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1.
Medicine (Baltimore) ; 98(43): e17616, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651874

RESUMO

RATIONALE: Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is caused by mutations in GPC3 or in both GPC3 and GPC4. Physical manifestations of SGBS1 include fetal overgrowth and macrostomia, macroglossia. Subclinical hypothyroidism has never been reported in SGBS1 cases. PATIENT CONCERNS: An 8-days-old boy was referred to our hospital with persistent hypoglycemia and special facies. And the infant showed elevated levels of thyroid-stimulating hormone (TSH). Free T4 and free T3 were normal. DIAGNOSES: Definitive diagnosis of SGBS1 depends on clinical features and genetic testing. A nonsense mutation (c.1515C > A, p. Cys505*) was tested by whole-exome sequencing. INTERVENTIONS: Normal blood glucose levels were maintained with glucose infusions. Levothyroxine was given to the patient for treating subclinical hypothyroidism. OUTCOMES: The parents decided to abandon the treatment of the patient. We learned that the patient died of a lung infection by a telephone follow-up. LESSONS: Subclinical hypothyroidism could be added to the known clinical manifestations of SGBS1.


Assuntos
Arritmias Cardíacas/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Gigantismo/diagnóstico , Cardiopatias Congênitas/diagnóstico , Hipotireoidismo/diagnóstico , Deficiência Intelectual/diagnóstico , China , Diagnóstico Diferencial , Evolução Fatal , Humanos , Recém-Nascido , Masculino
2.
Arch Endocrinol Metab ; 63(4): 385-393, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365626

RESUMO

INTRODUCTION: Gigantism is a rare pediatric disease characterized by increased production of growth hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal abnormalities, and multiple comorbidities. MATERIALS AND METHODS: Case series of 6 male patients with gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010 and 2016. RESULTS: All patients had macroadenomas and their mean final height was 2.01 m. The mean age at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%). All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm. All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant (n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1 normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), fulfilling the diagnostic criteria of familial isolated pituitary adenoma. CONCLUSIONS: This is the largest case series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be considered in familial cases of GH-producing adenomas.


Assuntos
Adenoma/terapia , Gigantismo/terapia , Neoplasias Hipofisárias/terapia , Adenoma/diagnóstico , Adolescente , Colômbia , Seguimentos , Gigantismo/diagnóstico , Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos , Fator de Crescimento Insulin-Like I/análise , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Mutação/genética , Linhagem , Neoplasias Hipofisárias/diagnóstico , Estudos Retrospectivos , Distribuição por Sexo , Resultado do Tratamento , Adulto Jovem
4.
Biol Lett ; 15(5): 20190175, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31039728

RESUMO

Baleen whales (Mysticeti) are major ecosystem engineers, thanks to their enormous size and bulk filter feeding strategy. Their signature gigantism is thought to be a relatively recent phenomenon, resulting from a Plio-Pleistocene mode shift in their body size evolution. Here, we report the largest whale fossil ever described: an Early Pleistocene (1.5-1.25 Ma) blue whale from Italy with an estimated body length of up to 26 m. Macroevolutionary modelling taking into account this specimen, as well as additional material from the Miocene of Peru, reveals that the proposed mode shift occurred either somewhat earlier, or perhaps not at all. Large-sized mysticetes comparable to most extant species have existed since at least the Late Miocene, suggesting a long-term impact on global marine ecosystems.


Assuntos
Ecossistema , Gigantismo , Animais , Tamanho Corporal , Fósseis , Humanos , Itália
5.
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
6.
Oecologia ; 189(4): 1005-1015, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850885

RESUMO

We utilized natural experiment opportunities presented by differential conditions (presence/absence of seabirds and invasive species) on cays in the Bahamas to study whether interisland variations in food resources contributed to gigantism in Allen Cays Rock Iguanas (Cyclura cychlura inornata). We analyzed the stable carbon (δ13C) and nitrogen (δ15N) isotope values from iguana tissues and resources from each island food web to test the predictions that (1) food webs on islands with seabirds exhibit the influence of marine subsidies from seabird guano, whereas those from non-seabird islands do not, and (2) size differences in iguanas among cays were due to either (a) supplemental food availability from mice and/or seabird carcasses killed by barn owls (Tyto alba) and/or (b) access to more nutrient-rich vegetation fertilized by seabird guano. Food web components from the seabird island (Allen Cay) had 5-9‰ higher δ15N values than those on the other cays and Allen Cay plants contained nearly two times more nitrogen. Bayesian stable isotope mixing models indicated that C3 plants dominated iguana diets on all islands and showed no evidence for consumption of mice or shearwaters. The iguanas on Allen Cay were ~ 2 times longer (48.3 ± 11.6 cm) and ~ 6 times heavier (5499 ± 2847 g) than iguanas on other cays and this was likely from marine-derived subsidies from seabird guano which caused an increase in nitrogen concentration in the plants and a resultant increase in the δ15N values across the entire food web relative to non-seabird islands.


Assuntos
Gigantismo , Iguanas , Animais , Bahamas , Teorema de Bayes , Ilhas , Camundongos
7.
Prog Mol Biol Transl Sci ; 161: 47-67, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30711029

RESUMO

X-linked acrogigantism (XLAG) is a recently described early-onset gigantism due to GPR101 duplication that induces growth hormone (GH) oversecretion. GPR101, which belongs to Family A rhodopsin-like family of G protein-coupled receptors, is predominantly expressed in hypothalamus and pituitary, suggesting that GPR101 might be important in regulating diverse functions such as energy balance and reproduction. Most mammalian GPR101s have extremely long third intracellular loops (ICL3); however, zebrafish GPR101 has a much shorter ICL3, but a longer C-terminus. GnRH-(1-5), a GnRH metabolite, can modulate the hypothalamus-pituitary-gonad axis and cancer cell migration via activating GPR101. GPR101 couples to both Gαs and Gαi proteins. GPR101 duplication has a causative role in XLAG, while GPR101 variants, especially c.924G>C (E308D), located at ICL3, are attributed to acromegaly. Some GPR101 mutations that are associated with a small proportion of pituitary tumors without GH oversecretion have also been identified recently. This chapter will summarize studies on GPR101, including its molecular cloning and tissue distribution, physiology, pharmacology, and pathophysiology.


Assuntos
Acromegalia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/genética , Receptores Acoplados a Proteínas-G/genética , Sequência de Aminoácidos , Humanos , Modelos Biológicos , Mutação/genética , Receptores Acoplados a Proteínas-G/química
8.
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
10.
J Stomatol Oral Maxillofac Surg ; 120(5): 483-488, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30553040

RESUMO

Simpson-Golabi-Behmel Syndrome (SGBS) is an X-linked overgrowth syndrome characterized by pre- and post-natal overgrowth, typical facial appearance and multiple visceral, skeletal, and neurological anomalies. There is only few information in the current literature, on clinical and particularly dentofacial findings due to recent identification of the syndrome and its clinical overlap with other overgrowth syndromes. The aim of this case report is to present dentofacial findings in a 16-year-old boy who had been diagnosed with SGBS. Following comprehensive clinical, radiographic and histopathological examinations, six pathologically distinct lesions including odontogenic keratocyst, ameloblastoma, lateral periodontal cyst, dentigerous cyst and mucous retention cyst in both mandible and maxilla were identified. The clinical report is followed by a discussion aimed to clarify unique features of this condition and how practitioners should consider similar cases.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Gigantismo , Cardiopatias Congênitas , Deficiência Intelectual , Adolescente , Arritmias Cardíacas , Humanos , Masculino
11.
Artigo em Inglês | MEDLINE | ID: mdl-30537625

RESUMO

Breath analysis offers a non-invasive and rapid diagnostic method for detecting various volatile organic compounds that could be indicators for different diseases, particularly metabolic disorders including type 2 diabetes mellitus. The development of type 2 diabetes mellitus is closely linked to metabolic dysfunction of adipose tissue and adipocytes. However, the VOC profile of human adipocytes has not yet been investigated. Gas chromatography with mass spectrometric detection and head-space needle trap extraction (two-bed Carbopack X/Carboxen 1000 needle traps) were applied to profile VOCs produced and metabolised by human Simpson Golabi Behmel Syndrome adipocytes. In total, sixteen compounds were identified to be related to the metabolism of the cells. Four sulphur compounds (carbon disulphide, dimethyl sulphide, ethyl methyl sulphide and dimethyl disulphide), three heterocyclic compounds (2-ethylfuran, 2-methyl-5-(methyl-thio)-furan, and 2-pentylfuran), two ketones (acetone and 2-pentanone), two hydrocarbons (isoprene and n-heptane) and one ester (ethyl acetate) were produced, and four aldehydes (2-methyl-propanal, butanal, pentanal and hexanal) were found to be consumed by the cells of interest. This study presents the first profile of VOCs formed by human adipocytes, which may reflect the activity of the adipose tissue enzymes and provide evidence of their active role in metabolic regulation. Our data also suggest that a previously reported increase of isoprene and sulphur compounds in diabetic patients may be explained by their production by adipocytes. Moreover, the unique features of this profile, including a high emission of dimethyl sulphide and the production of furan-containing VOCs, increase our knowledge about metabolism in adipose tissue and provide diagnostic potential for future applications.


Assuntos
Adipócitos/metabolismo , Arritmias Cardíacas/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Gigantismo/metabolismo , Cardiopatias Congênitas/metabolismo , Deficiência Intelectual/metabolismo , Compostos Orgânicos Voláteis/análise , Biomarcadores/análise , Biomarcadores/metabolismo , Células Cultivadas , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Compostos Orgânicos Voláteis/metabolismo
12.
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
13.
Front Neuroendocrinol ; 52: 113-143, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30448536

RESUMO

Individuals with acromegaloid physical appearance or tall stature may be referred to endocrinologists to exclude growth hormone (GH) excess. While some of these subjects could be healthy individuals with normal variants of growth or physical traits, others will have acromegaly or pituitary gigantism, which are, in general, straightforward diagnoses upon assessment of the GH/IGF-1 axis. However, some patients with physical features resembling acromegaly - usually affecting the face and extremities -, or gigantism - accelerated growth/tall stature - will have no abnormalities in the GH axis. This scenario is termed pseudoacromegaly, and its correct diagnosis can be challenging due to the rarity and variability of these conditions, as well as due to significant overlap in their characteristics. In this review we aim to provide a comprehensive overview of pseudoacromegaly conditions, highlighting their similarities and differences with acromegaly and pituitary gigantism, to aid physicians with the diagnosis of patients with pseudoacromegaly.


Assuntos
Acromegalia/diagnóstico , Transtornos Cromossômicos/diagnóstico , Diagnóstico Diferencial , Gigantismo/diagnóstico , Transtornos do Metabolismo de Glucose/diagnóstico , Hipotireoidismo/diagnóstico , Lipodistrofia/diagnóstico , Síndrome de Marfan/diagnóstico , Anormalidades Musculoesqueléticas/diagnóstico , Osteocondrodisplasias/diagnóstico , Acromegalia/metabolismo , Transtornos Cromossômicos/metabolismo , Gigantismo/metabolismo , Transtornos do Metabolismo de Glucose/metabolismo , Humanos , Lipodistrofia/metabolismo , Anormalidades Musculoesqueléticas/metabolismo
14.
Nat Ecol Evol ; 2(11): 1687-1688, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30323209
15.
Pediatr Endocrinol Rev ; 16(1): 171-177, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30371035

RESUMO

Overgrowth syndromes are rare genetic disorders characterized by excessive pre- and postnatal growth accompanied by dysmorphic features and developmental disorders. In addition to other health hazards, the life expectancy of affected children may be compromised due to an increased risk of developing tumors. To demonstrate the need for early recognition, correct diagnostic evaluation and adequate follow-up, we present a family with recurrent Simpson-Golabi-Behmel syndrome (SGBS). SGBS is a X-linked neonatal overgrowth syndrome caused by mutations in the GPC3 or GPC4 genes. All three affected males manifested with congenital diaphragmatic hernia. When fetal overgrowth and congenital diaphragmatic hernia co-occur, the choice for a possible cause is limited among SGBS, Marfan syndrome and Pallister-Killian syndrome. Their different phenotypes allow clinical assessment and correct diagnosis in most cases and should be followed by genetic testing. Regular oncologic screening aimed towards early recognition of malignant tumors may improve long-term outcomes in SGBS as well as in all other overgrowth syndromes.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Gigantismo , Arritmias Cardíacas , Glipicanas , Cardiopatias Congênitas , Humanos , Recém-Nascido , Deficiência Intelectual , Masculino
16.
Nat Rev Endocrinol ; 14(12): 705-720, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30361628

RESUMO

In the general population, height is determined by a complex interplay between genetic and environmental factors. Pituitary gigantism is a rare but very important subgroup of patients with excessive height, as it has an identifiable and clinically treatable cause. The disease is caused by chronic growth hormone and insulin-like growth factor 1 secretion from a pituitary somatotrope adenoma that forms before the closure of the epiphyses. If not controlled effectively, this hormonal hypersecretion could lead to extremely elevated final adult height. The past 10 years have seen marked advances in the understanding of pituitary gigantism, including the identification of genetic causes in ~50% of cases, such as mutations in the AIP gene or chromosome Xq26.3 duplications in X-linked acrogigantism syndrome. Pituitary gigantism has a male preponderance, and patients usually have large pituitary adenomas. The large tumour size, together with the young age of patients and frequent resistance to medical therapy, makes the management of pituitary gigantism complex. Early diagnosis and rapid referral for effective therapy appear to improve outcomes in patients with pituitary gigantism; therefore, a high level of clinical suspicion and efficient use of diagnostic resources is key to controlling overgrowth and preventing patients from reaching very elevated final adult heights.


Assuntos
Adenoma/complicações , Predisposição Genética para Doença/epidemiologia , Gigantismo/etiologia , Fator de Crescimento Insulin-Like I/genética , Neoplasias Hipofisárias/complicações , Acromegalia/etiologia , Acromegalia/genética , Acromegalia/terapia , Adenoma/diagnóstico , Adenoma/genética , Diagnóstico Precoce , Gigantismo/genética , Gigantismo/terapia , Hormônio do Crescimento Humano/metabolismo , Humanos , Masculino , Mutação , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética , Prognóstico , Medição de Risco , Fatores Sexuais
17.
Int J Mol Sci ; 19(9)2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30208657

RESUMO

Radiotherapy is a widely used treatment option for cancer patients as well as for patients with musculoskeletal disorders. Adipocytes, the dominant cell type of adipose tissue, are known to constitute an active part of the tumor microenvironment. Moreover, adipocytes support inflammatory processes and cartilage degradation in chronic inflammatory diseases, i.e., rheumatoid and osteoarthritis. Since the production of inflammatory factors is linked to their differentiation stages, we set out to explore the radiation response of pre-adipocytes that may influence their inflammatory potential and differentiation capacity. This is the first study investigating the effects of X-ray irradiation on the proliferation and differentiation capacity of human primary pre-adipocytes, in comparison to Simpson⁻Golabi⁻Behmel Syndrome (SGBS) pre-adipocytes, an often-used in vitro model of human primary pre-adipocytes. Our results demonstrate a dose-dependent reduction of the proliferation capacity for both cell strains, whereas the potential for differentiation was mostly unaffected by irradiation. The expression of markers of adipogenic development, such as transcription factors (PPARγ, C/EBPα and C/EBPß), as well as the release of adipokines (visfatin, adiponectin and leptin) were not significantly changed upon irradiation. However, after irradiation with high X-ray doses, an increased lipid accumulation was observed, which suggests a radiation-induced response of adipocytes related to inflammation. Our results indicate that pre-adipocytes are radio-resistant, and it remains to be elucidated whether this holds true for the overall inflammatory response of adipocytes upon irradiation.


Assuntos
Adipócitos/efeitos da radiação , Adipogenia/efeitos da radiação , Proliferação de Células/efeitos da radiação , Adipócitos/citologia , Adipócitos/metabolismo , Adipocinas/metabolismo , Arritmias Cardíacas/metabolismo , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Gigantismo/metabolismo , Cardiopatias Congênitas/metabolismo , Humanos , Deficiência Intelectual/metabolismo , Raios X
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