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The Role of Type 1 and Type 2 5'-Deiodinase in the Pathophysiology of the 3,5,3'-Triiodothyronine Toxicosis of McCune-Albright Syndrome

Clinical Endocrinology Branch (F.S.C., G.C., A.C.), National Institute of Diabetes and Digestive and Kidney Diseases, and Skeletal Clinical Studies Unit (M.K., B.A.B., N.C., M.T.C.), Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, Radiology Department (T.S.), Mark O. Hatfield Clinical Center, National Human Genome Research Institute (P.P.F.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Francesco Saverio Celi, M.D., Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Clinical Research Center, Room 6–3940, 10 Center Drive MSC 1613, Bethesda, Maryland 20892-1613. E-mail: fc93a{at}nih.gov.

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: The objective of the study was to characterize the clinical and molecular features of the MAS-associated thyroid disease in a large cohort of patients.

Design: This was a retrospective analysis. Setting: The study was conducted at the National Institutes of Health Clinical Center.

Patients: The study included 100 consecutive MAS patients.

Interventions: There were no interventions.

Main Outcome Measure: Functional and morphological evaluation of the thyroid was measured. 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 with patients without abnormal findings, had higher T₃ to T₄ ratio, indicating an elevated 5'-deiodinase activity. Thyroid samples from MAS subjects, compared with 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 ± 43.7 fmol/min·mg, P < 0.001). Compared with 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 to T₄ ratio is at least in part secondary to a cAMP-mediated intrathyroidal activation of D2 and to elevated D1 activity.

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