The second wave of the Controlled Antenatal Thyroid Screening (CATS II) study: the cognitive assessment protocol

Background Children whose mothers had low thyroid hormone levels during pregnancy have been reported to have decreased cognitive function. The reported research is part of the follow-on study of the Controlled Antenatal Thyroid Screening Study (CATS I), a randomised controlled trial which investigated the impact of treated vs. untreated low thyroid hormone level in women during pregnancy with the primary outcome being the child’s IQ at age 3. No significant differences in IQ were found between the treated and untreated groups. These children are now aged between 7 and 10 years and aspects of their cognitive functioning including their IQ are being reassessed as part of CATS II. Methods/Design Cognitive assessments generate an IQ score and further tests administered will investigate long term memory function and motor coordination. The aim is to complete the assessments with 40% of the children born to mothers either in the treated or untreated low thyroid hormone groups (n = 120 per group). Also children born to mothers who had normal thyroid functioning during CATS I are being assessed for the first time (n = 240) to provide a comparison. Assessments are conducted either in the research facility or the participant’s home. Discussion The study is designed to assess the cognitive functioning of children born to mothers with low thyroid hormone levels and normal thyroid functioning during pregnancy. This is the largest study of its type and also is distinguishable in its longitudinal design. The research has the potential to have a significant impact on public health policy in the UK; universal screening of thyroid hormone levels in pregnancy may be the recommendation. Keywords: Hypothyroidism; Pregnancy; Child; Intelligence; IQ; Cognition; Motor coordination; Long term memory; Thyroid functio

Controlled antenatal thyroid screening II: Effect of treating maternal sub-optimal thyroid function on child behaviour

The Controlled Antenatal Thyroid Screening (CATS) study was the first randomised controlled trial to investigate effects of treating suboptimal-gestational-thyroid-function (SGTF) on child cognition. Since observational studies indicated that SGTF may also increase symptoms of autism and attention deficit hyperactivity disorder (ADHD), the CATS cohort was used to investigate whether treatment of mothers affected their children’s behavior

CATS II long-term anthropometric and metabolic effects of maternal sub-optimal thyroid function in offspring and mothers

Context and Objectives The Controlled Antenatal Thyroid Screening Study I (CATS-I) was a randomized controlled trial investigating the effects of levothyroxine therapy for suboptimal gestational thyroid function (SGTF), comparing outcomes in children of treated (SGTF-T) with untreated (SGTF-U) women during pregnancy. This follow-up study, CATS-II, reports the long-term effects on anthropometric, bone, and cardiometabolic outcomes in mothers and offspring and includes a group with normal gestational thyroid function (NGTF). Design & Participants 332 mothers (197 NGTF, 56 SGTF-U, 79 SGTF-T) aged 41.2±5.3 years (mean±SD) and 326 paired children assessed 9.3±1.0 years after birth for (i) body mass index (BMI); (ii) lean, fat, and bone mass by dual-energy X-ray absorptiometry; (iii) blood pressure, augmentation index, and aortic pulse-wave-velocity; and (iv) thyroid function, lipids, insulin, and adiponectin. The difference between group means was compared using linear regression. Results Offspring’s measurements were similar between groups. Although maternal BMI was similar between groups at CATS-I, after 9 years (at CATS-II) SGTF-U mothers showed higher BMI (median [interquartile ratio] 28.3 [24.6-32.6] kg/m2) compared with NGTF (25.8 [22.9-30.0] kg/m2; P = 0.029), driven by fat mass increase. At CATS-II SGTF-U mothers also had higher thyroid-stimulating hormone (TSH) values (2.45 [1.43-3.50] mU/L) than NGTF (1.54 [1.12-2.07] mU/L; P = 0.015), since 64% had never received levothyroxine. At CATS-II, SGTF-T mothers had BMI (25.8 [23.1-29.8] kg/m2, P = 0.672) and TSH (1.68 [0.89-2.96] mU/L; P = 0.474) values similar to NGTF mothers. Conclusions Levothyroxine supplementation of women with SGTF did not affect long-term offspring anthropometric, bone, and cardiometabolic measurements. However, absence of treatment was associated with sustained long-term increase in BMI and fat mass in women with SGTF

An InDel in Phospholipase-C-B-1 is linked with euthyroid multinodular goiter

Background: Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC). Methods: Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM. Results: Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the PLCB1 gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of “healthy” Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since PLCB1 contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27–59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ2 = 5.076; p = 0.024. PLCB1 transcript levels were significantly higher in thyroids with the InDel than without (p < 0.02). Conclusions: The intronic PLCB1 InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration

Reevaluating thyrotropin receptor-induced mouse models of Graves' disease and ophthalmopathy

We aimed to establish and extend the characterization of murine models of thyroiditis and Graves’ ophthalmopathy, induced by transfer of TSH receptor (TSHR) primed T cells. Experiments were performed in a different animal unit but using female BALB/cbyJico mice from the same supplier as previously. We report our findings together with a reevaluation of the earlier studies. In the first experiment, genetic immunization or TSHR fusion protein induced TSHR antibodies in all nine mice. Some of the antibodies functioned as thyroid-stimulating antibodies and/or TSH binding inhibiting Igs with two of seven mice having elevated T4. Thyroiditis and orbital changes were absent. Splenocyte transfer induced no immune response in naive BALB/cbyJico recipients. Subsequently genetic immunization or fusion protein-treated mice were maintained in either local or Brussels conditions (water, chow, and bedding). TSHR antibodies were induced in nine of nine Brussels (with decreased T4 in one of nine) but five of nine local mice. No thyroiditis or orbital changes were induced, but misleading fixation artefacts in extraocular muscles were noted. Nonspecific in vitro stimulation induced more CD-4+/IL-4+ cells in Brussels maintained. TSHR stimulation produced a significant increase in IL-4 secretion in six of nine local but one of seven Brussels mice. Thyroids from many TSHR-treated and control mice contained ectopic thymus. Our results confirm that thyroiditis is required for disease transfer but indicate the heterogeneity in TSHR-induced immune response in an inbred strain. Ectopic thymus can masquerade as thyroiditis, and care is required to avoid muscle artefacts. Because neither animal unit is pathogen free, microbial environment may contribute to determining TSHR-induced responses

The W546X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population

Congenital hypothyroidism (CH) occurs in approximately 1 in 3000 births and can be caused by mutations in 9 known genes, including that encoding the TSH receptor (TSHR). We report on two Welsh siblings, detected by neonatal screening, who had normal sized and placed glands but negative isotope uptake. Genomic DNA was obtained from both siblings and parents, the TSHR amplified using pairs of intronic and/or overlapping exonic primers and the PCR products sequenced automatically. Both siblings were homozygous for a previously described G to A transition producing a missense mutation, W546X, in the fourth membrane spanning region of the TSHR, rendering it unresponsive to TSH. Both parents were heterozygous and unrelated; furthermore, the W546X has been described in three further families (one of which is Welsh), suggesting that it may be a relatively common mutation. We genotyped 368 euthyroid Welsh individuals using single nucleotide primer extension, and found 366 homozygous wild-type (G:G) and 2 heterozygous (G:A) for the mutation. In conclusion, CH in the siblings is due to the missense mutation, W546X, in their TSHR gene. The W546X allele was detected in approximately 1 in 180 individuals and may be a major contributor to hypothyroidism in the Welsh population

Potent thyrotrophin receptor-blocking antibodies: a cause of transient congenital hypothyroidism and delayed thyroid development

OBJECTIVE: We describe an infant with surprisingly severe neonatal hypothyroidism due to transplacental passage of thyrotrophin receptor (TSH-R)-blocking antibodies (TBAb). DESIGN AND METHODS: TBAb were detected using a cell line which stably expresses the human TSH-R and a cAMP-responsive luciferase reporter by their ability to inhibit TSH-stimulated luciferase expression. Potent TBAb were detected in maternal serum and initially in the infant's serum but, in the latter, TBAb decreased over time to within the reference range by 3-4 months of age, illustrating the transient nature of this condition. RESULTS: The thyroid function of this child did not return to normal on withdrawal of thyroxine therapy at 16 months of age when he developed transient compensated hypothyroidism. CONCLUSIONS: We propose that the presence of potent TBAb in utero and in the first weeks of life may have implications for the development of a normally sized thyroid gland. We have demonstrated the presence of TBAb in the mother's milk and, as far as we are aware, this is the first such report. However, the TBAb in the milk probably did not contribute significantly to hypothyroidism in the child, given the reducing antibody titre in his circulation