PAX8 – Congenital Hypothyroidism

Clinical Validity

The association between PAX8 and Congenital Hypothyroidism is classified as Strong based on multiple autosomal dominant families with a total of 13 affected individuals across four generations (PMID:27207603) and concordant functional data demonstrating loss of transcriptional activity.

Genetic Evidence

Congenital hypothyroidism due to PAX8 follows an autosomal dominant inheritance pattern with incomplete penetrance. Segregation analysis revealed 13 affected relatives in a single pedigree (9 males, 4 females) (PMID:27207603). In a cohort of 118 patients with thyroid dysgenesis, 6 index patients harbored distinct PAX8 mutations across three unrelated families (PMID:25214233). The variant spectrum includes missense substitutions within the paired domain (e.g., c.160A>G (p.Ser54Gly)) and small deletions/frameshifts.

Functional Evidence

In vitro assays of PAX8 mutants reveal loss of DNA-binding and transactivation. The p.Ser54Gly variant fails to bind a thyroperoxidase promoter element and is unable to synergize with Titf1 on thyroglobulin enhancer assays, confirming a loss-of-function mechanism (PMID:15356023). These studies support haploinsufficiency as the primary pathogenic mechanism.

Phenotypic Spectrum

Affected individuals exhibit variable thyroid dysgenesis—hypoplasia, ectopy, or gland-in-situ—with clinical severity ranging from mild subclinical hypothyroidism to severe permanent CH. Extrathyroidal features include unilateral renal agenesis (HP:0000122) in some carriers.

Clinical Integration

Targeted sequencing of PAX8 is recommended for patients with congenital hypothyroidism and thyroid dysgenesis, particularly in familial cases or when urogenital malformations are present. Early molecular diagnosis enables prompt thyroid hormone replacement and informs genetic counseling.

Key Take-home: PAX8 haploinsufficiency is a well-established cause of dominantly inherited congenital hypothyroidism, accounting for ~2–3% of thyroid dysgenesis cases.

References

• The Journal of clinical endocrinology and metabolism • 2004 • Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid. PMID:15356023
• European journal of endocrinology • 2014 • Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations. PMID:25214233
• Hormone research in paediatrics • 2016 • A Novel Mutation (S54C) of the PAX8 Gene in a Family with Congenital Hypothyroidism and a High Proportion of Affected Individuals. PMID:27207603

Evidence Based Scoring (AI generated)