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.

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.

45,X/46,X,psu dic(Y) gonadal dysgenesis: influence of the two cell lines on the clinical phenotype, including gonadal histology.

A child born with ambiguous genitalia (Prader III) was found to have a 45,X[92.2%]/46,X,psu dic(Y)(p12)[7.8%] karyotype in peripheral blood lymphocytes. The testosterone level was consistent with that of a normal male; however, gonadotropins were elevated. Ultrasound and endoscopy of the urogenital sinus revealed well-developed Müllerian structures. At 3.5 months, the child was operated for right-sided incarcerated hernia, and the gonad situated at the inguinal region was biopsied and classified as primitive testis. Based on the presence of Müllerian structures, anatomy of external genitalia and wish of the parents, the child was assigned female gender. She underwent removal of the left gonad at 4 months during another acute surgery; histology was similar to the right gonad. The rest of the right gonad was removed at 16 months, and feminizing genitoplasty took place at 3 years. The right and left gonad contained 28 and 22% of cells with a Y chromosome, respectively. During further histological examination, dysgenetic features of the gonads were discovered. Some germ cells displayed abnormal development based on the specific expression of immunohistochemical markers (OCT3/4, TSPY, KITLG), indicating a possible risk for future malignant germ cell tumor development. Contribution of the 45,X cell line to the phenotype was also observed: the patient developed celiac disease, and her growth pattern resembled that of Turner syndrome responding to growth hormone treatment.

Prepubertal girls with Turner syndrome and children with isolated SHOX deficiency have similar bone geometry at the radius.

CONTEXT: The low bone mineral density (BMD) and alterations in bone geometry observed in patients with Turner syndrome (TS) are likely caused by hypergonadotropic hypogonadism and/or by haploinsufficiency of the SHOX gene. OBJECTIVE: Our objective was to compare BMD, bone geometry, and strength at the radius between prepubertal girls with TS and children with isolated SHOX deficiency (SHOX-D) to test the hypothesis that the TS radial bone phenotype may be caused by SHOX-D. DESIGN AND SETTING: This comparative cross-sectional study was performed between March 2008 and May 2011 in 5 large centers for pediatric endocrinology. PATIENTS: Twenty-two girls with TS (mean age 10.3 years) and 10 children with SHOX-D (mean age 10.3 years) were assessed using peripheral quantitative computed tomography of the forearm. MAIN OUTCOMES: BMD, bone geometry, and strength at 4% and 65% sites of the radius were evaluated. RESULTS: Trabecular BMD was normal in TS (mean Z-score = -0.2 ± 1.1, P = .5) as well as SHOX-D patients (mean Z-score = 0.5 ± 1.5, P = .3). At the proximal radius, we observed increased total bone area (Z-scores = 0.9 ± 1.5, P = .013, and 1.5 ± 1.4, P = .001, for TS and SHOX-D patients, respectively) and thin cortex (Z-scores = -0.7 ± 1.2, P = 0.013, and -2.0 ± 1.2, P < .001, respectively) in both groups. Bone strength index was normal in TS as well as SHOX-D patients (Z-scores = 0.3 ± 1.0, P = .2, and 0.1 ± 1.3, P = .8, respectively). CONCLUSIONS: The similar bone geometry changes of the radius in TS and SHOX-D patients support the hypothesis that loss of 1 copy of SHOX is responsible for the radial bone phenotype associated with TS.

Treatment options for children with monogenic forms of obesity.

Mutations in genes involved in energy balance regulation within the central nervous system lead to monogenic forms of obesities. Individuals with these mutations are characterized by early-onset obesity and in some cases by endocrine abnormalities. Carriers of leptin gene mutations are able to normalize their body weight after daily subcutaneous leptin administration. Pharmacotherapy targeting the specific-gene deficiencies has not clinically been tested in other monogenic obesities. Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common monogenic cause of human obesity. Several treatment options have been investigated in subjects with MC4R mutations. Few studies showed that an intensive life-style intervention induces similar weight reduction in MC4R mutation carriers in comparison to MC4R mutation noncarriers. However, long-term body weight maintenance is hardly ever achieved in MC4R mutation carriers. Sibutramine, serotonin and noradrenalin reuptake inhibitor, in MC4R mutation carriers induced weight reduction and improved cardiometabolic health risks. This result was also found in our homozygous MC4R mutation carrier. In vitro studies of melanocortin agonists efficiently activate mutated MC4R with impaired endogenous agonist functional response and thus, further research in the development of drugs for MC4R mutations is needed. An administration of intranasal adrenocorticotropic hormone was not shown to be effective in subjects with pro-opiomelanocortin gene mutations. Bariatric surgery has also been performed in few of MC4R mutation carriers. After gastric banding, lower body weight reduction and worse improvement of metabolic complications was found in MC4R mutation carriers versus noncarriers. However, preliminary results suggest that diversionary operations as gastric bypass represent a suitable method also for MC4R mutation carriers. In conclusion, the management of monogenic obesities still remains a challenge.

Bone geometry and volumetric bone density at the radius in patients with isolated SHOX deficiency.

UNLABELLED: The short stature homeobox-containing gene (SHOX) plays an important role in bone development and growth. We aimed to assess bone geometry and volumetric bone mineral density at the radius in patients with isolated SHOX deficiency and to relate these bone parameters to the severity of disproportion between the upper and the lower body segment. 17 patients with isolated SHOX deficiency (median age 12.3 yrs, range 6.7-37.2, 12 children and 5 adults) were examined by peripheral quantitative CT (pQCT) at the non-dominant forearm. Results were expressed as Z-scores using published reference data. Linear regression analyses were performed to describe associations between pQCT parameters and the severity of disproportion expressed as sitting height to standing subischial leg height ratio. Trabecular volumetric bone mineral density (vBMD) at the distal radius was normal, whereas cortical vBMD was decreased (mean Z-scores 0.34±1.5, n.s., and -2.2±2.2, p<0.001, respectively). Total bone cross-sectional area was enlarged at the diaphysis (2.1±1.2, p<0.001), while cortical bone cross-sectional area was normal (-0.51±1.4, n.s.). Consequently, cortical thickness was decreased (-1.2±1.3, p<0.01). The polar strength-strain index as a surrogate of long bone strength was normal (0.40±1.4, n.s.). We found no associations between pQCT parameters and the severity of disproportion. CONCLUSIONS: Patients with isolated SHOX deficiency are characterized by decreased cortical vBMD and cortical thickness and enlarged diaphysis. As similar changes have been described in girls with Turner syndrome, these findings suggest that haploinsufficiency of SHOX could cause characteristic skeletal anomalies at the radius.

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.

Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism.

CONTEXT: Gonadectomy is avoided whenever possible in boys with 45,X/46,XY. However, no clinical markers are currently available to guide clinicians in predicting gonadal tumor risk or hormone production. OBJECTIVE: The objective of the study was to test the hypothesis that gonadal histology and risk for development of a malignant germ cell tumor are reflected by the clinical presentation of a 45,X/46,XY individual. DESIGN: The design of the study was the correlation of clinical data [external masculinization score (EMS), pubertal outcome] with pathology data (gonadal phenotype, tumor risk). SETTING: This was a multicenter study involving two multidisciplinary disorder of sex development teams. PATIENTS: Patients included genetically proven 45,X/46,XY (and variants) cases, of whom at least one gonadal biopsy or gonadectomy specimen was available, together with clinical details. INTERVENTIONS: Patients (n = 48) were divided into three groups, based on the EMS. Gonadal histology and tumor risk were assessed on paraffin-embedded samples (n = 87) by morphology and immunohistochemistry on the basis of established criteria. MAIN OUTCOME MEASURES: Gonadal differentiation and tumor risk in the three clinical groups were measured. Clinical outcome in patients with at least one preserved gonad was also measured. RESULTS: Tumor risk in the three groups was significantly related to the gonadal differentiation pattern (P < 0.001). In boys, hormone production was sufficient and was not predicted by the EMS. CONCLUSIONS: The EMS reflects gonadal differentiation and tumor risk in patients with 45,X/46,XY. In boys, testosterone production is often sufficient, but strict follow-up is warranted because of malignancy risk, which appears inversely related to EMS. In girls, tumor risk is limited but gonads are not functional, making gonadectomy the most reasonable option.

Tumor risk in disorders of sex development.

Certain patients with disorders of sex development (DSD), who bear Y chromosome material in their karyotype, are at increased risk for the development of type II germ cell tumors (GCT), which arise from early fetal germ cells. DSD gonads frequently harbor immature germ cells which express early fetal germ cell markers. Some of them (e.g. OCT3/4 and NANOG) seem to be of pathogenetic relevance in GCT development providing cells with the ability of pluripotency, proliferation and apoptosis suppression. Also TSPY (testis-specific protein Y-encoded), the main candidate for the so-called gonadoblastoma locus on Y chromosome, is overexpressed in germ cells of DSD patients and possibly contributes to their survival and proliferation. Nowadays, the use of immunohistochemical methods is highly relevant in identifying DSD gonads at risk. The risk for GCT development varies. While the prevalence of GCT is 15% in patients with partial androgen insensitivity, it may reach more than 30% in patients with gonadal dysgenesis. Patients with complete androgen insensitivity and ovotesticular DSD develop malignancies in 0.8% and 2.6% of cases, respectively. However, these data may be biased for various reasons. To better estimate the risk in individual groups of DSD, further investigations on large patient series are needed.

[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.

[Ocular manifestations in Turner's syndrome]. / Ocní projevy u Turnerova syndromu.

Turner's syndrome belongs to the most common chromosomal aberrations. It is caused by the deficiency or structural anomaly of one X chromosome, possibly by chromosomal mosaic. In this syndrome, some ocular diseases are more common. During the seven years period, we repeatedly examined 81 girls and women with Turner's syndrome; the range of age was 7-26 years. We observed the eye diseases appearance and their possible association with the karyotype. In these girls, the most common is myopia (29%), item hyperopia (24%), epicanthus (20%), color vision disturbances (17%), amblyopia (12%), strabismus (10%) and ptosis (5%). The color vision disturbances were defined as protanopia in 8.5%, deuteranopia in 3.4% a tritanopia in 5.2%. The occurrence of strabismus and ptosis were higher than in the average population. The total incidence of refractive errors was slightly higher than in normal population, with different incidence according to the karyotype. Hyperopia was found more often in karyotype 45, X (28%), whereas in chromosomal mosaic in 18% only. Inverse proportion was in myopia--in chromosomal mosaic was found in 31% and in karyotype 45, X in 26%. Generally, while comparing the incidence of separate ocular diseases in karyotype 45, X and in chromosomal mosaic, the findings were similar.

[Contrast sensitivity and fluorescein angiography in evaluating the ocular changes in the relation to the diabetes mellitus type I compensation in young adult patients]. / Citlivost na kontrast a fluorescencní angiografie pri hodnocení ocních zmen v rámci posouzení kompenzace diabetes mellitus 1. typu u mladých dospelých pacientu.

UNLABELLED: The authors performed simultaneous contrast sensitivity examination (CS) and fluorescein angiography (FAG) in 42 patients older than 18 years of age; in 65% of them the duration of the diabetes mellitus type I (T1DM) was longer than 10 years. In these 27 patients, the diagnosis of non-prolipherative diabetic retinopathy (NPDR) was established by means of FAG in 44%, in contrast to only 19% by means of the direct ophthalmoscopy solely. The other findings (56%) were corresponding with diabetic preretinopathy (DpR) due to rare micro-aneurysms (establishes by means of FAG), and changes of the macular structure and pronounced dilation and tortuosity of the capillaries (by means of direct ophthalmoscopy). Out of the other 15 patients with T1DM duration of less than 10 years, the NPDR was established in 3 patients, and DpR confirmed in other 7 patients from the group. The authors compared the decrease in every single space frequency marked on the CS curvature for 31 eyes with NPDR and 39 eyes with DpR with the normal findings in patients without T1DM established in previous studies. Comparing NPDR with the norm, the authors found important and fundamental pathological defect of the CS (p = 0.0058). DpR comparing with the norm showed significant defect of the CS (p = 0.0197). Comparing NPDR and DpR, the difference was found in more noticeable pathological defect of the CS (p = 0.0228). The compensation of the metabolic state was evaluated from average year long values of the glycolated hemoglobin (Hb1Ac) in the last 10 years of the T1DM duration by means of DCCT method. The group of followed-up patients consisted of pairs of matched patients with NPDR and DpR of the same gender, time of beginning and duration of the metabolic disease. In the NPDR patients, the compensation was not good in 72% of this period, whereas in DpR patients the satisfactory compensation lasted for 53% of this period. During the follow up period, in NPDR the average Hb1Ac level was 8.49 +/- 0.88%, and in DpR this Hb1Ac value was 7.61 +/- 0.28%, with statistically significant difference (p = 0.0033). During the period, in DpR patients no serious complication was marked, in the NPDR group, the incipient diabetic nephropathy twice and slight diabetic neuropathy were noticed. The occasional pathological values of the microalbuminuria were not possible to correlate with beginning of the NPDR. CONCLUSION: The contrast sensitivity (CS) represents in the differential diagnosis of the NPDR and DpR a screening examination method. To specify the NPDR, the FAG is suitable and for both clinical entities specifies the extent of foveolar and perifoveolar involvement. Only the many years lasting follow up of Hb1Ac values documents the importance of long-term T1DM compensation in the prevention of pathological ocular changes development.

[The human lens' transparence changes in children, adolescents, and young adults with diabetes mellitus type I]. / Zmeny transparence cocky u detí, mladistvých a mladých dospelých s diabetes mellitus 1. typu.

Authors followed up the changes' development of the human lens' transparence in 213 children and young adult patients with diabetes mellitus type I. As initial changes of the lens' transparence they considered the posterior "Y" suture accentuation, because it was noticed in 44.4 % of lenses during the first 10 years of the metabolic disease duration, in contrast to 28.1 % representation of this dissociation in the control group of patients without diabetes (p = 0.012), and it was always markedly more often in patients with myopia. Substantial changes were detected predominantly during the sixth until the tenth year of duration of the basic disease as fine subcapsular opacities graded as first degree of lens transparency changes in 48 % of eyes. After 10 years of the disease duration, the lenses were never clear. Consequently, the changes in the transparency in the anterior subcapsular layer associated in 18 %. After 15 years of diabetes duration, we detected opacities in the anterior and posterior subcapsular layers of the lenses, graded as second degree of lenses transparence changes in 85 % of eyes. This subjective evaluating of lenses' opacity changes by means of the slit lamp examination was correlated with densitometric examination by means of Pentacam camera in a representative sample of 29 patients. In the first degree of lenses' transparence changes, the posterior subcapsular layer was affected in 50 %, and in the second degree, the opacities in this layer were found practically in 90 % of cases. False positive result in clear lenses or congenital opacities or "Y" suture was not detected. In general, the affected lens transparency did not basically influence the visual acuity and the decrease of contrast sensitivity was not statistically significant (p = 0.34). For the initial change of the lenses' transparency is also determining the patient's age at the onset of the diabetes mellitus type I. The changes are more common if the onset of the disease is after the fifteenth year of age as before that (p = 0.026). The authors also detected sporadic opacities in 4.2 % of eyes, probably of congenital origin (out of them, in two patients there was bilateral finding of the cerulean cataract) without visual acuity decrease.

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.