INTRODUÇÃO: Pacientes com deficiência de GH e síndrome de Turner, associados a baixa estatura, são beneficiados com o tratamento com GH. Há controvérsias sobre a atuação deletéria do GH no crescimento craniofacial, porém a maioria dos trabalhos é retrospectiva. Nosso objetivo foi realizar estudo prospectivo para avaliar o crescimento craniofacial de pacientes em tratamento com GH e o possível desenvolvimento de traços acromegálicos. CASUÍSTICA: 30 pacientes com idade cronológica de 4,6 a 23 anos e idade óssea de 1,5 a 13 anos divididos em 3 grupos baseados no diagnóstico e uso de GH: grupo 1- pacientes virgem de tratamento com GH portadores de hipopituitarismo e deficiência isolada (n=6); grupo 2: pacientes já em tratamento com GH: portadores de hipopituitarismo e deficiência isolada (n=16); grupo 3: pacientes com síndrome de Turner em tratamento com GH (n=8). A dose do GH utilizada foi de 0.1 a 0.15 U/kg/dia, via subcutânea, à noite, por 2 a 11 anos. MÉTODOS: medidas antropométricas (altura, pés e mãos), radiografia panorâmica, telerradiografia seguida pela análise cefalométrica de Ricketts e medidas lineares da base do crânio, altura facial, terço inferior da face, mandíbula e maxila, e fotografia facial de frente e perfil anualmente, por no mínimo 3 anos. As medidas lineares citadas foram comparadas com a média da população brasileira e entre si para avaliar o desenvolvimento craniofacial individual. As medidas de mãos e pés foram comparadas com atlas de morfometria e consideradas alteradas quando >P97. Os níveis de IGF1 e IGFBP3 foram mensurados a cada 6 meses para adequação da dose de GH. Os resultados foram analisados estatisticamente tomando-se como significantes valores de p<0,05. RESULTADOS: grupos 1 e 2 (deficiência isolada de GH ou hipopituitarismo): 3 pacientes com perfil desarmonioso obtiveram harmonia, 2 pacientes devido ao crescimento mandibular e um paciente devido ao crescimento maxilar, nenhum paciente desenvolveu desarmonia facial; observamos aumento significante da base posterior do crânio, mandíbula e terço inferior da face (p<0,05). Grupo 3 (síndrome de Turner): 2 pacientes com face desarmoniosa obtiveram harmonia, devido ao crescimento mandibular e nenhuma paciente desenvolveu desarmonia facial. Todos os pacientes, quando comparadas a análise cefalométrica de Ricketts inicial e final, mantiveram o mesmo padrão de crescimento facial. Observamos aumento das mãos em 2 pacientes (1 do sexo masculino com deficiência de GH e outra com síndrome de Turner), enquanto que o aumento dos pés foi observado em 50% das pacientes com síndrome de Turner e em 32% dos pacientes com deficiência de GH. CONCLUSÕES: A comparação das medidas cefalométricas do grupo de pacientes com deficiência de GH, virgem de tratamento, demonstrou maior atuação do GH no crescimento da base posterior do crânio e mandíbula; todos os pacientes mantiveram o mesmo padrão de crescimento craniofacial durante o acompanhamento; não houve correlação estatisticamente significante entre as medidas cefalométricas e a harmonia da face, portanto a associação dos métodos de cefalometria e análise facial por fotografia é necessária para avaliar a atuação do GH no crescimento craniofacial, houve melhora da harmonia facial em 28% dos pacientes retrognatas, devido ao crescimento mandibular, portanto pacientes retrognatas podem ser beneficiados com o tratamento com GH; não observamos desenvolvimento de desproporções faciais e nenhum paciente desenvolveu desarmonia facial no decorrer do tratamento com doses padronizadas de GH. Observamos, no entanto, aumento das extremidades, principalmente dos pés. / INTRODUCTION: Patients with GH deficiency and Turner syndrome, associated to short stature can benefit from GH treatment. There are controversies on the deleterious effect of GH on craniofacial growth; however, most of the studies are retrospective. Our objective was to carry out a prospective study to evaluate the craniofacial growth of patients in treatment with GH and the possible development of acromegalic features. PATIENTS: 30 patients with chronological age of 4.6 to 23 years and bone age of 1.5 to 13 years divided in 3 groups based on the diagnosis and GH use: group 1- patients with hypopituitarism and isolated GH deficiency naïve to GH treatment (n=6); group 2: patients with hypopituitarism and isolated GH deficiency (n=16) and group 3: patients with Turner syndrome, both already on GH treatment (n=8). GH treatment (0.1 to 0.15 U/kg/day, subcutaneously) was carried out at the night for 2 to 11 years. METHODS: Anthropometrical (height, hands and feet) measurements, panoramic x-ray, teleradiography followed by cephalometric analysis according to Ricketts and linear measurements of the skull base, facial height, lower third of the face, lower jaw and maxilla, and frontal and profile analysis of face by photography were made annually, for at least 3 years. The mentioned linear measurements were compared with the average Brazilian population and among themselves to evaluate the individual craniofacial development. The hand and foot size measurements were compared with a morphometric atlas and were considered increased when >P97. The levels of IGF1 and IGFBP3 were measured each 6 months for GH dose adequacy. The results were analyzed statistically and p values < 0.05 were considered statistically significant. RESULTS: Group 1 and 2 with isolated GH deficiency or hypopituitarism: 3 patients with disharmonious profile attained harmony, 2 due to the mandibular growth and 1 patient due to maxillary growth; no patient developed facial disharmony; we observed a significant increase of the posterior skull base, inferior jaw and lower third of the face (P<0.05). Group 3 with Turner syndrome: 2 patients with facial disharmony obtained harmony due to the mandibular growth and no patient developed facial disharmony. All of the patients maintained the same pattern of facial growth when the initial and final cephalometric analyses according to Ricketts were compared. Hand size increase was observed in 2 patients (1 with GH deficiency and another with Turner syndrome); foot size increase was observed in 50% of the patients with Turner syndrome and in 32% of the patients with GH deficiency. CONCLUSIONS: The comparison of the cephalometric measurements of the group with GH deficiency naïve to GH treatment, demonstrated a greater GH effect on the growth of the posterior skull base and jaw; all of the patients had kept the same craniofacial growth pattern during the follow-up; there was no statistically significant correlation between the cephalometric measurements and facial harmony; therefore, the association of the methods of cephalometric and facial analysis through photography is mandatory to evaluate the effect of GH on craniofacial growth. There was an improvement in the facial harmony in 28% of the retrognathic patients due to mandibular growth; therefore, patients with mandibular retrognathism can benefit from GH treatment. None of the patients treated with standardized doses of GH developed facial disharmony during treatment. We observed however, an increase of the extremities, mainly of the feet.

Einleitung: Wachstumsprozesse beim gesunden Menschen sind weitgehend untersucht und bekannt. Über die Auswirkungen von stark erniedrigtem bzw. fehlendem Wachstumshormon auf das Längen- und Breitenwachstum einzelner auxiologischer Parameter und die Folgen einer Wachstumshormonsubstitutionstherapie auf die Körperproportionen im Einzelnen weiß man außer den Kenntnissen über die Körperhöhenveränderungen wenig. Fragestellung: Ziel dieser Arbeit war die auxiologische Untersuchung von Kindern mit Wachstumshormonmangel vor und unter einer Substitutionstherapie mit Wachstumshormon. im Vordergrund stand die Erkennung bestimmter auxiologischer Muster vor und die Frage nach Veränderungen der Körperproportionen unter der Therapie. Methode: Grundlage der Daten sind 62 Kinder mit idiopathischem und 20 Kindern mit organischem Wachtumshormonmangel, bei denen über einen maximalen Zeitraum von fünf Jahren halbjährlich 22 verschiedene Parameter vermessen und drei weitere berechnet worden sind. Ergebnisse: Die phänotypischen Merkmale des hypophysären Kleinwuchses vor Substitutionsbeginn (Puppengesicht, Akromikrie, pyknomorpher Körperbau) sind Ausdruck bestimmter auxiologischer Konstellationen, die Längenparameter weichen signifikant stärker als die Breitenparameter vom Altersnormwert ab. In Abhängigkeit von der Therapiedauer kommt es durch unterschiedlich stark ausgeprägte Größenzuwachsraten im Verhältnis zum Längenwachstum insbesondere bei der Unterarmlänge, den Breiten- und Tiefenmaßen des Thorax und den Kopfmaßen zu Veränderungen der Körperproportionen. In der Regel verbessern sich die Ausgangsproportionen. Der relative Körperfettgehalt, sowie die Umfänge (Brust-, Taillen- und Hüftumfang) nehmen unter der Therapie in Relation zur Körperhöhe ab. Schlussfolgerung: Anhand der vorliegenden Daten wird gezeigt, dass die Substitutionstherapie mit Wachstumshormon beim hypophysären Kleinwuchs Auswirkungen auf das Längen- und Breitenwachstum einzelner auxiologischer Parameter hat und sich von physiologischem Wachstum unterscheidet. Für die Bestätigung unserer Beobachtungen sind weitere prospektive Untersuchungen in größeren Kollektiven notwendig. / Introduction: Processes of growth in healthy children are well established. However, little is known about the effects of strongly degraded or missing growth hormone on the lengths and breadths growth of single axiological parameters. In particular, changes of body proportions under hormone replacement therapy are not known. Objective: The aim of the study was to estimate the influence of growth hormone deficiency of single axiological parameters and changes in body proportions during replacement therapy with growth hormone. Patients/Material and Methods: Subjects studied include 62 children with idiopathic growth hormone deficiency and 20 children with organic reason of growth hormone deficiency. 22 anthropometric measurements per person were taken by the same trained examiner prior to the start of GH-treatment and then every six months over a maximal period of 5 years. Results: Results give a distinct anthropometric picture before start of therapy. All linear parameters were significantly below average, while width measurements differed less. During treatment changes of the body proportions occur due to different growth rates of measured distances compared to height growth. The most positive changes were seen in the upper arm, hand and feet growth under GH-therapy. A comparable low growth was seen in forearm length, chest width and depth and head measures. The growth dynamics of the other parameters correspond to that of height itself. Conclusion: It is shown that the replacement therapy with growth hormone has different effects on the length and width growth of different bones. The growth is different from physiological growth processes in patient with growth hormone deficiency. Further prospective examinations are necessary to confirm our observations in larger collectives.

<p>The goals of this thesis are to evaluate quality of life (QoL) in adult patients with growth hormone deficiency (GHD) in relation to population normative data, to construct a preference-weighted index (utility) from a disease-specific QoL measure and to assess it in a clinical context.</p><p>The study included samples from the general population and patients with GHD from four European populations: England & Wales, the Netherlands, Spain and Sweden. The country-specific patient cohorts were retrieved from KIMS (Pfizer International Metabolic Database). </p><p>A questionnaire was developed that contained items from existing QoL questionnaires including, among others, Quality of Life Assessment in Growth Hormone Deficiency in Adults (QoL-AGHDA) and the EQ-5D. The QoL-AGHDA is a disease-specific measure for use in adults with GHD. The EQ-5D is a generic instrument which describes health states for which country-specific preference-based weights are available. Thus, it was possible to generate preference-weighted indices (utilities) based on data generated by both instruments. </p><p>This thesis reports QoL-AGHDA normative values for the populations of England & Wales, the Netherlands, Spain and Sweden, and confirms the extent of QoL impairment in patients with GHD in comparison with the general population. Long-term GH replacement resulted in sustained improvements in overall QoL towards normative country-specific values, as well in most of the dimensions that were impaired before treatment. </p><p>For use in health economic evaluations, models for generating utilities (QoL-AGHDA_utility) from QoL-AGHDA were developed. It is believed that these models may facilitate medical decision making, given that they provide a tool for obtaining utilities in the absence of directly collected preference-weighted indices.</p><p>QoL-AGHDA_utility effectively monitored treatment effects in patients with GHD. Moreover, this study confirmed a QoL-AGHDA_utility deficit before treatment and a gain after starting GH replacement. </p><p>The novel aspect of the present approach was to apply preference-weighted indices derived from a disease-specific measure to assess QoL in the clinical context, together with patient demographic and clinical characteristics. The robustness of this analysis is reinforced by the fact that utilities in both general and patient populations were generated using the same methodology. </p>

The goals of this thesis are to evaluate quality of life (QoL) in adult patients with growth hormone deficiency (GHD) in relation to population normative data, to construct a preference-weighted index (utility) from a disease-specific QoL measure and to assess it in a clinical context. The study included samples from the general population and patients with GHD from four European populations: England &amp; Wales, the Netherlands, Spain and Sweden. The country-specific patient cohorts were retrieved from KIMS (Pfizer International Metabolic Database). A questionnaire was developed that contained items from existing QoL questionnaires including, among others, Quality of Life Assessment in Growth Hormone Deficiency in Adults (QoL-AGHDA) and the EQ-5D. The QoL-AGHDA is a disease-specific measure for use in adults with GHD. The EQ-5D is a generic instrument which describes health states for which country-specific preference-based weights are available. Thus, it was possible to generate preference-weighted indices (utilities) based on data generated by both instruments. This thesis reports QoL-AGHDA normative values for the populations of England &amp; Wales, the Netherlands, Spain and Sweden, and confirms the extent of QoL impairment in patients with GHD in comparison with the general population. Long-term GH replacement resulted in sustained improvements in overall QoL towards normative country-specific values, as well in most of the dimensions that were impaired before treatment. For use in health economic evaluations, models for generating utilities (QoL-AGHDAutility) from QoL-AGHDA were developed. It is believed that these models may facilitate medical decision making, given that they provide a tool for obtaining utilities in the absence of directly collected preference-weighted indices. QoL-AGHDAutility effectively monitored treatment effects in patients with GHD. Moreover, this study confirmed a QoL-AGHDAutility deficit before treatment and a gain after starting GH replacement. The novel aspect of the present approach was to apply preference-weighted indices derived from a disease-specific measure to assess QoL in the clinical context, together with patient demographic and clinical characteristics. The robustness of this analysis is reinforced by the fact that utilities in both general and patient populations were generated using the same methodology.

Η αυξητική ορμόνη (GH) παίζει ιδιαίτερα σημαντικό ρόλο, καθώς προάγει κυρίως τη μεταγεννητική κατά μήκος αύξηση, και ελέγχει το μεταβολισμό των λιπιδίων και των υδατανθράκων, τη σύνθεση των πρωτεϊνών και τη διέγερση του ανοσοποιητικού συστήματος. Η ανεπάρκεια GH (GHD) διαγιγνώσκεται είτε με παθολογικές συγκεντρώσεις της GH στον ορό μετά από πρόκληση με φαρμακολογικούς παράγοντες που διεγείρουν την έκκριση της (κλασσική GHD), είτε με φυσιολογικές προκλητές δοκιμασίες αλλά παθολογικό 24ωρο εκκριτικό ρυθμό της GH (GH νευροεκκριτική δυσλειτουργία, GHND). Οι GHD και GHND ασθενείς έχουν σοβαρή καθυστέρηση αύξησης και ανταποκρίνονται καλά στην εξωγενή θεραπεία με hGH. Κοντό ανάστημα που σχετίζεται με ανεπάρκεια αυξητικής ορμόνης (GHD) μπορεί να είναι σποραδικού τύπου και ιδιοπαθής, αλλά στο 5-30% των περιπτώσεων υπάρχει προσβεβλημένος πρώτου βαθμού συγγενής, που υποδηλώνει γενετική αιτιολογία. Μεταλλάξεις του γονιδίου της GH (GH1) ευθύνονται για την εκδήλωση οικογενούς μεμονωμένης ανεπάρκειας GH (IGHD). Ο εγγύς υποκινητής του GH1 γονιδίου παρουσιάζει υψηλού βαθμού πολυμορφισμό, με τουλάχιστον 16 αναγνωρισμένους πολυμορφισμούς (SNPs) σε έκταση 535 βάσεων, που εκδηλώνονται σε σύνολο 40 απλότυπων, κάποιοι από τους οποίους επηρεάζουν την έκφραση της GH. Σκοπός της παρούσας εργασίας ήταν η ανεύρεση αλλαγών στην αλληλουχία του GH1 γονιδίου της αυξητικής ορμόνης (GH) και του εγγύς υποκινητή του σε ασθενείς με οικογενή μεμονωμένη ανεπάρκεια GH (IGHD), αλλά και η ανάλυση του τρόπου κληρονομικότητας αυτών των αλλαγών. Μελετήθηκαν 33 IGHD ασθενείς (29 GHD και 4 GHND), τα μέλη των οικογενειών τους (22 οικογένειες) και 31 μάρτυρες. Απομονώθηκε γονιδιωματικό DNA από λεμφοκύτταρα περιφερικού αίματος και πραγματοποιήθηκε πολλαπλασιασμός του GH1 γονιδίου και του υποκινητή του με την αλυσιδωτή αντίδραση πολυμεράσης (PCR). Τα δείγματα αλληλουχήθηκαν και προσδιορίστηκαν αλλαγές της αλληλουχίας με βάση την NCBI, blast- Μ28466.1-βάση δεδομένων. Στους ασθενείς μετρήθηκαν τα επίπεδα IGF-1, τα επίπεδα των άλλων ορμονών του πρόσθιου λοβού του αδένα της υπόφυσης, η μέγιστη τιμή GH μετά από προκλητές δοκιμασίες με κλονιδίνη και L-Dopa, και στους 4 GHND ασθενείς πραγματοποιήθηκε 24ωρη καταγραφή της αυθόρμητης έκκρισης της GH. Οι πολυμορφισμοί (SNPs) που ανιχνεύθηκαν στο GH1 γονίδιο και τον υποκινητή του σε ασθενείς και μάρτυρες, ελέγχθηκαν για τη συχνότητα των γονοτύπων τους, και συσχετίστηκαν με κλινικοεργαστηριακά χαρακτηριστικά, ενώ ο δυνητικός λειτουργικός ρόλος των μεταλλάξεων ελέγχθηκε με λογισμικά προγράμματα. Η αλληλούχιση του GH1 γονιδίου και του υποκινητή του ανέδειξε 18 γνωστούς από τη βιβλιογραφία SNPs στον υπό μελέτη πληθυσμό και τρεις νέες (novel) μεταλλάξεις στις 3 από τις 22 οικογένειες. Ανάλυση με το λογισμικό πρόγραμμα MatΙinspector των 2 ετερόζυγων σημειακών μεταλλάξεων που εντοπίστηκαν στον GH1 υποκινητή, -485G>C and -400G>A, αποκάλυψε θέση πρόσδεσης για τον μεταγραφικό παράγοντα E-twenty six-1 (ETS-1). Ανάλυση της τρίτης ετερόζυγης μετάλλαξης (G>A) στη θέση +300 του εσωνίου 1 του GH1 γονιδίου με τα λογισμικά ESEfinder3 και ASSP αποκάλυψε τη δημιουργία μιας κρυφής θέση ματίσματος και διάσπαση της περιοχής ματίσματος εξωνίου (ESE) ενός ψευδοεξωνίου, μειώνοντας τον αριθμό προσδενόμενων πρωτεϊνών πλούσιων σε σερίνη-αργινίνη (SR). Η στατιστική ανάλυση των συχνοτήτων των γονοτύπων στους πολυμορφισμούς υψηλής συχνότητας, και η συσχέτιση τους με παραμέτρους που σχετίζονται με την αύξηση, την έκκριση της GH, αλλά και την ανταπόκριση στην hGH αγωγή, έδειξε ότι οι GHD ασθενείς πιθανόν να εμφανίζουν διαφορετική μεταγραφική δραστηριότητα στο GH1 γονίδιο λόγω των θέσεων -278, -57 του υποκινητή, -6 της 5΄ UTR περιοχής και της θέσης +1169 του γονιδίου, που έρχεται σύμφωνο και με άλλες μελέτες, αλλά και της θέσης -31, που αναφέρεται για πρώτη φορά. Αυτοί οι πολυμορφισμοί συσχετίστηκαν με μειωμένα επίπεδα IGF-1. Από την άλλη, οι SNPs που αναγνωρίσθηκαν στους GHND ασθενείς, παρόλο που είναι παρόμοιοι με αυτούς των GHD ασθενών, συσχετίστηκαν με παραμέτρους αύξησης και όχι με τα επίπεδα IGF-1. Οι 18 πολυμορφισμοί και οι 3 μεταλλάξεις που εντοπίστηκαν στους GHD και GHND ασθενείς φαίνεται να συμβάλουν μερικώς και μεμονωμένα ή συνεργικά στη μεταγραφή του GH1 γονιδίου και συνεπώς στην έκκριση της GH, ενώ η διαφορετική συμμετοχή των SNPs στους GHD και GHND ασθενείς πιθανόν αντανακλά και τη διαφορετική εκδήλωση της νόσου. Η κατανόηση της φαινοτυπικής ποικιλότητας των ασθενών με IGHD και των γενετικών αιτιών μπορεί να βοηθήσει στη κατανόηση των μηχανισμών που ενέχονται στον έλεγχο της αύξησης, αλλά και στη βελτίωση της παρακολούθησης και της θεραπείας των ασθενών. / Growth hormone (GH) plays a pivotal role in a number of physiological processes by promoting postnatal longitudinal body growth, lipid and carbohydrate metabolism, protein biosynthesis and activation of the immune system. GH deficiency (GHD) is diagnosed either by subnormal levels of serum GH during two hGH stimulation tests by pharmacological agents that physiologically stimulate GH secretion (classic form of GHD), or normal serum GH levels, but subnormal 24hr GH profile (Neurosecretory GH deficiency, GHND). Children with GHD and GHND have severe growth retardation and respond to exogenous human GH (hGH) therapy with significant catch-up growth. Short stature associated with isolated GH deficiency (GHD) is both sporadic and idiopathic, but between 5 and 30% have an affected first degree relative consistent with a genetic etiology. Mutations identified on the GH gene (GH1) associate with the manifestation of familial isolated GH deficiency (IGHD). The proximal promoter region of GH1 exerts a highly polymorphic region, with at least 16 single nucleotide polymorphisms (SNPs) identified over a region of 535bp, manifested by a total of 40 haplotypes, some of which affect the GH1 expression. The aim of this study was to identify possible changes in the sequence of the GH1 gene of growth hormone (GH) and its promoter region in patients with familial isolated GH deficiency (IGHD), together with the analysis of the inheritance pattern of such genetic changes. 33 IGHD patients (29 GHD and 4 GHND), their 1st degree relatives (22 families) and 31 controls were investigated. Genomic DNA was extracted from the lymphocytes of the subjects peripheral blood and the GH1 gene was amplified by the Polymerase Chain Reaction (PCR). The samples were sequenced and the changes were identified according to the sequence M28466.1 of the NCBI blast database. The levels of IGF-1 and other hormones of the pituitary were measured in the patients and the highest level of GH during the clonidine and L-Dopa hGH stimulation test were recorded, whereas in the 4 GHND patients a spontaneous 24hr GH profile was conducted. The sequencing results were analyzed for the frequencies of the genotypes of the identified SNPs and for any possible correlations with the clinical or biochemical characteristics of the patients and the controls. Additionally, the possible functional role of the found mutations was assessed using specific programs. The sequencing of GH1 and its promoter revealed 18 SNPs in the whole sample and 3 novel mutations in 3 of the 22 investigated families. Analysis with MatInspector of the 2 heterozygous nucleotide mutations located at the promoter regions -485GC and -400GA, respectively, revealed a binding sequence for the transcription factor E-twenty six-1 (ETS-1). Analysis of the third heterozygous mutation (GA) at the +300 region of intron 1 with ESEfinder3 και ASSP revealed a cryptic splicing position and disruption of the exon splicing enhancement (ESE) region by reducing the binding affinity of serine-arginine proteins (SRs). The frequency and correlation analysis showed that the GHD patients possible exert differential transcriptional activity at the GH1 gene via the SNPs at positions -278, -57 of the promoter, -6 of 5΄ UTR region, +1169 of intron 4, which is in accordance to previous studies, and also the newly reported SNP at -31 region. These SNPs associated also with decreased IGF-1 levels. On the other hand, the SNPs identified in the GHND patients, although similar to the GHD patients, correlated with several growth parameters, irrespective to the IGF-1 levels. The 18 SNPs and 3 mutations identified in the sample seem to contribute partially and individually or in synergy to the transcriptional regulation of GH1 in the GHD and GHND patients. The SNPs contribution is differentially exerted in the GHD patients, when compared to the GHND patients and this possibly reflects the different expression of the disease. The investigation of phenotypic variance in IGHD patients and their genetic predisposition can potentially improve our perception of the underlying mechanisms of growth and offer valuable information for the better therapeutic management of IGHD patients.

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...

INTRODUÇÃO: Pacientes com deficiência de GH e síndrome de Turner, associados a baixa estatura, são beneficiados com o tratamento com GH. Há controvérsias sobre a atuação deletéria do GH no crescimento craniofacial, porém a maioria dos trabalhos é retrospectiva. Nosso objetivo foi realizar estudo prospectivo para avaliar o crescimento craniofacial de pacientes em tratamento com GH e o possível desenvolvimento de traços acromegálicos. CASUÍSTICA: 30 pacientes com idade cronológica de 4,6 a 23 anos e idade óssea de 1,5 a 13 anos divididos em 3 grupos baseados no diagnóstico e uso de GH: grupo 1- pacientes virgem de tratamento com GH portadores de hipopituitarismo e deficiência isolada (n=6); grupo 2: pacientes já em tratamento com GH: portadores de hipopituitarismo e deficiência isolada (n=16); grupo 3: pacientes com síndrome de Turner em tratamento com GH (n=8). A dose do GH utilizada foi de 0.1 a 0.15 U/kg/dia, via subcutânea, à noite, por 2 a 11 anos. MÉTODOS: medidas antropométricas (altura, pés e mãos), radiografia panorâmica, telerradiografia seguida pela análise cefalométrica de Ricketts e medidas lineares da base do crânio, altura facial, terço inferior da face, mandíbula e maxila, e fotografia facial de frente e perfil anualmente, por no mínimo 3 anos. As medidas lineares citadas foram comparadas com a média da população brasileira e entre si para avaliar o desenvolvimento craniofacial individual. As medidas de mãos e pés foram comparadas com atlas de morfometria e consideradas alteradas quando >P97. Os níveis de IGF1 e IGFBP3 foram mensurados a cada 6 meses para adequação da dose de GH. Os resultados foram analisados estatisticamente tomando-se como significantes valores de p<0,05. RESULTADOS: grupos 1 e 2 (deficiência isolada de GH ou hipopituitarismo): 3 pacientes com perfil desarmonioso obtiveram harmonia, 2 pacientes devido ao crescimento mandibular e um paciente devido ao crescimento maxilar, nenhum paciente desenvolveu desarmonia facial; observamos aumento significante da base posterior do crânio, mandíbula e terço inferior da face (p<0,05). Grupo 3 (síndrome de Turner): 2 pacientes com face desarmoniosa obtiveram harmonia, devido ao crescimento mandibular e nenhuma paciente desenvolveu desarmonia facial. Todos os pacientes, quando comparadas a análise cefalométrica de Ricketts inicial e final, mantiveram o mesmo padrão de crescimento facial. Observamos aumento das mãos em 2 pacientes (1 do sexo masculino com deficiência de GH e outra com síndrome de Turner), enquanto que o aumento dos pés foi observado em 50% das pacientes com síndrome de Turner e em 32% dos pacientes com deficiência de GH. CONCLUSÕES: A comparação das medidas cefalométricas do grupo de pacientes com deficiência de GH, virgem de tratamento, demonstrou maior atuação do GH no crescimento da base posterior do crânio e mandíbula; todos os pacientes mantiveram o mesmo padrão de crescimento craniofacial durante o acompanhamento; não houve correlação estatisticamente significante entre as medidas cefalométricas e a harmonia da face, portanto a associação dos métodos de cefalometria e análise facial por fotografia é necessária para avaliar a atuação do GH no crescimento craniofacial, houve melhora da harmonia facial em 28% dos pacientes retrognatas, devido ao crescimento mandibular, portanto pacientes retrognatas podem ser beneficiados com o tratamento com GH; não observamos desenvolvimento de desproporções faciais e nenhum paciente desenvolveu desarmonia facial no decorrer do tratamento com doses padronizadas de GH. Observamos, no entanto, aumento das extremidades, principalmente dos pés. / INTRODUCTION: Patients with GH deficiency and Turner syndrome, associated to short stature can benefit from GH treatment. There are controversies on the deleterious effect of GH on craniofacial growth; however, most of the studies are retrospective. Our objective was to carry out a prospective study to evaluate the craniofacial growth of patients in treatment with GH and the possible development of acromegalic features. PATIENTS: 30 patients with chronological age of 4.6 to 23 years and bone age of 1.5 to 13 years divided in 3 groups based on the diagnosis and GH use: group 1- patients with hypopituitarism and isolated GH deficiency naïve to GH treatment (n=6); group 2: patients with hypopituitarism and isolated GH deficiency (n=16) and group 3: patients with Turner syndrome, both already on GH treatment (n=8). GH treatment (0.1 to 0.15 U/kg/day, subcutaneously) was carried out at the night for 2 to 11 years. METHODS: Anthropometrical (height, hands and feet) measurements, panoramic x-ray, teleradiography followed by cephalometric analysis according to Ricketts and linear measurements of the skull base, facial height, lower third of the face, lower jaw and maxilla, and frontal and profile analysis of face by photography were made annually, for at least 3 years. The mentioned linear measurements were compared with the average Brazilian population and among themselves to evaluate the individual craniofacial development. The hand and foot size measurements were compared with a morphometric atlas and were considered increased when >P97. The levels of IGF1 and IGFBP3 were measured each 6 months for GH dose adequacy. The results were analyzed statistically and p values < 0.05 were considered statistically significant. RESULTS: Group 1 and 2 with isolated GH deficiency or hypopituitarism: 3 patients with disharmonious profile attained harmony, 2 due to the mandibular growth and 1 patient due to maxillary growth; no patient developed facial disharmony; we observed a significant increase of the posterior skull base, inferior jaw and lower third of the face (P<0.05). Group 3 with Turner syndrome: 2 patients with facial disharmony obtained harmony due to the mandibular growth and no patient developed facial disharmony. All of the patients maintained the same pattern of facial growth when the initial and final cephalometric analyses according to Ricketts were compared. Hand size increase was observed in 2 patients (1 with GH deficiency and another with Turner syndrome); foot size increase was observed in 50% of the patients with Turner syndrome and in 32% of the patients with GH deficiency. CONCLUSIONS: The comparison of the cephalometric measurements of the group with GH deficiency naïve to GH treatment, demonstrated a greater GH effect on the growth of the posterior skull base and jaw; all of the patients had kept the same craniofacial growth pattern during the follow-up; there was no statistically significant correlation between the cephalometric measurements and facial harmony; therefore, the association of the methods of cephalometric and facial analysis through photography is mandatory to evaluate the effect of GH on craniofacial growth. There was an improvement in the facial harmony in 28% of the retrognathic patients due to mandibular growth; therefore, patients with mandibular retrognathism can benefit from GH treatment. None of the patients treated with standardized doses of GH developed facial disharmony during treatment. We observed however, an increase of the extremities, mainly of the feet.

IGF-I, the circulating effector of growth hormone (GH) action, is essential for differentiation and survival of neurons and maturation of inner ear cells. Isolated GH deficiency (IGHD) represents an ideal model to study the impact of GH/IGF-I axis on hearing. In Itabaianinha County, Northeast Brazil, it had been described the most extend kindred with severe IGHD due to a GH-releasing hormone receptor gene homozygous mutation. (GHRHR). The aim of this transversal study was to evaluate hearing IGHD subjects. 26 IGHD dwarfs individuals (13 females) and 25 controls (15 females) matched by sex and age were studied. They were submitted to a questionnaire on hearing complaints and hearing health history and hearing tests like audiometry, logoaudiometry, acoustic immitance and stapedial reflex. To assess the outer hair cell function in the cochlea, transient evoked otoacoustic emissions (TEOAEs) were done. To assess the auditory nerve and auditory brainstem, auditory brainstem evoked responses (ABR) were obtained. Variables with normal and not normal distribution were compared in the two groups by t test and Mann-Whitney test, respectively. Misophonia and dizziness were more frequent in IGHD than controls (p=0.011). IGHD subjects presented higher thresholds in 250 Hz (p=0.005), 500 Hz (p=0.006), 3 kHz (p=0.008), 4 kHz (p=0.038), 6 kHz (p=0.008) and 8 KHz (p=0.048), and mild high-tones hearing loss (p=0.029).Stapedial reflex (p<0.001) and TEOAEs (p<0.001) were more frequent in controls. There were no statistic differences in ABRs latencies between groups. Hearing loss in IGHD occurred earlier than controls. Conclusions: subjects with untreated, congenital lifetime IGHD report more misophonia and dizziness, have predominance of mild high-tones sensorineural hearing loss, absence of stapedial reflex and of TEOAEs when compared to normal controls from the same area. Hearing loss in IGHD occurred earlier than controls. These data suggest an effect of the GH-IGF-I axis on hearing function and hearing aging. / O principal efetor circulante do hormônio do crescimento (GH), Insulin-like growth factor I (IGF-I), é essencial para a diferenciação, sobrevivência e maturação dos neurônios das células do orelha interna. A deficiência isolada do hormônio do crescimento (DIGH) representa um modelo ideal para estudar o impacto do eixo GH/IGF-I na audição. Na cidade de Itabaianinha-SE, foi descrito o maior agrupamento familiar com DIGH severa devido a uma mutação homozigótica no gene do receptor do hormônio liberador do hormônio do crescimento (GHRHR). O objetivo deste estudo transversal foi avaliar a audição em indivíduos com DIGH. 26 indivíduos com DIGH (13 mulheres) e 25 indivíduos controles (15 mulheres) pareados por sexo e idade, foram estudados. Eles foram submetidos a um questionário sobre queixas auditivas e história pregressa por entrevista e testes auditivos como audiometria tonal, logoaudiometria, imitanciometria e reflexo acústico estapediano. Para acessar a função das células ciliadas externas da cóclea, foram utilizadas as emissões otoacústicas evocadas transientes (EOAEvT). O potencial evocado auditivo de tronco encefálico (PEATE) foi utilizado para se avaliara atividade neural desde a cóclea até o tronco encefálico.. Para comparação entre os grupos foram utilizados os testes t para variáveis de distribuição normal e Mann-Whitney para variáveis de distribuição não normal O valor de p<0.05 foi considerado estatisticamente significante. As queixas de misofonia e tontura foram mais frequentes no grupo DIGH (p=0.011). 24 indivíduos DIGH realizaram a audiometria tonal com limiares mais altos nas frequências 250 Hz (p=0.005), 500 Hz (p=0.006), 3 kHz(p=0.008), 4 kHz (p=0.038), 6 kHz (p=0.008) e 8 kHz (p=0.048) e a maioria apresentou perda leve em agudos (p=0.024). A presença do reflexo acústico estapediano e das emissões otoacústicas transientes foi mais frequente no grupo controle (p<0.001). Não houve diferença estatística entre os grupos para as latências do PEATE e não houve alteração da morfologia das ondas em ambos os grupos. A perda auditiva ocorreu mais precoce no grupo DIGH. Conclusões: Os indivíduos com DIGH congênita, não tratada, relatam mais misofonia e tontura, têm predominância de perda auditiva neurossensorial leve em agudos, ausência de reflexo acústico estapediano e EOAEvT quando comparados com o grupo controle da mesma área. A perda auditiva neurossensorial ocorreu em idade mais precoce no grupo DIGH do que no controle. Esses dados sugerem os efeitos do eixo GH-IGF-I na função auditiva e no envelhecimento da audição.

GH and its principal mediator IGF-I have important effects on metabolic and cardiovascular (CV) status. While acquired GH deficiency (GHD) is often associated to increased CV risk, the consequences of congenital GHD are not known. We have described a large group of patients with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G>A) in the GH releasing hormone receptor gene, and shown that adult GH-naïve individuals have no evidence of clinically evident premature atherosclerosis. To test weather subclinical atherosclerosis is anticipated in untreated IGHD, we ruled a cross-sectional study of 25 IGHD and27 adult controls matched for age and gender. A comprehensive clinical and biochemical panel and coronary artery calcium scores by multi-detector tomography were evaluated. Height, weight, IGF-I, homeostasis model assessment of insulin resistance, creatinine and creatinokinase were lower in IGHD group. Median and interquartile range of calcium scores distribution was similar in the two groups: IGHD 0 (0) and control 0 (4.9). The vast majority of the calcium scores [20 of 25 IGHD (80%) and 18 of 27 controls (66.6%)] were equal to zero (difference not significant). There was no difference in the calcium scores classification. None of IGHD subjects had minimal calcification, which were present in 4 controls. Three IGHD and four controls had mild calcification. There were two IGHD individuals with moderate calcification and one control with severe calcification. Our study provides evidence that subjects with congenital isolated lifetime and untreated severe IGHD do not have accelerated subclinical coronary atherosclerosis. / O GH e seu principal mediador IGF-I têm importantes efeitos no perfil metabólico e cardiovascular (CV). Enquanto a deficiência adquirida do hormônio do crescimento (DGH) está frequentemente associada ao aumento no risco CV, as consequências da deficiência congênita não são conhecidas. Descrevemos um grande grupo de pacientes com deficiência isolada de hormônio do crescimento (DIGH) secundária a mutação homozigótica (c.57+1G>A) no gene do receptor do hormônio liberador do GH, e mostramos que indivíduos adultos depletados de GH não têm evidência de aterosclerose prematura clinicamente manifesta. Para testar se a aterosclerose subclínica se antecipa na DIGH não tratada, realizamos um estudo transversal com 25 portadores de DIGH e 27 controles adultos pareados por sexo e idade. Características clínicas e bioquímicas e escore de cálcio (EC) coronário pela tomografia computadorizada por múltiplos detectores, foram avaliados. Altura, peso, IGF-I, modelo de homeostase de avaliação da resistência a insulina (HOMAIR), creatinina e creatinoquinase foram menores no grupo DIGH. Mediana e intervalo interquartis da distribuição do EC foram similares entre os dois grupos: DIGH 0(0) e controles 0 (4.9). A vasta maioria dos EC [20 de 25 DIGH (80%) e 18 de 27 controles (66.6%)] foi igual a zero (diferença não significativa). Não houve diferença na classificação de EC. Nenhum dos indivíduos portadores de DIGH apresentou calcificação mínima, a qual estava presente em 4 controles. Três portadores de DIGH e 4 controles tinham calcificação leve. Dois portadores de DIGH com moderada calcificação e 1 controle com calcificação severa. Nosso estudo fornece evidências de que indivíduos com DIGH congênita, isolada, vitalícia e não tratada não têm aterosclerose coronariana subclínica precoce.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The impact of isolated growth hormone deficiency (IGHD) in physiology and clinical presentation of climateric it s not known. Climateric state in normal persons, presents hormonal profile alteration, principally increase in FSH and estradiol decrease, characterizing a hypergonadotrophic and hypoestrogenic state, due to the ovarian follicular decrease. IGHD limits linear growth, but overcoat to accented diminution of insuline like growth factor (IGF1) and consequently promote alteration in muscle, bone, fat, glucosis metabolism and corporal mass index. Our objectives are evaluating intensity of climateric symptoms, hormonal alterations, and metabolic alterations and identify morbidity on this period. It was realized transversal cut study in two groups. Goup 1 with 7 persons with isolated growth hormone deficiency in Itabaianinha-SE city , homozygots to growth hormone receptor s mutation. Group 2, with 13 persons with normal growth hormone. All persons with age between 40 and 65 years old and FSH above 20mUI/ml. It was utilized clinical card, Kupperman s menopause index, blood dosage of FSH, LH, prolactin, estradiol, total cholesterol, LDL, HDL, triglycerides and glycemia. Oncotic colpocytology and image exams like pelvic ultra-sound, mammography and mammary ultra-sound. Statistical analyses were provided by hypotheses comparation utilizing SPSS software, version 12. To comparate variables media, T-Student, Mann-Witney and frequency test x2 was utilized, with p<0.05. Results presented antropometric data, like weight and high, IGHD (36.41kg ± 7.29 and 117cm ± 4.08) and control (62.26kg ± 11.42 and 154.12cm ± 6.38) with p<0.05. Kupperman s menopause index in IGHD and control groups had small intensity (13.20 ± 9.30 and 16.00 ± 10.50). In climateric symptoms proportion of insomnia in IGHD and control groups (57% and 46%) with p=0.053. Reproductive aspects in IGHD and control groups presented, in menarche age (17 and 13 years old, with p<0.05), first sexual relationship age (28 and 19 years old, with p=0.065), gestation number (2 and 5, with p<0.05). Hormonal profile characteristic for climateric, just prolactin in IGHD and control groups (3.90ng ± 1.90 and 6.60ng ± 3.26) p<0.05. On metabolic profile, glycemia in IGHD and control groups (105.90mg/dl ± 13.40 and 91.43mg/dl ± 13.18) with p<0.05, showing IGHD group biologically being the group probally disglycemic. Uterus volume in IGHD and control groups (42.30cm3 ± 9.78 and 88.68cm3 ± 63.13) were normal, but IGHD group presented this volume in minumum limit of normality. In IGHD and control groups, endometrial volume (0.64cm ± 0.14 and 0.67cm ± 0.30) and ovary volume (3.13cm3 ± 1.52 and 4.00cm3 ± 2.85) had not significance. Mammography in IGHD group 85,2% BI-RADS 1 normal breast and 61.5% in control group. Oncotic colpocytology in IGHD group presented inflammatory process 42.9% and in control group 61.5%. Conclusion: Climateric in IGHD patients had not presented differences in clinical aspects and hormonal profile. However, morbidity in IGHD group was benign with breast cysts, vaginal inflammation, tendency to a small hypertension and disglycemia. / O impacto da deficiência isolada do hormônio de crescimento na fisiologia e na apresentação clínica do climatério não é conhecido. O climatério em indivíduos normais apresenta alteração do perfil hormonal, principalmente elevação do FSH e diminuição do estradiol, caracterizando um estado hipergonadotrófico e hipoestrogênico, decorrência da diminuição folicular ovariana. A deficiência isolada do hormônio de crescimento tem como pressuposto a limitação do crescimento linear, mas, sobretudo leva diminuição acentuada do fator de crescimento semelhantes à insulina (IGFI) e como conseqüência promove alteração no metabolismo muscular, ósseo, da gordura, do hidrato de carbono e do índice de massa corpórea. O nosso objetivo é avaliar a intensidade da sintomatologia do climatério, as alterações hormonais, metabólicas e identificar morbidade própria deste período. Foi realizado um estudo de corte transversal em dois grupos. O grupo 1 com 7 indivíduos com deficiência isolada do hormônio de crescimento da cidade de Itabaianinha-SE, homozigotos para mutação do receptor do hormônio de crescimento (GHRH-R) e o grupo 2 com 13 indivíduos com GH normal. Todos com idade dos 40 aos 65 anos e FSH acima de 20mUI/ml. Foram utilizados ficha clínica, índice de menopausa de Kupperman, dosagem sérica de FSH, LH, Prolactina, estradiol, colesterol total, LDL, HDL, triglicerídeos e glicemia. Colpocitologia oncótica e exames de imagem como ultra-sonografia pélvica, mamografia e ultra-som mamário. Análise estatística através de teste de comparação de hipóteses utilizando programa estatístico SPSS versão 12. Para comparação das medias das variáveis, T-Student, Mann-Whitney e teste de freqüência x2. O valor do p<0,05 foi estatisticamente significante. Os resultados apresentaram os dados antropométricos, como peso e altura, DIGH (36,41 kg ±7,29 e 117 cm ± 4,08) e controle (62,26kg ± 11,42 e 154,12 cm ± 6,38) com p<0,05 e a pressão sistólica foi discretamente elevada no DIGH e controle (131,43 ± 19,52 e 129,23 ± 12,56) embora não significante. Índice de Kupperman no grupo DIGH e controle (13,20 ± 9,30 e 16,00 ± 10,50) intensidade leve. Nos sintomas climatéricos a proporção insônia nos grupos DIGH e controle (57% e 46%) com p = 0,053. Os aspectos reprodutivos no grupo DIGH e controle apresentaram a idade da menarca (17 anos e 13 anos com p < 0,05), a idade da primeira relação sexual (28 anos e 19 anos com p = 0,065), número de gestação (2 e 5 gestações com p<0,05), número de parto (2 e 5 partos com p<0,05). O perfil hormonal típico do climatério, apenas a prolactina nos grupos DIGH e controle (3,90 ng ± 1,90 e 6,60 ng ± 3,26) p<0,05 foi significante. No perfil metabólico a glicemia nos grupos DIGH e controle (105,90mg/dl ± 13,40 e 91,43mg/dl ± 13,18) com p<0,05, sendo o grupo DIGH parcialmente disglicêmico. O volume do útero no grupo DIGH e controle (42,30 cm³± 9,78 e 88,68 cm³± 63,13) embora volume normais, o grupo DIGH apresentou volume no limite inferior de normalidade com p<0.05. No grupo DIGH e controle o volume endometrial (0,64 cm ± 014 e 0,67cm ± 0,30) e o volume dos ovários (3,13 cm³± 1,52 e 4,00 cm³± 2,85) não foram significativos. A mamografia no grupo DIGH 85,2% BI-RADS 1 mamas normais e no grupo controle foi de 69,24%. A colpocitologia oncótica no grupo DIGH apresentou processo inflamatório 42,9% e no grupo controle 61,5%. Conclusão: o climatério de portadoras de DIGH não apresentou diferenças nos aspectos clínicos e no perfil hormonal. Entretanto, a morbidade no grupo DIGH foi de caráter benigno como cisto mamário, vaginite, tendência à hipertensão leve e disglicemia.