PAX8 – Athyreosis

PAX8 is a paired-box transcription factor essential for thyroid organogenesis. Athyreosis, defined as complete absence of the thyroid gland, leads to severe congenital hypothyroidism and requires early genetic diagnosis to guide lifelong management of thyroid hormone replacement. Although multiple transcription factors have been implicated in thyroid dysgenesis, the contribution of PAX8 to athyreosis remains incompletely defined.

In a cohort of 100 unrelated Chinese patients with congenital hypothyroidism and athyreosis, targeted next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR identified two heterozygous PAX8 variants—one promoter change (c.-26G>A) and one missense substitution (p.Ala355Val)—in 2% of cases (PMID:28455095). The low mutation rate in PAX8 contrasts with a higher frequency of TSHR defects in the same cohort and suggests a limited role for PAX8 in isolated athyreosis. No familial segregation or functional assays specific to these PAX8 variants in athyreosis were reported.

Based on these data, the clinical validity of a PAX8–athyreosis association is classified as Limited: only two heterozygous cases without segregation or experimental confirmation. Genetic evidence is Limited due to the small number of probands and absence of family studies. No functional evidence directly supports pathogenicity of these variants in athyreosis.

Key Take-home: Routine screening of PAX8 in athyreosis identifies rare variants; however, low detection rates and lack of validation limit its standalone diagnostic utility.

References

• Clinica chimica acta; international journal of clinical chemistry • 2017 • Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis. PMID:28455095

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