Efecto combinado de la interacción genética sobre el desarrollo del bocio nodular con tiroiditis autoinmune y adenoma tiroideo en los habitantes de Bucovina del Norte / Combined effect of gene-gene interaction on the development of nodular goiter with autoimmune thyroiditis and thyroid adenoma in the inhabitants of Northern Bukovyna

ABSTRAC This article presents the results of a comprehensive analysis of the combined influence of genetic polymorphisms associated with various links of apoptosis regulation (BCL-2, CTLA-4 and APO-1/Fas) on the development of nodular goiter with autoimmune thyroiditis and thyroid adenoma in the studied population. The analysis was performed using the Multifactor Dimensionality Reduction (MDR) method by calculating the prediction potential. Graphic models of gene-gene interaction with the highest cross-validation consistency created by the MDR method showed complex "synergistic or independent" impact of polymorphic loci of the CTLA-4 (+49G/A), Fas (-1377G/A) and BCL-2 (63291411 A>G) genes on the onset of thyroid pathology in general, or its individual types (nodular goiter with autoimmune thyroiditis and thyroid adenoma) in the population of Northern Bukovyna.

RESUMEN Este artículo presenta los resultados de un análisis exhaustivo de la influencia combinada de polimorfismos genéticos asociados a diversos enlaces en la regulación de la apoptosis (BCL-2, CTLA-4 y APO-1/FAS) sobre el desarrollo de bocio nodular con tiroiditis autoinmune y adenoma tiroideo en la población estudiada. Para ello, se utilizó el método de reducción de dimensionalidad multifactorial (MDR) mediante el cálculo de los potenciales de predicción. Los modelos gráficos de interacción gen-gen con la mayor consistencia de validación cruzada creada por el método MDR mostraron un complejo impacto «sinérgico o independiente¼ de los loci polimórficos de los genes CTLA-4 (+49G/A), FAS (-1377G/A) y BCL-2 (63291411A>G) en el inicio de la patología tiroidea en general, o sus tipos individuales (bocio nodular con tiroiditis autoinmune y adenoma tiroideo) en la población de Bucovina septentrional.

Mutation screening of the SLC26A4 gene in a cohort of 192 Chinese patients with congenital hypothyroidism

ABSTRACT Objective Pendred syndrome (PS) is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by biallelic mutations in the SLC26A4 gene encoding for pendrin. Hypothyroidism in PS can be present from birth and therefore diagnosed by neonatal screening. The aim of this study was to examine the SLC26A4 mutation spectrum and prevalence among congenital hypothyroidism (CH) patients in the Guangxi Zhuang Autonomous Region of China and to establish how frequently PS causes hearing impairment in our patients with CH. Subjects and methods Blood samples were collected from 192 CH patients in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the SLC26A4 gene together with their exon-intron boundaries were screened by next-generation sequencing. Patients with SLC26A4 mutations underwent a complete audiological evaluation including otoscopic examination, audiometry and morphological evaluation of the inner ear. Results Next generation sequencing analysis of SLC26A4 in 192 CH patients revealed five different heterozygous variations in eight individuals (8/192, 4%). The prevalence of SLC26A4 mutations was 4% among studied Chinese CH. Three of the eight were diagnosed as enlargement of the vestibular aqueduct (EVA), no PS were found in our 192 CH patients. The mutations included one novel missense variant p.P469S, as well as four known missense variants, namely p.V233L, p.M147I, p.V609G and p.D661E. Of the eight patients identified with SLC26A4 variations in our study, seven patients showed normal size/location of thyroid gland, and one patients showed a decreased size one. Conclusions The prevalence of SLC26A4 pathogenic variants was 4% among studied Chinese patients with CH. Our study expanded the SLC26A4 mutation spectrum, provided the best estimation of SLC26A4 mutation rate for Chinese CH patients and indicated the rarity of PS as a cause of CH.

Defeito bioquimico de bocio disormonogenetico identificado através de estudo imuno-histoquimico / Immunohistochemical identification of dishormonogenetic goiter biochemical defect

Apresentamos dois casos de bocio congenito nos quais foi possivel indicar, através do metodo imuno-histoquimico, o defeito na sintese hormonal. Um dos casos, era de mulher de 16 anos, com bocio desde a infancia e que, ha 10 anos, fazia uso de reposiçäo hormonal tireoideana. O exame anatomopatologico demonstrou bocio coloide de aspecto disormonogenetico com adenoma folicular. O estudo imuno-histoquimico revelou positividade intensa para tireoglobulina nas celulas foliculares, principalmente em porçäo apical e negatividade no coloide, caracterizando o quadro de defeito na exocitose de tireoglobulina. A reaçäo para tireoide peroxidase foi adequada para a idade. O outro caso, era de um menino de 13 anos, com bocio e reposiçäo hormonal tireoidiana desde um ano idade. Apresentava discretos retardos mental e do desenvolvimento pondo-estatural. O exame anatomopatologico, também, revelou bocio coloide com aspecto disormonogenetico e adenoma folicular. Já o estudo imuno-histoquimico, demonstrou reaçäo muito fraca e difusa para tireoide peroxidase e padräo normal para tireoglobulina, caracterizando o quadro como defeito quantitativo de tireoide peroxidase. Estes dois casos constituem-se em exemplos da possibilidade de identificar, imuno-histoquimicamente, a possivel causa de bocio disormonogenetico