ESPE Abstracts

Case report: 6 yrs. old boy presented with high total T4, free T4, reverse T3, and normal total T3 and TSH. He has a history of tic disorder. Blood pressure, and heart rate were normal, no palpitations, no weight loss. Thyroid peroxidase and thyroglobulin antibodies were normal. Thyroid sonogram was normal. Family is of Hispanic origin. There was a family history of elevated T4 in the paternal uncle (half-brother of the father)

Methods: Blood was shipped for analysis to the Thyroid Study Unit at The University of Chicago. Written consents were obtained from all family members for evaluation of thyroid function and DNA sequencing. TSH levels were measured by direct method using automated immunoassay on the Siemens Centaur™ platform and by a direct equilibrium dialysis method. Free T4 was high when measured at Quest Diagnostics by direct method using the automated immunoassay (T4, Free, test code 866).

Results: Total T4 and rT3 were high, but not T3 suggested the presence of FDH. Father, paternal grandmother and paternal uncle have elevated total T4, normal TSH. The diagnosis of FDH was confirmed by sequencing the albumin gene which showed the rare variant (gnomAD MAF=0.00007) in exon 7 causing this condition. Using the American College of Medical Genetics and Genomics (ACMG) guidelines (Richards et al 2015), this variant was classified pathogenic (PS3+PM2+PM5+PP1+PP5). It is a missense variant, a substitution of a guanidine (G) to adenine (A), resulting in the replacement of the normal arginine 218 with a histidine (R218H; rs75002628). Patient and his father inherited his mutation from paternal grandmother (PGM). Both patient and father, PGM, and paternal uncle have a double peak (black for G and green for A). Both are thus heterozygous in agreement with the dominant inheritance of a defect causing a gain-of-function (an increase in the binding affinity for T4).

Conclusion: Familial FDH is a familial autosomal dominant condition. It is caused by an abnormal albumin molecule with an increased affinity for thyroxine (T4). Genetic analysis in cases of elevated total and free T4 and normal TSH is important for proper diagnosis and avoiding potentially unnecessary treatment.