A case of transient hypothyroidism: Sequential serum measurements of autoantibodies inhibiting thyrotropin-stimulated thyroid cAMP production in a neonate

Abstract

Transient neonatal hypothyroidism has been observed in three successive offspring of a mother with autoimmune thyroiditis. Thyroxine replacement therapy was initiated in a 23-year-old woman with overt clinical and laboratory findings of non-goitrous primary hypothyroidism. While on such treatment, she gave birth to three infants manifesting hypothyroidism immediately after birth. The neonates were treated with thyroxine replacement therapy which was discontinued in the three siblings at ages 2\m=1/2\ years, 3\m=1/2\ years, and 13 months. Continuous observation following cessation of therapy revealed clinical and biochemical euthyroidism in the children. Thyroid scanning during the neonatal period in the first child failed to identify functional thyroid tissue, suggesting thyroid agenesis, whereas thyroid scan performed on subsequent follow-up revealed a normal gland. Sequential serum measurements of autoantibodies directed towards the thyrotropin receptor were made in the mother and third child by a cAMP bioassay. High titres (five-six fold above normal) of blocking antibodies (tested by measuring the inhibition of TSH-stimulated cAMP production of cultured human thyroid cells by serum immunoglobulin preparations) were present in the mother and newborn 10 days after birth. The levels remained persistently high in the mother, whereas they declined and were undetectable in the child at four months. Thyroid-stimulating immunoglobulin was absent in both mother and child. The data are compatible with transient neonatal hypothyroidism caused by transplacental transfer of antibodies which block thyroid response to TSH. The half-life of the maternally-derived blocking antibody in the infant was estimated as 1-2 months. This is the first report on sequential serum measurements and estimate of half-life of the blocking antibodies performed by a cAMP bioassay (using thyroid cells of human origin). Unlike the radioreceptor assay employed so far in such cases, this assay can distinguish between stimulating and blocking TSH receptor antibodies. Transient thyroid disease may occur during the neonatal period owing to the transfer across the placenta of autoantibodies directed toward the thyrotropin receptor. The clinical manifestations in the newborn depend on the functional character¬ istics of the transferred antibody: transient neona¬ tal hyperthyroidism results from transplacental passage of thyroid-stimulating immunoglobulin (TSIg) (reviewed by Fisher (1)), whereas transfer of maternal TSH receptor blocking antibodies may cause transient hypothyroidism in the neonate (re¬ viewed by Delange (2)). The recent observation of euthyroidism, transient hyperthyroidism, and transient hypothyroidism in three children of a mother with autoimmune thyroiditis vividly dem¬ onstrate that different syndromes can occur in the newborn depending on whether stimulating or blocking antibodies predominate in the mother (3). We report here transient neonatal hypothyroidism in three successive offspring born to a mother with non-goitrous primary h...

Diagnostic Value of a Chimeric TSH Receptor (Mc4)-Based Bioassay for Graves' Disease

“…Later, the introduction of cell lines that stably expressed both TSHR and a luciferase reporter gene simplified the bioassays and made them more reliable, but it still took 3 days to measure TSI [5,14,15]. TB Abs that target functional epitopes on the C-terminal of the TSHR extracellular domain and that block TSHR function may exist coincidentally with TSI in 25.6% of patients with GD [11,12,16]. These TB Abs can block TSI as well as TSH and interfere with measurements of the stimulative activity of TSHR autoantibodies; therefore, a C-terminal-substituted chimeric TSHR was designed to exclude the effect of TB Abs present in the blood in one quarter of all patients with GD [8].…”

“…This substituted C-terminal area of TSHR contains epitopes for TB Abs. The Mc4 was designed to limit the effect of TB Abs that exist coincidentally with TSI in up to 25% of patients with GD and that can interfere with TSI measurements [11,12]. …”

A Novel Bioreporter Assay for Thyrotropin Receptor Antibodies Using a Chimeric Thyrotropin Receptor (Mc4) Is More Useful in Differentiation of Graves' Disease from Painless Thyroiditis Than Conventional Thyrotropin-Stimulating Antibody Assay Using Porcine Thyroid Cells

“…There are TSBAbs that bind to epitopes on N-terminus of the extracellular domain of TSHR and those that bind to epitopes on the C-terminus of the extracellular domain of TSHR (9). The TSBAbs associated with the C-terminal epitopes appear to be able to block stimulating TSHRAbs as well as TSH activity, whereas the TSBAbs associated with the N-terminal epitopes appear to be able to block only TSH activity (10,11). These findings suggest that stimulating TSHRAbs detected by a bioassay using porcine thyroid cells would be interfered with by the TSBAbs associated with the C-terminal epitopes of TSHR.…”

“…Recently, Grasso et al reported that 47% of GD sera had TSBAbs that targeted epitopes on the N-terminal of the extracellular domain of TSHR, 25% of GD sera had TSBAbs that bound to epitopes on the C-terminal, and 28% had no TSBAb activity (9). The TSBAbs associated with the C-terminal epitopes appear to be able to block stimulating TSHRAbs as well as TSH activity, whereas the TSBAbs associated with the N-terminal epitopes appear to be able to block only TSH activity (10,11). These findings suggest that a C-terminus-substituted chimeric TSHR may be more useful for the detection of stimulating TSHRAbs in GD sera.…”

Measurement of TSH receptor blocking immunoglobulins using 3H‐adenine incorporation into FRTL‐5 and JPO9 cells: use in a child with neonatal hypothyroidism

“…These Igs may be either thyroid stimulating antibodies (TSAb), which are TSH receptor agonists and result in thyroid hyperfunction, or thyroid blocking antibodies (TBAb), which are TSH receptor antagonists and result in inhibition of thyroid function. In pregnant women with autoimmune thyroid disease, maternal Igs may be transplacentally transferred resulting in neonatal hyperthyroidism (with transfer of TSAb) (McKenzie, 1964;Adams et al, 1964;Munro et al, 1978), hypothyroidism (with transfer of TBAb) (Matsuura et al, 1980;Iseki et al, 1983;Takasu et al, 1984) or delayed neonatal hyperthyroidism (when both are transferred) (Zakarija et al, 1983). The clinical status of the neonate will be a reflection of which type of Ig is transferred, or in the situation where there is a mixture of Igs, which is the predominant type (Zakarija et al, 1990).…”