This thesis deals with extraction of data from cell images and their visualisation. Cell images are processed by FISH method. It discusses theory of diagnosis evaluation automation and cell features visualization. That concerns image processing, cell nuclei segmentation, feature extraction and data visualization.

Various skeletal abnormalities, including chest deformity, have been reported with Turner's syndrome. We report radiologic findings of the sternum on lateral chest roentgenograms in 15 children and adolescents with Turner's syndrome, whose ages ranged between 2 weeks and 20 years. Eight had associated congenital heart disease (CHD). Twelve patients (80 percent) had various sternal abnormalities; 5 had short sternum, 3 had premature fusion of the manubrio-sternal junction, and 4 had premature fusion of the mesosternum. Five had decreased ratio of sternal body to manubrium. Three patients had two ossification centers of the manubrium. Four patients had bowing of the mesosternum; three of these had mild pectus excavatum also. In this series, children with and without CHD had similar sternal abnormalities. Although not pathognomonic, sternal abnormalities on a lateral chest roentgenogram are common skeletal abnormalities associated with Turner's syndrome and are independent of associated CHD. In our series of 15 patients, 10 had monosomy (45,X) on blood karyotype; 7 of them had associated CHD. This is the first systematic analysis of radiologic abnormalities of the sternum in Turner's syndrome and includes findings not previously reported.

The focus of this diploma thesis is on mosaic numerical and structural chromosomal aberrations. In its theoretical part, general problems of mosaicism, its phenotypic effect, mechanisms of origin, related epigenetic modifications, and diagnostic options are described. The methodical part of the thesis then primarily refers to fluorescence in situ hybridization (FISH) and its application in the diagnostics of mosaicism. This method was used in the examination of 29 patients with numerical as well as structural abnormalities of autosomes or gonosomes with proven or suspected mosaicism. On the basis of this analysis, possible errors of measurement were determined and data for statistic evaluation were retrieved. For the examinations of three patients an alternative of the comparative genomic hybridization, the array CGH technique, was applied. The FISH method, although being based on random selection and human factor, proved sufficient sensitivity as well as specificity in the field of low-frequency mosaicism diagnostics. The main critical factors responsible for potential misinterpretation of the data arose from inherent characteristics of the biological material, incorrect targeting of the analysis, probe instability, bleed through effect and absence of mitosis during the structural aberrations analysis.

Objetivos: Descrever a frequência, e investigar fatores preditivos, de óbito fetal espontâneo (OF), em gestações com anomalias cromossômicas. Métodos: Trata-se de estudo retrospectivo, abrangendo o período de novembro de 2004 a maio de 2012, realizado na Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Foram incluídas gestações únicas com diagnóstico pré-natal de trissomia dos cromossomos 21 (T21), 18, 13 (T13/18) e monossomia do X (45X), realizado até a 26ª semana de gestação. Resultados: Foram incluídas 92 gestantes com idade materna média de 32,7 ± 8,7 anos. O diagnóstico das anomalias cromossômicas (T21 n=36, T13/T18 n=25, 45X n=31) foi realizado em idade gestacional média de 18,3 ± 3,7 semanas, por meio de biópsia de vilo corial (n=22, 24%), amniocentese (n=66, 72%) e cordocentese (n=4, 4%). Malformação major estava presente em 45 (49%); e hidropisia foi identificada em 32 (35%) fetos, sendo mais frequente no grupo 45X (n=24/31 (77%) versus T21: n=6/36 (17%) e T13/18: n=2/25 (8%), p < 0,001). Exame ecocardiográfico fetal especializado foi realizado em 60% (55/92) das gestações. Dessas, 60% (33/55) apresentaram alterações na morfologia e/ou função cardíaca, sendo o achado mais frequente a comunicação interventricular (39%). Fetos com T13/18 apresentaram incidência maior de anomalias cardíacas (60% versus 25% (T21) e 29% (45X), p= 0,01). Óbito fetal ocorreu em 55 (60%) gestações e foi mais frequente no grupo 45X (n=26/31 (84%) versus T21: n=13/36 (36%) e T13/18: n=16/25 (64%), p < 0,01). A análise multivariada stepwise demonstrou associação entre hidropisia e OF em fetos com trissomia 21 (LR= 4,29; IC95%= 1,9-8,0, p< 0,0001). Em fetos com monossomia X, a presença de alterações ecocardiográficas esteve associada com menor risco de OF (LR= 0,56; IC95% = 0,27-0,85, p= 0,005). Não foram identificados fatores preditores no grupo T13/18. Conclusão: A letalidade intrauterina de fetos com anomalias cromossômicas é elevada. A presença de hidropisia aumenta o risco de óbito fetal, em gestações com trissomia 21. Enquanto, em gestações com monossomia X, a ocorrência de alterações ecocardiográficas reduz esse risco / Objectives: To describe the frequency, and associated factors, of intrauterine fetal death (IUD), in pregnancies with chromosomal abnormality. Methods: This was a retrospective (November 2004 to May 2012) performed at de department of obstetrics, Hospital das Clínicas, São Paulo University Medical School. Inclusion criteria were: singleton pregnancies with prenatal diagnosis of trisomy 21 (T21), 18, 13 (T13/18) and X monosomy (45X), performed up to 26 weeks gestation. Results: 92 women were included in the study with a mean maternal age of 32.7 ± 8.7 years. Fetal chromosomal abnormalities (T21 n=36, T13/T18 n=25, 45X n=31) were diagnosed at a mean gestational age of 18.3 ± 3.7 weeks, by chorionic villus sampling (n=22, 24%), amniocentesis (n=66, 72%) and cordocentesis (n=4, 4%). Major fetal structural abnormality was present in 45 (49%) cases; hydrops was diagnosed in 32 (35%) fetuses, and was more common in 45X group (n=24/31 (77%) versus T21: n=6/36 (17%) and T13/18: n=2/25 (8%), p < 0.001). Specialist fetal echocardiography was performed in 55 (60%) pregnancies and showed structural and/or functional abnormalities in 33 (60%) fetuses; ventricular septal defect was the most common finding (39%). T13/18 fetuses showed a higher incidence of cardiac abnormalities (60% versus 25% (T21) and 29% (45X), p= 0.01). IUD occurred in 55 (60%) pregnancies and was more common in 45X group (n=26/31 (84%) versus T21: n=13/36 (36%) and T13/18: n=16/25 (64%), p < 0.01). Stepwise logistic regression analysis demonstrated an association between hydrops and IUD in T21 pregnancies (LR= 4.29; 95%CI= 1.9-8.0, p < 0.0001). In 45X pregnancies, cardiac abnormalities were associated with a lower risk of IUD (LR= 0.56; 95%CI = 0.27-0.85, p= 0.005). No predictors of IUD were identified in T13/18 group. Conclusion: Intrauterine death rate is high in pregnancies with a fetal chromosomal abnormality. Presence of hydrops increases the risk of this complication in trisomy 21 fetuses. Whereas the presence of a cardiac abnormality is protective in X monosomy pregnancies

Objetivos: Descrever a frequência, e investigar fatores preditivos, de óbito fetal espontâneo (OF), em gestações com anomalias cromossômicas. Métodos: Trata-se de estudo retrospectivo, abrangendo o período de novembro de 2004 a maio de 2012, realizado na Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Foram incluídas gestações únicas com diagnóstico pré-natal de trissomia dos cromossomos 21 (T21), 18, 13 (T13/18) e monossomia do X (45X), realizado até a 26ª semana de gestação. Resultados: Foram incluídas 92 gestantes com idade materna média de 32,7 ± 8,7 anos. O diagnóstico das anomalias cromossômicas (T21 n=36, T13/T18 n=25, 45X n=31) foi realizado em idade gestacional média de 18,3 ± 3,7 semanas, por meio de biópsia de vilo corial (n=22, 24%), amniocentese (n=66, 72%) e cordocentese (n=4, 4%). Malformação major estava presente em 45 (49%); e hidropisia foi identificada em 32 (35%) fetos, sendo mais frequente no grupo 45X (n=24/31 (77%) versus T21: n=6/36 (17%) e T13/18: n=2/25 (8%), p < 0,001). Exame ecocardiográfico fetal especializado foi realizado em 60% (55/92) das gestações. Dessas, 60% (33/55) apresentaram alterações na morfologia e/ou função cardíaca, sendo o achado mais frequente a comunicação interventricular (39%). Fetos com T13/18 apresentaram incidência maior de anomalias cardíacas (60% versus 25% (T21) e 29% (45X), p= 0,01). Óbito fetal ocorreu em 55 (60%) gestações e foi mais frequente no grupo 45X (n=26/31 (84%) versus T21: n=13/36 (36%) e T13/18: n=16/25 (64%), p < 0,01). A análise multivariada stepwise demonstrou associação entre hidropisia e OF em fetos com trissomia 21 (LR= 4,29; IC95%= 1,9-8,0, p< 0,0001). Em fetos com monossomia X, a presença de alterações ecocardiográficas esteve associada com menor risco de OF (LR= 0,56; IC95% = 0,27-0,85, p= 0,005). Não foram identificados fatores preditores no grupo T13/18. Conclusão: A letalidade intrauterina de fetos com anomalias cromossômicas é elevada. A presença de hidropisia aumenta o risco de óbito fetal, em gestações com trissomia 21. Enquanto, em gestações com monossomia X, a ocorrência de alterações ecocardiográficas reduz esse risco / Objectives: To describe the frequency, and associated factors, of intrauterine fetal death (IUD), in pregnancies with chromosomal abnormality. Methods: This was a retrospective (November 2004 to May 2012) performed at de department of obstetrics, Hospital das Clínicas, São Paulo University Medical School. Inclusion criteria were: singleton pregnancies with prenatal diagnosis of trisomy 21 (T21), 18, 13 (T13/18) and X monosomy (45X), performed up to 26 weeks gestation. Results: 92 women were included in the study with a mean maternal age of 32.7 ± 8.7 years. Fetal chromosomal abnormalities (T21 n=36, T13/T18 n=25, 45X n=31) were diagnosed at a mean gestational age of 18.3 ± 3.7 weeks, by chorionic villus sampling (n=22, 24%), amniocentesis (n=66, 72%) and cordocentesis (n=4, 4%). Major fetal structural abnormality was present in 45 (49%) cases; hydrops was diagnosed in 32 (35%) fetuses, and was more common in 45X group (n=24/31 (77%) versus T21: n=6/36 (17%) and T13/18: n=2/25 (8%), p < 0.001). Specialist fetal echocardiography was performed in 55 (60%) pregnancies and showed structural and/or functional abnormalities in 33 (60%) fetuses; ventricular septal defect was the most common finding (39%). T13/18 fetuses showed a higher incidence of cardiac abnormalities (60% versus 25% (T21) and 29% (45X), p= 0.01). IUD occurred in 55 (60%) pregnancies and was more common in 45X group (n=26/31 (84%) versus T21: n=13/36 (36%) and T13/18: n=16/25 (64%), p < 0.01). Stepwise logistic regression analysis demonstrated an association between hydrops and IUD in T21 pregnancies (LR= 4.29; 95%CI= 1.9-8.0, p < 0.0001). In 45X pregnancies, cardiac abnormalities were associated with a lower risk of IUD (LR= 0.56; 95%CI = 0.27-0.85, p= 0.005). No predictors of IUD were identified in T13/18 group. Conclusion: Intrauterine death rate is high in pregnancies with a fetal chromosomal abnormality. Presence of hydrops increases the risk of this complication in trisomy 21 fetuses. Whereas the presence of a cardiac abnormality is protective in X monosomy pregnancies

No description available.

In dieser retrospektiven klinischen Studie wurden die Akten von 89 Patientinnen mit Ullrich-Turner-Syndrom ausgewertet, die zwischen 1974 und 2004 in der Universitätsklinik und Poliklinik für Kinder und Jugendliche in Leipzig behandelt worden sind. Berücksichtigt wurde die Verteilung der Karyotypen im Patientenkollektiv sowie das Auftreten von assoziierten Begleiterkrankungen. Das Alter bei Diagnosestellung, die Größe bei Diagnosestellung und die Gründe für die Verdachtsdiagnose Ullrich-Turner-Syndrom wurden analysiert. Darüber hinaus untersuchte der Autor die durchgeführten Maßnahmen zur Pubertätsinduktion im Hinblick auf ihren Beginn und Erfolg sowie deren Einfluss auf die Wachstumraten. Gut 50% der Patientinnen besaßen den Karyotyp 45,X, die anderen Karyotypen setzten sich aus Mosaiken zusammen. Assoziierte Begleiterkrankungen waren im Patientenkollektiv unterrepräsentiert. Das durchschnittliche Alter bei Diagnosestellung betrug 8,21 Jahre, es fiel während des Beobachtungszeitraumes signifikant ab. Der durchschnittliche Größen-SDS zum Zeitpunkt der Diagnosestellung betrug -2,86. Es wurde, verglichen mit den Empfehlungen der Leitlinien, eine verspätete Diagnosestellung konstatiert. Die Pubertätsinduktion begann mit durchschnittlich 13,93 Jahren mit einer signifikanten Reduktion im Verlauf. Die Dauer vom Beginn der Pubertätsinduktion bis zum Eintreten der Menarche betrug 2,51 Jahre, die Dauer vom Tannerstadium B2 zum Stadium B5 betrug gut 27 Monate. Eine Menarche wurde bei nur 65% der Patientinnen sicher beobachtet. Die Ergebnisse wurden kritisch überprüft und in den Kontext anderer Studien eingeordnet. Aus den Ergebnissen wurde gefolgert, dass das Ullrich-Turner-Syndrom, trotz einer positiven Entwicklung in den letzten Jahren, noch immer zu spät diagnostiziert wurde. Die Pubertätsinduktion verlief trotz der verzögerten Diagnosestellung hinsichtlich der Entwicklung der Tannerstadien erfolgreich. Demgegenüber blieb die Induktion der Menarche nur mäßig erfolgreich. Eine Beeinflussung der Wachstumraten durch die Östrogentherapie wurde nicht beobachtet.

<p>Hormon rasta ima ključnu ulogu u mnogim fiziolo&scaron;kim procesima, anabolički efekti, stimulisanje rasta dugih kostiju, regulacija transkripcije gena u ciljnim ćelijama su uglavnom posredovani preko mitogenog polipeptida, insulinu sličan faktor rasta tip 1 (insulin like growth factor 1-IGF-1). Hormon rasta indukuje proizvodnju IGF-1 u jetri, koji reaguje sa receptorima ciljnih organa indukujući rast, odnosno IGF-1 posreduje svim stimulativnim dejstvima hormona rasta na kost, hrskavicu, rast mi&scaron;ić a i na metabolizam masti i ugljenih hidrata. U proceni redovnosti, bezbednosti i efikasnosti terapije hormonom rasta koristi se merenje koncentracije IGF-1 u serumu. Istraživanje je urađeno kao retrospektivno-prospektivna studija, a obuhvatilo je 80 pacijenata na terapiji hormonom rasta koja se kontroli&scaron;u i leče na Odeljenju za endokrinologiju, dijabetes i bolesti metabolizma Instituta za zdravstvenu za&scaron;titu dece i omladine Vojvodine u Novom Sadu. Istraživani uzorak je obuhvatio 80 pacijenata, od kojih 35 dece sa nedostatkom hormona rasta, 24 dece rođene male za gestacionu dob i 21 devojčicu sa Tarnerovim sindromom. Svi ispitanici su praćeni od početka primene hormona rasta i tokom prve dve godine terapije hormonom rasta. U ovom istraživanju su praćeni auksolo&scaron;ki i laboratorijski parametri u cilju ispitivanja odgovora na terapiju hormonom rasta. Praćene su bazalne vrednosti IGF-1 i promene nivoa IGF-1 u serumu tokom terapije hormonom rasta i kori&scaron;ćene da bi se ispitao odgovor na terapiju hormonom rasta, praćenjem brzine rasta, promena skora standardnih devijacija - SSD za telesnu visinu i ko&scaron;tanog sazrevanja. Ciljevi istraživanja su bili da se utvrdi povezanost vrednosti insulinu sličnog faktora rasta tip 1, brzine rasta i ko&scaron;tanog sazrevanja tokom terapije hormonom rasta. Takođe je poređena brzina rasta dece sa deficitom hormona rasta, devojčica sa T arnerovim sindromom i dece rođene male za gestaciono doba na terapiji hormonom rasta. U istraživanom uzorku, dvogodi&scaron;njim praćenjem terapije hormonom rasta je postignut dobar odgovor na terapiju, među decom sa nedostatkom hormona rasta je 71,5% postiglo normalnu telesnu visinu (&plusmn;2 SSDTV) posle dve godine terapije hormonom rasta, 79,2% dece rođene male za gestacionu dob i 42,9% devojčica sa Tarnerovim sindromom. Značajna zastupljenost dece prepubertetskog uzrasta na početku terapije hormonom rasta, među decom sa nedostatkom hormona rasta 77,2%, među decom rođenom malom za gestacionu dob 79,1% i među devojčicama sa Tarnerovim sindromom 90,5% &scaron;to je značajno uticalo na uspe&scaron;nost terapije. Tokom terapije hormonom rasta je utvrđeno povećanje brzine rasta i SSD TV kod sve tri grupe ispitanika. U sve tri grupe ispitanika je tokom terapije hormonom rasta utvrđen porast nivoa IGF-1 seruma i SSDIGF-1 i ubrzanje ko&scaron;tanog sazrevanja tokom terapije hormonom rasta. Za prvih &scaron;est meseci terapije nema statistički značajnih razlika među grupama u brzini rasta (p&gt;0,05), dok je za period prve i druge godine terapije hormonom rasta utvrđeno da postoji statistički značajna razlika među grupama (p&lt;0,05), da je brzina rasta kod devojčica za Tarnerovim sindromom statistički značajno manja i od brzine rasta kod dece sa nedostatkom hormona rasta (p &lt;0,05), i od brzine rasta kod dece rođene male za gestacionu dob (p&lt;0,05). Među decom sa nedostatkom hormona rasta i dece rođene male za gestacionu dob nema statistički značajne razlike u brzini rasta (p&gt;0,5). U ovom istraživanju je praćenjem auskolo&scaron;kih i laboratrijskih parametara tokom dvogodi&scaron;nje primene hormona rasta, konstruisano vi&scaron;e matematičkih modela za predviđanje odgovora na terapiju hormona rasta koji su statistički veoma značajani sa visokim koeficijentom vi&scaron;estruke linearne korelacije. U ovom istraživanju nije dobijena statistički značajna korelacija izmedju nivoa promene IGF-1 i brzine rasta za ceo uzorak, kao ni za decu sa nedostatkom hormona rasta, decu rođenu malu za gestacionu dob i devojčice za Tarnerovim sindromom. Nije dobijena statistički značajna korelacija izmedju nivoa promene IGF-1 i ubrzanja ko&scaron;tanog sazrevanja za ceo uzorak i za tri grupe pacijenata.</p> / <p>Growth hormone plays a key role in many physiological processes. The anabolic effects, the stimulation of growth of the long bones and the regulation of gene transcription in the target cells are mediated mainly via mitogenic polypeptide and insulin-like growth factor type 1 (insulin like growth factor 1-IGF-1). Growth hormone induces the production of IGF-1 in the liver, which interacts with receptors of the target organs inducing growth, that is, IGF-1 mediates all the stimulating effects of growth hormone on bone, cartilage, muscle growth and the metabolism of fats and carbohydrates. In assessing the regularity, safety and efficacy of growth hormone therapy, measuring the concentration of IGF-1 in serum is used. The survey was conducted as a retrospective-prospective study and involved 80 patients treated with growth hormone, monitored and treated at the Department of Endocrinology, Diabetes and Metabolic Diseases, at the Institute for Health Protection of Children and Youth of Vojvodina in Novi Sad. Investigated sample included 80 patients, of whom 35 children have growth hormone deficiency, 24 children were born small for gestational age and 21 girls with Turner syndrome. All the patients were monitored from the beginning of the administration of growth hormone and during the first two years of growth hormone therapy. In this study, auxological and laboratory parameters were monitored for the purpose of examining the response to treatment of growth hormone. The basal values of IGF-1 and changes in IGF-1 levels in serum, along with monitoring the rate of growth velocity and recent changes in standard deviation - SSD for body height and bone maturation, were monitored during growth hormone therapy and used for the evaluation of the response to growth hormone therapy. The objectives of the study were to determine the correlation of insulin-like growth factor type 1 values, the growth velocity and maturation of bone during growth hormone therapy. Also, the growth velocity in children with growth hormone deficiency was compared with the growth velocity in girls with Turner syndrome and in children born small for gestational age while treated with growth hormone. Two-year monitoring of growth hormone therapy in the study sample has show n good response to therapy. 71.5% of children with growth hormone deficiency, 79.2% of children born small for gestational age, and 42.9% of girls with Turner syndrome achieved normal body height (&plusmn; 2 SSDTV) after two years of growth hormone therapy. There was a significant share of children at prepubertal age at the beginning of growth hormone therapy: 77.2% of children with growth hormone deficiency, 79.1% of children born small for gestational age and 90.5% of girls with Turner syndrome, which significantly influenced the success of the therapy. During the growth hormone therapy there was an increase of growth velocity and SSD TV in all three groups of children. An increase in levels of IGF-1 serum and SSDIGF-1 and acceleration of bone maturation were determined in all three groups of patients during growth hormone therapy. For the first six months of therapy there was no statistically significant difference between groups in growth velocity (p&gt; 0.05), while the period of the first and second year of growth hormone therapy showed a statistically significant difference between groups (p &lt;0.05). The growth velocity in girls with Turner syndrome was significantly lower than the growth velocity in children with growth hormone deficiency (p &lt;0.05) and in children born small for gestational age (p &lt;0.05). Between children with growth hormone deficiency and children born small for gestational age there was no statistically significant difference in growth velocity (p&gt; 0.5). By monitoring auxological and laboratory parameters during the two years of application of growth hormone, several highly statistically significant mathematical models for predicting the response to treatment of growth hormone were constructed in this study with a high coefficient of multiple linear correlation. In this study, there was no statistically significant correlation between the level of change in IGF-1 and growth velocity for the entire sample, as well as for children with growth hormone deficiency, children born small for gestational age and girls for Turner syndrome. There was no statistically significant correlation between the level of change in IGF-1 and acceleration of bone maturation for the entire sample and for the three groups of patients.</p>

A resposta individual ao tratamento com hormônio de crescimento recombinante humano (rhGH) na síndrome de Turner (ST) é muito variável. A falta de individualização da dose pode justificar a variabilidade de respostas e os resultados insatisfatórios de algumas pacientes mesmo quando diagnosticadas e tratadas em condições ideais. Como a resposta ao tratamento com rhGH reflete fatores genéticos e não genéticos, o objetivo do presente estudo é avaliar a influência de fatores genéticos no tratamento com rhGH das portadoras de ST. Foram estudadas 112 pacientes com ST, em tratamento ou que interromperam a terapia, após atingir a altura final. O DNA genômico de todas as pacientes foi obtido para estudo de três polimorfismos em genes envolvidos na ação do GH: a presença ou ausência do éxon 3 do receptor do GH (GHR), VNTR presente na região promotora do gene do fator de crescimento insulina-símile-1(IGF1) e polimorfismo de único nucleotídeo (SNP) presente na região promotora do gene da Proteína 3 de Ligação a Fator de Crescimento Insulina-símile (IGFBP3). Os achados moleculares foram correlacionados com a velocidade de crescimento no primeiro ano de tratamento (n=112) e com altura adulta (n=65)) após uso de rhGH por meio de análises de regressão linear simples e múltipla, ajustadas para as demais variáveis clínicas relacionadas à resposta ao tratamento com rhGH em ST. Dois desses polimorfismos - a presença (GHR-fl) ou ausência (GHR-d3) do éxon 3 do GHR e o polimorfismo - 202 A/C IGFBP-3- influenciaram de forma independente e interativa a capacidade de resposta ao tratamento com rhGH em pacientes com ST; e o VNTR de repetições (CA)n da região promotora do IGF1 não demonstrou influência sobre nenhum dos parâmetros analisados. Pacientes carreadoras de, pelo menos, um alelo GHR-d3 apresentaram melhor velocidade de crescimento e maior altura final após tratamento com rhGH do que as homozigotas para o alelo GHR-fl. Similarmente, as carreadoras de, pelo menos, um alelo -202 A-IGFBP3 apresentaram melhor velocidade de crescimento e maior altura final após tratamento com rhGH, além de maiores concentrações séricas de IGFBP-3, do que as homozigotas para o alelo -202 CIGFBP3. Finalmente, a análise conjunta dos genótipos GHR-éxon 3 e -202 A/C IGFBP3 mostrou uma clara influência epistática, parcialmente aditiva, desses dois polimorfismos comuns na altura adulta de pacientes com ST tratadas com rhGH (efeito isolado do GHR-éxon 3, R2 = 0,27; efeito isolado do -202 A/C IGFBP3, R2 = 0,24; influência combinada desses polimorfismos, R2 = 0,37). Em conjunto com as variáveis clinicas, altura ao início do tratamento (p<0,001) e idade cronológica ao início da puberdade (p<0,001), estes dois polimorfismos são capazes de predizer 61% da variabilidade da altura adulta, após uso de rhGH. Embora estudos de validação sejam ainda necessários, acredita-se que as informações geradas por este e outros estudos - direcionados a um melhor entendimento das bases moleculares envolvidas na capacidade de resposta ao tratamento com rhGH - possam servir no futuro como importante ferramenta de individualização do tratamento com rhGH / Individual response to treatment with recombinant human growth hormone (rhGH) in Turner syndrome (TS) is very variable. The lack of individualization of rhGH dosing may explain the variability of response and the unsatisfactory results for some patients even when diagnosed and treated in ideal conditions. As the response to treatment with rhGH reflects genetic and nongenetic factors, the objective of this study is to evaluate the influence of genetic factors on rhGH treatment of patients with TS. We studied 112 patients with TS in rhGH therapy or who have discontinued therapy after adult height. Genomic DNA from all patients was obtained for the study of three polymorphisms in genes involved in GH action: the presence or absence of éxon 3 of the GH receptor (GHR), VNTR in the promoter region of the gene for insulin-like growth factor- 1 (IGF1) and a single nucleotide polymorphism (SNP) in the promoter region of the gene insulin-like growth factor-binding protein 3 (IGFBP3). Molecular findings were correlated with the first-year growth velocity (n = 112) and adult height (n = 65)) after rhGH therapy using simple and multiple linear regressions analysis adjusting for other clinical variables related to the response to rhGH treatment on TS. Two of these polymorphisms - the presence (GHR-fl) or absence (GHR-d3) of the GHR éxon 3 polymorphism and -202 A / C IGFBP-3 independently and interactively influenced the response to rhGH treatment in patients with TS, whereas the VNTR in the promoter region of the gene for IGF1 showed no influence on any of the parameters analyzed. Patients carrying at least one d3-GHR allele have better first-year growth velocity and greater adult height after rhGH treatment than those homozygous for GHR-fl allele. Similarly, the carriers of at least one -202 A-IGFBP3 allele showed better first-year growth velocity and greater adult height after rhGH treatment, besides higher serum IGFBP-3 levels, than those homozygous for -202 C-IGFBP3 allele. Finally, the combined analysis of GHR-éxon 3 and -202 A / C IGFBP3 genotypes have demonstrated a clear epistatic influence, partially additive, of these two common polymorphisms on adult height of patients with TS treated with rhGH (isolated effect of GHR-éxon 3, R2 = 0.27; isolated effect of the -202 A / C IGFBP3, R2 = 0.24; combined influence of these polymorphisms, R2 = 0.37). In conjunction with the clinical variables, baseline height (SDS) (p <0.001) and chronological age at onset of puberty (p <0.001), these two polymorphisms are able to predict 61% of the variability in adult height after rhGH therapy. Although validation studies are still needed, we believe that the information brought by this and other studies whose efforts are to understand the molecular basis involved in responsiveness to rhGH treatment can serve as an important tool in the future individualization of treatment with rhGH

A resposta individual ao tratamento com hormônio de crescimento recombinante humano (rhGH) na síndrome de Turner (ST) é muito variável. A falta de individualização da dose pode justificar a variabilidade de respostas e os resultados insatisfatórios de algumas pacientes mesmo quando diagnosticadas e tratadas em condições ideais. Como a resposta ao tratamento com rhGH reflete fatores genéticos e não genéticos, o objetivo do presente estudo é avaliar a influência de fatores genéticos no tratamento com rhGH das portadoras de ST. Foram estudadas 112 pacientes com ST, em tratamento ou que interromperam a terapia, após atingir a altura final. O DNA genômico de todas as pacientes foi obtido para estudo de três polimorfismos em genes envolvidos na ação do GH: a presença ou ausência do éxon 3 do receptor do GH (GHR), VNTR presente na região promotora do gene do fator de crescimento insulina-símile-1(IGF1) e polimorfismo de único nucleotídeo (SNP) presente na região promotora do gene da Proteína 3 de Ligação a Fator de Crescimento Insulina-símile (IGFBP3). Os achados moleculares foram correlacionados com a velocidade de crescimento no primeiro ano de tratamento (n=112) e com altura adulta (n=65)) após uso de rhGH por meio de análises de regressão linear simples e múltipla, ajustadas para as demais variáveis clínicas relacionadas à resposta ao tratamento com rhGH em ST. Dois desses polimorfismos - a presença (GHR-fl) ou ausência (GHR-d3) do éxon 3 do GHR e o polimorfismo - 202 A/C IGFBP-3- influenciaram de forma independente e interativa a capacidade de resposta ao tratamento com rhGH em pacientes com ST; e o VNTR de repetições (CA)n da região promotora do IGF1 não demonstrou influência sobre nenhum dos parâmetros analisados. Pacientes carreadoras de, pelo menos, um alelo GHR-d3 apresentaram melhor velocidade de crescimento e maior altura final após tratamento com rhGH do que as homozigotas para o alelo GHR-fl. Similarmente, as carreadoras de, pelo menos, um alelo -202 A-IGFBP3 apresentaram melhor velocidade de crescimento e maior altura final após tratamento com rhGH, além de maiores concentrações séricas de IGFBP-3, do que as homozigotas para o alelo -202 CIGFBP3. Finalmente, a análise conjunta dos genótipos GHR-éxon 3 e -202 A/C IGFBP3 mostrou uma clara influência epistática, parcialmente aditiva, desses dois polimorfismos comuns na altura adulta de pacientes com ST tratadas com rhGH (efeito isolado do GHR-éxon 3, R2 = 0,27; efeito isolado do -202 A/C IGFBP3, R2 = 0,24; influência combinada desses polimorfismos, R2 = 0,37). Em conjunto com as variáveis clinicas, altura ao início do tratamento (p<0,001) e idade cronológica ao início da puberdade (p<0,001), estes dois polimorfismos são capazes de predizer 61% da variabilidade da altura adulta, após uso de rhGH. Embora estudos de validação sejam ainda necessários, acredita-se que as informações geradas por este e outros estudos - direcionados a um melhor entendimento das bases moleculares envolvidas na capacidade de resposta ao tratamento com rhGH - possam servir no futuro como importante ferramenta de individualização do tratamento com rhGH / Individual response to treatment with recombinant human growth hormone (rhGH) in Turner syndrome (TS) is very variable. The lack of individualization of rhGH dosing may explain the variability of response and the unsatisfactory results for some patients even when diagnosed and treated in ideal conditions. As the response to treatment with rhGH reflects genetic and nongenetic factors, the objective of this study is to evaluate the influence of genetic factors on rhGH treatment of patients with TS. We studied 112 patients with TS in rhGH therapy or who have discontinued therapy after adult height. Genomic DNA from all patients was obtained for the study of three polymorphisms in genes involved in GH action: the presence or absence of éxon 3 of the GH receptor (GHR), VNTR in the promoter region of the gene for insulin-like growth factor- 1 (IGF1) and a single nucleotide polymorphism (SNP) in the promoter region of the gene insulin-like growth factor-binding protein 3 (IGFBP3). Molecular findings were correlated with the first-year growth velocity (n = 112) and adult height (n = 65)) after rhGH therapy using simple and multiple linear regressions analysis adjusting for other clinical variables related to the response to rhGH treatment on TS. Two of these polymorphisms - the presence (GHR-fl) or absence (GHR-d3) of the GHR éxon 3 polymorphism and -202 A / C IGFBP-3 independently and interactively influenced the response to rhGH treatment in patients with TS, whereas the VNTR in the promoter region of the gene for IGF1 showed no influence on any of the parameters analyzed. Patients carrying at least one d3-GHR allele have better first-year growth velocity and greater adult height after rhGH treatment than those homozygous for GHR-fl allele. Similarly, the carriers of at least one -202 A-IGFBP3 allele showed better first-year growth velocity and greater adult height after rhGH treatment, besides higher serum IGFBP-3 levels, than those homozygous for -202 C-IGFBP3 allele. Finally, the combined analysis of GHR-éxon 3 and -202 A / C IGFBP3 genotypes have demonstrated a clear epistatic influence, partially additive, of these two common polymorphisms on adult height of patients with TS treated with rhGH (isolated effect of GHR-éxon 3, R2 = 0.27; isolated effect of the -202 A / C IGFBP3, R2 = 0.24; combined influence of these polymorphisms, R2 = 0.37). In conjunction with the clinical variables, baseline height (SDS) (p <0.001) and chronological age at onset of puberty (p <0.001), these two polymorphisms are able to predict 61% of the variability in adult height after rhGH therapy. Although validation studies are still needed, we believe that the information brought by this and other studies whose efforts are to understand the molecular basis involved in responsiveness to rhGH treatment can serve as an important tool in the future individualization of treatment with rhGH