Context. Two families from Galicia (NW Spain) with Pendred syndrome (PS) and unusual thyroid phenotypes. In family A, the proposita had a large goiter and hypothyroxinemia but normal TSH and free T3. In family B some affected members showed deafness but not goiter.

Objective. To identify the mutations causing PS and molecular mechanisms underlying the thyroid phenotypes.

Interventions. Extraction of DNA and of thyroid tissue.

Patients. Propositi and ten members of the two families.

Main Outcome Measures. SLC26A4 gene analysis. Deiodinase activities in thyroid tissue. c.416–1G>A effects on SLC26A4 splicing. A primary PS thyrocyte culture, T-PS2, obtained from propositus B and compared with another culture of normal human thyrocytes, NT, by Western blotting, confocal microscopy and iodine uptake kinetics.

Results. Proposita A, heterozygous for c.578C>T and c.279delT, presented goiter, normal TSH and FT3 but low FT4 attributable to high D1 and D2 activities in the goiter. Propositus B bore c.279delT and a novel mutation c.416–1G>A; some deaf relatives homozygous for c.416–1G>A present not goiter. The c.279delT mutation was associated with identical haplotype in the two families. T-PS2 showed truncated pendrin retained intracellularly and high iodine uptake with low efflux leading to iodine retention.

Conclusions. c.279delT is a founder mutation in Galicia. Proposita A adapted to poor organification by increasing deiodinase activities in the goiter, avoiding hypothyroidism. Lack of goiter in subjects homozygous for c.416–1G>A was due to incomplete penetrance allowing synthesis of some wildtype pendrin. Intracellular iodine retention, as seen in T-PS2, could play a role in thyroid alterations in PS.