Congenital Hypothyroidism Caused by a PAX8 Gene Mutation Manifested as Sodium/Iodide Symporter Gene Defect

Loss-of-function mutations of the PAX8 gene are considered to mainly cause congenital hypothyroidism (CH) due to thyroid hypoplasia. However, some patients with PAX8 mutation have demonstrated a normal-sized thyroid gland. Here we report a CH patient caused by a PAX8 mutation, which manifested as iodide transport defect (ITD). Hypothyroidism was detected by neonatal screening and L-thyroxine replacement was started immediately. Although I scintigraphy at 5 years of age showed that the thyroid gland was in the normal position and of small size, his iodide trapping was low. The ratio of the saliva/plasma radioactive iodide was low. He did not have goiter; however laboratory findings suggested that he had partial ITD. Gene analyses showed that the sodium/iodide symporter (NIS) gene was normal; instead, a mutation in the PAX8 gene causing R31H substitution was identified. The present report demonstrates that individuals with defective PAX8 can have partial ITD, and thus genetic analysis is useful for differential diagnosis.

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Novel, Missense, and Loss-of-Function Mutations in the Sodium/Iodide Symporter Gene Causing Iodide Transport Defect in Three Japanese Patients

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.9.5243 ◽

1998 ◽

Vol 83 (9) ◽

pp. 3365-3368 ◽

Cited By ~ 7

Author(s):

Shinji Kosugi ◽

Shinobu Inoue ◽

Akira Matsuda ◽

Sissy M. Jhiang

Keyword(s):

Sodium Iodide ◽

Japanese Patients ◽

Sodium Iodide Symporter ◽

Loss Of Function ◽

Iodide Transport ◽

Transport Defect

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A Homozygous Missense Mutation of the Sodium/Iodide Symporter Gene Causing Iodide Transport Defect

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.82.12.3966 ◽

1997 ◽

Vol 82 (12) ◽

pp. 3966-3971 ◽

Cited By ~ 25

Author(s):

A. Matsuda

Keyword(s):

Missense Mutation ◽

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Homozygous Missense Mutation ◽

Iodide Transport ◽

Transport Defect

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

Acta Endocrinologica ◽

10.1530/eje-13-1006 ◽

2014 ◽

Vol 171 (4) ◽

pp. 499-507 ◽

Cited By ~ 23

Author(s):

H E Ramos ◽

A Carré ◽

L Chevrier ◽

G Szinnai ◽

E Tron ◽

...

Keyword(s):

Thyroid Gland ◽

Congenital Hypothyroidism ◽

Screening Program ◽

Phenotypic Variability ◽

Cross Sectional Study ◽

The Novel ◽

Loss Of Function ◽

Cross Sectional ◽

Clinical Presentations ◽

Pax8 Gene

ContextWithin 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.ObjectivesTo search for PAX8 mutations in a cohort of patients with congenital hypothyroidism (CH) and various types of thyroid gland defects.DesignA cross-sectional study was conducted in a cohort of patients.SettingThe French neonatal screening program was used for recruiting patients.PatientsA 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.ResultsWe 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 (n=2), hypoplasia (n=2), eutopic lobar asymmetry (n=1), and eutopic gland compatible with dyshormonogenesis (n=1). The previously reported p.R31C and the novel p.I47T PAX8 mutations are devoid of activity.ConclusionFour 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.

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