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1.
Nat Rev Endocrinol ; 15(5): 299-311, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30842651

RESUMO

Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.


Assuntos
Neoplasias/epidemiologia , Neoplasias/genética , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/epidemiologia , Gigantismo/genética , Gigantismo/patologia , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Megalencefalia/epidemiologia , Megalencefalia/genética , Megalencefalia/patologia , Neoplasias/patologia , Gravidez , Fatores de Risco , Síndrome de Sotos/epidemiologia , Síndrome de Sotos/genética , Síndrome de Sotos/patologia , Síndrome
2.
Eur J Med Genet ; 62(4): 243-247, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30048822

RESUMO

GPC3 and GPC4 are the only two genes in which mutations are known to cause Simpson-Golabi-Behmel syndrome type 1 (SGBS1). The majority of SGBS1 patients have point mutations or deletions in GPC3. Only one SGBS1 family has been reported with duplication of both GPC3 and GPC4. Although clinical presentation of SGBS1 in affected males is well defined, the phenotype in female carriers is less clear. In total, six female carriers with clinical expression of SGBS1 have been reported to date. In this study, we provide description of two families with rare duplications in both GPC3 and GPC4. These imbalances resulted in SGBS1 in males, while female carriers with skewed X-inactivation exhibited significant features of SGBS1 including congenital heart defect, hernias, intellectual disability and coarse facial features. In family 2, a SGBS diagnosis was not considered in the father until after the diagnosis had been first considered and made in the affected daughter. We emphasize on the importance of testing at risk females and careful examination of those who are found to be carriers of SGBS1. We also discuss and provide supportive evidence for the role of skewed X-inactivation in clinical expression of SGBS1 in female carriers.


Assuntos
Arritmias Cardíacas/genética , Duplicação Gênica , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/genética , Glipicanas/genética , Cardiopatias Congênitas/genética , Heterozigoto , Deficiência Intelectual/genética , Inativação do Cromossomo X , Adulto , Arritmias Cardíacas/patologia , Criança , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/patologia , Masculino , Linhagem
3.
Pediatr Dev Pathol ; 22(1): 70-74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29652239

RESUMO

Simpson-Golabi-Behmel syndrome type I (SGBS, OMIM312870), caused by defects of the GPC3 and GPC4 genes on chromosome Xq26, is an X-linked recessive macrosomia/multiple congenital anomaly disorder characterized by somatic overgrowth, coarse facial features, variable congenital anomalies, increased tumor risk, and mild-to-moderate neurodevelopmental anomalies. We report the postmortem findings in 3 second-trimester male siblings with SGBS who displayed ambiguous genitalia (in all 3) and gonadal dysgenesis (ovotestis) (in 1), thus expanding the SGBS spectrum to include these disorders of sex development.


Assuntos
Anormalidades Múltiplas/diagnóstico , Arritmias Cardíacas/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Gigantismo/diagnóstico , Cardiopatias Congênitas/diagnóstico , Deficiência Intelectual/diagnóstico , Transtornos Ovotesticulares do Desenvolvimento Sexual/diagnóstico , Anormalidades Múltiplas/patologia , Arritmias Cardíacas/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/patologia , Masculino , Transtornos Ovotesticulares do Desenvolvimento Sexual/patologia , Natimorto
5.
Best Pract Res Clin Endocrinol Metab ; 32(2): 125-140, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29678281

RESUMO

X-linked acrogigantism (X-LAG) is a recently described form of familial or sporadic pituitary gigantism characterized by very early onset GH and IGF-1 excess, accelerated growth velocity, gigantism and/or acromegaloid features. Germline or somatic microduplications of the Xq26.3 chromosomal region, invariably involving the GPR101 gene, constitute the genetic defect leading to X-LAG. GPR101 encodes a class A G protein-coupled receptor that activates the 3',5'-cyclic adenosine monophosphate signaling pathway. Highly expressed in the central nervous system, the main physiological function and ligand of GPR101 remain unknown, but it seems to play a role in the normal development of the GHRH-GH axis. Early recognition of X-LAG cases is imperative because these patients require clinical management that differs from that of other patients with acromegaly or gigantism. Medical treatment with pegvisomant seems to be the best approach, since X-LAG tumors are resistant to the treatment with somatostatin analogues and dopamine agonists; surgical cure requires near-total hypophysectomy. Currently, the efforts of our research focus on the identification of GPR101 ligands; in addition, the long-term follow-up of X-LAG patients is of extreme interest as this is expected to lead to better understanding of GPR101 effects on human pathophysiology.


Assuntos
Acromegalia/genética , Acromegalia/patologia , Gigantismo/genética , Gigantismo/patologia , Receptores Acoplados a Proteínas-G/fisiologia , Predisposição Genética para Doença , Humanos , Fator de Crescimento Insulin-Like I/fisiologia , Receptores Acoplados a Proteínas-G/genética
6.
Hum Mutat ; 39(6): 790-805, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29637653

RESUMO

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies and overgrowth syndrome caused by a defect in the glypican-3 gene (GPC3). Until now, GPC3 mutations have been reported in isolated cases or small series and the global genotypic spectrum of these mutations has never been delineated. In this study, we review the 57 previously described GPC3 mutations and significantly expand this mutational spectrum with the description of 29 novel mutations. Compiling our data and those of the literature, we provide an overview of 86 distinct GPC3 mutations identified in 120 unrelated families, ranging from single nucleotide variations to complex genomic rearrangements and dispersed throughout the entire coding region of GPC3. The vast majority of them are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss-of-function. Missense mutations are rare and the two which were functionally characterized, impaired GPC3 function by preventing GPC3 cleavage and cell surface addressing respectively. This report by describing for the first time the wide mutational spectrum of GPC3 could help clinicians and geneticists in interpreting GPC3 variants identified incidentally by high-throughput sequencing technologies and also reinforces the need for functional validation of non-truncating mutations (missense, in frame mutations, duplications).


Assuntos
Arritmias Cardíacas/genética , Genes Ligados ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/genética , Glipicanas/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Arritmias Cardíacas/patologia , Códon sem Sentido/genética , Feminino , Mutação da Fase de Leitura/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/patologia , Masculino , Linhagem , Fenótipo
7.
Histochem Cell Biol ; 149(6): 593-605, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29574488

RESUMO

The Simpson-Golabi-Behmel syndrome (SGBS) cell strain is widely considered to be a representative in vitro model of human subcutaneous white pre-adipocytes. These cells achieve a transient expression of classical brown markers, such as uncoupling protein 1, peaking at day 14 of differentiation and decreasing thereafter. Adipocyte browning process involves dynamic changes in lipid droplet (LD) dimension, in mitochondria morphology, and in the expression of brown-specific marker genes. This study analyzes SGBS transient phenotypic transformation by quantifying the heterogeneity of LDs, mitochondrial dynamics, and a panel of genes involved in adipocyte differentiation and browning. LDs at 21 days of differentiation were larger than in the previous stages, without any change in the number per cell. The expression of genes such as peroxisome peroxisome proliferator-activated receptor γ, leptin, and lipase E significantly raised from 0 to 21 days. Adiponectin was significantly upregulated at 14 days of differentiation. Brown-specific marker PR domain containing 16 was highly expressed at D0. The variability of mitochondrial shape and interconnectivity reflects differences in the relative rates of fusion and fission, resulting in a significant shift from a networked shape at D7 to a fragmented and swollen one at D14 and D21. The transient phenotype experienced by this cellular model should be considered whether used in studies involving the stimulation of adipocyte browning and could be an interesting human model to further elucidate the browning process in the absence of any stimulation.


Assuntos
Adipócitos/patologia , Arritmias Cardíacas/patologia , Diferenciação Celular , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Deficiência Intelectual/patologia , Adipócitos/metabolismo , Arritmias Cardíacas/metabolismo , Células Cultivadas , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Gigantismo/metabolismo , Cardiopatias Congênitas/metabolismo , Humanos , Deficiência Intelectual/metabolismo , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fenótipo
11.
Ann Endocrinol (Paris) ; 78(2): 131-136, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28457479

RESUMO

X-linked acrogigantism (XLAG) is a new, pediatric-onset genetic syndrome, due to Xq26.3 microduplications encompassing the GPR101 gene. XLAG has a remarkably distinct phenotype with disease onset occurring before the age of 5 in all cases described to date, which is significantly younger than in other forms of pituitary gigantism. These patients have mixed GH and prolactin positive adenomas and/or mixed-cell hyperplasia and highly elevated levels of GH/IGF-1 and prolactin. Given their particularly young age of onset, the significant GH hypersecretion can lead to a phenotype of severe gigantism with very advanced age-specific height Z-scores. If not adequately treated in childhood, this condition results in extreme final adult height. XLAG has a clinical course that is highly similar to some of the tallest people with gigantism in history.


Assuntos
Gigantismo/genética , Idade de Início , Feminino , Duplicação Gênica , Gigantismo/história , Gigantismo/patologia , História do Século XIX , História do Século XX , Humanos , Masculino , Hormônios Hipofisários/sangue , Prolactinoma/genética , Prolactinoma/patologia , Receptores Acoplados a Proteínas-G/genética
12.
Recurso na Internet em Português | LIS - Localizador de Informação em Saúde, LIS-bvsms | ID: lis-45196

RESUMO

Muitos fatores contribuem para que uma pessoa tenha problemas de crescimento, desde a herança genética até alterações na produção hormonal. Nesta edição do “10 Coisas que Você Precisa Saber Sobre”, confira as principais informações sobre os problemas de crescimento, suas causas e tratamentos.


Assuntos
Hormônio do Crescimento/deficiência , Nanismo/patologia , Nanismo Hipofisário/patologia , Gigantismo/patologia
13.
Mol Cell Endocrinol ; 443: 106-113, 2017 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-28088466

RESUMO

Under certain conditions UCP1 expressing adipocytes arise in white adipose tissue depots of both mice and humans. It is still not fully understood whether these cells differentiate de novo from specific progenitor cells or if they transdifferentiate from mature white adipocytes. Performing expression pattern analysis comparing adipocyte progenitor cells from deep and subcutaneous neck adipose tissue, we recently identified teneurin-2 (TENM2) enriched in white adipocyte progenitor cells. Here we tested whether TENM2 deficiency in adipocyte progenitor cells would lead to a brown adipocyte phenotype. By targeting TENM2 in SGBS preadipocytes using siRNA, we demonstrate that TENM2 knockdown induces both UCP1 mRNA and protein expression upon adipogenic differentiation without affecting mitochondrial mass. Furthermore, TENM2 knockdown in human SGBS adipocytes resulted in increased basal and leak mitochondrial respiration. In line with our previous observation these data suggest that TENM2 deficiency in human adipocyte precursors leads to induction of brown adipocyte marker genes upon adipogenic differentiation.


Assuntos
Adipócitos Marrons/citologia , Adipócitos Marrons/metabolismo , Diferenciação Celular/genética , Proteínas de Membrana/deficiência , Proteínas do Tecido Nervoso/deficiência , Proteína Desacopladora 1/genética , Adipócitos Brancos/citologia , Adipócitos Brancos/metabolismo , Adipogenia/genética , Tecido Adiposo Branco/citologia , Arritmias Cardíacas/patologia , Biomarcadores/metabolismo , Respiração Celular/genética , Técnicas de Silenciamento de Genes , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/patologia , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , RNA Interferente Pequeno/metabolismo , Células-Tronco/metabolismo , Proteína Desacopladora 1/metabolismo
14.
Pituitary ; 20(1): 22-32, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27812777

RESUMO

BACKGROUND: Acromegaly is a rare and underdiagnosed disorder caused, in more than 95% of cases, by a growth hormone (GH)-secreting pituitary adenoma. The GH hypersecretion leads to overproduction of insulin-like growth factor 1 (IGF-1) which results in a multisystem disease characterized by somatic overgrowth, multiple comorbidities, physical disfigurement, and increased mortality. OBJECTIVE: This article aims to review the clinical features of acromegaly at diagnosis. DISCUSSION/CONCLUSION: Acromegaly affects both males and females equally and the average age at diagnosis ranges from 40 to 50 years (up to 5% of cases < the age 20). Due to insidious onset and slow progression, acromegaly is often diagnosed five to more than ten years after its onset. The typical coarsening of facial features include furrowing of fronthead, pronounced brow protrusion, enlargement of the nose and the ears, thickening of the lips, skin wrinkles and nasolabial folds, as well as mandibular prognathism that leads to dental malocclusion and increased interdental spacing. Excessive growth of hands and feet (predominantly due to soft tissue swelling) is present in the vast majority of acromegalic patients. Gigantism accounts for up to 5% of cases and occurs when the excess of GH becomes manifest in the young, before the epiphyseal fusion. The disease also has rheumatologic, cardiovascular, respiratory, neoplastic, neurological, and metabolic manifestations which negatively impact its prognosis and patients quality of life. Less than 15% of acromegalic patients actively seek medical attention for change in appearance or enlargement of the extremities. The presentation of acromegaly is more often related to its systemic comorbidities or to local tumor effects.


Assuntos
Acromegalia/diagnóstico , Acromegalia/patologia , Feminino , Gigantismo/diagnóstico , Gigantismo/patologia , Humanos , Masculino
15.
Sci Rep ; 6: 38339, 2016 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-27922090

RESUMO

The obesity-associated inflammation of white adipose tissue (WAT) is one of the factors leading to the development of related diseases such as insulin resistance and liver steatosis. Recently, microRNAs (miRNAs) were identified as important regulators of WAT functions. Herein, we cultured human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes with macrophage-conditioned medium (MacCM) and performed an Affimetrix miRNA array to identify miRNAs differentially expressed under inflammatory conditions. We identified 24 miRNAs differentially expressed upon inflammation in human adipocytes and miR-146a was the most up-regulated miRNA species. In subcutaneous WAT, miR-146a was elevated in both human and murine obesity. Transfection of miR-146a mimics prevented the MacCM-induced inflammatory response in SGBS adipocytes as seen by reduced levels of IL-8 and MCP-1 mRNA and protein. We identified IRAK1 and TRAF6 as targets of miR-146a in human adipocytes and detected a reduced inflammation-induced activation of JNK and p38 upon miR-146a transfection. Taken together, we could show that miR-146a reduces the inflammatory response in human adipocytes. In a negative feedback loop miR-146a might contribute to the regulation of inflammatory processes in WAT and possibly prevent an overwhelming inflammatory response.


Assuntos
Adipócitos Brancos/metabolismo , Arritmias Cardíacas/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Quinases Associadas a Receptores de Interleucina-1/genética , MicroRNAs/genética , Fator 6 Associado a Receptor de TNF/genética , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/patologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Meios de Cultivo Condicionados/farmacologia , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/metabolismo , Gigantismo/patologia , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Humanos , Inflamação , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Mimetismo Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Cell Death Dis ; 7(10): e2412, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27735943

RESUMO

Tumor necrosis factor-α (TNFα) and other ligands of the TNF superfamily are potent regulators of adipose tissue metabolism and play a crucial role in the obesity-induced inflammation of adipose tissue. Adipose tissue expression levels of TRAIL (TNF-related apoptosis-inducing ligand) and its receptor were shown to be upregulated by overfeeding and decreased by fasting in mice. In the present study we aimed to elucidate the impact of TRAIL on adipogenesis. To this end, human Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes as well as stromal-vascular cells isolated from human white adipose tissue were used as model systems. Human recombinant TRAIL inhibited adipogenic differentiation in a dose-dependent manner. It activated the cleavage of caspase-8 and -3, which in turn resulted in a downregulation of the key adipogenic transcription factors C/EBPα, C/EBPδ, and PPARγ. The effect was completely blocked by pharmacological or genetic inhibition of caspases. Taken together we discovered a so far unrecognized function of TRAIL in the regulation of adipogenesis. Targeting the TRAIL/TRAIL receptor system might provide a novel strategy to interfere with adipose tissue homeostasis.


Assuntos
Adipócitos/citologia , Adipócitos/enzimologia , Adipogenia/efeitos dos fármacos , Caspases/metabolismo , Diferenciação Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Fatores de Transcrição/metabolismo , Adipócitos/efeitos dos fármacos , Adulto , Arritmias Cardíacas/patologia , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/patologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia
17.
Acta Neuropathol Commun ; 4(1): 56, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27245663

RESUMO

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.


Assuntos
Duplicação Gênica , Gigantismo/genética , Receptores Acoplados a Proteínas-G/genética , Acromegalia/complicações , Acromegalia/genética , Acromegalia/patologia , Adenoma/complicações , Adenoma/genética , Adenoma/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa , Gigantismo/complicações , Gigantismo/patologia , Gigantismo/terapia , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Resultado do Tratamento , Adulto Jovem
18.
J Pediatr Endocrinol Metab ; 29(5): 597-602, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26887033

RESUMO

BACKGROUND: Pituitary gigantism (PG) is a rare pediatric disease with poorly defined long-term outcomes. Our aim is to describe the longitudinal clinical course in PG patients using a single-center, retrospective cohort study. METHODS: Patients younger than 19 years diagnosed with PG were identified. Thirteen cases were confirmed based on histopathology of a GH secreting adenoma or hyperplasia and a height >2 SD for age and gender. Laboratory studies, initial pathology, and imaging were abstracted. RESULTS: Average age at diagnosis was 13 years with an average initial tumor size of 7.4×3.8 mm. Initial transsphenoidal surgery was curative in 3/12 patients. Four of the nine patients who failed the initial surgery required a repeat procedure. Octreotide successfully normalized GH levels in 1/6 patients with disease refractory to surgery (1/6). Two out of five patients received pegvisomant after failing octreotide but only one patient responded to treatment. Five patients were ultimately treated with radiosurgery or radiation patients were followed for an average of 10 years. CONCLUSIONS: PG is difficult to treat. In most patients, the initial transsphenoidal surgery failed to normalize GH levels. If the initial surgery was unsuccessful, repeat surgery was unlikely to control GH secretion. Treatment with octreotide or pegvisomant was successful in less than half the patients failing surgery. Radiosurgery was curative, but is not an optimal treatment for pediatric patients. Despite the small sample, our study suggests that the treatment outcome of pediatric PG may be different than adults.


Assuntos
Adenoma/patologia , Gigantismo/patologia , Hormônio do Crescimento Humano/análogos & derivados , Neoplasias Hipofisárias/patologia , Adenoma/sangue , Adenoma/tratamento farmacológico , Adolescente , Adulto , Estatura , Criança , Feminino , Seguimentos , Gigantismo/sangue , Gigantismo/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/análise , Estudos Longitudinais , Masculino , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/tratamento farmacológico , Prognóstico , Receptores da Somatotropina/antagonistas & inibidores , Estudos Retrospectivos , Adulto Jovem
19.
Gen Dent ; 64(1): e12-5, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26742178

RESUMO

Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked recessive overgrowth disorder with prominent craniofacial manifestations. Macrodontia is also an uncommon dental anomaly that can be an isolated finding and has been associated with numerous systemic conditions and syndromes. This case report describes this previously unreported dental anomaly, macrodontia, in a patient with SGBS, which may broaden the phenotype of this syndrome. A brief review of the literature on orofacial findings associated with SGBS is also presented.


Assuntos
Arritmias Cardíacas/patologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Deficiência Intelectual/patologia , Anormalidades Dentárias/etiologia , Tomografia Computadorizada de Feixe Cônico , Humanos , Masculino , Radiografia Dentária , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/patologia , Adulto Jovem
20.
Diabetes ; 65(4): 956-66, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26718500

RESUMO

Obesity is associated with an increased risk for the development of type 2 diabetes and vascular complications. Advanced glycation end products are increased in adipose tissue and have been associated with insulin resistance, vascular dysfunction, and inflammation of adipose tissue. Here, we report that delayed intervention with pyridoxamine (PM), a vitamin B6 analog that has been identified as an antiglycating agent, protected against high-fat diet (HFD)-induced body weight gain, hyperglycemia, and hypercholesterolemia, compared with mice that were not treated. In both HFD-induced and db/db obese mice, impaired glucose metabolism and insulin resistance were prevented by PM supplementation. PM inhibited the expansion of adipose tissue and adipocyte hypertrophy in mice. In addition, adipogenesis of murine 3T3-L1 and human Simpson-Golabi-Behmel Syndrome preadipocytes was dose- and time-dependently reduced by PM, as demonstrated by Oil Red O staining and reduced expression of adipogenic differentiation genes. No ectopic fat deposition was found in the liver of HFD mice. The high expression of proinflammatory genes in visceral adipose tissue of the HFD group was significantly attenuated by PM. Treatment with PM partially prevented HFD-induced mild vascular dysfunction. Altogether, these findings highlight the potential of PM to serve as an intervention strategy in obesity.


Assuntos
Inflamação/prevenção & controle , Resistência à Insulina , Obesidade/tratamento farmacológico , Paniculite/prevenção & controle , Piridoxamina/administração & dosagem , Células 3T3-L1 , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Células Cultivadas , Dieta Hiperlipídica , Esquema de Medicação , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/metabolismo , Gigantismo/patologia , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Humanos , Inflamação/metabolismo , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Paniculite/metabolismo , Tempo para o Tratamento
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