Treatment of young patients with HNF1A mutations (HNF1A-MODY).

AIM: Children and adolescents with a molecular diagnosis of HNF1A-MODY should be treated with oral sulfonylurea according to current International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines. METHODS: We surveyed the German-Austrian DPV database of 50 043 people and included 114 patients with a confirmed molecular-genetic diagnosis of HNF1A mutation and diabetes onset at below age 18 years. We analysed hypoglycaemic episodes, metabolic control (HbA1c ) and other clinical variables according to treatment groups. RESULTS: People with HNF1A-MODY were included and analysed according to treatment with insulin alone (n = 34), sulfonylurea (n = 30), meglitinides (n = 22) or lifestyle (n = 28). In those receiving any drug treatment (n = 86), severe hypoglycaemia did not occur with meglitinide and was highest (at 3.6 events per 100 patient-years) with insulin. HbA1c was highest with insulin treatment (insulin = 58 mmol/mol, 7.5%; sulfonylurea = 55 mmol/mol, 7.2%; meglitinides = 52 mmol/mol, 6.9%; P = 0.008), whereas weight (BMI SD score), serum lipids and blood pressure were not different. CONCLUSIONS: Of note, 40% of people with HNF1A-MODY and medical treatment were receiving insulin alone and thus were not being treated in line with up-to-date International Society for Pediatric and Adolescent Diabetes/International Diabetes Federation guidelines, despite insulin treatment being associated with worse metabolic control and the risk of hypoglycaemia. The unlicensed use of oral drugs in patients below age 18 years and adherence by both doctors and patients to the initial insulin treatment might contribute to this finding.

Basal inhibin B and the testosterone response to human chorionic gonadotropin correlate in prepubertal boys.

During childhood, the quiescent phase of testicular activity, the hCG stimulation test is widely used to evaluate testicular function. Inhibin B, a gonadal peptide regulating FSH secretion, is an established marker of Sertoli cell function and spermatogenesis in adults. In contrast to the other hormones of the hypothalamo-pituitary-gonadal axis, inhibin B is also secreted in detectable amounts during childhood. The aim of this study was to determine whether basal inhibin B levels are able to predict prepubertal testicular function, so as to avoid a stimulation test. Inhibin B and testosterone before and after hCG stimulation were measured in 54 male children with various testicular disorders by an immunoassay specific for inhibin B. Basal inhibin B was compared to the testosterone increase after hCG. Inhibin B and the hCG-induced testosterone increment correlated strongly (r = 0.84; P<0.0001). Patients with anorchia were clearly distinguishable from those with abdominal testes, having undetectable (inhibin B, <15 pg/mL) respective normal inhibin B levels for age. Inhibin B and the testosterone response to hCG were low in boys with testicular damage (delayed diagnosis of cryptorchidism; after testicular torsion) and in patients with gonadal dysgenesis, but were normal or increased in children with androgen insensitivity syndrome. We conclude that basal inhibin B predicts the testosterone response to hCG in boys and therefore gives reliable information about both the presence and function of the testes. The diagnostic procedure in cryptorchidism may be reduced to a single inhibin B measurement. Furthermore, inhibin B levels show specific alterations in patients with sexual ambiguity, adding a valuable diagnostic tool to the complex differential diagnosis of male pseudohermaphroditism.

Growth retardation in Turner syndrome: aneuploidy, rather than specific gene loss, may explain growth failure.

The etiology of short stature (SST) in Turner syndrome (TS) is still a subject of speculation. A variety of hypotheses have been put forward, from SST as a result of increased intrauterine tissue pressure after fetal lymphedema to haploinsufficiency of a specific growth gene(s). These hypotheses have various statistical-auxological implications on the growth distribution in TS. Empirical research has provided no clear evidence for any of these theories, but the well known correlation between patients' and midparental height (MPH) could be established. The influence of undetected mosaic status has often been cited as a major problem in the investigation of growth in TS. However, an assessment of mosaic status (simultaneous analysis of karyotype and phenotype) and its effect on growth with inclusion of MPH has been not yet carried out for a large sample. The aim of this study was to evaluate growth and its complex relationship to mosaic status and MPH in TS. In a mixed cross-sectional and longitudinal study we retrospectively analyzed the auxological and clinical data of 447 patients with a pure loss of X-chromosomal material (n = 381 with 45,X0; n = 66 mosaics). The 447 patients were selected from a series of 609 consecutive patients with TS. To assess the effect of mosaic status on growth, we computed a bifactorial analysis of variance (phenotype, karyotype), including MPH as a covariate. In line with the mosaic hypothesis, we found a correlation between individual loss of X-chromosomal material and phenotypical expressivity. In contrast, no correlation was found with respect to growth. With respect to MPH, we found growth retardation (GR) even in those patients with "normal" height above the third percentile (-2 or more SD score). The interindividual variance of GR in TS (comparable to growth variance in the normal population) seems to be unrelated to other TS-specific factors (e.g. mosaic status or single gene loss). Instead, both interindividual variance and the global growth shift distribution are best explained by the presence of an unspecific aneuploidic effect. Furthermore, consideration of patient height in relation to MPH should lead to a better understanding of the nature of GR in TS than the commonly used, strictly qualitative definition of SST.

Congenital hydrocephalus internus and aqueduct stenosis: aetiology and implications for genetic counselling.

UNLABELLED: Genetic counselling in families with congenital hydrocephalus internus (CHI) in combination with aqueduct stenosis (AS) is often difficult due to an uncertain aetiology. We present a series of 35 patients with CHI and AS focusing on the aetiology and presumed recurrence risk for siblings. In 13 patients (37.1%) a genetic aetiology was identified with an increased recurrence risk for siblings. The relative frequency of patients with X-linked hydrocephalus in our sample was in accordance with the literature (2/35), but was more frequent in other diseases with Mendelian inheritance. CONCLUSION: In addition to the well-known X-linked and autosomal recessive forms of aqueduct stenosis with hydrocephalus, this malformation can occur in other diseases with Mendelian inheritance. This finding is of considerable importance for genetic counselling and prognosis.

[Subacute sclerosing panencephalitis (SSPE) as differential diagnosis in severe personality changes and ataxia--case report and literature review]. / Subakute, sklerosierende Panenzephalitis (SSPE) als Differentialdiagnose einer schweren Wesensveränderung und Ataxie--Fallbericht und Literaturüberblick.

An 8 year old girl presented with progressive change of personality and spastic ataxia since 4 weeks. A year before she had developed focal grand-mal-seizures; at this time laboratory and radiologic findings were normal. The EEG on admission demonstrated marked changes with partially focal, partially generalized hypersynchronic activity, but no SSPE-typical Radermecker-complexes. There were no cells in the cerebrospinal fluid (CSF), a slightly increased level of protein and a normal glucose. Isoelectric focusing showed predominantly measles-specific oligoclonal IgG bands in the CSF. In the magnetic resonance tomography multiple focal white matter lesions in the basal ganglia as well as in cortical and occipitoparietal regions could be seen. At the age of two the girl had suffered from measles, the child didn't receive any vaccination. The combination of history, CSF-, MRI-results and EEG lead to the diagnosis of subacute sclerosing panencephalitis (SSPE). After 3 months the clinical and radiological abnormalities had markedly increased. On the background of this history SSPE should be considered as differential diagnosis in patients with changes of personality.

Epidemiology of ingestions in a regional poison control center over twenty years.

This analysis was conducted to demonstrate the pattern and changes of potential intoxications reported to a German regional poison control center from 1974 to 1993. During this period 155,654 calls were reported of which 111,313 were analyzed. The remaining 44,341 were either of minor importance of preventive calls; 56% referred to children and 44% to adults. Substance categories most commonly implicated were drugs, with a yearly average of 37.6% of the total, followed by household articles (31.2%), plants (9.7%) and chemicals (5.9%). In pediatric cases household articles were the most frequent source of ingestion followed by drugs, plants and nutritional substances, whereas in adults drugs were followed by household articles, chemicals and pesticides. Only 13.4% of all ingestions were classified as toxic or very toxic. There were no major changes in the incidences of the different substance categories during the 20 years. However, there were some changes in the pharmaceuticals, probably due to the introduction of new drugs or the withdrawal of the OTC-status of selected drugs.

Co-expression of M-CSF transcripts and protein, FMS (M-CSF receptor) transcripts and protein, and steroid receptor content in adenocarcinomas of the ovary.

The co-expression of M-CSF (CSF-1) and its receptor in specimens of ovarian cancer has recently been reported. Preliminary results have already suggested a possible influence of steroids on FMS (M-CSF receptor) expression. Fifty-five non-pretreated FIGO stage III/IV ovarian adenocarcinomas were studied for M-CSF transcripts and protein, as well as FMS transcripts and protein, using standard molecular biological techniques (Northern blot, slot blot analysis) and immunocytochemistry (ICC). Steroid receptor content was measured by DCC analysis in 44/55 specimens; in addition, ER/PR (oestrogen/progesterone) ICC was performed in 32/55 specimens. All tumours were shown to contain M-CSF-specific mRNA. Likewise, M-CSF protein was detected by ICC in the stroma and over the epithelium in all specimens. However, while most tumours were shown to contain FMS-specific mRNA, only 64 per cent of cases showed significant expression of FMS protein by tumour epithelium as shown by ICC. A statistically significant positive correlation was found between M-CSF and FMS mRNA expression levels. A week non-significant positive correlation was noted between FMS mRNA expression levels and tumour grade. Carcinomas were ER-positive in 66 per cent (DCC) or 34 per cent (ICC), and PR-positive in 73 per cent (DCC) or 34 per cent (ICC). A statistically significant positive correlation between ER (DCC) and M-CSF mRNA expression levels was found. Weak non-significant correlations were present between ER (ICC) and FMS (ICC), as well as between PR (DCC) and FMS mRNA expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of transcripts for CSF-1 and for the "macrophage" and "epithelial" isoforms of the CSF-1R transcripts in human ovarian carcinomas.

Levels of CSF-1 and CSF-1 receptor (CSF-1R) (fms) transcripts were quantified by Northern and dot blotting in total RNA extracts from 68 human ovarian carcinomas and positive and negative controls. Overall, very high levels of CSF-1 and CSF-1R transcripts were found in 11 and 21% of ovarian carcinoma specimens, respectively. When probes specific for CSF-1R exon1 were employed, which hybridize with the "epithelial" but not with the "hematopoietic" isoforms of the CSF-1R transcripts, the results suggested that both isoforms of the CSF-1R transcript were present in the tumor specimens. When levels of CSF-1 and CSF-1R were compared, a positive correlation was observed. Taken together, these results confirm prior observations of high levels of CSF-1 and CSF-1R in ovarian carcinoma specimens and that the latter include both "epithelial" and "macrophage" CSF-1R transcript isoforms, as might be expected for specimens composed of malignant epithelial cells and stromal macrophages.

Ovarian adenocarcinomas express members of different cytokine pathways - analysis and quantification of transcripts from the tgf-alpha and m-csf fms pathways and the transcription factor cjun.

The expressions of two mitogenic signals, M-CSF/FMS and TGFalpha/EGF-R together with the amounts of JUN mRNA were analyzed and quantified from freshly frozen specimens of 71 primary ovarian cancers, 5 other malignant ovarian tumors, 6 myometria, 4 normal ovaries and 4 placentae. JUN was analyzed by RNAase protection assay. The percentages of tumor specimens with high amounts of specific RNA were: 11% FMS, 21% M-CSF, 23% TGFalpha and 21% JUN. Whereas 34% of tumors were TGFalpha negative, only a few cases had no detectable FMS or M-CSF signals. The comparison of the quantified RNA results achieved positive correlations between FMS and M-CSF, TGFalpha and JUN, respectively. No correlation was found between the TGFalpha and M-CSF/FMS signals neither between the M-CSF/FMS and JUN signals. The M-CSF/FMS signals were also found in the non-malignant specimens. The tumor cells of ovarian cancers are endowed to express and to produce a panel of different growth factors and cytokines and their composition could be responsible for some individual properties of tumors.

Children's cognitive concepts of obesity: a developmental study.

Children's thoughts about human fatness were studied in interviews with children (n = 96) of three age groups (4-5 years, 8-9 years, and 12-13 years). Using a Piagetian theoretical framework, tasks were devised to measure concepts of body identity and causes of obesity which could be compared to measures of physical conservation and physical causality. Older children demonstrated higher levels of reasoning on all tasks than did younger children, with significant differences between each age group for each of four tasks (P less than 0.001). Correlations between tasks were high across all subjects but moderate within age groups. Body identity was understood at higher levels than was physical conservation (P less than 0.0001) among only the youngest group. The levels of understanding causes of fatness and of other natural physical events were not different in the youngest group. However, physical causality was understood and at a higher level than obesity causality among both the 8- to 9-year-olds (P less than 0.0001) and 12- to 13-year-olds (P less than 0.0001). Body identity and obesity causality scores were significantly different only among 12- to 13-year-olds at which time identity scores were higher (P less than 0.003). Physical causality was understood at higher levels than physical conservation among all age groups.