Effect of long-term growth hormone treatment on final height of children with Russell-Silver syndrome.

BACKGROUND: The aim of this study was to determine the beneficial effects of long-term growth hormone (GH) treatment on final height (FH) in 26 children with Russell-Silver syndrome (RSS). METHODS: Twenty-six patients (16 males) were diagnosed with RSS at a median age of 2.9 years according to clinical criteria. All patients were prepubertal at the commencement of treatment. They received treatment with biosynthetic human GH for 9.8 years (median) and all attained FH. RESULTS: The median height at the commencement of treatment was -2.7 SDS and increased to -1.3 SDS (p = 0.001). However, FH did not reach target height (-0.90 SDS, p = 0.003). Predictors of FH outcome were: the height at the start of treatment (r(2) = 0.419, p < 0.001) (inversely related) and the height gain at onset of puberty (r(2) = 0.257, p < 0.001) (positively related). The overall prediction model accounted for 67.6% of height gain. Sitting height improved gradually during GH treatment (-3.3 to -1.0 SDS, p = 0.012), as did weight (-3.3 to -1.3 SDS, p < 0.001) and BMI (-1.5 to -0.2 SDS, p < 0.001). CONCLUSIONS: A significant improvement of growth in RSS children has been shown after 10 years of GH treatment with a FH of -1.3 SDS. The shorter the patient at the start of treatment is, the greater the increment in FH. A significant response is also shown at the onset of puberty. GH treatment may also have a beneficial effect on the spinal length of RSS children.

Bioequivalence studies of omnitrope, the first biosimilar/rhGH follow-on protein: two comparative phase 1 randomized studies and population pharmacokinetic analysis.

This article discusses the bioequivalence of Omnitrope (Sandoz's rhGH biosimilar) and Genotropin (reference rhGH product), assessed in the first 2 clinical phase 1 studies conducted during the development of Omnitrope. Both of these phase 1 studies were randomized, double-blind, crossover studies, each involving 24 healthy volunteers who underwent pituitary somatrope cell down-regulation using octreotide. Three different formulations of recombinant human growth hormone (rhGH) were compared: Omnitrope lyophilisate, Omnitrope liquid and Genotropin (lyophilized powder for injection). Both pharmacokinetics (area under the curve [AUC], C(max), t(max) and t(1/2)) and pharmacodynamics (serum levels of insulin-like growth factor 1, insulin-like growth factor binding protein-3 and non-esterified fatty acid) were assessed after a single subcutaneous injection of 5 mg rhGH. The 3 formulations had comparable pharmacokinetics and pharmacodynamics. All the 90% confidence intervals of the ratios of the least squares means for the pharmacokinetic and pharmacodynamic parameters AUC and C(max) were within the predefined FDA and EMEA acceptance range of 80%-125% for bioequivalence. In addition, a comparative population pharmacokinetic analysis further supports that Omnitrope lyophilisate, Omnitrope liquid and Genotropin can be regarded as equivalent in terms of pharmacokinetics. Therefore, Omnitrope lyophilisate was demonstrated to be bioequivalent to both Genotropin and the Omnitrope liquid formulation.

Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3.

CONTEXT: Congenital deficiency of the neuroendocrine-specific enzyme prohormone convertase (PC) 1/3 leads to a syndrome characterized by obesity, small intestinal dysfunction, and dysregulation of glucose homeostasis in humans. To date, only two unrelated subjects with this disorder have been reported. RESEARCH DESIGN AND METHODS: We now report a third proband, a 6-yr-old boy, offspring of a consanguineous union of parents of North African origin, who was homozygous for a novel missense mutation Ser307Leu. We characterized the functional properties of the mutant PC1/3 and characterized the clinical phenotype of the patient. RESULTS: In vitro this mutation markedly impairs the catalytic activity of the convertase. However, in contrast to other previously described naturally occurring mutations, intracellular trafficking of this mutant enzyme appeared normal. The Ser307Leu mutant retained some autocatalytic activity, even though it was completely inactive on other substrates. As with the previous two patients, this child had obesity and persistent diarrhea, however, there was no history of reactive hypoglycemia. The patient showed markedly increased food intake at an ad libitum test meal, confirming that hyperphagia makes a major contribution to the obesity seen in this syndrome. CONCLUSION: This case extends the clinical and molecular spectrum of human congenital PC1/3 deficiency.

Phenotypic variability in 17beta-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls.

OBJECTIVE: 17beta-hydroxysteroid dehydrogenase type 3 isoenzyme (17beta-HSD3) is required to produce testosterone for male sex differentiation. Mutations in the HSD17B3 gene cause 17betaHSD3 deficiency and result in XY sex reversal of varying degree. We report the phenotypes of 14 subjects with 17betaHSD3 deficiency in relation to sex of rearing, androgen production, and HSD17B3 mutations. DESIGN: Cases were identified through the Cambridge Disorders of Sex Development Database where detailed clinical information was recorded, results of hCG stimulation tests were available, and HSD17B3 mutation was identified. RESULTS: Fourteen subjects from seven pedigrees (four consanguineous) had the following seven mutations: A56T, N130S, E215D, S232L, C268Y, V205E, and a novel mutation M197K. XY sex reversal was classified as complete in 10 infants at birth. Inguinal masses suggestive of androgen insensitivity syndrome (AIS) occurred in five infants. Contrasexual virilization reminiscent of 5alpha-reductase deficiency occurred in four subjects at puberty. The median (range) testosterone : androstenedione (T/A) ratio after a short hCG stimulation test was 0.32 (0.12-3.4). The S232L mutation identified in three affected family members caused isolated, severe hypospadias in one member who was raised male; virilization occurred despite in vitro studies showing an inactive mutant enzyme. Ratios of T/A in this pedigree were more than 0.8. CONCLUSION: XY sex reversal is sufficiently variable in 17betaHSD3 deficiency to cause problems in accurate diagnosis, particularly in distinguishing it from AIS. It should be considered in undervirilized male infants with normal Wolffian duct structures, absent Müllerian ducts, and normal adrenal steroid biosynthesis; or when an assigned female subject virilizes at puberty. Elevated hCG-stimulated T/A ratio may occur, and sex of rearing may not be concordant within affected families with the same HSD17B3 mutation. The T/A ratio, mutation analysis and functional analysis of the mutant enzyme taken in isolation, respectively, may not conclusively establish a diagnosis of 17betaHSD3 deficiency in undervirilized male subjects; the reasons for these discrepancies remain unknown.

Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.

BACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

McCune-Albright syndrome: growth hormone and prolactin hypersecretion.

McCune-Albright syndrome (MAS) has a special interest for endocrinologists as its pathogenesis results in hypersecretion of hormones in peripheral endocrine tissues. This can be expressed as precocious puberty, mainly in girls, primary hyperthyroidism, growth hormone (GH) and/or prolactin excess, hyperparathyroidism and hypercortisolism. The incidence of GH excess among patients with MAS has been assessed as up to 21%. The pathogenesis of GH hypersecretion in MAS is not completely understood, whereas it seems to be different from the aetiology of acromegaly/gigantism in non-MAS patients. The clinical expression of GH excess can be masked because of precocious puberty or craniofacial fibrous dysplasia, indicating the necessity for screening. Medical treatment is usually the only option in MAS patients with GH excess, as transsphenoidal surgery is usually restricted due to massive thickening of the skull base, whereas radiotherapy is contraindicated due to probable higher predisposition to sarcomatous transformation. The use of bromocriptine, cabergoline and octreotide, or the combination of these, has shown variable results, whereas pegvisomant, a GH receptor antagonist, is a new promising option, although not yet used in patients with MAS.

Morbidity and mortality associated with vasopressin analogue treatment.

DDAVP is a drug that should be used with caution for each patient individually. Particular care is needed to avoid fluid overload and rapid fluctuations in sodium concentration. Not only families but physicians as well should be educated and aware of the adverse effects of DDAVP, especially in high risk patients. Extreme caution is needed in children with severe neurological and developmental problems who cannot control their fluid intake themselves. Similarly, caution is needed in patients with hypodipsia and DI who have difficulty in balancing water intake and DDAVP dose. The treatment of DI is water; however, DDAVP is given to avoid a large fluid intake which can result in medullary washout. Frequent home monitoring of body weight and regular determinations of serum sodium may help to disclose the early phase of over-hydration or dehydration. DDAVP therapy should be temporarily interrupted during acute illness, febrile episodes, hot days and other conditions with increased water intake. It should be used with considerable caution in patients with cystic fibrosis, or renal or cardiovascular diseases. In patients with enuresis, it is recommended that DDAVP medication should not be continued for longer than 3 months without stopping for 1 week for full reassessment. Fluid intake should be limited 1 hour before and 8 hours after the dose. Generally, undertreatment with vasopressin analogue is safer than overtreatment. A simple measure to avoid overtreatment is to miss one dose once a week; a rapid onset diuresis ('washout' effect) provides considerable reassurance.

Growth hormone / insulin-like growth factor-1 axis during puberty.

Puberty is a dynamic, transitional period of life which is characterized by the acquisition of secondary sexual characteristics leading to the development of fertility. Puberty is accompanied by sexually dimorphic changes in linear growth, body proportions and body composition. The pubertal growth spurt is influenced by a number of factors such as hormones, nutrition, physical activity and general health, acting mostly in concert in order to modify a genetic potential for growth. Growth hormone (GH) is traditionally considered to be the main regulator of growth. During puberty, elevated sex steroid concentrations (especially oestrogens) stimulate GH production, leading to an activation of the whole GH/Insulinlike growth factor-1 (IGF-1) axis. This activation is mostly characterized by an increase in the amplitude of GH pulses rather than an increase in frequency or in duration. Interactions between GH and sex steroids (especially androgens) express an anabolic effect on muscle mass, bone mineralization and body proportion which constitutes the male and the female adult body composition.

The role of growth hormone in determining birth size and early postnatal growth, using congenital growth hormone deficiency (GHD) as a model.

OBJECTIVE: The role of GH in early human growth is unclear. Congenital GH deficiency (CGHD) provides a useful tool to explore this putative role. We have assessed the effects of CGHD on birth size and early postnatal growth, and the further impact of the presence of additional pituitary hormone deficiencies and midline brain defects on these parameters. DESIGN, PATIENTS AND MEASUREMENTS: Weight, length and BMI expressed as standard deviation scores (SDS), over the first two years of life, were retrospectively compared in 44 GH-deficient children (M:F 26 : 18). Thirty-eight of 44 patients underwent GH provocation testing and all patients had neuro-imaging of the brain. The patients were divided into three groups of increasing phenotypic complexity {group A [n = 12, isolated GHD, no midline defects], group B [n = 10, combined pituitary hormone deficiency (CPHD); no midline defects], group C (n = 22, CPHD with midline defects)}. RESULTS: Mean birth weight, length and BMI SDS were -0.4, -0.9 and +0.1 SDS, respectively. The differences were significant for weight (P = 0.03) and BMI (P = 0.003), but not length (P = 0.3) SDS, between groups A and C. Of the three groups, group A had a lower weight and BMI SDS than group C. The prevalence of postnatal complications (n = 25) was significantly different in the three groups [group A (8%), group B (80%), group C (73%); P < 0.001] and particularly between patients with isolated GH deficiency (IGHD) (group A) and CPHD (groups B and C; P < 0.0001). No patients in group A presented with neonatal hypoglycaemia as compared with 70% of those in group B and 59% in group C (P = 0.001). A reduced length SDS was observed in all patients within 6 months of birth and the reduction was greatest in group B (P = 0.03). Group C remained significantly (P < 0.05) heavier at 12, 18 and 24 months compared to group A. BMI SDS was significantly (P < 0.05) greater at all study points in CPHD patients (groups B and C) as compared with IGHD. Serum GH concentrations at testing did not correlate significantly with birth length (r = -0.08, P = 0.7), birth weight (r = -0.08, P = 0.6) or the age at induction of GH treatment (r = 0.12, P = 0.5). There were no significant differences between peak serum GH concentrations in patients in groups A (7.8 +/- 6.3 mU/l), B (3.9 +/- 4.8 mU/l) or C (8.7 +/- 5.4 mU/l). CONCLUSIONS: Length, weight and BMI data from our study groups suggest that GH per se has a minimal effect on intrauterine growth but a significant effect during the infancy period. Early growth may also be influenced by the complexity of the hypopituitary phenotype reflected by the presence of additional pituitary hormone deficiencies and midline forebrain defects.

Transition from paediatric to adult endocrinology: hypopituitarism.

For patients at the transition stage between childhood and adulthood, cooperation between paediatric and adult endocrinologists is essential for optimum care. Evaluations of patients in transition consist of retrospective assessments of what happened in childhood combined with prospective planning for treatment and follow up into adult life. Successful transfer of patients in transition from paediatric to adult care should follow a general sequence tailored to local circumstances. First, all patients with GH deficiency and their families should be informed by their paediatric endocrinologist about the long term consequences of GH deficiency in adulthood and the potential need for life-time GH replacement therapy. Second, retesting will be needed for evaluating hypothalamic pituitary function, re-evaluation of the need for replacement therapy for other pituitary hormone deficits, measurement of fasting lipid concentration and assessment of skeletal integrity. Third, the patient and physicians should consider the option of attending an out-patient clinic having both a paediatric and an adult endocrinologist. Regardless, the wishes of the patient should be respected as much as possible. It is essential that those patients who had childhood-onset GH deficiency and who were treated with GH be followed throughout adult life.

Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children.

To determine the value of the TRH test, we analyzed the unstimulated serum T(4) and TSH concentrations in 54 children with central hypothyroidism. A TRH test was performed in 30 patients. Midline brain defects (septo-optic dysplasia, 28; holoprosencephaly, 2) and combined pituitary hormone deficiencies were present in 30 and 52 patients, respectively. The mean serum free T(4), total T(4), and basal TSH concentrations were 0.6 ng/dl, 4.0 microg/dl, and 2.8 microU/ml, respectively. Five patients demonstrated elevated basal serum TSH concentrations. A normal TRH test [increase (delta) in TSH, 4.5-17.8], based on data from 30 controls, was documented in 23.3% of patients. Brisk (deltaTSH, >17.8), absent/blunted (deltaTSH, <4.5), and delayed responses were documented in 16.7%, 30%, and 30% of patients, respectively. The mean age at diagnosis was 2.8 yr, with 8 patients evolving into TSH deficiency. It was not possible to differentiate patients as having pituitary or hypothalamic disease based solely on the TRH test results. Patients with septo-optic dysplasia were diagnosed earlier and had elevated basal serum TSH and PRL concentrations, diabetes insipidus, and evolving disease. Although full pituitary function assessment is mandatory to identify combined pituitary hormone deficiencies, a TRH test is not essential, and the diagnosis should be made by serial T(4) measurements.

Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene.

The type 1 IGF receptor (IGF1R) is required for normal embryonic and postnatal growth. The aim of this study was to determine whether we could detect abnormal IGF1R function in skin fibroblasts from children with an abnormal copy number of the IGF1R gene. We report two children with altered copy number of the IGF1R gene who presented with abnormal growth. Case 1 is a girl with intrauterine growth retardation, postnatal growth failure, and recurrent hypoglycemia. Pituitary function tests were normal. Routine karyotype analysis identified a deletion on 15q26.2, and a fluorescence in situ hybridization study using IGF1R probes showed only a single IGF1R gene. Case 2 was large for gestational age, with birth weight and length at or above 97th percentile, and showed rapid early postnatal growth. He was found to have a recombinant chromosome 15 containing a partial duplication at 15q (q25-qter). A fluorescence in situ hybridization study using the same probes showed three copies of the IGF1R gene. In a mitochondrial activity assay, skin fibroblasts from the subject with only one copy of IGF1R showed slower growth, whereas cells from the subject with three copies of IGF1R showed accelerated growth compared with controls. IGF1R phosphorylation, as assessed by Western blot, and IGF1R binding studies were decreased compared with controls in the child with one copy of the IGF1R and increased in the child with three copies of the gene. Our data are consistent with the concept that IGF1R gene copy number is of functional and clinical importance in humans.