Congenital hypothyroidism (CH) may be primary, due to a defect affecting the thyroid gland itself, or central, due to impaired thyroid-stimulating hormone (TSH)-mediated stimulation of the thyroid gland as a result of hypothalamic or pituitary pathology. Primary CH is the most common neonatal endocrine disorder, traditionally subdivided into thyroid dysgenesis (TD), referring to a spectrum of thyroid developmental abnormalities, and dyshormonogenesis, where a defective molecular pathway for thyroid hormonogenesis results in failure of hormone production by a structurally intact gland. Delayed treatment of neonatal hypothyroidism may result in profound neurodevelopmental delay; therefore, CH is screened for in developed countries to facilitate prompt diagnosis. Central congenital hypothyroidism (CCH) is a rarer entity which may occur in isolation, or (more frequently) in association with additional pituitary hormone deficits. CCH is most commonly defined biochemically by failure of appropriate TSH elevation despite subnormal thyroid hormone levels and will therefore evade diagnosis in primary, TSH-based CH-screening programmes. This review will discuss recent genetic aetiological advances in CH and summarize epidemiological data and clinical diagnostic challenges, focussing on primary CH and isolated CCH.
C Peters, A S P van Trotsenburg and N Schoenmakers
M de Fost, A S P van Trotsenburg, H M van Santen, E Endert, C van den Elzen, E J Kamsteeg, D F Swaab and E Fliers
Familial neurohypophyseal (central) diabetes insipidus (DI) is caused by mutations in the arginine vasopressin–neurophysin II (AVP–NPII) gene. The majority of cases is inherited in an autosomal dominant way. In this study, we present the clinical features of a mother and her son with autosomal dominant neurohypophyseal DI caused by a novel mutation.
A thirty-four-year-old woman and her three-year-old son were evaluated because of polyuria and polydipsia since the age of 1.5 years onwards. Both patients were subjected to a water deprivation test confirming the diagnosis of central DI. Magnetic resonance imaging of the brain of the mother showed a hypothalamus without apparent abnormalities and a relatively small neurohypophysis without a hyperintense signal. Mutation analysis showed a c.322G>T (p.?/p.Glu108X) in Exon 2 of the AVP–NPII gene in both mother and son.
This study reports neurohypophyseal DI in a mother and her son due to a novel mutation in Exon 2 of the AVP–NPII gene. Clinical and pathophysiological aspects of this disease are shortly reviewed and discussed.
Anna M E Noten, Eva M Loomans, Tanja G M Vrijkotte, Peter M van de Ven, A S Paul van Trotsenburg, Joost Rotteveel, Manon van Eijsden and Martijn J J Finken
Overt hypothyroidism in pregnant women is associated with a lower intelligence quotient in their children. More recently, subtle decreases in maternal thyroid function have also been associated with neurodevelopmental impairment in offspring. We tested the effect of hypothyroxinaemia during early pregnancy on school performance.
This was a longitudinal study that included the data of 1196 mother-child pairs from the Amsterdam Born Children and Their Development study.
Maternal serum free thyroxine (T4) and TSH were obtained at a median gestational age of 12.9 (interquartile range: 11.9–14.3) weeks. School performance was assessed at age 5 years and based on scores obtained in arithmetic and language tests from the national monitoring and evaluation system. Poor school performance was defined as a test result <25th percentile and subnormal school performance as a result <50th percentile of the norm population. To estimate the impact of possible non-response bias, we conducted inverse-probability weighted analyses.
Maternal hypothyroxinaemia (i.e., a maternal free T4 in the lowest 10% of distribution) was associated with a 1.61 (95% CI: 1.05–2.47) -fold increased odds of subnormal arithmetic performance after adjustment for confounders (P=0.03). However, the odds ratio dropped to 1.48 (95% CI: 0.94–2.32) after inverse-probability weighting (P=0.09). No such relations were found with TSH.
Maternal hypothyroxinaemia at the end of the first trimester was associated with reduced performance in an arithmetic test, but not in a language test, in 5-year-old offspring. However, our results should be interpreted carefully because of possible non-response bias.
Nitash Zwaveling-Soonawala, M Emma Witteveen, Jan Pieter Marchal, Femke C C Klouwer, Nadine A Ikelaar, Anne M J B Smets, Rick R van Rijn, Erik Endert, Eric Fliers and A S Paul van Trotsenburg
The hypothalamus–pituitary–thyroid (HPT) axis set point develops during the fetal period and first two years of life. We hypothesized that thyroxine treatment during these first two years, in the context of a randomized controlled trial (RCT) in children with Down syndrome, may have influenced the HPT axis set point and may also have influenced the development of Down syndrome-associated autoimmune thyroiditis.
We included 123 children with Down syndrome 8.7 years after the end of an RCT comparing thyroxine treatment vs placebo and performed thyroid function tests and thyroid ultrasound. We analyzed TSH and FT4 concentrations in the subgroup of 71 children who were currently not on thyroid medication and had no evidence of autoimmune thyroiditis.
TSH concentrations did not differ, but FT4 was significantly higher in the thyroxine-treated group than that in the placebo group (14.1 vs 13.0 pmol/L; P = 0.02). There was an increase in anti-TPO positivity, from 1% at age 12 months to 6% at age 24 months and 25% at age 10.7 years with a greater percentage of children with anti-TPO positivity in the placebo group (32%) compared with the thyroxine-treated group (18.5%) (P = 0.12). Thyroid volume at age 10.7 years (mean: 3.4 mL; range: 0.5–7.5 mL) was significantly lower (P < 0.01) compared with reference values (5.5 mL; range: 3–9 mL) and was similar in the thyroxine and placebo group.
Thyroxine treatment during the first two years of life led to a mild increase in FT4 almost 9 years later on and may point to an interesting new mechanism influencing the maturing HPT axis set point. Furthermore, there was a trend toward less development of thyroid autoimmunity in the thyroxine treatment group, suggesting a protective effect of the early thyroxine treatment. Lastly, thyroid volume was low possibly reflecting Down-specific thyroid hypoplasia.
J C Naafs, L M Vendrig, J Limpens, H J van der Lee, R G Duijnhoven, J P Marchal, A S van Trotsenburg and N Zwaveling-Soonawala
To provide an overview of cognitive and motor outcome, and quality of life (QoL) in patients with congenital central hypothyroidism (CH-C).
Systematic review with individual patient data (IPD) meta-analysis.
OVID MEDLINE, EMBASE and PsycInfo were searched from inception to June 11th, 2019. Studies in patients with CH-C, either isolated or with multiple pituitary hormone deficiency (MPHD), were included if CH-C patients could be separated from any additional patient groups. Primary outcomes were full-scale intelligence quotient (FSIQ) and motor outcome; secondary outcome was QoL. Following data-extraction, one-stage IPD meta-analysis was performed, fitting a linear mixed model with FSIQ as dependent variable. Random intercepts were fitted for each study.
Six studies measuring FSIQ were eligible for meta-analysis, comprising 30 CH-C patients (20 males; 27 MPHD patients). FSIQ range was wide (64–123). Mean weighted FSIQ was 97 (95% CI: 88–105). Twenty-seven percent had an FSIQ below 85 (≥1 s.d. below norm score), and 10% below 70 (≥2 s.d. below norm score). There was no significant association between FSIQ and sex or age. Age at treatment initiation was available from three studies only, thus impeding a reliable analysis of this parameter. Motor outcome and QoL were each studied in one study; no quantitative analyses could be performed for these outcomes.
A wide range in FSIQ scores was observed in CH-C patients. Results should be interpreted with caution, because included patients mainly had MPHD and age at treatment initiation was unknown for the majority of patients.
Charlotte A Heinen, Zhi Zhang, Lars P Klieverik, Tim C de Wit, Edwin Poel, Maqsood Yaqub, Anita Boelen, Andries Kalsbeek, Peter H Bisschop, A S Paul van Trotsenburg, Hein J Verberne, Jan Booij and Eric Fliers
Brown adipose tissue (BAT) activity in humans is stimulated by cold and by a limited number of pharmacological agents, including β3-adrenergic agonists and bile acids. Although thyrotropin-releasing hormone (TRH) is known to activate BAT in several mammals, this has not been reported in humans.
A randomized, placebo-controlled, double-blind, cross-over trial.
We investigated the effects of intravenous bolus administration of 400 µg TRH or 2 mL saline on BAT activity in healthy, lean men. BAT activity was measured as standardized 18F-fluorodeoxyglucose (18F-FDG) uptake and glucose metabolic rate (MRglu) using dynamic PET/CT imaging. The first six individuals were studied at room temperature, while subsequently nine were exposed to mild cold (17°C ± 1°C) for 60 min before imaging. During the dynamic scan, blood was withdrawn for measurement of thyroid hormone and catecholamine concentrations. This trial is registered with The Netherlands National Trial Register (number NTR5512).
Sixteen participants were recruited. Six men studied at room temperature showed no visible BAT activity during either session. After exposure to mild cold, four of nine men (44.4%) showed clear increase of 18F-FDG uptake after TRH administration compared to placebo. Maximal standardized 18F-FDG uptake showed a trend toward increase after TRH compared to placebo (P = 0.066). MRglu showed a significant increase after TRH administration (P = 0.014). The increase in 18F-FDG uptake was not paralleled by changes in plasma thyroid hormone or catecholamine concentrations.
Systemic TRH administration can increase the activity of cold-stimulated BAT in adult men. These findings may assist developing pharmacological strategies for modulating BAT activity in the management of obesity.