Open Access Research article

Identification of a novel pax8 gene sequence variant in four members of the same family: from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism

Monica Vincenzi1, Marta Camilot12, Eleonora Ferrarini3, Francesca Teofoli12, Giacomo Venturi1, Rossella Gaudino12, Paolo Cavarzere2*, Giuseppina De Marco3, Patrizia Agretti3, Antonio Dimida3, Massimo Tonacchera3, Attilio Boner12 and Franco Antoniazzi12

Author Affiliations

1 Department of Life and Reproduction Sciences, University of Verona, Piazzale Scuro 10, 37126 Verona, Italy

2 Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy

3 Department of Endocrinology, Centro di Eccellenza AmbiSEN, University of Pisa, Pisa, Italy

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BMC Endocrine Disorders 2014, 14:69  doi:10.1186/1472-6823-14-69

Published: 22 August 2014



Congenital hypothyroidism is often secondary to thyroid dysgenesis, including thyroid agenesis, hypoplasia, ectopic thyroid tissue or cysts. Loss of function mutations in TSHR, PAX8, NKX2.1, NKX2.5 and FOXE1 genes are responsible for some forms of inherited congenital hypothyroidism, with or without hypoplastic thyroid. The aim of this study was to analyse the PAX8 gene sequence in several members of the same family in order to understand whether the variable phenotypic expression, ranging from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism, could be associated to the genetic variant in the PAX8 gene, detected in the proband.


We screened a hypothyroid child with thyroid hypoplasia for mutations in PAX8, TSHR, NKX2.1, NKX2.5 and FOXE1 genes. We studied the inheritance of the new variant R133W detected in the PAX8 gene in the proband’s family, and we looked for the same substitution in 115 Caucasian European subjects and in 26 hypothyroid children. Functional studies were performed to assess the in vitro effect of the newly identified PAX8 gene variant.


A new heterozygous nucleotide substitution was detected in the PAX8 DNA-binding motif (c.397C/T, R133W) in the proband, affected by congenital hypothyroidism with thyroid hypoplasia, in his older sister, displaying a subclinical hypothyroidism associated with thyroid hypoplasia and thyroid nodules, in his father, affected by hypothyroidism with thyroid hypoplasia and thyroid nodules, and his first cousin as well, who revealed only a subclinical hypothyroidism. Functional studies of R133W-PAX8 in the HEK293 cells showed activation of the TG promoter comparable to the wild-type PAX8.


In vitro data do not prove that R133W-PAX8 is directly involved in the development of the thyroid phenotypes reported for family members carrying the substitution. However, it is reasonable to conceive that, in the cases of transcriptions factors, such as Pax8, which establish several interactions in different protein complexes, genetic variants could have an impact in vivo.

PAX8 gene; Thyroid; Congenital hypothyroidism; Variable phenotypic expressivity; R133W-PAX8