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 , SíndromeRESUMO
The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.
Assuntos
Acromegalia/epidemiologia , Acromegalia/genética , Predisposição Genética para Doença , Gigantismo/epidemiologia , Gigantismo/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Acromegalia/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Mapeamento Cromossômico , Estudos Transversais , Feminino , Frequência do Gene , Genótipo , Gigantismo/diagnóstico , Heterozigoto , Humanos , Irlanda/epidemiologia , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Fenótipo , Risco , Adulto JovemAssuntos
Transtorno Bipolar/epidemiologia , Síndrome de Klippel-Trenaunay-Weber/epidemiologia , Adulto , Transtorno Bipolar/diagnóstico , Comorbidade , Feminino , Pé/diagnóstico por imagem , Gigantismo/diagnóstico , Gigantismo/epidemiologia , Humanos , Índia/epidemiologia , Síndrome de Klippel-Trenaunay-Weber/diagnóstico , RadiografiaAssuntos
Acromegalia , Síndrome de Cushing , Gigantismo , Hipopituitarismo , Acromegalia/epidemiologia , Acromegalia/terapia , Fatores Etários , Síndrome de Cushing/epidemiologia , Síndrome de Cushing/terapia , Feminino , Gigantismo/epidemiologia , Gigantismo/terapia , Humanos , Hipopituitarismo/epidemiologia , Hipopituitarismo/terapia , Japão/epidemiologia , Masculino , Neuro-Hipófise , Prognóstico , Fatores Sexuais , Fatores de TempoRESUMO
Se estudió 618 bebés macrosómicos de una población de 8,880 recién nacidos vivos (6.9%). Para los propósitos de nuestro análisis se consideró 500 casos, encontrándose la asociación de ciertos factores maternos y fetales con macrosomía, como paridad y edad (43%), edad gestacional de 39 semanas o más (90%), diabetes materna (1.9%) sexo masculino (65%). La aplicación del vacuum extractor fue el doble con respecto a la población general (4.6%: 2.1%). La morbilidad del macrosómico fue el doble de la del recién nacido de peso normal (28%: 14%). La incidencia de asfixia, aspiración de meconio y trauma al nacimiento se incrementó en relación al peso. La tasa de mortalidad neonatal en los macrosómicos fue de 8%, la causa de muerte relacionada en especial al tamaño fetal. Para mejorar el pronóstico del infante macrosómico, se debe establecer un manejo combinado pediátrico-obstétrico orientado a identificar la población en riesgo y la detección antenatal de la macrosomía, en un intento de disminuir la morbilidad asociada al evento del parto
