Thomas Vulsma

Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3‐year follow‐up study

objective To evaluate the impact of maternal hypothyroxinaemia during early gestation (fT4 below the lowest tenth percentile and TSH within the reference range: 0·15–2·0 mIU/l) on infant development, together with any subsequent changes in fT4 during gestation.

Motor and cognitive development in children with congenital hypothyroidism: A long-term evaluation of the effects of neonatal treatment

Although neonatal thyroid screening programs have been of value in preventing cerebral damage, it is still controversial whether patients with congenital hypothyroidism achieve normal motor and cognitive skills. We studied the motor and cognitive skills of 72 children with early-treated congenital hypothyroidism and 35 control subjects at the ages of 7 1/2 and 9 1/2 years. The relative influence of cause, blood thyroxine concentration at the time of screening, and age at the start of thyroxine replacement therapy on motor and cognitive development was investigated. Despite having received treatment at a mean age of 23 days, children with low neonatal thyroxine concentrations (< 50 nmol/L) at screening, particularly children with thyroid agenesis, had significant motor problems and borderline intelligence scores as late as 9 1/2 years of age. Balance and gross motor functions seemed to decline between 7 1/2 and 9 1/2 years of age, whereas language and memory functions seemed to be maintained. Significant correlations between the start of therapy and both motor scores and performance IQ scores at the age of 7 1/2 years in children with severe hypothyroidism show the importance of early treatment for these patients.

Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement

Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.

Clinical effectiveness and cost-effectiveness of the use of the thyroxine/thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program

Context. Since the introduction of screening for congenital hypothyroidism (CH) in 1974, the optimal laboratory strategy has been the subject of debate. Objective. To assess the clinical effectiveness and cost-effectiveness of various types of thyroxine (T4)-based strategies to screen for CH. Design, Setting, and Participants. In the Netherlands, since January 1, 1995, a primary T4 determination with supplemental thyroid-stimulating hormone (TSH) and T4-binding globulin (TBG) measurements has been used. Results were calculated from cumulative findings for 1181079 children screened between January 1, 1995, and December 31, 2000. Main Outcome Measures. Rates of detection of patients with CH of thyroidal origin (CH-T) or CH of central origin (CH-C), false-positive rates, laboratory costs, and costs of initial diagnostic evaluations. Results. All known infants (n = 393) with CH-T and 92% (n = 66) of infants with CH-C were detected on the basis of low T4 levels, TSH elevation, and/or low T4/TBG ratios. If the decision to refer had been based solely on TSH elevation, then 94% of patients with CH-T and none of the patients with CH-C would have been detected. If low T4 levels (≤−3.0 SD) and TSH elevation had been used as the criteria for referral, then the rates of detection would have been 96% for CH-T and 31% for CH-C. The false-positive rates for the 3 approaches were 0.5, 3.3, and 4.7 cases per case detected, respectively. The introduction of the T4/TBG ratio into a program using a primary T4 with supplemental TSH approach generates an extra cost of

High incidence of thyroid dysfunction despite prophylaxis with potassium iodide during 131I‐meta‐iodobenzylguanidine treatment in children with neuroblastoma

11206 per additional case detected. The average costs to detect 1 patient are comparable for the 3 approaches. In addition, our data revealed a substantially greater prevalence of CH-C than reported previously (1 case per 16404 children, compared with earlier estimates of 1 case per 26000 infants to 1 case per 29000 infants). Conclusions. The T4 plus TSH plus TBG approach is a recommendable strategy for neonatal CH screening. It offers outstanding detection of patients with CH-C, in addition to those with CH-T, with acceptable costs.

Sustained attention problems in children with early treated congenital hypothyroidism

Treatment modalities like targeted radiotherapy with 131I‐meta‐iodobenzylguanidine (131I‐MIBG) improve survival rates after neuroblastoma (NB). Radiation to the thyroid gland can lead to hypothyroidism and even malignancy. Because hypothyroidism after 131I‐MIBG treatment was reported, the current KI prophylaxis against thyroidal radiation damage was evaluated.

Use of amiodarone during pregnancy

Sustained attention was studied in 48 children with early treated congenital hypothyroidism and 35 healthy controls, using a computer‐paced and a self‐paced continuous performance task. The performance of the patients, particularly those in the low T4 group (38 patients with T4 levels < 50 nmol/1 at neonatal screening), declined in the final stage of the computer‐paced task, suggesting a problem in remaining attentive over time. The performance of all children declined in the first and improved in the final stage of the self‐paced task. This pattern was most pronounced in the low T4 group, reflecting greater variability in their task performance over time, again indicating a problem in sustaining attention. No correlation was found between onset of treatment and sustained attention. The small size of the intermediate T4 group (10 patients with T4 levels ≥ 250 nmol/1 at neonatal screening) made the results more difficult to interpret and may have concealed a problem with sustained attention in this group.

Adult height and age at menarche in childhood cancer survivors

UNLABELLED Five cases are studied in which amiodarone (AM) was given during pregnancy, in two of them also during the breast feeding period, to estimate the risks for adverse effects. We measured the concentrations of AM and its major metabolite desethylamiodarone (DEA) in maternal plasma, cord plasma, infant plasma, placental tissue and breast milk and the thyroid hormones were measured in maternal and neonatal serum. Also, the neonates were examined for AM-associated adverse effects over a period varying from 8 months up to 5 years. We observed a limited maternal-fetal transfer of AM and DEA, while the concentration of DEA in placental tissue is relatively high. Considerable amounts of AM and DEA were present in breast milk. One infant appeared to be hypothyroid, detected by the neonatal thyroid screening. He was treated with triiodothyronine for weeks, until it was clear that the thyroid dysfunction was resolved. The other infants had normal screening results. No effect of the AM medication was observed on growth, liver function or cornea and skin. IN CONCLUSION although pregnancy and lactation are no absolute contraindications for use of AM, special precautions are necessary. It is unavoidable that in some cases the pregnant mother, and especially her infant, becomes hypothyroid. AM has to be administered in the lowest possible dose, and the maternal and neonatal thyroid function must be controlled as long as the exposure to AM lasts.

Dynamics of the plasma concentrations of TSH, FT4 and T3 following thyroxine supplementation in congenital hypothyroidism.

The aim of this study was to assess the long-term effects of cancer treatments on adult height and age at menarche in survivors of various types of childhood cancer. 285 childhood cancer survivors (161 men and 124 women), at least 18 years old and having been off treatment for at least 5 years, were examined. The effects of cranial (CrRT) and craniospinal irradiation (CrSpRT), other treatments and age at diagnosis on adult height and age at menarche were investigated. Patients who did not receive CrRT or CrSpRT, reached normal adult heights. However, a significant reduction in adult height was observed in men and women treated with CrRT or CrSpRT, especially if the treatment was given at the age of 8 years or younger. In girls, CrRT resulted in a significantly earlier menarche, compared with the Dutch population. Chemotherapy, radiation dose and age at menarche did not affect adult height. The relative risk (RR) of attaining an adult height below the 3rd percentile (20% 49/244) of the study population) was 6 times increased (RR=6.4; 95% confidence interval (CI) 1.46-28.52) after CrSpRT, 4 times (RR=4.2; 95% CI 1.81-9.63) after Crth and 5 times (RR=51; 95% CI 2.23-11.59) when irradiation was administered at the age of 8 years or younger. CrRT and CrSpRT and age at treatment are the main determinants of short stature in male and female childhood cancer survivors.

Improved Radiation Protection of the Thyroid Gland with Thyroxine, Methimazole, and Potassium Iodide during Diagnostic and Therapeutic Use of Radiolabeled Metaiodobenzylguanidine in Children with Neuroblastoma

objective The dynamics of the plasma concentrations of various diagnostic determinants of thyroid function were analysed in children with congenital hypothyroidism (CH) after the start of T4 supplementation. The description of the biochemical dynamics of TSH and free T4 (FT4) during the first period of thyroxine treatment is important to depict the practical outlines of the initial dosage of T4 and dosage adjustments for newborns with variable forms of CH.