A 4-year-8-month-old girl was referred for evaluation of hyperactivity and palpitations. She was previously healthy, with the only past history being early-onset tooth development. She reportedly had her first tooth erupt at 3 months of age, and, recently, she shed two primary teeth. Her birth history was normal, and, developmentally, she was on target for all milestones. Her family history was notable for teenage Graves' disease in her mother, treated by thyroidectomy.
On physical examination, all vital signs were normal for age. Her weight was 19.4 kg (79th percentile), her height was 103.5 cm (35th percentile), and her body mass index was 18 kg/m2 (94th percentile). Her growth velocity was 5 cm/year, without any note of acceleration. Her eye exam result was normal, with no proptosis or lid lag. Her thyroid gland was palpable, with no gross enlargement or tenderness. Her heart rate and peripheral pulses were normal, and the extremities were well perfused, with no tremor or hyperreflexia. Her neurologic exam result was normal, and she was Tanner stage I. The remainder of her examination result was normal.
Initial laboratory evaluations showed an elevated serum total T4 level of 22.03 mug/dL (reference range 4.5-12 mug/dL), elevated free T4 level of 3.03 ng/dL (reference range 0.58-1.64 ng/dL) (measured by direct automated immunometric assay), and a normal thyroid-stimulating hormone (TSH) concentration of 2.38 mIU/L (reference range 0.34-5.6 mIU/L). Her bone age was 5 years at a chronological age of 5 years. Repeat testing confirmed these results as well as elevated thyroperoxidase and thyroglobulin (TG) antibody titers. Thyroid-stimulating immunoglobulin and thyrotropin-binding inhibitory immunoglobulins were not detected. On subsequent follow-up, laboratory evaluations showed persistence of high serum total T4 levels with a non-suppressed TSH. A free T4 level measured using direct equilibrium dialysis coupled with tandem mass spectrometry was also elevated at 2.9 ng/dL (reference range 0.58-1.64). Specific tests to rule out antibody interference with the TSH assay produced negative results. Given these results, along with her mother's thyroid history and the advanced dental age, an evaluation was undertaken to rule out a TSH-secreting pituitary tumor or resistance to thyroid hormone (RTH). She had normal levels of the alpha subunit of TSH, and no mutations in the thyroid hormone receptor beta ( THRB ) gene were identified, ruling out a TSH-secreting pituitary tumor and RTH, respectively.
Without a clear diagnosis, further testing including genetic analysis was undertaken in the patient and members of her immediate family. The study was approved by the Institutional Review Board of the University of Chicago, where the analyses were performed. After obtaining informed consents, we investigated the family members in terms of their thyroid function tests ( Figure 1 ). The normal free T4 index, calculated from the total T4 and the resin T4 uptake ratio, combined with increased T4-binding capacity not due to excess T4-binding globulin (TBG), suggested the presence of an abnormal serum T4-binding substance. Furthermore, the normal total serum T3 with high rT3 concentrations, together with similar abnormalities found in the father, was compatible with a dominantly inherited defect, likely FDH. The presence of an abnormal T4-binding albumin was confirmed by isoelectric focusing analysis. Sequencing of the ALB gene revealed the most common mutation associated with FDH, c.653G > A producing p.R218H, in both the patient (proband) and her father. In light of this finding, a free T4 level was again measured, this time using equilibrium dialysis coupled with RIA. This assay produced a normal free T4 measurement of 2.4 ng/dL (reference range 0.8-2.7), consistent with the genetic diagnosis of FDH. The symptoms of hyperactivity and palpitations were not replicated during any of the examinations and ultimately resolved spontaneously during the course of the evaluation. At follow-up 2 years later, the girl was asymptomatic, growing and developing appropriately, and euthyroid without requiring anti-thyroid therapy.