Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations

Abstract

Context: Within the last two decades, heterozygous loss-of-function PAX8 mutations have been reported in patients with a wide degree of thyroid gland dysfunction and growth despite the presence of identical mutations. Objectives: To search for PAX8 mutations in a cohort of patients with congenital hypothyroidism (CH) and various types of thyroid gland defects. Design: A cross-sectional study was conducted in a cohort of patients. Setting: The French neonatal screening program was used for recruiting patients. Patients: A total of 118 patients with CH, including 45 with familial and 73 with sporadic diseases, were included in this study. The thyroid gland was normal in 23 patients had hypoplasia, 25 had hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy. Results: We found four different PAX8 mutations (p.R31C, p.R31H, p.R108X, and p.I47T) in ten patients (six patients with CH and four family members), two with sporadic and eight with familial diseases. Imaging studies performed in the index cases showed ectopic thyroid gland (nZ2), hypoplasia (nZ2), eutopic lobar asymmetry (nZ1), and eutopic gland compatible with dyshormonogenesis (nZ1). The previously reported p.R31C and the novel p.I47T PAX8 mutations are devoid of activity. Conclusion: Four different PAX8 mutations were detected in six index patients with CH (ten total subjects). The p.R31C, p.R31H, and p.R108X mutations have been reported. The novel p.I47T PAX8 mutation presented loss of function leading to CH. Thyroid ectopy was observed in two cases of PAX8 (p.R31H) mutation, a finding that has not been reported previously. We observed a high inter-individual and intra-familial variability of the phenotype in PAX8 mutations, underlining that population genetic studies for CH should include patients with various clinical presentations.

TUBB 1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

“…TUBB1 mutations constitute a model of dominant inheritance of CH with TD. Most known mutations responsible for TD and previously described TUBB1 mutations causing macrothrombocytopaenia are also dominant (Kunishima et al , , ; Guillot et al , ; Ramos et al , ; Carré et al , ; Fiore et al , ). Our data indicate high penetrance for platelet alterations and incomplete penetrance with variable expressivity for TD, ranging from TD without CH to TD with CH and leading to variable types of TD (ectopia, hypoplasia, hemithyroid or asymmetric thyroid gland).…”

“…Abnormalities at any step of thyroid development may result in TD associated with hypothyroidism or not (Maiorana et al , ). Previous studies of sporadic and familial TD covering a wide clinical spectrum identified mutations in nine genes: PAX8 , NKX2‐1 , FOXE1 , NKX2‐5 , TSHR, GLIS3, NTN1 , JAG1 and BOREALIN (Dentice et al , ; Senée et al , ; Carré et al , , , ; Sura‐Trueba et al , ; Ramos et al , ; Opitz et al , ; de Filippis et al , ). However, mutations in these genes are found in only 5% of all patients with TD and identification of causative mutations remains a challenging task.…”

Molecular defects in thyroid dysgenesis

“…The first is due to the phenotypic heterogeneity (either inter or intra‐familial) of subjects harboring mutation of the same gene. It has been widely shown, for example, that TD due to mutations in PAX8 NKX2‐1 displayed a variable thyroid phenotype. Furthermore, a second cause could be found in the genetic heterogeneity of this disease.…”

Resistance to thyrotropin

“…The presence of RTSH-associated PAX8 promoter variants [69–71], the observation of a frameshift mutation with demonstrated protein instability [72], and the autoregulation of PAX8 by binding to its own promoter [73] are also consistent with a haploinsufficiency mechanism. A noteworthy mutational hotspot is the CpG dinucleotide at codon 31, for which frequent mutational events (R31H and R31C) have been reported [61, 65, 67, 74–77]. For some of the reported mutations, the primary defect is the impaired synergism with other thyroid transcription factors (NKX2-1) or insufficient recruitment of coactivators (p300) without altering DNA binding [78–80].…”