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

UNLABELLED: In 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. RESULTS: At prepubertal age no association was found between perinatal dioxin exposure and verbal, performal and total IQ or with the Touwen's 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. CONCLUSION: We 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.

Neonatal thyroid screening results are related to gestational maternal thyroid function.

OBJECTIVE: To study the relationship between maternal thyroid function at each pregnancy trimester and neonatal screening results. BACKGROUND: Overt maternal thyroid dysfunction during gestation is associated with poor neonatal thyroid function. However, research on the relationship between suboptimal maternal thyroid function (assessed at three trimesters) and neonatal thyroid screening outcome is scarce. DESIGN/PATIENTS: Prospective follow-up study during three trimesters of gestation in 886 Dutch Caucasian healthy pregnant women followed from 12-week gestation until term delivery (>37 weeks) and their neonates. MEASUREMENTS: The relation between neonatal data from the Congenital Hypothyroidism (CH) screening and maternal thyroid determinants [TSH, FT4 and thyroid peroxidase (TPO)-Ab] assessed at 12-, 24- and 36-week gestation. RESULTS: Boys have lower screening TT4 levels and their mothers have higher TSH levels at 24- and 36-week gestation. Higher maternal TSH levels (>97·5th percentile, as defined in 810 women without TPO-Ab at 12 weeks) at one or more times during pregnancy (O.R: 2·26, 95% CI: 1·20-4·29) and lower gestational age (O.R: 1·22, 95% CI: 1·05-1·41) are independently related to lower screening TT4 levels. CONCLUSIONS: Maternal thyroid function during gestation is related to neonatal TT4 at screening. The finding of both lower neonatal TT4 levels in boys and higher TSH levels in mothers carrying boys is worthy of further investigation, as both observations may be meaningfully related.

Quality of life, developmental milestones, and self-esteem of young adults with congenital hypothyroidism diagnosed by neonatal screening.

CONTEXT: With advances in the treatment of congenital hypothyroidism (CH), the neuropsychological functioning of CH patients is considerably improved. Although much is written about cognitive and motor development, little is known about emotional and social consequences for patients growing up with CH, diagnosed by neonatal screening. OBJECTIVES: The objectives of the study were to: 1) compare health-related quality of life (HRQoL), developmental milestones also called course of life (CoL), sociodemographical outcomes, and self-esteem of CH patients with the general population; and 2) explore whether severity of CH was related to these outcomes. DESIGN/SETTING/PATIENTS: A total of 69 young adults with CH, born in The Netherlands in 1981-1982, completed the "TNO-AZL Questionnaire for Adult's Health related Quality of Life" questionnaire, the CoL survey (developmental milestones and sociodemographical outcomes), and a self-esteem questionnaire. MAIN OUTCOME MEASURES: HRQoL, CoL, social demographical outcomes, and self-esteem in young adults with CH were determined. RESULTS: CH patients are more often at risk for HRQoL impairment and reported lower HRQoL on several domains (cognitive functioning, P < 0.0001; sleeping, P < 0.004; pain, P < 0.0001; daily activities, P < 0.004; vitality, P < 0.0001; aggressiveness, P < 0.0001; and depressive moods, P < 0.0001) compared with healthy adults. Patients reported a lower self-esteem (P < 0.005) and had a delayed CoL on the domain of social development (P < 0.016). There were no significant within-group differences between the severity groups for HRQoL, CoL, and self-esteem. CONCLUSIONS: Negative consequences in terms of HRQoL, development, and self-esteem are prevalent in young adults with CH. Health care physicians should be attentive to these consequences and provide additional support (emotional and educational guidance) if necessary.

Neonatal screening for congenital hypothyroidism based on thyroxine, thyrotropin, and thyroxine-binding globulin measurement: potentials and pitfalls.

CONTEXT: The Dutch T(4)-TSH-TBG-based neonatal screening program detects patients with congenital hypothyroidism (CH) of thyroidal (CH-T) as well as central (CH-C) origin. The numbers and characteristics of true-positive and false-positive referrals will differ from other, predominantly TSH-based, screening methods. OBJECTIVE: The present study describes the characteristics of the referred neonates, both CH patients and false positives, and of the reported CH patients with a false-negative screening result born in the study period. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOME MEASURE: For each referred child born between April 1, 2002, and May 31, 2004, screening results and first venous sample results were recorded and classified as transient or permanent CH-T or CH-C or as no CH. RESULTS: In the study period, 430,764 children were screened. Of the 772 children with abnormal screening results, 224 (29%) had CH; another 13 CH patients did not have abnormal screening results, giving an overall CH incidence of 1:1800. Incidences of permanent CH, permanent CH-T, permanent CH-C, and transient CH were 1:2200, 1:2500, 1:21,000, and 1:12,000, respectively. The most frequent explanations for the 548 false-positive referrals (71% of the referred cohort) were severe illness and TBG deficiency (occurring in 198 and 200 children, respectively). CONCLUSIONS: The Dutch incidence figures for CH belong to the highest worldwide, suggesting that the T(4)-TSH-TBG screening program is an efficient method to detect CH of variable etiology and severity. Still, a small percentage of children with CH escaped detection via this screening approach. Severe illness and TBG deficiency appear to be responsible for the majority of false-positive referrals.

Endocrine intervention during irradiation does not prevent damage to the thyroid gland.

Radiation to the head-neck region may damage the thyroid gland, leading to hypothyroidism or thyroid carcinoma. Outcomes of radiation protection by lowering plasma thyroid-stimulating hormone (TSH) have thus far been ambiguous. Our aim was to evaluate the radioprotective effect of inhibiting the thyroid gland's activity during x-radiation. For this purpose, of 80 5-week old Wistar rats, 64 received cervical irradiation with 15 Gy (single dose). During irradiation, endocrine intervention was done, using thyroxine (T(4)), T(4) plus iodine, or iodine alone compared to placebo. During the endocrine interventions and follow-up, TSH and T(4) concentrations were measured periodically. Histologic examination of thyroid, pituitary gland, or the hypothalamus and any suspect lymph nodes, lungs, and liver was performed after 6 and 54 weeks. It was found that during the endocrine intervention, plasma levels of TSH were lower in rats given T(4) and higher in rats given iodine. After 6 and 54 weeks, no significant reduction in hypothyroidism or thyroid carcinoma was found between the different groups of rats given any endocrine intervention or no intervention. In conclusion, the administration of T(4), iodine or the combination during x-irradiation does not protect against radiation-induced thyroid damage.

Intellectual and motor development of young adults with congenital hypothyroidism diagnosed by neonatal screening.

CONTEXT: Long-term follow-up data on cognitive and motor functioning in adult patients with congenital hypothyroidism, diagnosed by neonatal screening, are scarce. Hence, it is still unclear whether the frequently reported cognitive and motor deficits observed during childhood persist in adulthood. OBJECTIVE: The objective of this study was to examine cognitive and motor functioning in young adults with congenital hypothyroidism, born in the first 2 yr after the introduction of the Dutch neonatal screening program. DESIGN/SETTING/PATIENTS: Seventy patients were tested (mean age, 21.5 yr); 49 of them were previously tested at 9.5 yr. The median age at the start of treatment was 28 d (range, 4-293 d). Congenital hypothyroidism was classified as severe, moderate, or mild, according to pretreatment T(4) concentrations. MAIN OUTCOME MEASUREMENT: The main outcome measurement was the influence of the severity of congenital hypothyroidism and age at which T(4) supplementation was started on cognitive and motor outcome. RESULTS: Patients, particularly those with severe congenital hypothyroidism, had significantly higher (i.e. worse) motor scores (total score, 7.8; ball skills, 2.0; balance, 4.1) compared with controls (total score, 3.2; ball skills, 0.7; balance, 1.1), and lower full-scale (95.8), verbal (96.4), and performance (95.6) intelligence quotient (IQ) scores than the normal population. No significant change in IQ from childhood to adulthood was found, and for the majority of patients, motor score classification remained the same. The severity of congenital hypothyroidism, but not the starting day of treatment, was correlated with IQ and motor scores. CONCLUSIONS: It is concluded that the severity of congenital hypothyroidism, but not the timing of treatment initiation, is an important factor determining long-term cognitive and motor outcome. Clearly, detrimental effects on developmental outcome in patients with congenital hypothyroidism persist over time.

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

OBJECTIVE: Normalization 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. PATIENTS AND METHODS: BMD was measured in 14 adult women with thyroidal CH and nine age-matched female controls. RESULTS: There 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). CONCLUSIONS: Although 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.

Endocrine late effects from multi-modality treatment of neuroblastoma.

Thyroid dysfunction has been reported after 131I-MIBG-treatment for neuroblastoma. In this study, we have evaluated all endocrine functions from patients who were given multi-modality treatment including 131I-MIBG. Twenty-five neuroblastoma survivors who were off therapy for a median period of 6.0 years (range 1.3-11.1) were evaluated and their median age was 8.1 years (range 2.2-14.7). All patients had received 131I-MIBG, 16 chemotherapy, and 16 surgery. Fourteen patients (56%) had permanently elevated thyrotropin levels and 9 received thyroxine. Two patients had a small thyroid volume while 6 had thyroid nodules or cysts. Two boys showed hypergonadotropic hypogonadism. Growth was retarded in 39% of children. Mean Target Height Standard Deviation Score of patients with thyrotropin elevation was lower than those without (P=0.019). Children treated for neuroblastoma with 131I-MIBG, chemotherapy and surgery were seen to be at risk from developing irreversible thyroid function loss, thyroid nodules, hypergonadotropic hypogonadism, and growth retardation. We recommend that during follow-up of neuroblastoma children, special attention should be paid to their endocrine state.

Disseminated medullary thyroid carcinoma despite early thyroid surgery in the multiple endocrine neoplasia-2A syndrome.

A 51/2-year-old boy, with a family history of multiple endocrine neoplasia (MEN)-2A syndrome, was evaluated for presence of MEN-2A and medullary thyroid carcinoma (MTC). DNA diagnostics confirmed MEN-2A. Basal (360 ng/L) and pentagastrin stimulated (430 ng/L) calcitonin (CT) levels were slightly elevated, plasma carcinoembryonic antigen (CEA) was normal. Within a year both tumor markers increased and total thyroidectomy was performed. Histologic examination did not show MTC. In the following years, both tumor markers increased progressively but despite the use of multiple imaging techniques no metastases were localized. After 6 years, biopsy of a palpable lymph node showed MTC. The boy was treated with total cervical, suprahyoidal, and mediastinal lymph node dissection, showing MTC in almost all nodes. Again, the tumor markers remained high. At this point in time, the disadvantages of further medical interventions were outweighed against the chance for cure and it was decided to shift the goal of treatment toward palliation rather than cure. At the last visit the boy was clinically well with persistent extremely high levels of plasma CEA and CT. In conclusion, when prophylactic thyroidectomy in the MEN-2A syndrome has failed, it may be best to withdraw from further interventions to prevent more damage.

The effect of cervical X-irradiation on activity index of thyrocytes and plasma TSH: a pre-clinical model for radiation-induced thyroid damage.

Because radiotherapy in the head and neck region is necessary in the treatment of childhood cancer, possibilities to prevent damage to the thyroid gland must be explored. We developed a model in which radiation-induced effects can be investigated in a way that these effects can be quantified, using thyroid dysmorphology and plasma TSH. Thirty-five Wistar rats, 5 weeks old, were X-irradiated on the cervical region, with a single dose varying from 0 to 20 Gy. After 6 weeks, TSH, T4 and T3 were determined, and thyroid glands were processed for histological examination by two independent pathologists. A histological classification scale was developed, using follicular size, colloid density and cell height of thyrocytes to measure hyperplasia and hypertrophy. By the sum of these scores, a cell-activity index was calculated, which was related to plasma TSH concentration. Numbers of PAS-positive droplets and epithelial desquamation were also counted. Inter-observer reliability was assessed. Good to very good reliability was found for scores of follicular size, colloid density and cell height. Significant increase of cell-activity index was found after 10, 15 and 20 Gy. The plasma TSH concentration was positively correlated to the cell-activity index, increasing with radiation-doses up to 15 Gy. The number of desquamated cells was significantly increased after radiation doses >10 Gy, with moderate reliability. In conclusion, this model using cell-activity index of thyrocytes together with plasma thyrotropin concentrations and desquamation of cells can be used for interpretation and future (pre-clinical) studies of prevention of radiation-induced thyroid damage.

Disturbance of the fetal thyroid hormone state has long-term consequences for treatment of thyroidal and central congenital hypothyroidism.

BACKGROUND: During T(4) supplementation of patients with thyroidal (primary) congenital hypothyroidism (CH) TSH concentrations are frequently elevated despite free T(4) (FT(4)) concentrations being well within the reference range. To examine the thyroid's regulatory system, we analyzed thyroid function determinants in children with congenital and acquired thyroid disorders and in controls. METHODS: Retrospectively, plasma FT(4), TSH, and T(3) concentrations were analyzed in T(4)-supplemented children aged 0.5-20.0 yr with thyroidal CH, central (secondary or tertiary) CH, or autoimmune thyroid disease and in control children with type 1 diabetes mellitus. RESULTS: When TSH was within the reference range (0.4-4.0 mU/liter), mean FT(4) in thyroidal CH [1.65 ng/dl; 95% confidence interval (CI), 1.62-1.67] was significantly higher than in autoimmune thyroid disease (1.15 ng/dl; 95% CI, 1.11-1.19) and diabetes (1.08 ng/dl; 95% CI, 1.06-1.10). In central CH, when TSH was less than or equal to 0.02 mU/liter, mean FT(4) was 1.27 ng/dl (95% CI, 1.24-1.29). When FT(4) was within the reference range (0.78-1.79 ng/dl), 43% of the TSH measurements in thyroidal CH were more than 4.0 mU/liter, compared with 18% in autoimmune thyroid disease and 0% in type 1 diabetes mellitus; in central CH, 95% of TSH measurements were less than 0.4 mU/liter. CONCLUSIONS: In T(4)-supplemented patients with thyroidal CH, when TSH concentrations are established within the reference range, FT(4) concentrations tend to be elevated, and vice versa. Because this phenomenon could not be observed in acquired thyroidal hypothyroidism, we hypothesize that a pre- and/or perinatal hypothyroid state shifts the setpoint of the thyroid's regulatory system. In central CH, when FT(4) concentrations are established within the reference range, the pituitary secretes only minute amounts of TSH. For monitoring T(4) supplementation, reference ranges for FT(4) and TSH should be adapted to the etiology of hypothyroidism.

Changes in thyroid hormone state in children receiving chemotherapy.

OBJECTIVE: 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. DESIGN: During a 3-month period all patients admitted for chemotherapy to the paediatric oncology ward were evaluated for inclusion. Patients with brain tumours, neuroblastoma (cranio)spinal irradiation and use of dexamethasone before the first blood sample were excluded. MEASUREMENTS: Plasma concentrations of T4, T3, rT3, thyroxine-binding globulin (TBG), thyroglobulin (Tg), TSH, IGF-1, cortisol, PRL and physical well-being by means of questionnaires were measured before and during chemotherapy. RESULTS: In 19 children, 46 courses of chemotherapy and 123 plasma samples were analysed. During chemotherapy, mean concentrations of TSH, T3, Tg and cortisol decreased to 53, 67, 69 and 15% of the baseline value, respectively. Mean plasma rT3 increased to 217% of baseline. In 87% of all courses, one or more thyroid parameter(s) was aberrant. Furthermore, in 23 samples (19%) from 10 patients (53%), the concentration of IGF-1 was below the reference value (adjusted for sex and age). Small changes were seen in scores for clinical condition but none was related to a change in thyroid function determinant. Most changes in thyroid hormones could be attributed to using dexamethasone. CONCLUSIONS: These results demonstrate that, in children, thyroid hormone state changes significantly during chemotherapy, apparently not related to physical well-being but to the drugs administered. Future investigations should focus on the impact for patient care and possibilities of (preventive) intervention.

Frequent adverse events after treatment for childhood-onset differentiated thyroid carcinoma: a single institute experience.

Since the mortality rate for childhood differentiated thyroid carcinoma is nearly zero, the focus must be to minimise morbidity following treatment. Our aim was to analyse early and late adverse events. Twenty-five of 26 children treated between 1962 and 2002 were evaluated. Median follow-up was 14.2 years (range 0.9-39.4 years). All underwent total thyroidectomy, 15 (60%) with lymph node dissection and 15 (60%) with adjuvant radio-iodide therapy. Mortality was zero. Seven developed recurrent disease, two developed a third recurrence. Twenty-one (84%) had > or =1 adverse event. Eight had permanent hypoparathyroidism (PH), six permanent recurrent nerve paralysis (PRNP) and two Horner's syndrome. Risk factors for PH and PRNP were total thyroidectomy with lymph node dissection (RR: 6.45, P = 0.015) and recurrent nerve tumour encasement (RR: 8.00, P = 0.001), respectively. Other adverse events were fatigue (n = 5), scar problems (n = 4) and chronic myeloid leukaemia (n = 1). These results emphasise the need to improve treatment strategies.

Lower neonatal screening thyroxine concentrations in down syndrome newborns.

There is an unexplained higher incidence of congenital hypothyroidism (CH) detected by T(4)-based neonatal screening programs and a very high prevalence of (mild) plasma TSH elevation in young children with Down syndrome (DS). To determine whether newborns with DS have decreased blood T(4) concentrations at the time of the neonatal screening, we conducted an observational study in a large and representative cohort of Dutch children with DS born in 1996 and 1997. CH screening results (T(4), TSH, and T(4)-binding globulin concentrations) were analyzed in comparison with clinical information obtained by interviewing the parents and data from the general newborn population and a large control group. The mean T(4) concentration of the studied children with DS (n = 284) was significantly decreased. The individual T(4) concentrations were normally (Gaussian) distributed but shifted to lower concentrations. This could not be explained by prematurity, nonthyroidal illness, or iodine exposure. Mean TSH and T(4)-binding globulin concentrations were significantly increased and normal, respectively. The decreased T(4) concentration, left-shifted normal distribution, and mildly elevated TSH concentrations point to a mild hypothyroid state in newborns with DS and support the existence of a DS-specific thyroid (regulation) disorder. The question remains whether this contributes to the brain maldevelopment.

Longitudinal analysis of growth and puberty in 21-hydroxylase deficiency patients.

AIMS: To evaluate growth from diagnosis until final height (FH) in 21-hydroxylase deficiency patients. METHODS: A retrospective longitudinal study was performed. Only patients treated with hydrocortisone and fludrocortisone (in case of salt wasting) were evaluated. This resulted in a sample of 34 (21 male, 13 female) salt wasting patients (SW) and 26 (13 male, 13 female) non-salt wasting patients (NSW). Auxological data were compared to recent Dutch reference values. RESULTS: In the first three months of life, the mean length SDS decreased to -1.50, probably because of the high average glucocorticoid dose (40 mg/m2/day). FH corrected for target height (FH(corr)TH) was -1.25 and -1.27 SDS in females and males, respectively. Patients treated with salt supplements during the first year, had a better FH(corr)TH (-0.83 SDS). In NSW patients, FH(corr)TH was -0.96 and -1.51 SDS in females and males, respectively. In SW and NSW, age at onset of puberty was within normal limits, but bone age was advanced. Mean pubertal height gain was reduced in males. Body mass index was only increased in NSW females. CONCLUSION: In SW, loss of final height potential might be a result of glucocorticoid excess in the first three months and sodium depletion during infancy. In NSW, loss of FH potential was caused by the delay in diagnosis. In SW and NSW, the advanced bone age at onset of puberty (undertreatment in prebertal years) resulted in loss of height gain during puberty. The effect of intensive sodium chloride support in early infancy should be examined prospectively. Neonatal screening is required if the height prognosis in NSW patients is to be improved.

Behavioural correlates of early-treated congenital hypothyroidism.

UNLABELLED: Parents' and teachers' ratings were used to evaluate the behavioural characteristics of children with early-treated congenital hypothyroidism (CH). Comparisons were made between 63 children with early-treated CH and 34 healthy controls at the ages of 7.5 and 9.5 y. Additional comparisons were made between the two largest CH subgroups (thyroid agenesis, thyroid dysgenesis) and controls. The most marked differences were found on the introversion cluster and the motor clumsiness scale within it. Children with CH, particularly those with thyroid agenesis, showed introversion and motor clumsiness rather than social negativity and inattention. It is suggested that this behavioural profile may well have its origins in the often-reported inefficient motor behaviour of these children. Results are discussed in the light of recent findings suggesting an association between thyroid hormone problems and attention deficit hyperactivity disorder. CONCLUSION: Early-treated CH is associated with introversion rather than with social negativity.

Serum thyroglobulin and urinary iodine concentration are the most appropriate indicators of iodine status and thyroid function under conditions of increasing iodine supply in schoolchildren in Benin.

Iodine deficiency control programs have greatly reduced iodine deficiency disorders worldwide. For monitoring changes in iodine status, different indicators may be used. The aim of this study was to evaluate the suitability of indicators of iodine status and thyroid function, thyroglobulin (Tg), thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in serum, thyroid volume and urinary iodine concentration, in iodine-deficient schoolchildren under conditions of increasing iodine supply. The study was established as a double-blind, placebo-controlled oral administration of a single dose of iodized oil to schoolchildren (7-10 y old), living in an iodine-deficient area of Benin, with an observation period of 10 mo. However, 3-4 mo after supplementation, iodized salt became available in the area. The study population therefore comprised an iodized oil-supplemented group and a nonsupplemented group, both of which had variable, uncontrolled intakes of iodized salt during the last 6 mo of the study. Initial mean serum concentrations of TSH and FT4 were within the normal range, whereas serum Tg concentration, urinary iodine concentration and thyroid volume were indicative of moderate-to-severe iodine deficiency. At the end of the study, all indicators had improved significantly, except thyroid volume, which had decreased only in the supplemented group. The supplemented group also still had significantly lower serum Tg and higher urinary iodine concentrations than the nonsupplemented group. Serum Tg and urinary iodine concentrations are the indicators most influenced by a changing iodine supply. Current normal reference ranges of serum concentrations of TSH and FT4 are too wide for detecting iodine deficiency in this age group.

Adult height and age at menarche in childhood cancer survivors.

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.