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.

We report the cases of two sibs of North African origin with AAAS gene mutation characterized by the heterogeneity of their phenotype. While an 8‐y‐old boy presented with acute adrenal insufficiency and mental retardation, the diagnosis was suggested by the clinical history of his 6‐y‐old sister who had symptomatic achalasia and chronic adrenal failure. Conclusion: Our observations corroborate the phenotypic heterogeneity reported in triple A syndrome, and underline the possibility of a variable intra‐familial expression.

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