Context. McCune-Albright syndrome (MAS) is caused by mutations in GNAS (most often R201C or R201H) leading to constitutive cAMP signaling and multiple endocrine dysfunctions, including morphological and functional thyroid involvement.

Objective. To characterize the clinical and molecular features of the MAS-associated thyroid disease in a large cohort of patients.

Design. Retrospective analysis.

Setting. NIH Clinical Center.

Patients. 100 consecutive MAS patients.

Interventions. None

Main outcome measure. Functional and morphological evaluation of the thyroid. Ex vivo experiments were performed on MAS thyroid samples to study the effects of the GNAS mutations on the 5'-deiodinases. Reconstitution experiments in HEK-293 cells were performed to study the effects of GNAS mutations on the type-2 5'-deiodinase.

Results. Fifty-four patients had abnormal thyroid ultrasound findings. This group, compared to patients without abnormal findings, had higher T3/T4 ratio indicating an elevated 5'-deiodinase activity. Thyroid samples from MAS subjects compared to normal tissue showed a significant increase in both type-1 (D1) and type-2 (D2) 5'-deiodinase activity (D1 control 5.9±4.5 vs. MAS 41.7±26.8 fmol/min/mg, p<0.001; D2 control 28.3±13.8 vs. MAS 153.1±43.7fmol/min/mg, p<0.001). Compared to cells transfected with the wild type R201 allele, the basal transcriptional activity of the D2 promoter was significantly increased in both mutants (C and H) (R 10733±2855, vs. C 18548±4514, vs. H 19032±4410 RLU±SD, p<0.001).

Conclusion. Thyroid pathology is a common occurrence in MAS. Consistent with the molecular etiology of the disease, the shift in T3/T4 ratio is at least in part secondary to a cAMP-mediated intrathyroidal activation of D2 and to elevated D1 activity.