RESUMO
Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first-degree relatives (and second-degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy-catecholamines and bi-annual rapid whole-body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre-symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow-up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.
Assuntos
Marcadores Genéticos/genética , Testes Genéticos/normas , Guias como Assunto , Paraganglioma/diagnóstico , Feocromocitoma , Vigilância da População , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Saúde Global , Humanos , Morbidade/tendências , Feocromocitoma/diagnóstico , Feocromocitoma/epidemiologia , Feocromocitoma/genéticaRESUMO
BACKGROUND AND AIMS: Type I hyperlipoproteinemia, also known as familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disorder caused by variants in LPL, APOC2, APOA5, LMF1 or GPIHBP1 genes. The aim of this study was to identify novel variants in the LPL gene causing lipoprotein lipase deficiency and to understand the molecular mechanisms. METHODS AND RESULTS: A total of 3 individuals with severe hypertriglyceridemia and recurrent pancreatitis were selected from the Lipid Clinic at Sahlgrenska University Hospital and LPL was sequenced. In vitro experiments were performed in human embryonic kidney 293T/17 (HEK293T/17) cells transiently transfected with wild type or mutant LPL plasmids. Cell lysates and media were used to analyze LPL synthesis and secretion. Media were used to measure LPL activity. Patient 1 was compound heterozygous for three known variants: c.337T > C (W113R), c.644G > A (G215E) and c.1211T > G (M404R); patient 2 was heterozygous for the known variant c.658A > C (S220R) while patient 3 was homozygous for a novel variant in the exon 5 c.679G > T (V227F). All the LPL variants identified were loss-of-function variants and resulted in a substantial reduction in the secretion of LPL protein. CONCLUSION: We characterized at the molecular level three known and one novel LPL variants causing type I hyperlipoproteinemia showing that all these variants are pathogenic.
Assuntos
Hiperlipoproteinemia Tipo I/genética , Lipase Lipoproteica/genética , Mutação , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Células HEK293 , Heterozigoto , Homozigoto , Humanos , Hiperlipoproteinemia Tipo I/sangue , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/enzimologia , Hipertrigliceridemia/sangue , Hipertrigliceridemia/enzimologia , Hipertrigliceridemia/genética , Lipídeos/sangue , Lipase Lipoproteica/metabolismo , Masculino , Pessoa de Meia-Idade , Pancreatite/sangue , Pancreatite/enzimologia , Pancreatite/genética , Fenótipo , Recidiva , TransfecçãoRESUMO
Sex steroids have been shown to influence longitudinal bone growth during sexual maturation, partially by increased GH secretion. Mice transgenic for metallothionein promoter bovine GH were developed by pronuclear injection as a model with sex steroid-independent GH secretion. Prepubertal normal and transgenic, male and female mice were either gonadectomized or sham operated. The growth was divided into two segments: peripubertal growth from 30-60 days of age and adult growth from 60-90 days of age. Orchidectomy resulted in a decreased growth rate of the lumbar spine and a decreased weight gain during the peripubertal growth, whereas tibia growth was unaffected. The alteration in proportions between the lumbar spine and the tibia was apparent for both normal and bovine GH transgenic mice, suggesting that the effect was not mediated via decreased GH secretion. Orchidectomy resulted in increased adult tibial growth, whereas weight gain and lumbar growth were unaffected. In female mice, gonadectomy did not influence these parameters during either time period studied. In summary, we present data indicating that the male gonads in a GH secretion-independent manner stimulate pubertal growth of the spine and inhibit the tibial growth of adult animals.
Assuntos
Desenvolvimento Ósseo , Castração , Hormônio do Crescimento/genética , Camundongos Transgênicos/genética , Camundongos Transgênicos/fisiologia , Aumento de Peso , Animais , Bovinos , Feminino , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/metabolismo , Masculino , Camundongos , RNA Mensageiro/metabolismo , Receptores da Somatotropina/genética , Valores de ReferênciaRESUMO
Both estrogens and GH are necessary for normal bone remodeling. This study investigates the effect of elevated GH levels on the amount and density of bone in young female mice and its dependence on intact ovarian function. Metallothionein promoter-GH-transgenic mice were either sham operated or ovariectomized at 25-29 days of age, and the bone measurements were made at about 90 days of age. A 6-mm high cylinder containing only cortical bone was cut from the right tibia, and lumbar vertebrae 6 was measured as a bone with predominantly cancellous bone. The amounts of tibial and vertebral bone, measured by dry weight, mineral weight, organic weight, bone mineral content (measured by dual energy x-ray analysis), and volume, were increased in GH-transgenic animals compared to those in normal littermates. This stimulatory effect of elevated GH levels was not seen in ovariectomized mice. The real density of the tibial bone were slightly decreased in GH-transgenic animals compared to normal littermates. In conclusion, elevated levels of GH increase the amounts of vertebral (predominantly cancellous) bone and tibial (cortical) bone in young mice. Intact ovaries are a prerequisite for the stimulatory effect of elevated levels of GH. The fact that ovariectomy decreases the stimulatory effect of elevated GH levels suggests that the effect of elevated GH levels in bone is dependent upon the presence of basic sex steroid secretion.
Assuntos
Densidade Óssea , Hormônio do Crescimento/sangue , Ovariectomia , Absorciometria de Fóton , Animais , Bovinos , Feminino , Camundongos , Camundongos Transgênicos , Tamanho do Órgão , Valores de Referência , Coluna Vertebral/anatomia & histologia , Coluna Vertebral/metabolismo , Tíbia/anatomia & histologia , Tíbia/metabolismoRESUMO
The liver size in adult mammals is tightly regulated in relation to body weight, but the hormonal control of this is largely unknown. We investigated the roles of interleukin-6 (IL-6) and tumor necrosis factor (TNF) receptor-1 in the regulation of intact liver weight in adult mice. The relative liver wet and dry weights of older adult (5- to 10-month-old) IL-6 knockout (IL-6(-/-)) mice were decreased by 22-28%, and total contents of DNA and protein were decreased compared with those in age-matched wild-type mice. Weights of other visceral organs were unaffected. Older adult (6- to 8-month-old) TNF receptor-1 knockout (TNFR1(-/-)) mice displayed decreased relative liver weight. Treatment with a single injection of IL-6 increased liver wet and dry weights in IL-6(-/-) and wild-type mice, but not TNFR1(-/-) mice. Treatment with TNFalpha enhanced liver weight and DNA synthesis of nonparenchymal liver cells at 24 h in wild-type, but not IL-6(-/-), mice. At 48 h, TNFalpha induced DNA synthesis in nonparenchymal cells and hepatocytes of both wild-type and IL-6(-/-) mice. In conclusion, TNF receptor-1 stimulation and IL-6 production are both necessary for normal liver weight gain in older adult mice. The results of TNFalpha and IL-6 treatment further indicate that the effects of TNF receptor-1 and IL-6 depend on each other for full stimulation of liver growth.
Assuntos
Interleucina-6/deficiência , Fígado/crescimento & desenvolvimento , Receptores do Fator de Necrose Tumoral/deficiência , Envelhecimento/fisiologia , Animais , Antígenos CD/genética , DNA/metabolismo , Hormônio do Crescimento/farmacologia , Humanos , Interleucina-6/genética , Interleucina-6/farmacologia , Fígado/anatomia & histologia , Fígado/efeitos dos fármacos , Camundongos , Camundongos Knockout/genética , Tamanho do Órgão/fisiologia , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Proteínas/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral , Valores de Referência , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Several recent studies have investigated the effects of growth hormone (GH) on the healing of fractures and bone ingrowth, but with conflicting results. The negative results may be due to antibody formation against injected GH or because some experimental models are able to prove only positive GH effects. In this study, we wanted to investigate the effect of GH on implant integration in bone. To avoid potential formation of antibodies against injected GH, we used a model with transgenic mice overexpressing bovine GH (bGH). Titanium implants were inserted in the forehead of the mice. 4 months after insertion, the implants were cut out en bloc with the surrounding bone. The calcified specimens were cut and ground to a thickness of approximately 10 microns. Histomorphometry demonstrated significantly more direct bone-to-metal contact in the transgenic mice than in the nontransgenic littermates. Our findings indicate that systemic administration of GH in humans may improve implant integration in bone.
Assuntos
Substitutos Ósseos , Modelos Animais de Doenças , Hormônio do Crescimento/sangue , Camundongos Transgênicos/sangue , Osseointegração/efeitos dos fármacos , Titânio , Animais , Bovinos , Avaliação Pré-Clínica de Medicamentos , Hormônio do Crescimento/uso terapêutico , Humanos , Camundongos , Fatores de TempoRESUMO
OBJECTIVES: The main purpose of the present study was to characterize cardiac muscle hypertrophy using both qualitative and quantitative microscopy in mice overexpressing the bovine growth hormone. RESULTS: Measurements of 30 fibres from each group revealed that fibre diameter in transgenic hearts was significantly larger than in control hearts. There was a significant decrease in interfibrillar space in transgenic hearts as compared with control hearts. The enlarged transgenic hearts displayed unchanged organelles such as normal myofibrils and mitochondria in a normal pattern, suggesting balanced growth. Myelin structures were occasionally observed between normal myofibrils. Moreover, myocardial beta-adrenergic receptors and muscarinic receptors in the hearts of transgenic mice overproducing GH were studied to see whether they are involved in the hypertrophic process. It was shown that the density of muscarinic receptors had decreased and the super-high affinity of muscarinic receptors was lost, without any significant changes in either the density or the affinity of beta-adrenergic receptors, as compared with controls. CONCLUSIONS: These results demonstrate that a GH excess was able to induce significant myocardial hypertrophy and that there was a downregulation of muscarinic receptors.