Michael B. Ranke

Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome

Growth retardation resulting in short stature is a major concern for parents and due to its great variety of causes, a complex diagnostic challenge for clinicians. A major locus involved in linear growth has been implicated within the pseudoautosomal region (PAR1) of the human sex chromosomes. We have determined an interval of 170 kb of DNA within PAR1 which was deleted in 36 individuals with short stature and different rearrangements on Xp22 or Yp11.3. This deletion was not detected in any of the relatives with normal stature or in a further 30 individuals with rearrangements on Xp22 or Yp11.3 with normal height. We have isolated a homeobox-containing gene (SHOX} from this region, which has at least two alternatively spliced forms, encoding proteins with different patterns of expression. We also identified one functionally significant SHOX mutation by screening 91 individuals with idiopathic short stature. Our data suggest an involvement of SHOX in idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients.

Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy

BACKGROUND Some studies have suggested that treatment with recombinant human growth hormone (rhGH) increases left-ventricular mass and improves haemodynamic and functional status in patients with heart failure due to dilated cardiomyopathy. We did a double-blind, randomised, placebo-controlled study of rhGH in patients with chronic heart failure due to dilated cardiomyopathy. METHODS 50 patients (43 men) were randomly allocated treatment with subcutaneous rhGH (2 IU daily) or placebo for a minimum of 12 weeks. The primary endpoints were the effects on left-ventricular mass and systolic wall stress. The secondary endpoints were the effects on left-ventricular size and function. Data were analysed by intention to treat. FINDINGS Patients in the rhGH group had an increase in left-ventricular mass compared with those in the placebo group (27%, p=0.0001). There was no significant difference in left-ventricular systolic wall stress, mean blood pressure, or systemic vascular resistance between the two groups. New York Heart Association functional class, left-ventricular ejection fraction, and distance on the 6 min walking test were unchanged. The change in serum insulin-like growth factor (IGF)-I concentrations (rhGH 77 ng/mL; placebo -19 ng/mL, GH vs placebo p=0.0001) was significantly related to the change in left-ventricular mass (r=0.55, p=0.0001). One patient in the rhGH group was withdrawn at 6 weeks because of worsening heart failure. INTERPRETATION There is a significant increase in left-ventricular mass in patients with dilated cardiomyopathy given rhGH but this is not accompanied by an improvement in clinical status. Changes in left-ventricular mass are related to changes in serum IGF-I concentrations. Whether a longer treatment period would provide clinical benefits and decrease mortality is unknown.

Serum Insulin-Like Growth Factor I Reference Values for an Automated Chemiluminescence Immunoassay System: Results from a Multicenter Study

Background: Analysis of insulin-like growth factor I in serum (S-IGF-I) is an integral component in the diagnosis of GH-related disorders and is going to be of interest in the diagnosis and follow-up of many disorders. The objective of the present study was to develop cross-sectional reference values for S-IGF-I measured by an automated chemiluminescence immunoassay (Nichols Advantage®). Methods: The study included samples from 3,961 healthy subjects (2,201 males, 1,760 females) aged 1 month to 88 years. Six laboratories were involved in this study and the samples were analyzed by one of seven automated immunoassay systems run in these laboratories. For data analysis, polynomial age and sex-specific models were fitted after transformation of S-IGF-I values. Results: The results show the well-known age dependency of S-IGF-I levels. At ages <20, higher S-IGF-I levels were seen in girls with an estimated mean peak of 410 µg/l at age 14 and an estimated mean peak of 382 µg/l at age 16 in boys. Thereafter, a rapid decrease was seen to approximately 25 years of age, followed by a slow age-dependent decrease. In adulthood, S-IGF-I in males were slightly, but significantly higher than in females. It could be shown that the mean values of some reference sample subgroups differed significantly from the total mean. However, the multicenter approach used in this study reduces the impact of systematic population, sample handling and laboratory differences on the calculated reference mean. Conclusion: The present study establishes age- and sex-specific reference values for a fully automated immunoassay system based on a large population of healthy subjects. The established reference values may be used for this immunoassay system in different laboratories provided that the systematic difference between systems is low.

Turner syndrome: Spontaneous growth in 150 cases and review of the literature

The spontaneous growth of 150 patients with Turner syndrome from three German centers-90 with 45,X0 constitution, 60 with other chromosomal abnormalities-has been analyzed. The mean adult height was found to be (n=14) 146.8 cm. It was observed that growth in these patients can be divided into four phases: (1) Intrauterine growth, which is retarded; (2) Height development, which is normal up to abone-age of about 2 years; (3) Between a bone-age of 2 and 11 years when stunting of growth is most marked; (4) After a bone-age of 11 years—the time at which puberty should normally start—the growth phase is prolonged, but total height gain is only little below normal levels. No difference in height could be observed between cases with X0 karyotype and other chromosomal variants. The data are compared with those in the literature.

Turner's syndrome

Summary Before chromosomal analysis became available, the diagnosis of Turners syndrome was based on the characteristics independently described by Otto Ullrich and Henry Turner, such as short stature, gonadal dysgenesis, typical, visible dysmorphic stigmata, and abnormalities in organs, which present in individuals with a female phenotype. Today, Turners syndrome or Ullrich-Turners syndrome may be defined as the combination of characteristic physical features and complete or part absence of one of the X chromosomes, frequently accompanied by cell-line mosaicism. The increasing interest in Turners syndrome over the past two decades has been motivated both by the quest for a model by which the multi-faceted features of this disorder can be understood, and the endeavour to provide life-long support to the patient. New developments in research allow patients with Turners syndrome to have multidisciplinary care.

The ratio between serum levels of insulin-like growth factor (IGF)-I and the IGF binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients

OBJECTIVE Several in‐vitro studies have suggested that the biological actions of IGF‐I can be modified by the presence of specific IGF binding proteins. In man, the 24‐hour serum levels of IGF‐I and IGFBP‐3 remain constant, but short‐term changes in the IGF‐l/IGFBP‐3 ratio have been described following GH administration. Serum levels of IGF‐I and IGFBP‐3 decrease with age in normal adults and are elevated In active acromegaly due to excessive GH secretion. However, the Individual ratios between serum levels of IGF‐I and IGFBP‐3 in acromegalic and healthy adults have not been described previously.

Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment

BACKGROUND Growth hormone (GH) contributes to insulin resistance, but whether children treated with GH are at increased risk of diabetes has not been established. We undertook a retrospective analysis of data from an international pharmacoepidemiological survey of children treated with GH to find out the incidence of impaired glucose tolerance and types 1 and 2 diabetes mellitus. METHODS Reports to the survey of abnormal glucose metabolism were investigated and classified. The incidence and age-distribution of type 1 diabetes were compared with values from a model of reference data. The incidence of type 2 diabetes was compared with data from two reports of children not treated with GH. FINDINGS 85 (0.36%) of 23333 children were reported with abnormal glucose metabolism. After investigation, 43 had confirmed glucose disorders (11 with type 1 diabetes, 18 with type 2 diabetes, and 14 with impaired glucose tolerance). The incidence and age at diagnosis of type 1 diabetes in children treated with GH did not differ from expected values. The incidence of type 2 diabetes was 34.4 cases per 100000 years of GH treatment which was six-fold higher than reported in children not treated with GH. Type 2 diabetes did not resolve after GH therapy was stopped. INTERPRETATION GH treatment did not affect the incidence of type 1 diabetes mellitus in any age group. We postulate that the higher than expected incidence of type 2 diabetes mellitus with GH treatment may be an acceleration of the disorder in predisposed individuals.

Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3)

Abstract Assays for insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) have become essential tools in the diagnostic work-up of disorders of the somatotropic axis in children and adults. The aim of this study was to evaluate the automated IMMULITE® IGF-I and IGFBP-3 assays and to establish reference limits–central 95% intervals, median, 0.1 and other centiles as clinically relevant–as a function of age from 797 females and 787 males, from the first week of life through the ninth decade. Pubertal children were classified by sex and by sexual maturation (Tanner stage). IGF-I and IGFBP-3 levels were also assayed in 20 pediatric patients each with growth hormone deficiency (GHD) and Turner syndrome (UTS), before and during 12 months of recombinant growth hormone (rhGH) therapy, as well as in 11 adult patients with GHD and seven with acromegaly before therapy. Both the IGF-I and IGFBP-3 assays were accurate, specific and sufficiently sensitive to measure IGF-I and IGFBP-3 in serum with good linearity and recovery. In the IGF-I assay, potential interference from IGFBPs was eliminated by blocking with excess IGF-II. Circulating IGF-I and IGFBP-3 concentrations, and their ratio IGF-I/IGFBP-3, were age-dependent, showing low levels immediately after birth, a typical pubertal peak for girls and boys, and a pronounced decline after puberty, reaching a plateau in early adulthood. In adults IGF-I and IGFBP-3 levels decreased smoothly but steadily with age. Children with GHD and UTS had low circulating IGF-I and IGFBP-3 levels which increased to normal reference limits under therapy with rhGH. Adult GHD patients showed IGF-I levels below the age-related median; untreated acromegalic patients mostly had IGF-I and IGFBP-3 levels above the age-related 97.5th centile. In conclusion, the automated IMMULITE® IGF-I and IGFBP-3 assays are reliable tools in the diagnosis of pathologies of the GH/IGF axis and in the follow-up of their therapies.

Growth hormone resistance and inhibition of somatomedin activity by excess of insulin-like growth factor binding protein in uraemia

Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) were studied in children with end-stage renal failure (ESRF,n=31) and chronic renal failure (n=11) with residual glomerular filtration. Somatomedin bioactivity in patient sera was found to be decreased while IGF-I and IGF-II levels by radio-immunoassay (RIA) were normal. In contrast, IGFBP-1 and IGFBP-3 levels (measured by RIA) were markedly increased in uraemia. Excess IGFBP was shown to be able to bind IGF by determination of the free IGF binding capacity. Using high-performance liquid chromatography a shift of the IGFBP-3 profile to low molecular weight components could be demonstrated in ESRF. Affinity crosslinking experiments showed that these low molecular weight IGFBP-3 immunoreactive forms are biologically active. In normal urine only IGFBP-3 forms smaller than 60 kDa were detected with a major peak at 12–20 kDa. Removal of excessive IGFBP from patient sera by affinity chromatography on an IGF-II Sepharose column resulted in a significant increase in somatomedin bioactivity. Model calculations on the interaction of IGF and IGFBP using empirical data suggested a reduction of IGF secretion in uraemia by an order of magnitude. It is concluded: (1) that renal failure causes an accumulation of low molecular weight IGFBP, (2) that the resulting excess of IGFBP acts as a somatomedin inhibitor, and (3) that in uraemia there is a relative growth hormone resistance with respect to IGF production.

Acquired growth hormone resistance in patients with chronic heart failure: Implications for therapy with growth hormone

OBJECTIVES We aimed to determine whether growth hormone (GH) resistance is present in patients with chronic heart failure (CHF) and whether it may be linked to the biochemical response to GH treatment. BACKGROUND Acquired GH resistance is a feature of severe illness, in particular, cachexia. In patients with CHF, the response to GH therapy appears to be variable. METHODS Biochemical markers of the GH-insulin-like growth factor-I (IGF-I) axis were compared in 21 cachectic patients with CHF, 51 noncachectic patients and 26 healthy control subjects. In separate studies, the predictive value of baseline biochemical variables for the IGF-I response to GH treatment was analyzed. RESULTS Cachectic patients showed an increase of total GH and immunologically intact GH (p < or = 0.0002) and a decrease of GH-binding protein (BP) (p = 0.005), IGF-BP3 (p = 0.01) and IGF-I (p = 0.06), compared with noncachectic patients. Similar changes were found when the cachectic group was compared with the control group. No differences were found between noncachectic patients and control subjects. Levels of GH-BP correlated with the IGF-I/GH ratio in all subgroups (all p < or = 0.002). Baseline GH-BP levels were related to the increase of IGF-I levels in response to GH treatment in patients with CHF after 24 h (r = 0.83, p = 0.005; n = 9; study 2), 44 days (r = 0.52, p = 0.007; n = 25; study 3) and 96 days (r = 0.54, p = 0.006; n = 24; study 3). CONCLUSIONS Most cachectic and some noncachectic patients with CHF show features of acquired GH resistance. The principal predictors of the biochemical features of GH resistance and of the poor biochemical response to short-term and longer-term GH treatment are GH-BP plasma levels. The presence of GH resistance is potentially a major factor determining the response to GH therapy in patients with CHF.