Les neuroleptiques s’utilisent toujours plus souvent depuis quelques annees aussi bien chez les enfants que chez les adolescents et les adultes. Les effets indesirables sont frequents.

Als Hypoglykamie wird grundsatzlich ein Blutzucker unter 2.5 mmol/l bezeichnet. Hypoglykamien sind immer Notfallsituationen, obwohl die primare Therapie einfach ist, setzen die differentialdiagnostischen Uberlegungen zur korrekten Interpretation der Laborresultate aber eine gute Kenntnis der Blutzucker Regulation voraus. Die Glukosezufuhr erfolgt hauptsachlich uber die Ernahrung. Beim Fasten oder in anderen katabolen Situationen werden unter der Kontrolle von Hormonen (Insulin, Glukagon, Adrenalin, Wachstumshormon, Cortisol) sequenziell verschiedene Stoffwechselwege (Glykogenolyse, Glukoneogenese, Lipolyse, Ketogenese) anrespektive abgeschaltet. Diese Mechanismen erlauben den Blutzucker pra-, postprandial und gefastet in einem engen Bereich von 2.5–7.7 mmol/l zu halten. Glukose ist wie Sauerstoff von fundamentaler Bedeutung fur die Funktion des Gehirns. Im ersten Lebensjahr wird bis 70 % der Energie im ZNS metabolisiert, beim Erwachsenen sind es nur noch rund 25%. Eine Hypoglykamie fuhrt daher vor allem bei Kindern haufig zu neurologischen Symptomen. Die Ursachen der Hypoglykamie konnen seltene, aber lebensbedrohliche Stoffwechselkrankheiten, endokrinologische Storungen, Intoxikationen oder am haufigsten sogenannte funktionelle ketotische Hypoglykamien sein. Die diagnostischen Parameter wie Glukose, freie Fettsauren, Ketonkorper und Hormone sind Momentaufnahmen der aktuellen Stoffwechsellage. Demzufolge muss vor Glukose Gabe, Blut und Urin fur weitere Abklarungen asserviert werden. Die primare Therapie ist einfach, jedoch unspezifisch und besteht in der raschen Normalisierung des Blutzuckers durch eine intravenose Zufuhr von Glukose. Ein einfaches Basislabor, gezielte anamnestische Angaben und die klinischen Befunde erlauben meistens eine rasche Differenzialdiagnose. Sie bestimmen auch die weiteren Untersuchungen aus den asservierten Proben und erlauben falls notig, rasch eine spezifische Therapie einzuleiten.

Treatment with growth hormone (GH) has become standard practice for replacement in GH-deficient children or pharmacotherapy in a variety of disorders with short stature. However, even today, the reported adult heights achieved often remain below the normal range. In addition, the treatment is expensive and may be associated with long-term risks. Thus, a discussion of the factors relevant for achieving an optimal individual outcome in terms of growth, costs, and risks is required. In the present review, the heterogenous approaches of treatment with GH are discussed, considering the parameters available for an evaluation of the short- and long-term outcomes at different stages of treatment. This discourse introduces the potential of the newly emerging prediction algorithms in comparison to other more conventional approaches for the planning and evaluation of the response to GH. In rare disorders such as those with short stature, treatment decisions cannot easily be deduced from personal experience. An interactive approach utilizing the derived experience from large cohorts for the evaluation of the individual patient and the required decision-making may facilitate the use of GH. Such an approach should also lead to avoiding unnecessary long-term treatment in unresponsive individuals.

CONTEXT:Steroidogenic factor-1 (SF-1/NR5A1) is a nuclear receptor that regulates adrenal and reproductive development and function. NR5A1 mutations have been detected in 46,XY individuals with disorders of sexual development (DSD) but apparently normal adrenal function and in 46,XX women with normal sexual development yet primary ovarian insufficiency (POI).OBJECTIVE:A group of 100 46,XY DSD and two POI was studied for NR5A1 mutations and their impact.DESIGN:Clinical, biochemical, histological, genetic, and functional characteristics of the patients with NR5A1 mutations are reported.SETTING:Patients were referred from different centers in Spain, Switzerland, and Turkey. Histological and genetic studies were performed in Barcelona, Spain. In vitro studies were performed in Bern, Switzerland.PATIENTS:A total of 65 Spanish and 35 Turkish patients with 46,XY DSD and two Swiss 46,XX patients with POI were investigated.MAIN OUTCOME:Ten novel heterozygote NR5A1 mutations were detected and characterized (five missense, one nonsense, three frameshift mutations, and one duplication).RESULTS:The novel NR5A1 mutations were tested in vitro by promoter transactivation assays showing grossly reduced activity for mutations in the DNA binding domain and variably reduced activity for other mutations. Dominant negative effect of the mutations was excluded. We found high variability and thus no apparent genotype-structure-function-phenotype correlation. Histological studies of testes revealed vacuolization of Leydig cells due to fat accumulation.CONCLUSIONS:SF-1/NR5A1 mutations are frequently found in 46,XY DSD individuals (9%) and manifest with a broad phenotype. Testes histology is characteristic for fat accumulation and degeneration over time, similar to findings observed in patients with lipoid congenital adrenal hyperplasia (due to StAR mutations). Genotype-structure-function-phenotype correlation remains elusive.

Neuroleptika werden sowohl im Kindes- und Jugendalter wie auch im Erwachsenenalter in den letzten Jahren immer haufiger eingesetzt. Metabolische Nebenwirkungen sind haufig.

After a proper medical history, growth analysis and physical examination of a short child, followed by radiological and laboratory screening, the clinician may decide to perform genetic testing. We propose several clinical algorithms that can be used to establish the diagnosis. GH1 and GHRHR should be tested in children with severe isolated growth hormone deficiency and a positive family history. A multiple pituitary dysfunction can be caused by defects in several genes, of which PROP1 and POU1F1 are most common. GH resistance can be caused by genetic defects in GHR, STAT5B, IGF1, IGFALS, which all have their specific clinical and biochemical characteristics. IGF-I resistance is seen in heterozygous defects of the IGF1R. If besides short stature additional abnormalities are present, these should be matched with known dysmorphic syndromes. If no obvious candidate gene can be determined, a whole genome approach can be taken to check for deletions, duplications and/or uniparental disomies.

CONTEXT AND OBJECTIVE:Despite the differences in the main characteristics between the autosomal dominant form of GH deficiency (IGHD II) and the bioinactive GH syndrome, a common feature of both is their impact on linear growth leading to short stature in all affected patients. DESIGN:The index patient, a boy, was referred for assessment of his short stature (-2.54 SD score) and a delayed bone age of 5.9 yrs at the chronological age of 7.7 yrs. The GHD was confirmed by standard GH provocation tests, which revealed modestly reduced GH and IGF-I concentrations. Further genetic analysis of GH-1 gene identified heterozygosity for GH-P59L mutation. The secretion of the GH-P59L following stimulation with forskolin was investigated and compared to that of the wt-GH after expression of both GH variants in AtT-20 cells. Based on the position of P59L mutation that lies within a patch of residues composing the GH binding site 1 for GHR, we performed the analysis of GH-P59L binding to GHR by in silico mutagenesis and molecular dynamics simulations, which suggested possible problems in correct binding of GH-P59L to the GHR. Therefore, the functional characterization of this GH mutant was assessed through studies of GHR binding and activation of Jak2/Stat5 signaling pathway. RESULTS:In line with the clinical data of the patient GH deficiency is suggested, underlined by GH-secretion studies revealing a moderate difference in secretion between GH-P59L and wt-GH. In addition, further functional characterization of the GH-P59L by studies of GH-receptor binding and activation of Jak2/Stat5 pathway presented with a reduced binding affinity of GH-P59L for GHR and decreased bioactivity compared to the wt-GH. CONCLUSIONS:The clinical data of the patient combined with the laboratory data support the diagnosis of partial IGHD type II. Since the GH deficiency was not total, additional binding and signaling studies were performed, which revealed that the GH-P59L variant displays some of the common features of bioinactive GH syndrome. Taken together, in this study we report a patient suffering from the combination of two growth disorders (alteration of secretion as well as bioactivity) caused by a GH-1 gene alteration highlighting the necessity of functional analysis of any GH variant, despite the presence of obvious clinical features of IGHD type II.

Normal somatic growth requires the integrated function of many of the hormonal, metabolic, and other growth factors involved in the hypothalamo-pituitary-somatotrope axis. Human growth hormone (hGH) causes a variety of physiological and metabolic effects in humans and its pivotal role in postnatal growth is undisputed. Disturbances that occur during this process often cause subnormal GH secretion and/or subnormal GH sensitivity/responsiveness resulting in short stature. Despite the complexity of this linear growth process, the growth pattern of children, if evaluated in the context of normal standards, is rather predictable. Children presenting with short stature (i.e out of normal standards) are treated with daily injections of recombinant human GH (rhGH), which leads in almost all cases to an increase of height velocity. Although it is becoming more and more evident that many genes are involved in controlling the regulation of growth, the main aim of this review is to focus on the GH-1 gene, the various gene alterations and their important physiological and pathophysiological role in growth.

Isolated GH deficiency type II (IGHD II) is the autosomal dominant form of GHD. In the majority of the cases, this disorder is due to specific GH-1 gene mutations that lead to mRNA missplicing and subsequent loss of exon 3 sequences. When misspliced RNA is translated, it produces a toxic 17.5-kDa GH (Delta3GH) isoform that reduces the accumulation and secretion of wild-type-GH. At present, patients suffering from this type of disease are treated with daily injections of recombinant human GH in order to maintain normal growth. However, this type of replacement therapy does not prevent toxic effects of the Delta3GH mutant on the pituitary gland, which can eventually lead to other hormonal deficiencies. We developed a strategy involving Delta3GH isoform knockdown mediated by expression of a microRNA-30-adapted short hairpin RNA (shRNA) specifically targeting the Delta3GH mRNA of human (shRNAmir-Delta3). Rat pituitary tumor GC cells expressing Delta3GH upon doxycycline induction were transduced with shRNAmir-Delta3 lentiviral vectors, which significantly reduced Delta3GH protein levels and improved human wild-type-GH secretion in comparison with a shRNAmir targeting a scrambled sequence. No toxicity due to shRNAmir expression could be observed in cell proliferation assays. Confocal microscopy strongly suggested that shRNAmir-Delta3 enabled the recovery of GH granule storage and secretory capacity. These viral vectors have shown their ability to stably integrate, express shRNAmir, and rescue IGHD II phenotype in rat pituitary tumor GC cells, a methodology that opens new perspectives for the development of gene therapy to treat IGHD patients.

Background/Aims: Growth hormone insensitivity syndrome (GHIS) is a rare cause of growth retardation characterized by high serum GH levels, and low serum insulin-like growth factor I (IGF-I) levels associated with a genetic defect of the GH receptor (GHR) as well post-GHR signaling pathway. Based on clinical, as well as biochemical characteristics, GHIS can be genetically classified as classical/Laron’s syndrome and nonclassical/atypical GHIS. Recombinant human IGF-I (rhIGF-I) treatment is effective in promoting growth in subjects who have GHIS. Further, pharmacological studies of a IGF-I compound containing a 1:1 molar complex of rhIGF-I and rhIGF-binding protein-3 (BP-3) demonstrated that the complex was effective in increasing levels of circulating total and free IGF-I and that the administration in patients with GHIS should be safe, well-tolerated and more effective than rhIGF-I on its own. Patient/Methods: We describe the long-term effect of various IGF-I preparations (rhIGF; rhIGF-I/rhIGFBP-3) in a single subject treated for more than 14 years while focusing on height, height velocity as well as on additional auxological and laboratory data. Results: This study confirms that rhIGF-I is effective in promoting growth in children with GHIS. However, on the combined rhIGF-I/rhIGFBP-3 treatment as well as off rhIGF-I therapy the height velocity decreased drastically (2 and 1.8 cm vs. overall 6.5 cm/year on rhIGF-I, respectively). On rhIGF-I treatment, serum IGF-I was found to be well within the normal range, whereas serum IGFBP-3 remained low. On the rhIGF-I/rhIGFBP-3 compound therapy, however, serum IGFBP-3 increased into the normal range, which was not the case for serum IGF-I. Importantly, the increase of the serum IGFBP-3 level excludes noncompliance. In addition, body mass index as well as dual-energy X-ray absorptiometry analysis underlined the positive effect of rhIGF-I treatment on body composition. Conclusions:The rhIGF-I/rhIGFBP-3 compound therapy seems to be not efficient in treating this individual patient with GHIS when compared with rhIGF-I alone.

It is becoming most clear that many genes are involved in controlling the regulation of growth. Ultimately however, at the level of growth hormone (GH), the relevant question may be not whether a patient is GH-deficient, but whether he is GH-responsive. As these disturbances can be divided into two gross categories, namely alterations causing subnormal GH secretion and/or those presenting with subnormal GH sensitivity/responsiveness, the main aim of this review is to focus on genes involved in growth regulation leading to short stature caused by an alteration of GH insensitivity/GH responsiveness; in other words, clinical circumstances where individually adapted GH replacement therapy may help to increase height velocity and eventually final height.

Growth is an inherent property of life, which has to be checked and controlled by any general physician following children. Therefore, the common knowledge about the normal pattern/course of growth is essential in order to act proactively whenever the child's growth does not progress adequately.

Insulin replacement is the only effective treatment of type 1 Diabetes mellitus (T1DM). Nevertheless, many complementary treatments are in use for T1DM. In this study we assessed by questionnaire that out of 342 patients with T1DM, 48 (14%; 13.4% adult, 18.5% paediatric; 20 male, 28 female) used complementary medicine (CM) in addition to their insulin therapy. The purpose of the use of CM was to improve general well-being, ameliorate glucose homeostasis, reduce blood glucose levels as well as insulin doses, improve physical fitness, reduce the frequency of hypoglycaemia, and control appetite. The modalities most frequently used are cinnamon, homeopathy, magnesium and special beverages (mainly teas). Thus, good collaboration between health care professionals will allow optimal patient care.