growth hormone (GH). The dosage was 4 IU/m2 body surface s.c. per day over the first 3 years. In the 4th year the dosage was increased to 6 IU/m2 per day in the 6 girls with a poor height increment and in 1 girl oxandrolone was added. Ethinyl oestradiol was added after the age of 13. Mean (SD) growth velocities were 3.4 (0.9), 7.2 (1.7), 5.3 (1.3), 4.3 (2.0) and 3.6 (1.5) cm/year before and in the 1st, 2nd, 3rd and 4th year of treatment. Skeletal maturation advanced faster than usual in Turner patients especially in the younger children. Although the mean height prediction increased by 5.6 cm and 11 of the 16 girls have now exceeded their predicted height, the height of the 4 girls who stopped GH treatment exceeded the predicted adult height by only 0 to 3.4 cm.

Growth hormone therapy in Turner's syndrome. Impact of injection frequency and initial bone age.

STUDY OBJECTIVE: To determine the influence of the injection frequency and the initial bone age on the efficacy of treatment with biosynthetic growth hormone in Turner's syndrome. DESIGN: Randomized study. SETTING: Referral-based pediatric endocrinology departments of seven university medical centers. PATIENTS: Fifty-two patients with Turner's syndrome confirmed with chromosomal analysis. TREATMENT: Somatotropin recombinant DNA (24 IU/m2 of body surface area) subcutaneously administered in three or six injections per week for 2 years. Patients who were older than 12 years at the beginning of the study received low doses of estrogen. RESULTS: The following statistically significant findings supported the use of six injections per week compared with three injections per week: the mean (+/- SD) increment in height during 2 years was 11.3 cm (3.8 cm) with six injections vs 8.6 cm (3.4 cm) with three injections; the increment in height standard deviation score was 0.9 cm (0.5 cm) vs 0.6 cm (0.3 cm); the growth velocity was 6.6 cm/y (2.0 cm/y) vs 5.2 cm/y (1.7 cm/y) in year 1 and 4.7 cm/y (2.0 cm/y) vs 3.4 cm/y (1.7 cm/y) in year 2; and the increment in height standard deviation score for bone age was 0.8 cm (0.5 cm) vs 0.4 cm (0.6 cm). For patients whose initial bone age was more than 13 years, growth velocity increased by 1 to 2 cm in year 1; in year 2 no increment was observed. We did not observe adverse effects. CONCLUSIONS: Biosynthetic growth hormone in a higher-frequency regimen in Turner's syndrome is more efficient in terms of increment in height, growth velocity, and height standard deviation score for bone age than treatment in a lower-frequency regimen. In patients with an initial bone age of more than 13 years, the response was poor. Longer follow-up is necessary to assess the effect on final height.

Two-year results of treatment with methionyl human growth hormone in children with Turner syndrome. Dutch Growth Hormone Working Group.

Methionyl growth hormone (somatrem) in a daily dosage of 4 IU/m2 body surface area was administered to 16 girls with Turner syndrome. Low dose ethinyl estradiol (0.1 microgram/kg body weight) was added in girls aged 13 years or more. Mean (SD) height velocity increased from 3.4 (0.9) to 7.2 (1.7) and 5.3 (1.3) cm/year in the first and second year, respectively. Bone age advanced 1.8 years over 2 years and predicted adult height was increased. Apart from the occurrence of anti-GH antibodies there were no side effects. In conclusion, somatrem is an efficacious and safe therapy for short stature in Turner syndrome over a period of 2 years. Longer follow-up is needed before conclusions about its effect on final height can be drawn.