OBJETIVO: No Brasil, a prevalência de doenças crônicas não transmissíveis (DCNT), especialmente obesidade, tem aumentado dramaticamente, constituindo-se em grave problema de saúde pública. Paradoxalmente, no país ainda são observadas altas taxas de desnutrição crônica em crianças de baixa renda, o que tem sido, recentemente, apontada como fator de risco para desenvolvimento de DCNT na vida adulta. O objetivo deste estudo foi verificar a prevalência de síndrome metabólica (SM) e sua relação com a baixa estatura, marcador de desnutrição pregressa na infância, em população adulta. MÉTODOS: Estudo transversal em população adulta, com idades entre 20 e 64 anos, residente em município da região metropolitana de São Paulo. A amostra foi composta por 287 indivíduos, sendo 214 (74,6%) do sexo feminino e 75 (25,4%) do sexo masculino. Foram obtidos dados antropométricos e clínico-bioquímicos através de exame físico e coleta de material biológico, respectivamente. Os dados socioeconômico-demográficos e de hábitos de vida foram obtidos por meio de entrevista. Para classificação da síndrome metabólica utilizou-se o critério do International Diabetes Federation e para o ponto de corte da baixa estatura utilizou-se o padrão do National Center for Health Statistics (homens <165cm e mulheres <154cm). RESULTADOS: A prevalência padronizada por sexo e idade para a síndrome metabólica foi de 40,0% no sexo feminino e 10,0% no sexo masculino e a de baixa estatura 30,0% entre as mulheres e 23,0% entre os homens. Em análise univariada, a baixa estatura demonstrou associação com a SM em ambos os sexos (Odds Ratio=1,308; p<0,001). Em análise multivariada, ajustada por sexo, idade, escolaridade, renda, tabagismo, etilismo, atividade física, antecedentes familiares e índice de massa corpórea, a baixa estatura mostrou-se associada a SM (Odds Ratio=1,299; IC95%:1,288-1,310). CONCLUSÃO: No presente estudo foi demonstrada possível associação entre SM e baixa estatura em adultos. / OBJECTIVE: In Brazil, the prevalence of chronic diseases, especially obesity, has increased dramatically, thus becoming a serious problem of public health. There are, however, high rates of undernutrition and stunting in low-income children, which have been appointed as risk factor to cause chronic diseases in later life. The objective of this study was to investigate the prevalence of metabolic syndrome and its relationship to short stature, as evidence of stunting in early life in adults. METHODS: Cross-sectional study of adult population (age 20 to 64 years old) living in the metropolitan area of Sao Paulo. The sample comprehended a total of 287 individuals, 214 (74,6%) were women and 73 (25,4%) were men. The anthropometric and clinical-biochemical data were collected through the physical exam and the biological material, respectively. The socio-economic-demographic data and life habit conditions were obtained through interview. The metabolic syndrome was defined by the criteria of International Diabetes Federation and the cut-off point for short stature was based on the standard given by National Center for Health Statistics (male <165cm and female <154cm). RESULTS: The standard prevalence for sex and age to metabolic syndrome was 40,0% among women and 10,0% among men and the prevalence of short stature were 30,0% in women and 30,0% in men. In univariate analyses the metabolic syndrome showed to be associated to short stature (Odds Ratio=1,308; p<0,001). The multiple regression analyses, adjusted by sex, age, education, income, smoking, alcohol consumption, family history and body mass index showed association between the metabolic syndrome and short stature (Odds Ratio=1,299; IC95%:1,288-1,310). CONCLUSIONS: In this study was demonstrated association between metabolic syndrome and short stature in adults.

OBJETIVO: No Brasil, a prevalência de doenças crônicas não transmissíveis (DCNT), especialmente obesidade, tem aumentado dramaticamente, constituindo-se em grave problema de saúde pública. Paradoxalmente, no país ainda são observadas altas taxas de desnutrição crônica em crianças de baixa renda, o que tem sido, recentemente, apontada como fator de risco para desenvolvimento de DCNT na vida adulta. O objetivo deste estudo foi verificar a prevalência de síndrome metabólica (SM) e sua relação com a baixa estatura, marcador de desnutrição pregressa na infância, em população adulta. MÉTODOS: Estudo transversal em população adulta, com idades entre 20 e 64 anos, residente em município da região metropolitana de São Paulo. A amostra foi composta por 287 indivíduos, sendo 214 (74,6%) do sexo feminino e 75 (25,4%) do sexo masculino. Foram obtidos dados antropométricos e clínico-bioquímicos através de exame físico e coleta de material biológico, respectivamente. Os dados socioeconômico-demográficos e de hábitos de vida foram obtidos por meio de entrevista. Para classificação da síndrome metabólica utilizou-se o critério do International Diabetes Federation e para o ponto de corte da baixa estatura utilizou-se o padrão do National Center for Health Statistics (homens <165cm e mulheres <154cm). RESULTADOS: A prevalência padronizada por sexo e idade para a síndrome metabólica foi de 40,0% no sexo feminino e 10,0% no sexo masculino e a de baixa estatura 30,0% entre as mulheres e 23,0% entre os homens. Em análise univariada, a baixa estatura demonstrou associação com a SM em ambos os sexos (Odds Ratio=1,308; p<0,001). Em análise multivariada, ajustada por sexo, idade, escolaridade, renda, tabagismo, etilismo, atividade física, antecedentes familiares e índice de massa corpórea, a baixa estatura mostrou-se associada a SM (Odds Ratio=1,299; IC95%:1,288-1,310). CONCLUSÃO: No presente estudo foi demonstrada possível associação entre SM e baixa estatura em adultos. / OBJECTIVE: In Brazil, the prevalence of chronic diseases, especially obesity, has increased dramatically, thus becoming a serious problem of public health. There are, however, high rates of undernutrition and stunting in low-income children, which have been appointed as risk factor to cause chronic diseases in later life. The objective of this study was to investigate the prevalence of metabolic syndrome and its relationship to short stature, as evidence of stunting in early life in adults. METHODS: Cross-sectional study of adult population (age 20 to 64 years old) living in the metropolitan area of Sao Paulo. The sample comprehended a total of 287 individuals, 214 (74,6%) were women and 73 (25,4%) were men. The anthropometric and clinical-biochemical data were collected through the physical exam and the biological material, respectively. The socio-economic-demographic data and life habit conditions were obtained through interview. The metabolic syndrome was defined by the criteria of International Diabetes Federation and the cut-off point for short stature was based on the standard given by National Center for Health Statistics (male <165cm and female <154cm). RESULTS: The standard prevalence for sex and age to metabolic syndrome was 40,0% among women and 10,0% among men and the prevalence of short stature were 30,0% in women and 30,0% in men. In univariate analyses the metabolic syndrome showed to be associated to short stature (Odds Ratio=1,308; p<0,001). The multiple regression analyses, adjusted by sex, age, education, income, smoking, alcohol consumption, family history and body mass index showed association between the metabolic syndrome and short stature (Odds Ratio=1,299; IC95%:1,288-1,310). CONCLUSIONS: In this study was demonstrated association between metabolic syndrome and short stature in adults.

Genome-wide association studies (GWAS) have greatly improved our understanding of the genetic basis of complex traits. However, there are two major limitations with GWAS. First, most common variants identified by GWAS individually or in combination explain only a small proportion of heritability. This raises the possibility that additional forms of genetic variation, such as rare variants, could contribute to the missing heritability. The second limitation is that GWAS typically cannot identify which genes are being affected by the associated variants. Examination of rare variants, especially those in coding regions of the genome, can help address these issues. Moreover, several studies have recently identified low-frequency variants at both known and novel loci associated with complex traits, suggesting that functionally significant rare variants exist in the human population.

Determining the genetic cause of short stature as a way to understand the pathophysiological mechanisms affecting human growth Abstract Short stature is one of the most common disorders followed-up by a paediatric endocrinologist. Pathophysiologic mechanisms leading to growth disorders are complex, however, the exact cause is mostly unknown. Our study is the first to evaluate the aetiopathogenesis of familial short stature (FSS). Using next-generation sequencing (NGS) techniques, we aimed to describe the monogenic aetiology of growth impairment in a group of FSS families, and therefore to elucidate mechanisms leading to this specific growth disorder. In selected genetic diagnoses, we additionally aimed to describe the phenotype including GH treatment response. Within Motol University Hospital centre for GH therapy, we formed a group of 98 FSS families with clear height definition in ≤-2 SD in both the child height before GH therapy and in his shorter parent. Using NGS, the FSS aetiology was elucidated in 40/98 (41%) families; 32/40 had a genetic growth plate disorder. Within the cohort, three genetically homogeneous subgroups of families were described (collagenopathies - 10/98 [10.2%] families, SHOX deficiency - 6/98 [6.1%] families, and C type natriuretic peptide receptor disorder - 4/98 [4.1%] families)....

Introdução: Obesidade é uma questão de saúde pública em muitos países, inclusive no Brasil. O excesso de peso atinge 1 bilhão de adultos no mundo e, no Brasil, já é um problema maior que a desnutrição. O glutamato monossódico (GMS) é um agente flavorizante utilizado em níveis crescentes nos alimentos industrializados. O GMS administrado em ratos ocasiona obesidade e diminuição do hormônio do crescimento (GH). Objetivo: Avaliar o efeito do GMS nos fetos de ratas prenhas através da comparação do peso, comprimento nasal-anal (CNA) e índice de Lee (IL) ao nascimento e com 21 dias de vida. Métodos: Utilizamos ratas prenhas da linhagem Wistar divididas em três grupos: grupo controle (GC), G10 e G20. Estes, respectivamente, foram alimentados com ração contendo 0, 10 e 20% de GMS desde o período de acasalamento até o final da amamentação. Resultados: O peso e o CNA não foram diferentes entre os grupos ao nascimento. O grupo G20, ao nascimento, teve IL menor que o grupo GC (p < 0,05) e, aos 21 dias de vida, apresentou peso e CNA menores que o grupo G10, o qual foi menor que o GC (p < 0,01). O grupo G20, aos 21 dias de vida, teve IL semelhante aos outros dois grupos. O percentual de ganho de peso do nascimento ao 21º dia de vida foi menor no G20 em relação aos outros dois grupos (p < 0,01). O grupo G20 teve percentual de aumento de CNA do nascimento ao 21º dia de vida menor que o grupo G10, e este menor que o grupo GC (p < 0,01). Conclusões: O GMS nas concentrações de 10 e 20% na ração de ratas prenhas Wistar apresentou uma relação dose-dependente nas variáveis peso e CNA. Houve diminuição no padrão de ganho de peso e de aumento de CNA do nascimento ao 21º dia de vida com uso de GMS. O IL na prole do grupo G20 aumentou em relação ao do grupo GC após 3 semanas de acompanhamento. / Objective: Determine the effects of the MSG (monosodium glutamate) in the offspring of pregnant rats through the comparison of the weight, NAL (nasal-anal length) and IL (Index of Lee) at birth and with 21 days of life. Research Methods & Procedures: We have investigated pregnant Wistar rats and their offspring and divided them into 3 groups: GC, G10 and G20. Each of the groups received 0%, 10% and 20% of MSG, respectively from coupling until the end of the weaning period. Results: Neither weight nor NAL were different among the groups at birth. The group G20 at birth had an IL lower than the group GC (p<0,05) and with 21 days of life presented weight and NAL lower than the groups G10 and this lower than the GC (p<0,01). Otherwise the G20 at 21 days of life had the IL similar to the other two groups. The weight profit percentage from birth to the 21st day of life was lower in the G20 regarding the other two groups (p<0,01). The G20 had a NAL increase percentage from birth to the 21st day of life lower than the G10 and this lower than the GC (p<0,01). Conclusions: MSG presented a dose-dependent relation in the variables weight and NAL. It caused a decrease in the growth pattern as well as in the weight gain pattern until the 21st day of life. The IL of the group 20% had an increased in relation to the control group after 3 weeks of follow up.

Introdução: Obesidade é uma questão de saúde pública em muitos países, inclusive no Brasil. O excesso de peso atinge 1 bilhão de adultos no mundo e, no Brasil, já é um problema maior que a desnutrição. O glutamato monossódico (GMS) é um agente flavorizante utilizado em níveis crescentes nos alimentos industrializados. O GMS administrado em ratos ocasiona obesidade e diminuição do hormônio do crescimento (GH). Objetivo: Avaliar o efeito do GMS nos fetos de ratas prenhas através da comparação do peso, comprimento nasal-anal (CNA) e índice de Lee (IL) ao nascimento e com 21 dias de vida. Métodos: Utilizamos ratas prenhas da linhagem Wistar divididas em três grupos: grupo controle (GC), G10 e G20. Estes, respectivamente, foram alimentados com ração contendo 0, 10 e 20% de GMS desde o período de acasalamento até o final da amamentação. Resultados: O peso e o CNA não foram diferentes entre os grupos ao nascimento. O grupo G20, ao nascimento, teve IL menor que o grupo GC (p < 0,05) e, aos 21 dias de vida, apresentou peso e CNA menores que o grupo G10, o qual foi menor que o GC (p < 0,01). O grupo G20, aos 21 dias de vida, teve IL semelhante aos outros dois grupos. O percentual de ganho de peso do nascimento ao 21º dia de vida foi menor no G20 em relação aos outros dois grupos (p < 0,01). O grupo G20 teve percentual de aumento de CNA do nascimento ao 21º dia de vida menor que o grupo G10, e este menor que o grupo GC (p < 0,01). Conclusões: O GMS nas concentrações de 10 e 20% na ração de ratas prenhas Wistar apresentou uma relação dose-dependente nas variáveis peso e CNA. Houve diminuição no padrão de ganho de peso e de aumento de CNA do nascimento ao 21º dia de vida com uso de GMS. O IL na prole do grupo G20 aumentou em relação ao do grupo GC após 3 semanas de acompanhamento. / Objective: Determine the effects of the MSG (monosodium glutamate) in the offspring of pregnant rats through the comparison of the weight, NAL (nasal-anal length) and IL (Index of Lee) at birth and with 21 days of life. Research Methods & Procedures: We have investigated pregnant Wistar rats and their offspring and divided them into 3 groups: GC, G10 and G20. Each of the groups received 0%, 10% and 20% of MSG, respectively from coupling until the end of the weaning period. Results: Neither weight nor NAL were different among the groups at birth. The group G20 at birth had an IL lower than the group GC (p<0,05) and with 21 days of life presented weight and NAL lower than the groups G10 and this lower than the GC (p<0,01). Otherwise the G20 at 21 days of life had the IL similar to the other two groups. The weight profit percentage from birth to the 21st day of life was lower in the G20 regarding the other two groups (p<0,01). The G20 had a NAL increase percentage from birth to the 21st day of life lower than the G10 and this lower than the GC (p<0,01). Conclusions: MSG presented a dose-dependent relation in the variables weight and NAL. It caused a decrease in the growth pattern as well as in the weight gain pattern until the 21st day of life. The IL of the group 20% had an increased in relation to the control group after 3 weeks of follow up.

Introdução: Obesidade é uma questão de saúde pública em muitos países, inclusive no Brasil. O excesso de peso atinge 1 bilhão de adultos no mundo e, no Brasil, já é um problema maior que a desnutrição. O glutamato monossódico (GMS) é um agente flavorizante utilizado em níveis crescentes nos alimentos industrializados. O GMS administrado em ratos ocasiona obesidade e diminuição do hormônio do crescimento (GH). Objetivo: Avaliar o efeito do GMS nos fetos de ratas prenhas através da comparação do peso, comprimento nasal-anal (CNA) e índice de Lee (IL) ao nascimento e com 21 dias de vida. Métodos: Utilizamos ratas prenhas da linhagem Wistar divididas em três grupos: grupo controle (GC), G10 e G20. Estes, respectivamente, foram alimentados com ração contendo 0, 10 e 20% de GMS desde o período de acasalamento até o final da amamentação. Resultados: O peso e o CNA não foram diferentes entre os grupos ao nascimento. O grupo G20, ao nascimento, teve IL menor que o grupo GC (p < 0,05) e, aos 21 dias de vida, apresentou peso e CNA menores que o grupo G10, o qual foi menor que o GC (p < 0,01). O grupo G20, aos 21 dias de vida, teve IL semelhante aos outros dois grupos. O percentual de ganho de peso do nascimento ao 21º dia de vida foi menor no G20 em relação aos outros dois grupos (p < 0,01). O grupo G20 teve percentual de aumento de CNA do nascimento ao 21º dia de vida menor que o grupo G10, e este menor que o grupo GC (p < 0,01). Conclusões: O GMS nas concentrações de 10 e 20% na ração de ratas prenhas Wistar apresentou uma relação dose-dependente nas variáveis peso e CNA. Houve diminuição no padrão de ganho de peso e de aumento de CNA do nascimento ao 21º dia de vida com uso de GMS. O IL na prole do grupo G20 aumentou em relação ao do grupo GC após 3 semanas de acompanhamento. / Objective: Determine the effects of the MSG (monosodium glutamate) in the offspring of pregnant rats through the comparison of the weight, NAL (nasal-anal length) and IL (Index of Lee) at birth and with 21 days of life. Research Methods & Procedures: We have investigated pregnant Wistar rats and their offspring and divided them into 3 groups: GC, G10 and G20. Each of the groups received 0%, 10% and 20% of MSG, respectively from coupling until the end of the weaning period. Results: Neither weight nor NAL were different among the groups at birth. The group G20 at birth had an IL lower than the group GC (p<0,05) and with 21 days of life presented weight and NAL lower than the groups G10 and this lower than the GC (p<0,01). Otherwise the G20 at 21 days of life had the IL similar to the other two groups. The weight profit percentage from birth to the 21st day of life was lower in the G20 regarding the other two groups (p<0,01). The G20 had a NAL increase percentage from birth to the 21st day of life lower than the G10 and this lower than the GC (p<0,01). Conclusions: MSG presented a dose-dependent relation in the variables weight and NAL. It caused a decrease in the growth pattern as well as in the weight gain pattern until the 21st day of life. The IL of the group 20% had an increased in relation to the control group after 3 weeks of follow up.

Η διαδικασία της αύξησης ελέγχεται από έναν πολύπλοκο συνδυασμό πολλών παραγόντων σε διάφορα επίπεδα, που περιλαμβάνουν ενδογενείς παράγοντες, όπως είναι ο γονότυπος, οι ορμόνες, οι παράγοντες αύξησης και εξωγενείς παράγοντες, όπως είναι η διατροφή και η επίδραση του περιβάλλοντος. Οι ορμονικοί παράγοντες, που επηρεάζουν την αύξηση είναι κυρίως η αυξητική ορμόνη (GH) και οι ινσουλινόμορφοι αυξητικοί παράγοντες (IGFs). Στην διαδικασία της αύξησης συμμετέχουν, όμως, και άλλες ορμόνες, όπως η θυροξίνη, τα επινεφριδιακά ανδρογόνα, τα στεροειδή του φύλου, τα γλυκοκορτικοειδή, η βιταμίνη D, η λεπτίνη και η ινσουλίνη, που αλληλεπιδρούν με τον άξονα GH-IGF. Η αυξητική ορμόνη εκκρίνεται στην κυκλοφορία από τα σωματότροπα κύτταρα του πρόσθιου λοβού της υπόφυσης, υπό την επίδραση δύο υποθαλαμικών ορμονών του εκλυτικού παράγοντα της αυξητικής ορμόνης (GHRH), που διεγείρει την έκκριση της GH και της σωματοστατίνης (SS), που αναστέλλει την έκκρισή της. Μέχρι σήμερα στην διεθνή βιβλιογραφία έχουν περιγραφεί πολλές μεταλλάξεις του γονιδίου της GH ως αιτία κοντού αναστήματος στα παιδιά. Η παρούσα μελέτη εξέτασε ομάδα 11 παιδιών με κοντό ανάστημα, ρυθμό αύξησης κάτω από την 2η εκατοστιαία θέση και καθυστερημένη οστική ηλικία. Όλοι οι ασθενείς υπεβλήθησαν σε λεπτομερή κλινική εξέταση και πλήρη εργαστηριακό έλεγχο. Από την κλινική εξέταση και τον εργαστηριακό έλεγχο αποκλείστηκε η παρουσία κάποιας συστηματικής πάθησης. Στην συνέχεια υπεβλήθησαν σε προκλητές δοκιμασίες έκκρισης της GH, με κλονιδίνη και L-Dopa, σε έλεγχο της 24ωρης έκκρισης της GH και τη δοκιμασία γένεσης του IGF-I. Με βάση τα εργαστηριακά αποτελέσματα της έκκρισης της GH η ομάδα των ασθενών διαχωρίστηκε σε αυτούς με ιδιοπαθές κοντό ανάστημα (10 περιπτώσεις) και ένα ασθενή με νευροεκκριτική δυσλειτουργία της GH (GHND), ο οποίος είχε μειωμένη 24ωρη έκκριση GH. Από τους ασθενείς αυτούς ελήφθησαν βιοψίες ούλων, στους καλλιεργημένους ινοβλάστες των οποίων έγιναν οι μελέτες αύξησης των ινοβλαστών και περιφερικό αίμα, από το οποίο έγινε εξαγωγή γονιδιωματικού DNA. Έγινε πολλαπλασιασμός των γονιδίων του υποδοχέα της GH (GHR) και του γονιδίου της GH (GH1) με την αλυσιδωτή αντίδραση πολυμεράσης (PCR) και προσδιορισμός της αλληλουχίας τους. Ανιχνεύτηκαν μεταλλαγές στους 6 από τους 11 ασθενείς, που μελετήθηκαν, οι οποίες εντοπίζονταν στο ιντρόνιο 4 του γονιδίου GH1 και ένας ακόμη ασθενής που έφερε μεταλλάξεις στα ιντρόνια 1 και 2. Οι μεταλλάξεις αυτές δεν επηρέαζαν την διαδικασία του ματίσματος και τον σχηματισμό του mRNA και απομακρύνονταν με το μάτισμα. Στην βιβλιογραφία αναφέρονται περισσότεροι από 10 πολυμορφισμοί του γονιδίου GH1 που εντοπίζονται κυρίως στα ιντρόνια του γονιδίου και κάποιοι από αυτούς έχουν συσχετιστεί με ελαττωμένη έκφραση του γονιδίου GH1. Στον ασθενή με την GHND περιγράφηκε μια μεταλλαγή στη θέση +7 του ιντρονίου 4 του γονιδίου GH1. RT-PCR του GH1 cDNA έδειξε ότι η μετάλλαξη αυτή είναι υπεύθυνη για το εσφαλμένο μάτισμα του mRNA, με αποτέλεσμα την απαλοιφή του εξονίου 5 από το ώριμο μετάγραφο. Ο ασθενής με τη μεταλλαγή είναι ετεροζυγώτης και η ίδια μεταλλαγή σε ετερόζυγη κατάσταση, βρέθηκε και στους δύο γονείς του ασθενούς, οι οποίοι έχουν επίσης κοντό ανάστημα. Η μεταλλαγή αυτή οδηγεί στην παραγωγή μικρότερου μορίου GH. Η βιοδραστικότητα του παραγόμενου ανώμαλου μορίου της GH εκτιμήθηκε με την προσθήκη ορού του ασθενούς σε καλλιέργειες φυσιολογικών ινοβλαστών, με τη μέθοδο ενσωμάτωσης στο DNA της βρώμο-δεοξυουριδίνης (BrDU), η οποία έδειξε μειωμένη σύνθεση DNA συγκρινόμενη με την σύνθεση DNA παρουσία ορού φυσιολογικών ατόμων. Δηλαδή η περίπτωση αυτή οικογενούς κοντού αναστήματος, το οποίο κληρονομείται κατά τον επικρατούντα χαρακτήρα, οφείλεται σε μεταλλαγή στο ιντρόνιο 4 του γονιδίου GH1. / Growth can be defined as an increase in size by accretion of tissue. The control of the growth process is affected by many complex interacting factors including internal cues such as the genotype, external factors such as nutrition and environment, and internal signaling systems such as hormones and growth factors. The principal hormones influencing growth are Growth Hormone (GH) and the Insulin-like Growth Factors (IGFs), but many other hormones contribute, such as thyroxine, adrenal androgens, sex steroids, glucocorticoids, vitamin D, leptin and insulin, often channeled through interaction with the GH-IGF axis. GH is secreted from the anterior pituitary into the circulation. The pattern of GH secretion is determined primarily by the interaction between the hypothalamic peptides Growth Hormone Releasing Hormone (GHRH) and somatostatin (SS). Many mutations of the GH1 gene have been described as the cause of short stature in children. The present study examined 11 children with severe short stature, growth velocity below the 2nd centile and delayed bone age. All patients underwent thorough clinical examination and laboratory investigation in order to exclude an underlying chronic disease. Also GH secretion provocative studies, 24 hr endogenous secretion studies and IGF-I generation test were carried out. According to the results of these tests the patients we studied were divided in two groups: 10 of the patients had idiopathic short stature (ISS) and 1 patient had GH neurosecretory dysfunction (GHND). Fibroblast cultures were established from gingival biopsies obtained from the patients and genomic DNA was extracted from peripheral blood leukocytes. GH1 and GH receptor (GHR) genes were amplified by PCR and sequenced. Hot spot mutations were detected in GH1 intron 4 in 6 patients and mutations in introns 1 and 2 were detected in 1 patient. These mutations did not affect the splicing of the primary RNA transcript. A novel deletion of thymine 7 bp downstream from the 3' splice site of intron 4 was found in the patient who had GHND. RT-PCR of GH1 cDNA showed that this mutation causes aberrant GH mRNA splicing, changes the read frame, creates a new stop codon and results in the deletion of exon 5. This was also confirmed by restriction enzyme analysis of the mutant cDNA. Both short parents and the patient are heterozygotes for this mutation. BrDU incorporation in the DNA of normal fibroblast cultures in the presence of the patient’s blood serum showed reduced DNA synthesis compared to fibroblasts cultured in medium with normal human serum. Addition of high concentrations of GH (4 μg/ml) to the culture medium containing the patient’s serum led to a near normal DNA synthesis. This is a new case of familial short stature inherited as a dominant trait, due to a mutation in intron 4 of the GH1 gene.

Hintergrund: Der Insulin-like growth factor receptor (IGF1R) spielt eine zentrale Rolle bei Wachstumsprozessen. Heterozygote IGF1R-Mutationen führen durch eine partielle IGF1-Resistenz zu Kleinwuchs. Methoden: Auxologische und endokrinologische Daten des Patienten wurden erhoben. Anhand von Fibroblasten wurde die IGF1R-Deletion charakterisiert und die Auswirkungen auf die mRNA- und Protein-Expression sowie die Signaltransduktion untersucht. Ergebnisse: Der Junge, der eine heterozygote Exon 6 Deletion im IGF1R – durch Alu-Rekombination verursacht – und eine heterozygote SHOX-Variante (p.Met240Ile) in seinem Genom vereint, kam ‚appropriate for gestational age‘ zur Welt, entwickelte aber postnatal eine Wachstumsretardierung. Die Endokrinologischen Daten waren unauffällig. Der Patient zeigt keine Stigmata, die bei anderen IGF1- oder SHOX-Mutationsträgern beschrieben wurden. Durch Nonsense-Mediated mRNA Decay kommt es zu einer Dosisreduktion der IGF1-Rezeptoren und einer entsprechenden verminderten Aktivierung der Rezeptoren, nicht aber des Signalwegs. Zusammenfassung: Der Patient trägt eine bisher unbeschrieben heterozygote IGF1R-Deletion, die zu Kleinwuchs führt. Ursächlich dafür ist eine durch die Mutation verursachte Dosisreduktion der IGF1-Rezeptoren.

Hintergrund: Der Insulin-like growth factor receptor (IGF1R) spielt eine zentrale Rolle bei Wachstumsprozessen. Heterozygote IGF1R-Mutationen führen durch eine partielle IGF1-Resistenz zu Kleinwuchs. Methoden: Auxologische und endokrinologische Daten des Patienten wurden erhoben. Anhand von Fibroblasten wurde die IGF1R-Deletion charakterisiert und die Auswirkungen auf die mRNA- und Protein-Expression sowie die Signaltransduktion untersucht. Ergebnisse: Der Junge, der eine heterozygote Exon 6 Deletion im IGF1R – durch Alu-Rekombination verursacht – und eine heterozygote SHOX-Variante (p.Met240Ile) in seinem Genom vereint, kam ‚appropriate for gestational age‘ zur Welt, entwickelte aber postnatal eine Wachstumsretardierung. Die Endokrinologischen Daten waren unauffällig. Der Patient zeigt keine Stigmata, die bei anderen IGF1- oder SHOX-Mutationsträgern beschrieben wurden. Durch Nonsense-Mediated mRNA Decay kommt es zu einer Dosisreduktion der IGF1-Rezeptoren und einer entsprechenden verminderten Aktivierung der Rezeptoren, nicht aber des Signalwegs. Zusammenfassung: Der Patient trägt eine bisher unbeschrieben heterozygote IGF1R-Deletion, die zu Kleinwuchs führt. Ursächlich dafür ist eine durch die Mutation verursachte Dosisreduktion der IGF1-Rezeptoren.:Inhaltsverzeichnis I Abkürzungsverzeichnis - 4 - 1 Bibliographische Beschreibung - 7 - 1.1 Referat - 7 - 2 Einleitung und Hintergrund - 9 - 2.1 Das menschliche Wachstum - 9 - 2.2 Das IGF-System als Regulator von Wachstum u. Entwicklung - 10 - 2.3 Der IGF1-Rezeptor - 11 - 2.4 Formen des Kleinwuchses - 12 - 2.5 IGF1R-Mutationen - 13 - 2.6 SHOX-Defizienz - 14 - 2.7 Der Nonsense-Mediated mRNA Decay - 15 - 2.8 Alu-Elemente - 16 - 2.9 Überleitung - 17 - 4 Originalpublikation - 18 - 5 Zusammenfassung der Arbeit - 31 - 5.1 Patientenbeschreibung - 32 - 5.2 Experimentelle Untersuchungen - 33 - 5.3 Interpretation - 35 - 5.4 Ausblick - 37 - 6 Literaturverzeichnis - 39 - III Curriculum vitae - 50 - IV Danksagung - 52 -