Guy Massa

Final height after long-term growth hormone treatment in Turner syndrome

OBJECTIVESnTo study final height after long-term growth hormone (GH) treatment in girls with Turner syndrome (TS).nnnPATIENTSnOne hundred fifty three patients with TS, participating in five European trials, were included. They started GH treatment in 1987-1989 at an age of 10 years or older. Mean age at start of treatment ranged between 11.7 and 14.6 years among countries and mean bone age between 9.4 and 11.8 years. Fourteen girls were lost to follow-up, leaving 139 for analysis. Most girls have now attained final height (FH), defined as a linear growth velocity (GV) of 4 mm/yr or less, measured over at least 6 months (group 1, n = 56), or near-FH, defined as a GV of 5 to 9 mm/yr (group 2, n = 22). Sixty-one girls were still growing 10 mm/yr or more.nnnMETHODS AND MAIN RESULTSnAt the last measurement, mean (SD) height was 150.7 (4.9) cm in group 1 and 148.5 (5.1) cm in group 2. The differences between FH and projected final height based on extrapolation of the initial height-standard deviation score on Turner syndrome reference values, were 2.9 (3.8) and 3.0 (3.3) cm, respectively. The mean gain over the Bayley-Pinneau prediction of FH was 3.3 (3.9) cm in both groups. No significant differences between countries were found. The range of gains over projected height (-4.7 to 12.1 cm) was large, and 25% of gains were 5 cm or more. Gain over initial projection was strongly related to initial growth delay and to growth response during the first 2 years of treatment. A logistic regression model is presented that predicts gain of more than 5 cm with a positive predictive value of 62% and a negative predictive value of 84%.nnnCONCLUSIONSnLong-term GH treatment in girls with TS, starting treatment at a relatively advanced age ( > 10 years) resulted in a modest mean gain in FH of 3 cm, with wide interindividual variation.

Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues

BACKGROUND AND OBJECTIVE Growth hormone treatment In children with Idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long‐term effect of GH therapy in children with Idiopathic short stature.

Final Height in a Large Cohort of Dutch Patients with Growth Hormone Deficiency Treated with Growth Hormone

Final height was evaluated in 203 patients with growth hormone (GH) deficiency, who had been treated with GH in childhood, and was related to other factors. Mean final height was 168.1 cm (men) and 154.7 cm (women), -2.07 and -2.20 SD of the population mean, respectively. Patients with GH deficiency due to cerebral tumour were taller than those with idiopathic GH deficiency, and patients with induced puberty were taller than those with spontaneous puberty. Target height (r = +0.37), birth length (r = 0.36), height SDS at the start of therapy (r = +0.51) and at the start of puberty (r = +0.58) were significantly correlated with final height. Multiple linear regression analysis revealed that after correction for height at the start of puberty, age at the start of puberty was also positively correlated with final height. Patients who were treated after 1983 (when treatment regimens were changed) were taller than patients who finished treatment before 1983. The results suggest the importance of preventing a large initial height deficit and attaining optimal height at the start of puberty.

Treatment with Two Growth Hormone Regimens in Girls with Turner Syndrome: Final Height Results

In 1987 a multicentre trial of recombinant human growth hormone (GH) was started in girls with Turner syndrome. Fifty-four patients were randomly assigned to receive GH, 8 IU/m2 3 times/week (group 1), or 4 IU/m2 6 times/week (group 2). In addition, the 35 patients older than 12 years received ethinyloestradiol, 100 ng/kg body weight/day, and after 2 years GH therapy was increased to 6 IU/m2 6 times/week. Recombinant human GH treatment was stopped when the height increment during the previous 6 months of treatment was less than 0.5 cm. Treatment has so far been stopped in 48 patients: treatment was stopped early in 2 patients due to lack of motivation, 1 patient died suddenly and the treatment protocol was completed in 45 patients. The last height measurement obtained, which was considered as (near) final height, was 152.3 +/- 5.3 cm (mean +/- SD) in these patients, which is higher (p < 0.001) than the adult height of 147.0 +/- 6.3 cm reported in 63 untreated adult Dutch patients with Turner syndrome. No differences in outcome were found between the two dose regimens.

Body Mass Index in Growth Hormone Deficient Children before and during Growth Hormone Treatment

Growth hormone deficiency (GHD) is associated with truncal obesity. We aimed at identifying factors that determine the body mass index (BMI) of untreated GHD children and the changes in BMI during 2 years of GH therapy in 348 Dutch GHD children registered in the National GH Registration Database. BMI was expressed as a standard deviation score (SDS). Before GH therapy, the mean (95% CI) BMI-SDS in all GHD children (0.09 (–0.05 to 0.24) SDS) was comparable to normal children. Patients with GHD due to a cranial tumour have a higher BMI (1.03 (0.69–1.36) SDS; p < 0.0001) as well as those with multiple pituitary hormone deficiencies (0.35 (0.14–0.57) SDS; p = 0.005) and patients who are in puberty at start of GH therapy (0.60 (0.13–1.08) SDS; p = 0.036). During GH therapy BMI initially decreased to reach a nadir of –0.28 (–0.35 to –0.21) SDS at 6 months. Thereafter BMI progressively increased to –0.09 (–0.18 to –0.04) SDS after 24 months. A higher initial BMI-SDS resulted in a larger decrease in BMI-SDS. We showed that this can be sufficiently explained by a regression to the mean effect.

Steroid 11-beta-hydroxylase deficiency caused by compound heterozygosity for a novel mutation, p.G314R, in one CYP11B1 allele, and a chimeric CYP11B2/CYP11B1 in the other allele

Aims: Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common (5–8%) cause of congenital adrenal hyperplasia (CAH), and results from homozygous or compound heterozygous mutations or deletions of the responsible gene CYP11B1. In order to better understand the molecular basis causing 11β-OHD, we performed detailed studies of CYP11B1 in a newly described patient diagnosed with the classical signs of 11β-OHD. Methods:CYP11B1 of the patient was investigated by polymerase chain reaction (PCR), sequencing, restriction fragment length polymorphism (RFLP) analysis, Southern blotting, and transient cell expression. Results: We identified two new mutated alleles in CYP11B1. In one allele CYP11B1 has a g.940G→C (p.G314R) missense mutation. On the other allele we found a chimeric gene that consists of part of the aldosterone synthase gene (CYP11B2) at exons 1–3 and part of the 11β-hydroxylase gene (CYP11B1) at exons 4–9. Inin vitro studies, the g.940G→C (p.G314R) mutation abolished all hydroxylase activity in comparison with the wild-type 11β-hydroxylase. The chimeric CYP11B2/CYP11B1 protein retained 11β-hydroxylase enzymatic activity in vitro. Conclusion: This case is caused by compound heterozygosity for a nonfunctional missense mutation and a chimeric CYP11B2/CYP11B1 gene with hydroxylase activity that is controlled by the CYP11B2 promoter. The most likely explanation is that the CYP11B2 promoter does not function in the zona fasciculata/reticularis where cortisol is exclusively synthesized.

Growth hormone-binding proteins during human pregnancy: maternal, fetal and neonatal data.

Abstract Serum levels of growth hormone-binding protein (GHBP) were measured by high-performance liquid chromatography (HPLC) gel filtration in serum of 30 pregnant women and in cord serum of 69 preterm and term infants. In pregnant women, the mean ± SD serum level of GHBP was 32.4% ± 5.6%. Polynomial regression analysis showed a significant (P = 0.01) second-order relationship between the duration of pregnancy and serum GHBP levels, with increasing levels during the first half of pregnancy and decreasing levels thereafter. In cord serum, the mean ± SD serum level of GHBP was 3.1% ± 1.4% (n = 51) in preterm and 4.2% ± 1.3% (n = 18) in term neonates. Serum GHBP concentrations were related to gestational age (r = 0.35; P < 0.005) and to intrauterine nutritional state as evaluated by the ponderal index (r = 0.30; P < 0.02). In four term neonates, serum levels of GHBP were measured before and after an exchange transfusion (ET). Before the ET the serum GHBP level was 6.7% ± 2.4% and at the end it was 25.3% ± 2.6%. Thereafter, serum GHBP levels decreased slowly. Analysis of the elimination curve by exponential stripping showed a biexponential elimination pattern: GHBP (%) = 40· e(-5.1E-03 × time) + 64 · e(-2.5E-04 × time). The serum half-life of the GHBP complex was estimated to be about 2 days.

A Novel Nonsense Mutation in the CYP11B1 Gene from a Subject with the Steroid 11β‐Hydroxylase Form of Congenital Adrenal Hyperplasia

11β‐Hydroxylase deficiency (11β‐OHD) inherited in an autosomal recessive manner accounts for about 5–8% of congenital adrenal hyperplasia (CAH). In order to clarify the underlying mechanism causing 11β‐OHD, we have done the molecular genetic analysis on the CYP11B1 gene in a patient diagnosed as 11β‐OHD. The nucleotide sequence of the patients CYP11B1 revealed a novel nonsense mutation that converts codon 265 CAG (glutamine) to TAG (stop) of exon 4. Restriction fragment length polymorphism (RFLP) data showed that the patient was homozygous for the mutation. The above results confirm that the patient suffers from complete loss of the final step in cortisol biosynthesis pathway because of the nonsense mutation.

Length Velocity Acceleration at 9 Months of Age in a Representative Birth Cohort of Dutch Infants

According to the ICP (infancy-childhood-puberty) growth model, statural growth can be divided into three partially superimposed components assumed to represent different physiologic mechanisms. This model predicts a sudden acceleration of length velocity (LV) at the onset of the childhood component around 9 months. The existence of such an infancy-childhood growth spurt has not yet been firmly corroborated by epidemiological studies. In the present study length measurements were made at the target ages of 1, 3, 6, 9, 12, 15, 18 and 24 months in a birth cohort of 2034 infants. In order to check whether length growth showed a continuous smooth pattern, different mathematical models were fitted to the individual growth curves. The models included Count and Guo functions, 5th order polynomial and combinations of 5th order polynomial with the logarithmic term of the Count function and the square root term of the Guo function. We showed that in boys and girls there is a small but systematic lack of fit of the mathematical modeling, due to a sudden acceleration of LV around 9 months. In addition there was an increase in variation of attained length at this age. Comparison of unbalanced ANOVA models with and without addition of dummy variables for the target ages confirmed that there was an acceleration around 9 months that, if corrected for, leads to a significantly improved model fit (likelihood ratio test p < 0.0001). In absolute terms of LV, the misfit at 9 months was not greater than 0.5 cm/year on average. We conclude that the results of this study support the existence of a late infancy growth spurt. In our opinion, however, the magnitude of the phenomenon does not legitimate construction and use of discontinuous growth references such as the ICP reference.