Substantial proportion of MODY among multiplex families participating in a Type 1 diabetes prediction programme.

AIMS: Patients with maturity-onset diabetes of the young (MODY) might be over-represented in families with histories of Type 1 diabetes. Our aim was to re-evaluate families participating in the Czech T1D Prediction Programme (PREDIA.CZ) with at least two members affected with diabetes to assess the proportion of MODY among these families and determine its most significant clinical predictors. METHODS: Of the 557 families followed up by the PREDIA.CZ, 53 (9.5%) had two or more family members with diabetes. One proband with diabetes from these families was chosen for direct sequencing of the GCK, HNF1A, HNF4A and INS genes. Non-parametric tests and a linear logistic regression model were used to evaluate differences between MODY and non-MODY families. RESULTS: MODY was genetically diagnosed in 24 of the 53 families with multiple occurrences of diabetes (45%). Mutations were detected most frequently in GCK (58%), followed by HNF1A (38%) and INS (4%). MODY families were more likely to have a parent with diabetes and had a higher proportion of females with diabetes than non-MODY families. Higher age (P < 0.001), a lower level of HbA1c (P < 0.001) at clinical onset and at least two generations affected by diabetes were the variables most predictive for probands of MODY families already presenting with diabetes. CONCLUSIONS: A prediction programme for Type 1 diabetes would provide a useful new source of patients with MODY most likely to benefit from an accurate diagnosis. This identification has implications for patient treatment and disease prognosis.

Artificially low cortical bone mineral density in Turner syndrome is due to the partial volume effect.

UNLABELLED: We aimed to show that the decrease in the cortical bone mineral density (BMD) in the radius in Turner syndrome (TS) is artificially caused by the partial volume effect. We confirmed that the partial volume effect-corrected cortical BMD is not decreased in TS compared to in the healthy controls. Other factors are responsible for the increased fracture rate in TS. INTRODUCTION: Decreased cortical bone mineral density (BMD) has been reported in Turner syndrome (TS), using peripheral quantitative computerised tomography, and it is perceived as one of the major factors leading to increased fracture risk. We tested the hypothesis that low cortical BMD in the radius is caused artificially by the partial volume effect. METHODS: A cross-sectional study was conducted at the university hospital referral centre between March and October 2013. Thirty-two participants with TS who consented to the study were included (mean age 15.3 ± 3.2 years). We assessed the cortical BMD in the radius as well as the tibia, where the cortex is thicker compared with the radius. RESULTS: Whereas the cortical BMD was decreased in the radius (mean ± SD Z-score -0.6 ± 1.5, p = 0.037), it was increased in the tibia (mean Z-score 0.83 ± 1.0, p < 0.001). After correcting the cortical BMD for the partial volume effect, the mean Z-score was normal in the radius in TS (0.4 ± 1.3, p = 0.064). The corrected cortical BMD values were similar in the radius and tibia (1108 ± 52 vs. 1104 ± 48, group difference p = 0.75). CONCLUSIONS: The cortical BMD is not decreased in TS. The partial volume effect is responsible for previous findings of decreased cortical BMD in the radius. Altered bone geometry or other factors rather than low cortical BMD likely play a role in the increased fracture risk in TS.

The dynamic changes of zinc transporter 8 autoantibodies in Czech children from the onset of Type 1 diabetes mellitus.

AIMS: The prevalence of autoantibodies to zinc transporter 8 (ZnT8) in Czech children at the onset of Type 1 diabetes mellitus and dynamic changes in ZnT8 autoantibody levels during disease progression were studied. The value of ZnT8 autoantibody measurements in diagnosis of Type 1 diabetes was assessed. METHODS: Serum samples from 227 children with newly diagnosed Type 1 diabetes and from 101 control children without diabetes were analysed in a retrospective cross-sectional study. One hundred and seventy-one samples from 116 of the patients with diabetes were analysed in a follow-up study at (median) intervals of 1, 3, 5 and 10 years after onset of Type 1 diabetes. ZnT8 autoantibodies were measured using a bridging enzyme-linked immunosorbent assay, while antibodies to glutamic acid decarboxylase, insulinoma antigen 2 and insulin were measured by radioimmunoassays. RESULTS: ZnT8 autoantibodies were detected in 163/227 (72%) of children at Type 1 diabetes onset and in 1/101 (1%) of the control subjects. Sixteen out of 227 (7%) patients with Type 1 diabetes were antibody negative based on three antibodies (glutamic acid decarboxylase, insulinoma antigen 2 and insulin). This false-negative rate was reduced to 10/227 (4.4%) (P < 0.05) after inclusion of ZnT8 autoantibody measurements. Of the children, 142/227 (63%) were positive for at least three antibodies and the most common combination was insulinoma antigen 2, glutamic acid decarboxylase and ZnT8. ZnT8 autoantibody levels decreased over time after Type 1 diabetes onset and the presence and level of ZnT8 autoantibodies correlated with IA-2 autoantibodies. CONCLUSIONS: A ZnT8 autoantibody enzyme-linked immunosorbent assay showed 72% disease sensitivity and 99% specificity at Type 1 diabetes onset. Measurements of ZnT8 autoantibodies are important for Type 1 diabetes diagnosis and should be included in the panel of autoantibodies tested at the onset of Type 1 diabetes.

Boys with haemophilia have low trabecular bone mineral density and sarcopenia, but normal bone strength at the radius.

Although a decreased areal bone mineral density (BMD) has been reported in patients with haemophilia, data are lacking that would reflect the three-dimensional structure of the bone and the muscle-bone relationship. We aimed to assess volumetric BMD, bone geometry and muscle-bone phenotype in boys with haemophilia, and to describe the association between clinical characteristics of haemophilia and bone quality and structure. A cross-sectional study was conducted in 41 boys with haemophilia (mean age 12.4, range 6.6-19.8 years) using peripheral quantitative CT (pQCT) at the nondominant forearm. Results were transformed into Z-scores using previously published reference data. Significant differences were tested by one-sample t-test or sign test. Two-sample t-test and anova were used to compare results between subgroups of patients divided according to the severity of the disease, the fracture history and the number of joint and muscle bleedings. Boys with haemophilia had a decreased trabecular volumetric BMD (mean Z-score -0.5, P < 0.01), while their cortical volumetric BMD was increased (mean Z-score 0.4, P < 0.05). The volumetric bone mineral content and the bone geometry at the radial diaphysis were normal when adjusted for patients' shorter body height. Muscle area was decreased (mean Z-score -1.0, P < 0.001), irrespective of age. No association was observed of bone quality parameters and bone geometry with the disease severity, fracture history or number of bleedings. Bone strength measured at the diaphysis of the radius is not impaired in boys with haemophilia. The finding of the decreased trabecular bone density can be most likely attributed to their sarcopenia.

Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1.

AIMS/HYPOTHESIS: The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits. METHODS: GCG was re-sequenced as a candidate gene in 865 European individuals. Twenty-nine variants were identified. Four variants that were considered to have a likelihood for altered functionality: rs4664447, rs7581952, Ile158Val and Trp169Ter, were genotyped in 17,584 Danes. RESULTS: When examined in 5,760 treatment-naive individuals, homozygous carriers of the low frequency (minor allele frequency 2.3%) G allele of rs4664447, predicted to disrupt an essential splice enhancer binding site, had lower levels of fasting plasma glucose (mean ± SD, 4.8 ± 1.2 vs 5.5 ± 0.8 mmol/l, p = 0.004); fasting serum insulin (22 ± 14 vs 42 ± 27 pmol/l, p = 0.04); glucose-stimulated serum insulin (159 ± 83 vs 290 ± 183 pmol/l, p = 0.01) and adult height (165 ± 10 vs 172 ± 9 cm, p = 0.0009) compared with A allele carriers. During oral glucose tolerance and hyperglycaemic arginine stimulation tests, the plasma AUC for GLP-1 (730 ± 69 vs 1,334 ± 288 pmol/l × min, p = 0.0002) and basal and stimulated levels of serum insulin and plasma glucagon were ∼50% decreased (p < 0.001) among three homozygous carriers compared with nine matched wild-type carriers. rs7581952, Ile158Val and Trp169Ter (where 'Ter' indicates 'termination') variants of GCG did not significantly associate or co-segregate with the metabolic traits examined. CONCLUSIONS/INTERPRETATION: Re-sequencing of GCG revealed a low frequency intronic variant, rs4664447, and follow-up physiological studies suggest that this variant in homozygous form may cause decreased fasting and stimulated levels of insulin, glucagon and GLP-1. Overall, our findings suggest that variation in GCG has no major impact on carbohydrate metabolism in the study populations examined.

[Pendred syndrome among patients with hypothyroidism: genetic diagnosis, phenotypic variability and occurrence of phenocopies]. / Pendreduv syndrom u pacientu s hypotyreózou: genetická diagnostika, fenotypová variabilita a výskyt fenokopií.

BACKGROUND: Pendred syndrome (OMIM274600) is one of the causes of congenital hypothyroidism due to thyroid dyshormonogenesis. It is an autosomal recessive disease classically characterized by dyshormonogenetic goitre and sensorineural deafness. It is caused by mutations in PDS/SLC26A4 gene encoding for pendrin--an anion transporter, mostly expressed in the thyroid gland and the inner ear. The thyroid impairment in Pendred syndrome develops only in 80% of affected individuals in form of a euthyroid or hypothyroid goitre, which is rarely present at birth, when it can be diagnosed by the neonatal screening for congenital hypothyroidism. The study was aimed to identify patients with Pendred syndrome among children with congenital or postnatal non-autoimmune hypothyroidism and subsequently confirm the diagnosis by finding mutations in the PDS/SLC26A4 gene. METHODS AND RESULTS: We examined two-hundred thirty-six Caucasians with hypothyroidism diagnosed by screening or developing later in childhood. The clinical diagnosis of Pendred syndrome was based on the laboratory and ultrasonographic signs of thyroid dyshormonogenesis (elevated TSH, low T4/fT4, goitre or normal thyroid volume) in association with sensorineural hearing loss. In subjects clinically diagnosed as Pendred syndrome, we sequenced all 21 exons of the PDS/SLC26A4 gene and their flanking intron-exon junctions. Among 236 children, nine fulfilled the diagnostic criteria of Pendred syndrome. In four, the diagnosis was confirmed by identification of mutations in the PDS/SLC26A4 gene, the remaining five patients were concluded phenocopies. CONCLUSIONS: Our study confirms the high phenotypic variability of thyroid impairment in Pendred syndrome and underlines the necessity of a molecular-genetic investigation for establishing the diagnosis in regard of the great number of phenocopies. However, from the endocrinologist's point of view, the genetic testing is only reasonable in patients with congenital hypothyroidism due to dyshormonogenesis in association with sever to profound sensorineural hearing loss.

Novel glucokinase gene mutation in the first Macedonian family tested for MODY.

We present a boy with mild hyperglycemia detected during an upper respiratory infection. Novel splicing mutation in the intron 1 of the GCK gene (c.45+1G>A) was detected, and was subsequently confirmed in his father. This is the first case of genetically confirmed Macedonian family with MODY.

Thyroid autoimmunity in children with coexisting type 1 diabetes mellitus and celiac disease: a multicenter study.

BACKGROUND: Children with type 1 diabetes mellitus (DM1) are more prone to developing thyroid autoimmunity (TAI); TAI also occurs more frequently in patients with celiac disease (CD). AIM: To determine whether TAI occurs more frequently in children with coexisting DM1 and CD compared to children with DM1 only, and whether the clinical course of DM1 is influenced by concomitant TAI. PATIENTS AND METHODS: We performed a multicenter retrospective case-control study comparing data from 84 diabetic children with CD (group 1) to 167 diabetic children without CD (group 2), matched by age at DM1 onset, duration of DM1 and center. Markers of TAI, thyroid function and HbA1c were recorded. The TAI follow-up lasted 4.9 +/- 2.8 years. RESULTS: TAI was diagnosed in 13% of children in group 1 and 19% of children in group 2 (ns). Diabetes control was not influenced by TAI in either group. CONCLUSIONS: Occurrence of TAI in diabetic children is not related to coexisting CD. TAI does not lead to worsening of metabolic control in children with DM1.

[Glibenclamide instead of insulin: a new chance for MODY 3 type diabetes patients: case report]. / Glibenklamid místo inzulinu: nová sance pro pacienty s diabetem MODY 3: kazuistika.

MODY 3 belongs to monogenic forms of diabetes mellitus and is caused by monoallelic mutation in gene for transcription factor HNF-1alpha, essential for regulation of beta-cell function. Clinical presentation of MODY 3 is similar to that of type 1 diabetes. Although MODY 3 patients are not threatened by ketoacidosis, tight metabolic control is important for prevention of chronic diabetic complications. In the sibbling pair diabetes was manifested by osmotic symptoms resulting from hyperglycaemia at the age of 18 years (brother) resp. 15 years (sister) and both of them started being treated with intensified insulin treatment. Metabolic control of the brother was very tight with HbA1c 3.3 % but frequent hypoglycaemias occured. On the contrary metabolic control of the sister was very poor due to her non-compliance (HbA1c 10.9 %, IFCC). Molecular-genetic testing proved HNF-1alpha gene mutation (Arg200Gly). In accordance with the references treatment with sulphonylurea derivate glibenclamide was initiated [at the doses 1.25 (brother) resp. 7.5 (sister) mg/day] and insulin treatment was discontinued. The treatment change led to better quality of life and metabolic control in both the patients and suprisingly to the lower frequency of the hypoglycaemias in the brother (HbA1c decreased from 3.3 % to 2.8 % in three months in the brother resp. from 10.9 % to 10.0 % in two months in the sister). Molecular-genetic testing enables the change of treatment leading to better quality of life and metabolic control, although its longterm safety and efficacy will have to be confirmed.

Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia.

OBJECTIVE: To analyze the mutational spectrum of steroid 21-hydroxylase (CYP21) and the genotype- phenotype correlation in patients with congenital adrenal hyperplasia (CAH) registered in the Middle European Society for Pediatric Endocrinology CAH database, and to design a reliable and rational approach for CYP21 mutation detection in Middle European populations. DESIGN AND METHODS: Molecular analysis of the CYP21 gene was performed in 432 CAH patients and 298 family members. Low-resolution genotyping was performed to detect the eight most common point mutations. High-resolution genotyping, including Southern blotting and sequencing was performed to detect CYP21 gene deletions, conversions, point mutations or other sequence changes. RESULTS: CYP21 gene deletion and In2 and Ile172Asn mutation accounted for 72.7% of the affected alleles in the whole study group. A good genotype-phenotype correlation was observed, with the exception of Ile172Asn and Pro30Leu mutations. In 37% of patients low resolution genotyping could not identify the causative mutation or distinguish homozygosity from hemizygosity. Using high-resolution genotyping, the causative mutations could be identified in 341 out of 348 analyzed patients. A novel mutation Gln315Stop was found in one simple virilising CAH (SV-CAH) patient from Austria. In the remaining seven patients polymorphisms were identified as the leading sequence alteration. The presence of elevated basal and ACTH-stimulated 17-hydroxyprogesterone, premature pubarche, advanced bone age and clitoral hypertrophy directly implicated Asn493Ser polymorphism in the manifestation of nonclassical- (NC) and even SV-CAH. CONCLUSIONS: By genotyping for the most common point mutations, CYP21 gene deletion/conversion and the 8 bp deletion in exon 3, it should be possible to identify the mutation in 94-99% of the diseased alleles in any investigated Middle European population. In patients with a mild form of the disease and no detectable mutation CYP21 gene polymorphisms should be considered as a plausible disease-causing mutation.

Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive disorder that results in several autoimmune diseases due to the mutations in the AIRE (autoimmune regulator) gene. APECED patients develop several autoimmune endocrine disorders and are characterized by the high titer autoantibodies to organ-specific antigens such as the steroidogenic P450 cytochromes. So far, 38 mutations have been identified in the AIRE gene. We report here the genetic and autoantibody analysis of 27 APECED patients of Eastern and Central European origins and one Egyptian patient. From 54 analyzed APECED chromosomes, eight mutations were detected, four of which (T16M, W78R, IVS1_IVS4, 30-53dup23bp) are novel. The most prevalent reason for APECED in these populations was the occurrence of R257X (36 chromosomes) that has been described earlier as a common and recurrent mutation in several other populations. The analysis of humoral immunity to steroidogenic P450 cytochromes by the immunoblotting of E. coli expressed antigens in the 18 APECED patients showed that 67%, 44%, and 61% of the Eastern and Central European APECED patients had autoantibodies to P450c17, P450c21, and P450scc, respectively.

Lessons from 30 years of clinical diagnosis and treatment of congenital adrenal hyperplasia in five middle European countries.

Despite the fact that congenital adrenal hyperplasia (CAH) is one of the most common inborn endocrine disorders, some patients are not identified, or may even die, in an acute salt-losing crisis. In a retrospective study covering the last 30 yr, we examined the time elapsing before diagnosis of CAH patients, in 5 Middle European countries, and the mortality rate in diagnosed patients and their siblings during childhood; we also attempted to estimate how many patients are not diagnosed clinically each year. Basic and follow-up clinical data and the family histories of 484 patients with classical forms of CAH diagnosed between 1969 and 1998 were collected and recorded in 5 Middle European countries. The sex-ratio, time elapsing before diagnosis, and mortality among siblings and patients were calculated, and the number of undiagnosed patients was estimated. We found significantly fewer genetic males (43.0%) than females (57.0%) among 484 classic CAH patients, and the percentage of diagnosed boys did not increase with time; 64.7% of them suffered from the salt-wasting (SW) form, and 35.3% from the simple virilizing (SV) form, of the disease. The diagnosis of CAH was established significantly later in males than in females in both forms [SW: 26 vs. 13 days (median), P < 0.0001; SV: 5.0 vs. 2.8 yr, P = 0.03]. Infant mortality in the general population was significantly lower than in either siblings (1.8% vs. 7.0%; P < 0.0001) or in SW (2.29% vs. 11.3%; P < 0.0001). According to our calculations, by our current praxis of clinical ascertainment, 2-2.5 SW and up to 5 SV stay undiagnosed, out of 40 expected CAH patients per year in the countries investigated. Both clinical detection and treatment of CAH patients, at least in males, were insufficient in the five Middle European countries examined during the last 30 yr. Neonatal mass screening and/or greater awareness of the medical community are discussed as ways of improving the efficacy of CAH management. Our experience may be applicable to other countries with similar health care systems.

GH and TSH deficiency.

Hypothyroidism is a recognised complication of GH therapy in GH deficient children. The mechanisms involved include direct effects on thyroid function but also result from the close interrelationship of pituitary cell-lines that differentiate during embryonic development of the anterior pituitary gland. Among numerous pituitary transcriptionfactors that orchestrate pituitary organogenesis Pit-1 was the first to be recognised and is the most extensively studied. Mutations in the Pit-1 gene account for a form of combined pituitary hormone deficiency for GH, Prolactin (Prl) and TSH (CPHD). Despite the variability of the clinical presentation of this syndrome at the time of initial diagnosis, all forms finally result in severe retardation of growth and development due to GH-deficiency and hypothyroidism. More than half of the families with a combined pituitary hormone deficiency have not disclosed any Pit-1 abnormalities. Evidence is accumulating that Prop-1, a transcriptionfactor expressed temporarily in the fetal anterior pituitary, could be a candidate for patients with a Pit-1 phenotype without any Pit-1 gene abnormalities.

Severe hypoglycemia and reduction of insulin requirement in a girl with insulin-dependent diabetes mellitus: first sign of a craniopharyngioma.

A girl with a history of insulin-dependent diabetes mellitus since 5.5 years, and Hashimoto's thyroiditis since 12 years, developed episodes of severe hypoglycemia from the age of 12 years. This was associated with falling insulin requirements, from 0.78 U/kg/day at 11 years to 0.34 U/kg/day at 16 years. At 16 years she was found to have GH, gonadotropin, ACTH, and probably also TSH deficiency with hyperprolactinemia. MRI scan revealed a cystic intrasellar craniopharyngioma with moderate suprasellar extension. In spite of cortisol replacement at 17 years, insulin requirement fell further to 0.25 U/kg/day at 18 years. In this girl, decreasing insulin requirements represented an early manifestation of combined growth hormone and cortisol deficiency.

IGF-I resistance and Turner's syndrome.

The pathogenesis of growth failure in Turner's syndrome is not clear but might be attributed to a decreased sensitivity to insulin-like growth factor-I (IGF-I) in distinct cell lines or to its reduced autocrine/paracrine action. Growth hormone (GH) therapy leads to increments in IGF-I levels and to growth acceleration. In order to evaluate the pattern of overcoming IGF-I resistance through childhood and adolescence, we measured IGF-I in 78 girls with Turner's syndrome aged 4.6-18.3 years on 160 occasions without or during GH (1 IU/kg/week [0.33 mg/kg/week]) or GH+estradiol (E2) therapy and compared them with local IGF-I standards. In untreated patients, IGF-I levels were low normal (-0.71+/-0.18 SDS, mean +/- SEM). In both GH or GH+E2 treated girls, circulating IGF-I levels were persistently supraphysiological (GH only: +3.61+/-0.23 SDS; GH + estradiol: +3.18+/-0.31 SDS). The age-dependent pattern of IGF-I secretion was conserved but the pubertal increase occurred earlier. The highest standardized IGF-I levels were observed at age 8.5-9.4 years (+6.62+/-1.00 SDS) and 9.5-10.4 years (+5.61+/-1.03 SDS). GH+E2 substitution had no additional effect on circulating IGF-I. We conclude that high IGF-I levels are needed to overcome the IGF-resistance in Turner's syndrome. They reflect the action of GH therapy but not of estrogens. The earlier pubertal increase of IGF-I might be caused by exaggerated adrenal androgens.

Treatment of peripubertal children after renal transplantation (RTX) with recombinant human growth hormone: auxological data and effects on insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) during 24 months.

OBJECTIVE: To evaluate growth and endocrine parameters in RTX children with GH treatment during 24 months. SUBJECTS: 18 children (13 boys), age 13.1 yr (8.0-16.6), bone age 10.1 yr (5.4-15.3). Patients were 2.8 yr (0.5-7.5) after RTX and had immunosuppressive therapy, prednisone 0.16 mg/kg/d (0.08-0.68). METHODS: GH (4 IU/m2/day s.c.) was given and patients were seen every 3 months for evaluation of height, height velocity, bone age, and hormone parameters. Serum IGF-I was determined by RIA, IGFBP-3 by RIA and Western ligand blotting (WLB). Renal function and adverse effects (GFR, glucose tolerance, rejection episodes) were monitored. RESULTS: Height (+1 SDS) and height velocity (+2.2 SDS) increased significantly during 24 months GH treatment, but delta BA/delta CA was 1.7 and 1.5 during the first and second treatment year, respectively, and all patients entered puberty during the treatment period. GFR decreased slightly during 2 yr (p = 0.048), two patients had chronic rejection and GH therapy was terminated in one patient because of glucose intolerance. The ratio IGF-I/IGFBP-3 rose during the first year (p = 0.002) indicating more bioavailable IGF-I. IGFBP-3 determined by WLB was decreased, but IGFBP-1, -2 and -4 were elevated as compared to a standard. CONCLUSIONS: GH treatment increased height and growth rate in children after RTX. This may be due to significant changes in IGF-I and IGFBP-3 relationship. However, bone maturation was also accelerated thus diminishing height potential. From month 12 to 24 a continuous decrease of IGF-I was observed. There was a slight but significant deterioration of graft function. Adverse events that led to termination of GH therapy were observed in 3 of 18 patients.

Premenarchal and postmenarchal girls with insulin-dependent diabetes mellitus: ovarian and other organ-specific autoantibodies, menstrual cycle.

STUDY OBJECTIVE: To estimate various organ-specific autoantibodies and detect other endocrine autoimmune disorders and menstrual cycle characteristics in girls with Type 1 insulin dependent diabetes mellitus (IDDM). DESIGN: Prospective cohort study from 1993 to 1998, duration 4.5 years. SETTING: Diabetes & Endocrine Clinic of the University Hospital, Motol, Prague. PATIENTS: 53 IDDM girls (group A--43 postmenarchal, group B--10 premenarchal), 15.5 +/- 2.5 (8-19) years old, 6.2 +/- 4.3 years after IDDM onset. MAIN OUTCOME MEASURES: Ovarian autoantibodies directed to ooplasm, zona pellucida, membrana granulosa, theca folliculi interna, and lutein cells, insulin autoantibodies, thyroid peroxidase and thyroglobulin autoantibodies. Menstrual cycle character, endocrine glands disturbance. Diabetes control, body mass index, duration of IDDM. RESULTS: Ovarian autoantibodies in at least one of the followed structures were found in 67.9% of the IDDM girls. In the control group of 21 healthy girls of corresponding age, the positive findings in lutein cells were found in only 4.8% of the girls (P < 0.01 versus IDDM girls). The lutein cells commonly associated with theca folliculi interna cells were the most frequent immunopositive structures in diabetic girls (P < 0.05 versus another positive ovarian autoimmune structure). Autoantibodies directed to ovarian steroid producing cells were frequent in IDDM patients with both irregular and normal menstrual cycles. Irregular menstrual cycles were diagnosed in 27.9% of IDDM girls, polymenorrhea in half of them, and oligomenorrhea in the remainder. Diabetes control in our patients (glycosylated hemoglobin HbA1c in postmenarchal girls 10.1 +/- 2.0%) did not differ between those with regular and those with irregular menstrual cycles. Over a follow-up period one-third of the girls with oligomenorrhea and a long-term noncompliance (HbA1c 13.5%) developed secondary amenorrhea. Insulin autoantibodies were found in 67.8%, thyroid peroxidase autoantibodies in 12.5%, and thyroglobulin autoantibodies in 10.4% of the IDDM girls. Autoimmune thyroiditis was diagnosed in 5 IDDM patients (9.4%); hypothyroidism developed in 3 of them. Menstrual cycle was irregular in 4 of the 5 girls with autoimmune thyroiditis (polymenorrhea in 1, oligomenorrhea in another 3 girls). CONCLUSIONS: An increased incidence of various circulating autoantibodies may be markedly demonstrated in IDDM girls. Their reproductive function might have an important relationship to an evidence of ovarian autoantibodies. Menstrual cycle disturbances could be linked to the poor diabetes control, to the presence of ovarian and other autoantibodies, and also to other autoimmune disease.

[Effect of estrogens on final body height in girls with a constitutionally tall stature--risk or benefit?]. / Ovlivnení definitivní telesné výsky estrogeny u dívek s konstitucne vysokým vzrustem--rizika nebo prínos?

OBJECTIVE: Investigation of the effect of a long-term oestrogen treatment on the growth and development of children, elaboration of a theoretical model for remaining growth of girls on a long-term oestrogen therapy predicting reduction of the final height in girls with constitutionally tall stature, analysis of early and late side-effects of therapy. TYPE OF STUDY: Open clinical study. NAME AND PLACE OF DEPARTMENT: Endocrine out-patient clinic of the Second Paediatric Department and gynaecological out-patient clinic for children and adolescents of the Gynaecological-Obstetric Department, Second Medical School--Charles University and University Hospital Prague--Motol. METHOD: Elaboration of theoretical model for remaining growth of girls on a long-term oestrogen therapy was based on an analysis of the remaining growth of upper and lower body segment of healthy Czech girls. RESULTS: The extent of assumed reduction of the final height in girls with constitutionally tall stature treated with oestrogen declines with advancing age at the onset of treatment. The optimal age for the onset of treatment is between 10 and 11 years. CONCLUSION: Treatment can be recommended only in girls with growth prediction above 185 cm and serious psychological difficulties resulting from excessive height, always after careful analysis of the biological development and growth prediction. In every case it is necessary to evaluate the possible benefit of treatment in relation to potential risks. The greatest problem is according to the authors late onset and overrating of the therapeutic possibilities.

[Stimulation of endogenous secretion of the growth hormone. Today in diagnosis, tomorrow in therapy?]. / Stimulace endogenní sekrece rustového hormonu. Dnes v diagnostice, zítra v terapii?

BACKGROUND: Treatment with growth hormone (GH) restores the natural growth rate in children with growth hormone deficiency (GHD). This is, however, achieved only after daily injections extending over many years and therefore daily short-term hypersomatotropinaemia. Stimulation of endogenous secretion of GH e.g. by oral administration of growth hormone-releasing peptide (GHRP) may help in future to eliminate these adverse aspects. This treatment could be beneficial in patients with a stimulable endogenous GH secretion. METHODS AND RESULTS: In order to find potential candidates for spontaneous secretion of GH the authors examined, using a test with sermoreline (GHRH1-29NH2), 31 children (21 boys) aged 5.8-16.5 years suffering from idiopathic (GHD), previously treated by daily GH injections. GH rose after stimulation with sermoreline to more than 14 mIU/l in 18/31 children (responders). The ratio of "responders" was higher in the sub-group of children with isolated GHD, as compared with multiple pituitary deficiency (p = 0.05) and insignificantly higher in the sub-group of children born by breech delivery (p = 0.13). CONCLUSIONS: More than half the children treated nowadays with GH could profit in future from the method of spontaneous GH secretions. The success of this procedure is more likely in children with isolated GHD and in breech delivered children.