T. Vulsma

Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks' gestation

BACKGROUNDnPremature infants who have transient hypothyroxinemia in the first weeks of life may have developmental delay and neurologic dysfunction. Whether thyroxine treatment during this period results in improved developmental outcomes is not known.nnnMETHODSnWe carried out a randomized, placebo-controlled, double-blind trial of thyroxine supplementation in 200 infants born at less than 30 weeks gestation. Thyroxine (8 microg per kilogram of birth weight) or placebo was administered daily, starting 12 to 24 hours after birth, for six weeks. Plasma free thyroxine concentrations were measured weekly for the first eight weeks after birth. Scores on the Bayley Mental and Psychomotor Development Indexes and neurologic function were assessed at 6, 12, and 24 months of age (corrected for prematurity).nnnRESULTSnMortality and morbidity up to the time of discharge from the hospital were similar in the study groups. At 24 months of age, 157 infants were evaluated. Overall, neither mental nor psychomotor scores differed significantly between the study groups at any time, nor was the frequency of abnormal neurologic outcome significantly different. In thyroxine-treated infants born at gestational ages of less than 27 weeks, the score on the Bayley Mental Development Index at 24 months of age was 18 points higher than the score for the infants with similar gestational ages at birth in the placebo group (P=0.01); for thyroxine-treated infants born at 27 weeks or later, the mental-development score was 10 points lower than that of their counterparts in the placebo group (P=0.03). There was no relation between the initial plasma free thyroxine concentration and the effect of treatment.nnnCONCLUSIONSnIn infants born before 30 weeks gestation, thyroxine supplementation does not improve the developmental outcome at 24 months.

Delayed initiation of breast development in girls with higher prenatal dioxin exposure; a longitudinal cohort study

OBJECTIVESnWhile many studies have assessed the health impacts of PCDD/Fs and PCBs on animals and humans, long-term consequences for especially adolescents, have not (yet) been well documented. This is certainly also true for the effects of PBDE exposure. As part of a longitudinal cohort study, now well into its second decade, effects of perinatal and current PCDD/F exposure, as well as current dl-PCB and PBDE exposures, on puberty, were assessed.nnnSTUDY DESIGNnPrenatal, lactational and current PCDD/F, dl-PCB and PBDE concentrations were determined using GC-MS. Pubertal development and growth were assessed by means of physical examination and the Tanner scale. 33 Children (born between 1986 and 1991) consented to the current follow-up study. Outcomes were evaluated using linear regression or the non parametric Spearmans correlation coefficient.nnnRESULTSnA delay in initiation of breast development was found in girls (n = 18) with higher prenatal (p = 0.023) and lactational PCDD/F exposure (p = 0.048). The males revealed a negative trend with age at first ejaculation. For other endpoints on puberty and growth (pubic hair, axillary hair, genital stage, length, BMI, testicular volume, menarche) no significant relation was found with any of the measured compounds.nnnDISCUSSION AND CONCLUSIONnA relation between prenatal PCDD/F exposure and later initiation of breast development was seen. A Belgian study found a delay in breast development with higher current serum concentrations of dioxin-like compounds. The initiation of puberty is a complex process and it is yet not clear how dioxin-like compounds precisely affect this process prenatally. Further follow-up into adulthood is warranted, in order to detect the possibility of developing malignancies and fertility problems.

Thyroid hormone metabolism and environmental chemical exposure

BackgroundPolychlorinated dioxins and –furans (PCDD/Fs) and polychlorinated-biphenyls (PCBs) are environmental toxicants that have been proven to influence thyroid metabolism both in animal studies and in human beings. In recent years polybrominated diphenyl ethers (PBDEs) also have been found to have a negative influence on thyroid hormone metabolism. The lower brominated flame retardants are now banned in the EU, however higher brominated decabromo-diphenyl ether (DBDE) and the brominated flame retardant hexabromocyclododecane (HBCD) are not yet banned. They too can negatively influence thyroid hormone metabolism. An additional brominated flame retardant that is still in use is tetrabromobisphenol-A (TBBPA), which has also been shown to influence thyroid hormone metabolism.Influences of brominated flame retardants, PCDD/F’s and dioxin like-PCBs (dl-PCB’s) on thyroid hormone metabolism in adolescence in the Netherlands will be presented in this study and determined if there are reasons for concern to human health for these toxins. In the period 1987-1991, a cohort of mother-baby pairs was formed in order to detect abnormalities in relation to dioxin levels in the perinatal period. The study demonstrated that PCDD/Fs were found around the time of birth, suggesting a modulation of the setpoint of thyroid hormone metabolism with a higher 3,3’, 5,5’tetrathyroxine (T4) levels and an increased thyroid stimulating hormone (TSH). While the same serum thyroid hormone tests (- TSH and T4) were again normal by 2 years of age and were still normal at 8-12 years, adolescence is a period with extra stress on thyroid hormone metabolism. Therefore we measured serum levels of TSH, T4, 3,3’,5- triiodothyronine (T3), free T4 (FT4), antibodies and thyroxine-binding globulin (TBG) in our adolescent cohort.MethodsVena puncture was performed to obtain samples for the measurement of thyroid hormone metabolism related parameters and the current serum dioxin (PCDD/Fs), PCB and PBDE levels.ResultsThe current levels of T3 were positively correlated to BDE-99. A positive trend with FT4 and BDE-99 was also seen, while a positive correlation with T3 and dl-PCB was also seen. No correlation with TBG was seen for any of the contaminants. Neither the prenatal nor the current PCDD/F levels showed a relationship with the thyroid parameters in this relatively small group.ConclusionOnce again the thyroid hormone metabolism (an increase in T3) seems to have been influenced by current background levels of common environmental contaminants: dl-PCBs and BDE-99. T3 is a product of target organs and abnormalities might indicate effects on hormone transporters and could cause pathology. While the influence on T3 levels may have been compensated, because the adolescents functioned normal at the time of the study period, it is questionable if this compensation is enough for all organs depending on thyroid hormones.

Neurodevelopmental retardation, as assessed clinically and with magnetoencephalography and electroencephalography, associated with perinatal dioxin exposure

UNLABELLEDnIn 1980s Western Europe, human perinatal exposure to background levels of dioxins was rather high. We therefore evaluated the neurodevelopment of our cohort during the prepubertal period and in adolescence. At prepubertal age (7-12 years) 41 children were tested. Both neuromotor functioning and psychological testing were performed (Dutch version of the Wechsler Intelligence Scale for Children (WISC-R) and the Dutch version of the Child Behavior Checklist for ages 4-18 years (CBCL 4-18) and the Teacher Report Form (TRF)). Neurophysiological tests were performed using magnetoencephalography and electroencephalography. In adolescence (14-18 years) the behavior of 33 children was studied again (CBCL and TRF). And the levels of dioxins and dioxin-like PCBs (dl-PCBs) were measured in serum.nnnRESULTSnAt prepubertal age no association was found between perinatal dioxin exposure and verbal, performal and total IQ or with the Touwens test for neuromotor development. There were behavioral problems associated with both prenatal and postnatal dioxin exposure. In adolescence there were problems associated with the current dioxin levels and dioxin-like-PCBs. Neurophysiological tests revealed clear negative dysfunction. An increase in latency time after a motion stimulus (N2b) of 13 ms (= a delay of 10%) is associated with the higher prenatal dioxin exposure. A similar delay was measured in testing cognitive ability by analyzing the odd ball measurements, N200 and P300, together with an amplitude decrease of 12 %. The delay is indicative of a defective myelinisation and the decrease in amplitude of a loss of neurons.nnnCONCLUSIONnWe found effects on behavior in association with the perinatal dioxin exposure and in adolescence in association with the current dioxin levels. Neurophysiological testing is instrumental in the detection of effects of perinatal background levels of chemicals on brain development in normal, healthy children. The clinical, neurological and psychological tests commonly used are not sensitive enough to detect important effects.

Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation

To the Editor: Permanent neonatal diabetes mellitus (PNDM) is mainly caused by activating mutations in the KCNJ11 or ABCC8 genes, encoding respectively the Kir6.2 and sulfonylurea receptor (SUR)1 subunits of the KATP channels in the pancreatic beta cells [1–3]. Developmental delay, epilepsy and neonatal diabetes syndrome (DEND) represents the most severe clinical form of PNDM [4]. Besides diabetes mellitus patients exhibit severe developmental delay, hypotonia and therapy-resistant epilepsy. As KCNJ11 and ABCC8 are expressed in neuronal tissue the neurological features in DEND syndrome are postulated to result from mutated KATP channels in the brain. Only a few cases of DEND syndrome have been described. More common is a milder clinical picture, without generalised epilepsy and with less severe developmental delay, referred to as intermediate DEND. n nSince 2006 many patients with PNDM due to KCNJ11 and ABCC8 mutations have been completely transferred from insulin to sulfonylurea drugs [5, 6]. However, in DEND syndrome only cases of intermediate DEND were sulfonylurea-responsive [7, 8]. Shimomura and colleagues reported the first patient with severe DEND syndrome, due to a KCNJ11 mutation, who did completely switch to sulfonylurea drugs [4]. Here we report a case of DEND syndrome due to a novel ABCC8 mutation and successful transfer to sulfonylurea treatment. n nA boy was born as second child of non-consanguineous white parents following an uneventful pregnancy and spontaneous term delivery. His birthweight was low (2,700xa0g, −2 standard deviation score [SDS]). At 7xa0weeks of age he presented with failure to thrive (weight 3,140xa0g, −3.8 SDS), severe hyperglycaemia (blood glucose 42xa0mmol/l), glucosuria, and ketoacidosis. Physical examination revealed severe generalised hypotonia without dysmorphic features or other abnormalities. Islet cell auto antibodies, serum insulin and C-peptide were undetectable. Abdominal ultrasound examination demonstrated a normally developed pancreas. Neonatal diabetes mellitus was concluded and continuous intravenous insulin therapy was started followed by continuous subcutaneous insulin pump therapy. This resulted in good glycaemic control without significant hypoglycaemia. At the age of 5xa0months HbA1c was 7.2% and catch-up growth (weight −2 SDS) was observed. n nOn the tenth day of admission, at the age of 2xa0months, he developed frequent subtle seizures unresponsive to increasing doses of the anti-epileptic drug phenobarbital. EEG examination showed a burst-suppression pattern (abnormal for the age of 8.5xa0weeks) and epileptic discharges later on. At the age of 3xa0months the seizures progressed to infantile spasms and EEG examination demonstrated a slowed high-voltage background pattern with multifocal epileptic discharges consistent with hypsarrhythmia and unresponsive to various antiepileptic drugs (phenobarbital, nitrazepam, adrenocorticotropic hormone and vigabatrin). At age 5xa0months the boy was severely hypotonic, with no visual contact, no babbling, hardly any facial expression and a psychomotor developmental age of 1xa0month. Magnetic resonance imaging of the brain at that age demonstrated no structural abnormalities but mild atrophy of frontal–temporal regions. DEND syndrome was suspected and the boy was tested for KATP channel defects. Genomic DNA isolated from peripheral lymphocytes was analysed by direct sequencing of all coding sequences as well as the relevant intron/exon boundaries. The KCNJ11 sequence was wild type. In exon 1 of the ABCC8 gene a monoallelic missense mutation was present (c.145Au2009>u2009T) that changed amino acid residue 49 from isoleucine to phenylalanine (p.I49F). This nucleotide change was not previously reported in any single-nucleotide polymorphism or mutation database, was absent in 70 control alleles and also absent in genomic DNA from both parents, indicating a de novo mutation. n nIn an attempt to influence both glycaemic control and neurological abnormalities, at the age of 5.5xa0months oral glibenclamide therapy was started in a daily dose of 0.2xa0mg/kg body mass in two doses followed by weekly increments of 0.2xa0mg/kg−1u2009day−1. The insulin dose could gradually be reduced and after 2xa0months, at a glibenclamide dose of 1.6xa0mg/kg, insulin therapy was stopped. Side effects of glibenclamide treatment were not noticed, and there were no episodes of hypoglycaemia. Gradually the daily glibenclamide dose was tapered and at the age of 17xa0months he continued to have excellent glycaemic control with 1.0xa0mg/kg (HbA1c 5.6%). No improvement was observed in seizure control despite anti-epileptic drug treatment with high dose vigabatrin and levetiracetam. At the age of 26xa0months his functional psychomotor age was 3xa0months and he continued to have infantile spasms with unchanged EEG hypsarrhythmia. n nTo our knowledge, this is the first report of a DEND patient with an ABCC8 mutation who successfully transfers to sulfonylurea therapy. Although functional studies were not performed the mutation is likely to be the molecular origin of the patient’s DEND syndrome, as it is a de novo mutation in a child of unaffected parents and affects an amino acid residue that shows evolutionary conservation across species. Based on the topology suggested by Conti and colleagues, amino acid residue 49 is located either in the N-terminal extracellular region or in the first predicted transmembrane domain [9]. The in silico prediction programs SIFT and PolyPhen both predicted that substitution at position 49 from isoleucine to phenylalanine would affect protein function. The excellent response to sulfonylurea treatment provides further evidence for the pathogenicity of the mutation. n nShimomura and colleagues reported the first patient with severe DEND syndrome, due to a KCNJ11 mutation, who completely switched to sulfonylurea drugs [4]. Their patient also showed neurological improvement on a dose of 2.3xa0mg/kg, suggesting that such extremely high doses might influence neurological symptoms. In our case glucose values dropped to 3.5xa0mmol/l with a sulfonylurea dose of 1.6xa0mg/kg and further increasing the sulfonylurea dosage was thought to be contraindicated by the risk of hypoglycaemia. As the main aim in the treatment of DEND syndrome is to influence neurological dysfunction, perhaps increasing sulfonylurea doses should have been considered together with an additional treatment to prevent hypoglycaemia. Furthermore it could be speculated that rather than a drug that targets both SUR1 and SUR2 isoforms, such as glibenclamide, a SUR1-specific drug, such as gliclazide, might influence neurological symptoms more effectively as only SUR1 isoforms are present in neuronal KATP channels. It is not clear to what extent sulfonylurea drugs are hindered by the blood–brain barrier. Administering sulfonylurea drugs at a very young age, when the blood–brain barrier is still immature, might lead to better brain penetration than at later ages. n nThis case report emphasises the importance of early genetic analysis in all cases of neonatal diabetes mellitus, including the most severely affected patients with DEND syndrome as in this group, sulfonylurea treatment may also completely restore glucose homeostasis. The effect on neurological features is a field of future research perhaps aiming at improved blood–brain barrier penetrance of sulfonylurea drugs and allowing higher doses by alternatively handling hypoglycaemia.

Changes in thyroid hormone state in children receiving chemotherapy.

Objectiveu2002 The concentrations of thyroid function determinants may change during severe illness. Our goal was to quantify their changes in children with cancer during chemotherapy, and to correlate them to clinical condition and type of drugs.

Protection of the maternal and fetal thyroid from radioactive contamination by the administration of stable iodide during pregnancy. An experimental evaluation in chimpanzees

The safety and efficacy of the administration of stable iodide to protect the fetal thyroid from exposure to radioactive iodide were investigated in chimpanzees in weeks 19 to 21 of pregnancy. The mean 24-h uptake of iodide in the fetal thyroid, determined with 123I-, was 1.8%. Administration of stable potassium iodide (KI), 0.65, 1.95 or 6.5 mg per kg body weight, 1 h before tracer injection reduced the fetal uptake satisfactorily. Only the higher doses were effective after 20 h. Excess iodide may impair a childs thyroid status. However, adverse effects were not found during the 11 days the animals ingested these doses. Tracer concentrations in the amniotic fluid were 30- to 130-fold lower than in the urine. The dose to the fetus from radioactivity in the maternal bladder was estimated by computer simulation. The potential increment of the risk from this dose during the ingestion of stable iodide is smaller than the reduction of risk achieved by inhibiting the uptake of radioactive iodide by the fetal thyroid. The conclusion of the experiments is that stable iodide can be used safely and effectively to protect the fetal thyroid against contamination with radioactive iodine.

The effect of life-long thyroxine treatment and physical activity on bone mineral density in young adult women with congenital hypothyroidism

OBJECTIVEnNormalization of plasma thyrotropin in T4-supplemented patients with thyroidal congenital hypothyroidism (CH) requires elevated plasma FT4-concentrations compared to patients with acquired thyroidal hypothyroidism. We investigated bone mineral density (BMD) in patients with CH.nnnPATIENTS AND METHODSnBMD was measured in 14 adult women with thyroidal CH and nine age-matched female controls.nnnRESULTSnThere were no significant differences between patients and controls for femoral neck bone mineral content (BMC) (38.6 vs 37.6 g), BMD (0.98 vs 1.01 g/cm(2)), T-score (0.1 vs 0.3 SD) and z-score (0.1 vs 0.3 SD) and for spine BMC (63.1 vs 71.9 g). The differences in spine BMD (0.97 vs 1.09 g/cm(2)), T-score (-0.7 vs 0.4 SD) and z-score (-0.5 vs 0.6 SD) were significant (p = 0.025, p = 0.023, and p = 0.021, respectively).nnnCONCLUSIONSnAlthough BMD in patients with CH was slightly lower compared to controls, all scores were within the reference range. This does not support the hypothesis that the upwards shifted plasma FT4-concentrations in patients treated for CH have a deleterious effect on BMD.

Health- related quality of life and self-worth in 10-year old children with congenital hypothyroidism diagnosed by neonatal screening

BackgroundMuch is written about cognitive and motor development; less is known about social and emotional consequences of growing up with congenital hypothyroidism (CH).The objectives of the study were: (1) to compare health related quality of life (HRQoL) and self-worth of 10 year old patients with CH with the general population; (2) to explore associations of disease factors, IQ and motor skills with the outcomes.MethodsChildren with CH and their parents completed several questionnaires. Patients were classified to ‘severe CH, nu2009=u200941’ or ‘moderate/mild CH, nu2009=u200941’ based on pre-treatment FT4 concentration.Differences between CH and the general population were tested by analysis of covariance and one sample t-tests (mean scale scores HRQoL and self-worth), chi-square tests and binomial tests (% at risk of impaired HRQoL and self-worth). Linear regression analyses corrected for gender were conducted to explore associations of the outcomes with disease factors, IQ and motor skills.ResultsPatients with CH reported lower mean HRQoL on motor, cognitive and social functioning, and on autonomy and positive emotions (pu2009<u20090.0001). Patients were also more often at risk for impaired HRQoL and self-worth. No differences were found between the severity groups. Lower IQ was only significant associated with worse cognitive HRQoL. Initial FT4 plasma, age at onset of therapy, initial T4 dose and motor skills were not significantly associated with HRQoL and self-worth.ConclusionsNegative consequences in terms of HRQoL and self-worth are prevalent in children with CH, independent of disease factors, IQ and motor skills. Physicians should to be attentive to these consequences and provide attention and supportive care.

Perinatal dioxin exposure in The Netherlands : a long-term follow-up

In 1987, a cohort study was initiated in the Amsterdam/Zaandam region of The Netherlands to study possible effects of dioxins on development and growth in a population of breastfed children selected after an optimal pregnancy and delivery and birth weight above 2500 grams. Effects on thyroid hormone metabolism, liver, haematology and immunology, and retinol binding protein were found in neonates. Follow-up was performed at the age of 2½ years, 8?12 years and 13?18 years. Neonatally an increase in free thyroxine and thyroid stimulating hormone was found, indicating a change in set point. An enhanced psychomotor maturation was seen at the age of 2½ years. Negative effects on lung function and on brain development (studied with neurophysiological tests of visuo-motoric and cognitive performance) were demonstrated in the age of 8?12 years. In adolescence preliminary results show a delay of almost 1 year in breast development in girls in association with higher (above 40 ng International Toxic Equivalents dioxin) prenatal dioxin exposure and again a negative effect on innate immunity. The abnormalities found indicate an increased vulnerability for more stressful circumstances. New chemicals comparable to dioxins or contaminated with dioxins should not be allowed on the market, or if already there, must be banned.