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Genetic and Hormonal Regulation of Children's Growth
Vosáhlo, Jan ; Lebl, Jan (advisor) ; Marek, Josef (referee) ; Vaňková, Markéta (referee)
Genetic and Hormonal Regulation of Children's Growth MUDr. Jan Vosáhlo Abstract Growth in childhood is a complex process of changing the body, which can be disrupted by various illnesses including endocrine disorders, particularly growth hormone deficiency. Tumors or other processes affecting hypothalamic-pituitary area can be a postnatal cause of GHD; prenatal causes include 1) developmental disorders of the pituitary as part of complex syndromes, 2) developmental disorders of the pituitary due to defects in regulatory genes and 3) defects in genes involved in the synthesis and secretion of GH. The first topic of the thesis was septo-optic dysplasia - a complex syndrome involving optic nerve hypoplasia, structural brain abnormalities and pituitary dysfunctions. We extensively described phenotype in 11 Czech patients; we observed both complete SOD and incomplete forms variously combining two of the three main components of the syndrome. The cohort then became a part of an international study of 68 patients, in which we studied the phenotype in dependence on the brain morphology. We found correlation between the severity of clinical symptoms and the degree of septum pellucidum abnormities and also a correlation between hippocampus and falx abnormities and neurological symptoms. As the second topic we studied...
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Selected monogenic endocrine conditions in childhood: patophysiological connections
Obermannová, Barbora ; Lebl, Jan (advisor) ; Marek, Josef (referee) ; Čáp, Jan (referee)
Monogenic conditions are based on a single gene mutation and therefore a "rare" allele formation. Such a mutation leads to a phenotypic abnormity with autosomal dominant, autosomal recessive, or gonosmal mode of inheritance. According to mutation severity, monogenic disorders manifest either in infancy or later in life. Phenotype of the disease is caused by a total or partial absence of the gene transcript (protein product). The protein product may represent either a structural molecule or an enzyme or receptor involved in regulation of physiological processes in organism and maintenance of homeostasis. In addition, the protein may act as a signal molecule or transcription factor regulating adequate organ development and function in embryogenesis or also later in life. Monogenic conditions represent a substantial number of paediatric endocrine diseases. Exact recognition of their etiopathogenesis allows understanding of the physiological processes in human body. The phenotype-genotype correlation supports to elucidate the complex physiology of endocrine regulations. The first part is devoted to the transcription factor PROP1 which regulates embryonic differentiation of anterior pituitary. We present a Czech study investigating the frequency of PROP1 gene mutations and its functional effect on hormonal...
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Pathophysiological mechanisms and optimization of diagnosing congenital adrenal hyperplasia
Malíková, Jana ; Lebl, Jan (advisor) ; Vrbíková, Jana (referee) ; Zapletalová, Jiřina (referee)
Autoreferát 5 Summary Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases which are characterized by inadequate secretion of steroid hormones of the adrenal cortex. The most common type of CAH is a deficiency of 21-hydroxylase (CYP21A2 gene), which leads to insufficient secretion of mineralocorticoids and glucocorticoids and excessive androgen production. There is apparent good correlation between the type of mutation and a 21-hydroxylase deficiency, and subsequently the clinical presentation. Neonatal screening for CAH was introduced to early and effectively recognize the most severe type of 21-hydroxylase deficiency (salt wasting form of CAH). Neonatal screening CAH is based on the detection 17-OHP level in dried blood spots by fluoroimmunoassay (Delfia). In the Czech Republic NS CAH was implemented to screening program in 2006. During the period of 2006 - 2011 we evaluated the results of NS CAH and we observed sensitivity of 98%, specificity of 99.5%, a low positive predictive value (PPV) of 1.6% and a high false positive rate (FPR) of 0.51% in the whole group examined newborns. Due to the low positive predictive value in the part of neonatal population (0.51%) the levels of 17-OHP are repeatedly checked for transiently elevated levels of 17-OHP above the cut-off limit of...
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Pathogenesis of germ cell tumor development: Application of current knowledge in early diagnostics in patient with disorders of sex development
Kaprová, Jana ; Lebl, Jan (advisor) ; Lisá, Lidka (referee) ; Zapletalová, Jiřina (referee)
Patients with disorders of sex development with an increased risk for development of gonadal germ cell tumors mostly undergo prophylactic gonadectomy, that always leads to a need for hormonal substitution, and moreover, in some cases prevents fertility. The aim of the thesis was to better determine the risk for tumor development in relation to the functional and phenotypical characteristics in patients with complete form of androgen insensitivity syndrome (CAIS) and patients with 45,X/46,XY gonadal dysgenesis (GD). Hematoxiline and eosine staining and immunohistochemical detection of OCT3/4, TSPY and KITLG were used to assess 37 and 36 gonadal tissue samples of 19 CAIS patients, respectively, and 84 samples from 47 patients with 45,X/46,XY GD. The results were correlated with gonadal position and expected level of androgen receptor activity in the first group. The gained data were compared with level of virilization of external gentalia in the second group. Due to an unequal distribution in relation to the age in patients with CAIS, it was not possible to independently assess the influence of gonadal position (inguinal versus abdominal) on the histological gonadal changes. Expected residual androgen receptor activity has a positive effect on survival of general germ cell population but not on the...
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Coincidental finding of hyperglycemia in children and adolescents
Feigerlová, Eva ; Lebl, Jan (advisor) ; Houšťková, Hana (referee) ; Haluzík, Martin (referee) ; Stárka, Luboslav (referee)
Donedávna se v souvislosti s diabetem v pediatrické populaci uvažovalo téměř výhradně O diabetu mellitu I. typu (Tl DM) s jeho typickou klinickou symptomatologií zahrnující polyurii, polydipsii, váhový úbytek a případně projevy ketoacidÓzy. Nyní na diabetes mellitus dětského věku a adolescence pohlížíme jako na heterogenní onemocnění zahrnující skupinu poruch s rozdílnou patogenezí, průběhem a odpovědí na léčbu (ADA 2005). V některých případech je klinická symptomatologie velmi sporá a může se omezit jen na náhodné zjištění mírné hyperglykémie v rámci vyšetřování pro různé klinické stavy. Náhodnou hyperglykémií se rozumí zvýšená glykémie nad referenční mez u jinak zdravého, klinicky asymptomatického jedince, stanovená z náhodného žilního odběru nalačno za bazálních podmínek (např. v rámci preventivní prohlídky) či během zátěžové situace (např. v průběhu akutně probíhající onemocnění, v souvislosti s chirurgickým zákrokem či úrazem). Dle definice (ADA 2005, WHO 1999) se za fyziologické považují hodnoty plazmatické glykémie nalačno nižší než 5,6 mmol/I za předpokladu dodržení podmínek preanalytické přípravy. Normální hodnota glykémie měřená 2 hodiny po standartní zátěži v průběhu OGTI (orálního glukózového tolerančního testu) je nižší než 7,8 mmolll. I přes existenci jasných kritérií nepovažuj í některé...
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Pathophysiology of primary congenital and early-onset non-autoimmune hypothyroidism
Al Taji, Eva ; Lebl, Jan (advisor) ; Dvořáková, Marcela (referee) ; Jiskra, Jan (referee) ; Stárka, Luboslav (referee)
Background: Thyroid dysgenesis (TD) and thyroid dyshormonogenesis clinically manifest as permanent primary congenital hypothyroidism (CH) and only rarely as non-congenital, postnatal non-autoimmune hypothyroidism. As basic molecular events underlying the regulation of thyroid development, growth and function were clarified in the last decade, molecular pathogenesis of TD and dyshormonogenesis has been intensively studied. Candidate genes for TD and dyshormonogenesis had been described and their mutations were subsequently detected in several patients with non-syndromic and syndromic CH. Nevertheless, no systematic population-based phenotype-focused molecular genetic analysis had been performed and concerning TD, the data regarded only a few individual patients. Aim: The aim of this extensive study was to identify monogenic forms of TD and dyshormonogenesis in a population-based cohort of Czech patients mostly with CH. Systematic mutation screening was based on a detailed clinical information and phenotype description, and thus focused on clinically defined subgroups of patients matching the phenotypes of already known candidate gene mutations.
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Pendrin in the pathogenesisof congenital hypothyroidism
Banghová, Karolína ; Lebl, Jan (advisor) ; Límanová, Zdeňka (referee) ; Houšťková, Hana (referee) ; Stárka, Luboslav (referee)
Pendrin is an anion transporter that is expressed in several organs. In the thyroid gland, pendrin is localized at the apical pole of thyrocytes and it is responsible for the iodide efflux from thyrocytes into the colloid in the follicular lumen where iodide is organificated. The extrathyroidal expression was shown in the inner ear, kidney, placenta and mammary gland. Carriers of mutations in the pendrin gene (PDS, SLC26A4) display variable phenotypical features following the autosomal recessive manner of the inheritance: combined thyroid and hearing affection (Pendred syndrome - OMIM274600), nonsyndromic autosomal recessive neurosensory deafness (DFNB4 - OMIM600791) or isolated enlarged vestibular aqueduct (EVA - OMIM603545). The thyroid affection is usually manifested as euthyroid or hypothyroid goitre in the second decade of life. In a minority of patients, dyshormonogenesis is present at birth, and the disease is diagnosed in the frame of the nation-wide neonatal screening for congenital hypothyroidism.
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Retrospective diagnosis of unknown cause of sudden infant death
Strnadová, Kristina ; Lebl, Jan (advisor) ; Janda, Jan (referee) ; Plavka, Richard (referee) ; Vízek, Martin (referee)
Background: Sudden infant death syndrome (SIDS) is defined as sudden unexpected death of an infant that remains unexplained after thorough post-mortem examination, investigation of the scene of death and case history. The autopsy findings and the physiological characteristics of these infants suggest a possible role of insufficient cardiorespiratory control and arousal mechanisms. The etiology is probably multifactorial based on a genetic predisposition combined with environmental factors. Several candidate genes have been studied, e.g. those involved in serotonin transport, autonomic nervous system embryology, inflammation, energy production, nicotine and glucose metabolism. A small number of cases may be caused by monogenic diseases that can lead to sudden death and leave no characteristic autopsy findings and thus imitate SIDS. Fatty acid beta-oxidation disorders (FAOD) have been associated with SIDS since 1976 and it is nowadays estimated that they may be responsible for about 1% of SIDS cases. Congenital long QT syndrome, a cardiac channelopathy, that may cause a fatal arrhythmia was a logical candidate for SIDS and indeed it was found out that about 9,5% of SIDS cases carry a mutation or a function changing variant in one of seven cardiac ion channel genes. We assumed that the severe salt...
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