Rosalind S. Brown

Developmental regulation of thyrotropin receptor gene expression in the fetal and neonatal rat thyroid: relation to thyroid morphology and to thyroid-specific gene expression.

The TSH receptor plays a pivotal role in thyroid gland function, growth, and differentiation, but little is known about its role or regulation in the fetus and neonate. To explore these questions, we systematically evaluated TSH receptor gene expression at the level of messenger RNA (mRNA) in thyroid glands obtained from rat fetuses and neonates, from 14 days gestation to day 5 of postnatal life. Results were compared with histological evidence of differentiation and to thyroid-specific gene expression. Northern blot and RT-PCR analysis revealed that TSH mRNA was first detected at low levels on fetal day 15, but it increased 3- to 15-fold on fetal days 17–18. Up-regulation of TSH receptor mRNA on fetal day 17–18 was accompanied by the first appearance of colloid formation and of follicular development on morphological examination. It was also paralleled by increased expression of the thyroid-specific genes thyroglobulin (Tg) and thyroid peroxidase. Unexpectedly, TSH mRNA abundance was 2- to 3-fold higher ...

Bioassay of thyrotropin receptor antibodies with Chinese hamster ovary cells transfected with recombinant human thyrotropin receptor: Clinical utility in children and adolescents with Graves disease☆☆☆★

OBJECTIVE The objective of this study was to compare the clinical utility of a new bioassay for thyrotropin (TSH) receptor antibodies (Abs) with the conventional radioreceptor assay and with measurement of thyroid peroxidase Abs in the diagnosis of Graves disease in childhood. STUDY DESIGN Serum samples obtained from 22 children and adolescents with Graves disease (19 hyperthyroid, 3 in remission), 13 children and adolescents with chronic lymphocytic thyroiditis, and 17 normal children in a control group were evaluated. RESULTS TSH receptor Abs were detected by bioassay in 10 (91%) of 11 patients with active Graves disease but in 0 of 2 patients in remission, 0 of 13 normal members of the control group, and 0 of 11 patients with chronic lymphocytic thyroiditis including 1 with thyrotoxicosis. The sensitivity and specificity of TSH receptor Abs detected by radioreceptor assay studied in the same 11 patients and in an additional 11 patients was similar to bioassay. In contrast, thyroid peroxidase Abs were detected in only 12 (71%) of 17 patients with Graves disease but in 11 of 11 patients with chronic lymphocytic thyroiditis and in 0 of 17 members of the control group. CONCLUSION Bioassay of TSH receptor Abs is both sensitive and specific for the diagnosis of active Graves disease in the young. When cost and simplicity are considered, however, bioassay offers no advantage over radioreceptor assay for initial diagnostic screening. Rather, bioassay for TSH receptor Abs may be useful in thyrotoxic patients who are negative initially in the radioreceptor assay or in treated patients whose clinical picture is discordant with results in the radioreceptor assay.

Outcome in three siblings with antibody-mediated transient congenital hypothyroidism

A woman receiving thyroxine substitution therapy for acquired hypothyroidism caused by autoimmune thyroiditis gave birth to three babies who had transient primary hypothyroidism. All three babies had elevated thyrotropin levels on neonatal screening, but one had normal thyroxine values. Thyrotropin receptor-blocking antibodies were present in maternal serum and in the three neonates. Each baby also had a different congenital malformation. The neurodevelopmental outcome of the children appeared related in part to maternal thyroxine levels, which suggests that transplacental transfer of thyroxine may protect the fetal brain.

Successful treatment of massive acute thyroid hormone poisoning with iopanoic acid

We report a toddler with massive thyroid hormone poisoning in whom the addition of iopanoic acid to the treatment regimen (propylthiouracil and propranolol) resulted in a dramatic clinical and biochemical improvement. Iopanoic acid is a safe and effective drug in the treatment of massive thyroid hormone poisoning in children.

Severe Maternal Hypothyroidism Corrected Prior to the Third Trimester Is Associated with Normal Cognitive Outcome in the Offspring

BACKGROUND Concern about potential harmful effects of early maternal hypothyroidism (MH) on fetal brain development has led to calls for universal screening early in, or even before, pregnancy. However, evidence in humans that adverse effects are irreversible if thyroid hormone replacement is initiated after the first trimester is limited. Severe MH due to thyrotropin (TSH) receptor blocking antibodies (Abs) is associated with profound cognitive delay in the offspring if MH is untreated or inadequately treated; here, we sought to determine the outcome if treatment is given in early pregnancy. METHODS We identified three women who had TSH receptor blocking Ab-induced MH during pregnancy and were treated with L-thyroxine (L-T4), starting at 27 weeks, 5 weeks, and the first month of gestation. The corresponding pretreatment serum TSH levels in the two women in whom data were available were 68 and 65 mU/L, falling to 6 mU/L at 25 and 24 weeks of gestation, respectively. The third woman with MH required 0.5 mg of L-T4 to normalize her thyroid hormone levels by 4 months of gestation. Their infants were also treated with L-T4 after neonatal screening that identified congenital hypothyroidism (CH). Neuropsychological tests to assess intelligence, language, memory, and visual-motor performance were administered to these three infants at 5.4 years of age (range 5.1-6.1) and to three sibling controls at 6.8 years (range 9.1-3.0). RESULTS Children born after MH had average or above average results on all parameters. Comparative scores of the neuropsychological tests in sibling pairs for full-scale intelligence quotient (IQ) and performance IQ were variable; some scores were higher and some were lower in CH children. CONCLUSIONS Although the findings do not exclude a subtle impact of MH during early gestation on intellectual function, the normal cognitive outcome despite overt MH should provide data with which to counsel mothers who have overt hypothyroidism early in pregnancy. Aggressive thyroid hormone replacement as soon as possible is important, but early termination of the pregnancy because of fear that the baby will have significant cognitive delay is not warranted.

Symptomatic non-insulin-dependent diabetes mellitus during therapy with recombinant human growth hormone

In a 12-year-old girl, hyperglycemia and an elevated glycohemoglobin concentration developed after therapy with growth hormone for familial short stature. Both clinical and biochemical abnormalities disappeared after therapy was discontinued. The insulin response to an oral glucose tolerance test was abnormal 3 months after discontinuation of growth hormone; 18 months later, it remained delayed but was normal quantitatively.

Unresolved Issues in the Wake of Newborn Screening for Congenital Hypothyroidism

Journal of Pediatrics, The - In Press.Proof corrected by the author Available online since lundi 4 avril 2016

OUTCOME OF 3 SIBLINGS WITH ANTIBODY-MEDIATED TRANSIENT CONGENITAL HYPOTHYROIDISM

Transient neonatal hypothyroidism due to transplacental transfer of maternal TSH receptor blocking antibodies (TBIIs) is a rare cause of congenital hypothyroidism. A woman with hypothyroidism secondary to Hashimotos thyroiditis diagnosed and treated since age 15 y delivered three babies at age 21, 23 and 25 y. TBII tilers were very high throughout this period in the mother and in the newborns. All three babies (2 boys, 1 girl) had high TSH on newborn screening (Table in SI units) and were started on thyroxine replacement (8-12 μg/kg) at age 16 d (#1 and 2) and 3 d(#3).Treatment was stopped at age 33 mo in sib #1 and at age 15 mo in sib #2; both have remained euthyroid since. In addition, #1 had artial septal defect, #2 had unilateral renal agenesis, and #3 died at 10 w of a complex cardiac malformation. During pregancy #1, maternal TSH levels were all normal, whereas during pregnancies #2 and #3, they were elevated (8-20 mIU/l). Developmental evaluation of sib #1 at age 4 y showed an IQ of 91 (Mc Carthy test), while sib #2 at age 2 1/2 y had a motor deficit (Bailey scale: motor 72, mental 88).Conclusions: transplacental transfer of TBIIs in this family was associated with 1) transient neonatal hypothyroidism in all children, with normal thyroid size at birth; 2) various congenital malformations in all children; 3) a developmental outcome that appeared related to maternal TSH levels but not to severity of hypothyroidism at diagnosis.