Alterations in the programming of energy metabolism in adolescents with background exposure to dioxins, dl-PCBs and PBDEs.

OBJECTIVES: Dioxins and PCBs are highly toxic and persistent environmental pollutants that are measurable in humans worldwide. These persistent organic pollutants are associated with a higher incidence of diabetes mellitus. We hypothesise that perinatal (background) exposure to industrial pollutants like dioxins also influences body mass development and energy metabolism in later life. STUDY DESIGN: In The Netherlands, the perinatal exposure (prenatal exposure and postnatal lactational intake) to dioxins has been studied prospectively since 1987. Fasting glucose, insulin, HbA1c and leptin were analysed in 33 children of the original cohort of 60. BMI, glucose:insulin and BMI:leptin ratios were calculated. Prenatal exposure, lactational intake and current serum levels of dioxins (PCDD/F), dl-PCBs and PBDE concentrations were determined using (HR)GC-MS. RESULTS: Prenatal dioxin (PCDD/F) exposure was positively correlated to the glucose:insulin ratio (p = 0.024) and negatively correlated to the fasting insulin concentration (p = 0.017) in adolescence. Postnatal lactational PCDD/F intake was also negatively correlated to fasting insulin concentration (p = 0.028). Current serum levels of PCDD/Fs and total TEQ (dl-PCBs+PCDD/Fs) were positively correlated to the fasting serum glucose concentration (p = 0.015 and p = 0.037, respectively).No metabolic effects were seen in association with current serum levels of PBDEs. A positive correlation between the insulin and leptin concentrations (p = 0.034) was observed. No effects were found on leptin levels, BMI:leptin ratio, HbA1c levels or BMI. DISCUSSION/CONCLUSION: This study indicates that prenatal and lactational exposure influences glucose metabolism in adolescents, presumably through a negative effect on insulin secretion by pancreatic beta cells. Additionally, the very low recent background exposure to dioxins in puberty possibly has an effect on the glucose level.

Changes in body mass index in long-term childhood cancer survivors.

BACKGROUND: Previous studies have reported changes in the body mass index (BMI) with time in childhood cancer survivors (CCSs) during follow-up. The limitations of these studies include that they described only a subgroup of survivors or used questionnaires with self-reported heights and weights. The goal of this study was to examine BMI in a large cohort of long-term CCSs and relate this to the BMI at diagnosis, age, sex, tumor type, treatment, and endocrine defects. METHODS: All patients treated for childhood cancer at the Emma Children's Hospital/Academic Medical Center between 1966 and 1996 who had survived for at least 5 years were eligible for inclusion. For 893 CCSs with a mean follow-up of 14.9 years, the BMI at the late effects outpatient clinic was compared with the BMI for the general Dutch population. RESULTS: For girls, an increased prevalence of obesity was found. Risk factors for developing a high BMI at follow-up were a younger age and a high BMI at diagnosis and treatment with cranial radiotherapy. A significantly increased prevalence of severe underweight was found in all adult subgroups except for females aged 26 to 45 years. An association was found between a low BMI at diagnosis and a low BMI at follow-up. No treatment-related variables could be related to changes in BMI. CONCLUSIONS: The BMI at diagnosis is one of the most important predictors for the BMI at follow-up, and this suggests an important genetic or environmental cause. Adult CCSs are at high risk for developing severe underweight at follow-up. Future studies should focus on the causes and clinical consequences of underweight.

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.

Frequent occurrence of the triphasic response (diabetes insipidus/hyponatremia/diabetes insipidus) after surgery for craniopharyngioma in childhood.

BACKGROUND/AIMS: It is not exactly known how many children develop the triphasic response (diabetes insipidus (DI)/hyponatremia/DI) immediately after surgery for childhood craniopharyngioma; neither is it known which factors predict this. We studied the occurrence of the triphasic response after primary surgery for craniopharyngioma in children, and aimed to identify possible predictors. METHODS: Patients <18 years old who had undergone a primary craniopharyngioma resection between January 1990 and February 2010 in either of the 2 academic centers in Amsterdam were studied retrospectively. RESULTS: Twenty-one patients (5 males) fulfilled the inclusion criteria. Median age at surgery was 9.1 (range: 4.0-15.1) years. Six patients developed a triphasic response (29%). Of all factors, only the duration of surgery was found to be a predictor of a triphasic response: 8.5 (6.0-11.0) versus 4.6 (3.5-11.5) h in patients who did not develop a triphasic response (p = 0.03). CONCLUSION: After primary surgery for a craniopharyngioma, a considerable number of patients develop a triphasic response in the regulation of the sodium and water balance. This is predicted by (factors associated with) a longer duration of surgery. Other predictors could not be identified, which may be due to the small sample size.

Morphological abnormalities in children with thyroidal congenital hypothyroidism.

Several groups of investigators have reported an increased incidence of congenital anomalies in patients with congenital hypothyroidism. Furthermore, in patients with congenital hypothyroidism and mutations in genes known to be involved in thyroid development, specific extra-thyroidal abnormalities have been observed. The goal of the present study was to gain insight in the types and patterns of morphological characteristics depending on the type of congenital hypothyroidism of thyroidal origin (CH-T). In 242 Dutch CH-T patients with a thyroid agenesis, a dystopic thyroid rudiment or a eutopic thyroid gland, we performed a careful physical examination of the body surface directed to visually detectable morphological abnormalities; results were compared to a group of 1,007 Dutch control subjects. The percentage of patients with one or more major abnormalities in the total CH-T cohort (33.1%) and in patients with CH-T dystopic thyroid (37.2%) was significantly higher than in the control population (21.8%; P < 0.001). Especially in the CH-T dystopic thyroid group specific major malformations (bilateral ear pits; oligodontia) were found more frequently. Also, the percentage of patients in the total CH-T group with one or more minor anomalies (96.3%) was significantly higher than in the control group (82.5%). The careful grouping of patients according to their CH-T etiology and the types and patterns in morphological findings may be helpful in the search for novel genes involved in thyroid development.

Role of corticotropin-releasing hormone testing in assessment of hypothalamic-pituitary-adrenal axis function in infants with congenital central hypothyroidism.

CONTEXT: The Dutch neonatal congenital hypothyroidism (CH) screening program detects infants with CH of central origin (CH-C). These infants have a high likelihood of multiple pituitary hormone deficiencies. ACTH deficiency especially poses an additional risk for brain damage and may be fatal. OBJECTIVE: Our objective was to evaluate different tools for assessment of the integrity of the hypothalamus-pituitary-adrenocortex (HPA) axis in young infants, aiming for a strategy for reliable and timely diagnosis. DESIGN, SETTING: This is a Dutch nationwide prospective study (enrollment 1994-1996). Patients were included if neonatal CH screening results were indicative of CH-C and HPA axis function could be tested within 6 months of birth. PATIENTS: Nine male and three female infants with CH-C and four infants with false-positive screening results or transient hypothyroidism were included in the study. MAIN OUTCOME MEASURES: CRH test results, multiple cortisol plasma concentrations, and cortisol excretion in 24-h urine were measured. RESULTS: Six (50%) of the CH-C patients had abnormal CRH test results. Three of them had discordant test results: impaired increase of plasma cortisol in response to CRH, despite substantial increase of plasma ACTH. The other three infants, with concordant impaired responses of both ACTH and cortisol to CRH, had a very low urinary cortisol excretion in comparison with the subjects with normal CRH test results. CONCLUSIONS: The CRH test proves to be a fast and reliable tool in the assessment of HPA axis (dys)function. It enables timely diagnosis in (asymptomatic) neonates at risk for serious morbidity and mortality. The discordant response type, which has not been described before, may be an early phase of HPA axis dysfunction. Alternatively, patients with this response type may constitute a separate pathogenetic subset of HPA axis-deficient patients.

Role of the thyrotropin-releasing hormone stimulation test in diagnosis of congenital central hypothyroidism in infants.

CONTEXT: A shortage of thyroid hormone during prenatal life and the first years after birth results in a spectrum of neuropsychological disorders, depending on the duration and severity of the deficiency. In the case of congenital hypothyroidism of central origin (CH-C), the majority of patients have multiple pituitary hormone deficiencies (MPHD). This condition poses an additional threat to postnatal central nervous system development, primarily on account of neuroglycopenia due to ACTH/cortisol deficiency with or without additional GH deficiency. Therefore, in CH-C, rapid diagnosis is even more urgent than in congenital hypothyroidism of thyroidal origin. OBJECTIVE: In the assessment of hypothalamic-pituitary-thyroid function, we considered the pituitary response to iv administration of TRH (TRH test) pivotal. We evaluated the usefulness of the TRH test in a cohort of infants with neonatal congenital hypothyroidism screening results indicative of CH-C by analyzing the results within the framework of investigations of the anatomical and functional integrity of the hypothalamo-hypophyseal system. DESIGN AND SETTING: The study was a Dutch nationwide prospective study (1994-1996). Patients were included if neonatal congenital hypothyroidism screening results were indicative of CH-C and patients could be tested within 3 months of birth. PATIENTS: Ten male and five female infants with CH-C, detected by neonatal screening, and six infants with false-positive screening results, nonthyroidal illness, or transient hypothyroidism, were included in the study. MAIN OUTCOME MEASURES: Results of TRH tests, within the framework of extensive endocrinological examinations and cerebral magnetic resonance imaging, were measured. RESULTS: All patients with type 3 TSH responses to TRH had MPHD, and the majority (67%) of patients with type 2 responses had isolated TSH deficiency. CONCLUSIONS: The TRH test has a pivotal role in the diagnosis of TSH deficiency in young infants. Abnormal TRH test results, especially a type 3 response, urge immediate assessment of integral hypothalamic-pituitary function because the majority of patients have MPHD.

Perinatal dioxin exposure, cytochrome P-450 activity, liver functions and thyroid hormones at follow-up after 7-12 years.

OBJECTIVES: Prenatal and lactational exposure to Dutch "background" dioxin levels may cause health effects spanning many years. In addition, perinatal studies have shown a relationship between dioxin exposure and thyroid disturbance. To assess the later health effects of prenatal and lactational dioxin exposure on liver function we measured plasma ALAT and ASAT levels amongst our longitudinal cohort, as was done perinatally and at 2(1/2) years. The children underwent a caffeine loading test to determine CYP1A2 activity. To assess the later effects on thyroid function we measured plasma TSH and FT4. STUDY DESIGN: A longitudinal cohort of 37 healthy children (age 7-12, mean 8.2 years), with documented prenatal and lactational dioxin exposure, ingested 3mg caffeine/kg BW 6h prior to blood withdrawal. Paraxanthine/caffeine molar ratio, ALAT, ASAT, TSH and FT4 were determined in venous blood. RESULTS: Linear regression of ASAT and ALAT revealed no relation with prenatal and lactational dioxin exposure. No correlation was found between the paraxanthine/caffeine molar ratio and prenatal and lactational dioxin exposure. Linear regression of TSH and FT4 revealed no relation with prenatal and lactational dioxin exposure. CONCLUSION: This follow-up has shown a normalisation of previously abnormal ALAT and ASAT levels, indicating a transient effect. CYP1A2 activity, measured by means of a caffeine-loading test, revealed no correlation with the prenatal and lactational exposures. A normalisation of previously abnormal thyroid hormone homeostasis was seen, also possibly indicating a transient effect. This study provides new data on long-term follow-up after perinatal dioxin exposure to background levels of dioxins.

Loss of integrity of thyroid morphology and function in children born to mothers with inadequately treated Graves' disease.

CONTEXT: Central congenital hypothyroidism (CH-C) in neonates born to mothers with inadequately treated Graves' disease usually needs T(4) supplementation. The thyroid and its regulatory system have not yet been extensively studied after T(4) withdrawal, until we observed disintegrated thyroid glands in some patients. OBJECTIVE: The aim was to study the occurrence and pathogenesis of disintegrated thyroid glands in CH-C patients. DESIGN, SETTING, PATIENTS, PARTICIPANTS: Thyroid function was measured and thyroid ultrasound imaging was performed in 13 children with CH-C due to inadequately treated maternal Graves' disease after T(4)-supplementation withdrawal (group Aa). In addition, thyroid ultrasound imaging was performed in six children with CH-C born to inadequately treated mothers with Graves' disease, in whom T(4) supplementation was not withdrawn yet (group Ab) or never initiated (group Ac), in six euthyroid children born to adequately treated mothers with Graves' disease (group B), and in 10 T(4)-supplemented children with CH-C as part of multiple pituitary hormone deficiency (group C). MAIN OUTCOME MEASURES: Thyroid function and aspect (volume, echogenicity, echotexture) were measured. RESULTS: In group A, five children had developed thyroidal hypothyroidism characterized by persistently elevated TSH concentrations and exaggerated TSH responses after TRH stimulation. In the majority of patients in groups A and C, thyroid echogenicity and volume were decreased, and echotexture was inhomogeneous. Thyroid ultrasound imaging was normal in group B children. CONCLUSIONS: Inadequately treated maternal Graves' disease not only may lead to CH-C but also carries an, until now, unrecognized risk of thyroid disintegration in the offspring as well. We speculate that insufficient TSH secretion due to excessive maternal-fetal thyroid hormone transfer inhibits physiological growth and development of the child's thyroid.

Early assessment of hypothalamic-pituitary-gonadal function in patients with congenital hypothyroidism of central origin.

CONTEXT: Early recognition of gonadotropic dysfunction could enable well-timed growth and maturation and prevent damage to gonads and external genitalia. The adaptation of the Dutch neonatal screening program for congenital hypothyroidism in the mid 1990s resulted in enhanced detection of congenital hypothyroidism of central origin (CH-C), with high likelihood of multiple pituitary hormone deficiency, including gonadotropin (Gn) deficiency. OBJECTIVE: We analyzed GnRH test results and baseline Gn and sex hormone measurements in 15 infants with CH-C to examine these diagnostic tools for assessment of the integrity of the hypothalamus-pituitary-gonad axis in young infants. DESIGN: In a nationwide prospective study (1994-1996), patients were referred to our department if neonatal CH screening results were indicative of CH-C. When CH-C was confirmed, GnRH tests and baseline Gn and sex hormone measurements took place at the age of 3 months, when euthyroid status had been accomplished by T4 supplementation, and if necessary, cortisol supplementation was installed. SETTING: The study took place at the Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam (referral center). PATIENTS: The study included 15 neonates (five girls and 10 boys) with CH-C, detected by neonatal screening, in whom investigation of the hypothalamus-pituitary-gonad axis could be performed at 3 months of age. MAIN OUTCOME MEASURES: Results of GnRH tests and baseline Gn and sex hormone measurements were assessed. RESULTS: GnRH tests at 3 months of age showed a pattern indicative of endogenous GnRH stimulation in nine infants and a blunted response in six. Baseline Gn and sex hormone concentrations except estradiol (P = 0.053) were significantly different between responders and nonresponders. CONCLUSIONS: The GnRH test and baseline measurements of Gn and sex hormone serum concentrations at 3 months of age are promising options in the assessment of hypothalamic-pituitary-gonadal function in infants with CH-C of both sexes.

Neonatal screening for congenital hypothyroidism in the Netherlands: cognitive and motor outcome at 10 years of age.

CONTEXT: Patients with thyroidal congenital hypothyroidism (CH-T) born in The Netherlands in 1981-1982 showed persistent intellectual and motor deficits during childhood and adulthood, despite initiation of T(4) supplementation at a median age of 28 d after birth. OBJECTIVE: The present study examined whether advancement of treatment initiation to 20 d had resulted in improved cognitive and motor outcome. DESIGN/SETTING/PATIENTS: In 82 Dutch CH-T patients, born in 1992 to 1993 and treated at a median age of 20 d (mean, 22 d; range, 2-73 d), cognitive and motor outcome was assessed (mean age, 10.5 yr; range, 9.6-11.4 yr). Severity of CH-T was classified according to pretreatment free T(4) concentration. MAIN OUTCOME MEASURE: Cognitive and motor outcome of the 1992-1993 cohort in comparison to the 1981 to 1982 cohort was the main outcome measure. RESULTS: Patients with severe CH-T had lower full-scale (93.7), verbal (94.9), and performance (93.9) IQ scores than the normative population (P < 0.05), whereas IQ scores of patients with moderate and mild CH-T were comparable to those of the normative population. In all three severity subgroups, significant motor problems were observed, most pronounced in the severe CH-T group. No correlations were found between starting day of treatment and IQ or motor outcome. CONCLUSIONS: Essentially, findings from the 1992-1993 cohort were similar to those of the 1981-1982 cohort. Apparently, advancing initiation of T(4) supplementation from 28 to 20 d after birth did not result in improved cognitive or motor outcome in CH-T patients.

Comorbidity, hospitalization, and medication use and their influence on mental and motor development of young infants with Down syndrome.

OBJECTIVE: Young infants with Down syndrome have an increased occurrence of several well-known medical conditions such as congenital heart and gastrointestinal disease. The aim of this study was to establish consequences like hospitalization and medication use rates and to determine their possible influence on early neurodevelopment. PATIENTS AND METHODS: This study compared 2 years of thyroxine treatment with placebo in 196 neonates with Down syndrome who were included in a previously reported randomized clinical trial. Parents were interviewed about comorbidity, hospitalization, and medication use at random assignment and regularly thereafter. Data were cross-checked with discharge letters when available. The influence of comorbidity on neurodevelopment at 2 years old (Bayley Scales of Infant Development II) was determined by stepwise multiple linear-regression analysis. RESULTS: Before trial entry, 163 infants with Down syndrome had been admitted to hospital for an average of 14.01 days, whereas during the trial, 95 of 181 infants who completed the trial were hospitalized for an average 19.75 days. Main hospitalization reasons during the trial were lung/airway and congenital heart and gastrointestinal disease. The 48 infants operated on for heart or gastrointestinal disease accounted for 1401 of the total number of 1876 hospital admission days during the trial and for 33 of 62 admissions for lung/airway infection. During their second year of life, approximately 60% of the infants were prescribed drugs, mostly antibiotics and pulmonary. Regression analysis showed infantile spasms, "other" central nervous system disease, and gastrointestinal disease necessitating surgery to be associated with greater developmental age delays at 24 months old (mental: 6.87, 3.52, and 1.69 months; and motor: 3.59, 2.54, and 1.68 months, respectively). CONCLUSIONS: Hospital admission and medication use rates in young infants with Down syndrome are still very high, mainly because of congenital heart and gastrointestinal disease and acquired respiratory disease. Central nervous system disease and gastrointestinal disease necessitating surgery were independently associated with a worse developmental outcome.

Trisomy 21 causes persistent congenital hypothyroidism presumably of thyroidal origin.

OBJECTIVE AND DESIGN: Lowered neonatal plasma thyroxine (T(4)) and mildly elevated thyrotropin concentrations together with developmental benefits from neonatally started T(4) treatment in a randomized clinical trial demonstrated Down syndrome (DS) neonates to be mildly hypothyroid, at least during their first weeks of life. To prove that this hypothyroid state persists beyond this period in all, and to elucidate its etiology, we evaluated the course of the thyroid function determinants in all DS infants participating in this 24-month trial. MAIN OUTCOME: Mean plasma thyrotropin concentrations and thyrotropin frequency distributions of 97 placebo-treated infants were persistently shifted to substantially higher concentrations, while free T(4) frequency distributions were in the lower two thirds of the reference interval. Mean thyroglobulin concentrations were normal. To normalize plasma thyrotropin, T(4)-treated DS infants (N = 99) needed rather high free T(4) concentrations, like T(4)- treated non-DS children with thyroidal congenital hypothyroidism. At ages 12 and 24 months, thyroid peroxidase antibodies were detected in 1.1% and 5.4% of all DS infants. CONCLUSIONS: These findings suggest that as a group DS infants have a novel type of persistent mild congenital hypothyroidism, presumably of thyroidal origin. The group character suggests a direct relation with the trisomic state of chromosome 21, hypothetically through genomic dosage imbalance of dosage-sensitive genes interfering with thyroid hormone production.

Median nerve conduction velocity and central conduction time measured with somatosensory evoked potentials in thyroxine-treated infants with Down syndrome.

OBJECTIVE: The aim of this study was to determine whether thyroxine treatment would improve nerve conduction in infants with Down syndrome. METHODS: A single-center, nationwide, randomized, double-blind, clinical trial was performed. Neonates with Down syndrome were assigned randomly to thyroxine (N = 99) or placebo (N = 97) treatment for 2 years. Daily thyroxine doses were adjusted regularly to maintain plasma thyrotropin levels in the normal range and free thyroxine concentrations in the high-normal range. The outcome measures were nerve conduction velocity and central conduction time, determined through median nerve somatosensory evoked potential recording, at the age of 24 months. RESULTS: At the age of 24 months, somatosensory evoked potential recordings for 81 thyroxine-treated and 84 placebo-treated infants were available for analysis. Nerve conduction velocity and central conduction time did not differ significantly between the 2 treatment groups (nerve conduction velocity: thyroxine: 51.0 m/second; placebo: 50.1 m/second; difference: 0.9 m/second; central conduction time: thyroxine: 8.83 milliseconds; placebo: 8.73 milliseconds; difference: 0.1 milliseconds). CONCLUSIONS: Postnatal thyroxine treatment of infants with Down syndrome did not alter somatosensory evoked potential-measured peripheral or central nerve conduction significantly. The absence of favorable effects suggests that pathologic mechanisms other than mild postnatal hypothyroidism underlie the impaired nerve conduction. The absence of adverse effects suggests that longstanding plasma free thyroxine concentrations in the high-normal range are not harmful to nerve maturation.

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 (T(4))-based strategies to screen for CH. DESIGN, SETTING, AND PARTICIPANTS: In the Netherlands, since January 1, 1995, a primary T(4) determination with supplemental thyroid-stimulating hormone (TSH) and T(4)-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 T(4) levels, TSH elevation, and/or low T(4)/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 T(4) levels (

Neonatal detection of congenital hypothyroidism of central origin.

Due to the high frequency of concurrent pituitary hormone deficiencies, congenital hypothyroidism (CH) of central origin (CH-C) is a life-threatening disorder. Yet only a minority of these patients are detected by neonatal CH screening programs worldwide. We conducted a prospective multicenter study involving a 2-yr cohort of neonatally diagnosed CH-C patients to determine whether a T(4)-TSH-based neonatal CH screening protocol extended with T(4) binding globulin determinations improves early detection of CH-C and to assess the extent of pituitary hormone deficiency among the identified CH-C patients. In all infants with screening results indicative of CH-C, the functional integrity of the hypothalamo-hypophyseal system was investigated by dynamic tests; the anatomical integrity was investigated by magnetic resonance imaging. Initial test results were evaluated after 5 yr of follow-up. Among 385,000 infants screened over the 2-yr period, 19 cases of permanent CH-C were detected (prevalence, 1:20,263; 95% confidence interval, 1:12,976 to 1:33,654), representing 13.5% of all detected cases of permanent CH. The majority (78%) had multiple pituitary hormone deficiency, whereas 53% had pituitary malformations on magnetic resonance imaging. We conclude that infants with CH-C can very well be detected by neonatal screening. The estimated prevalence and the severity of pituitary dysfunction of this treatable disorder call for explicit attention for this entity of CH in neonatal screening programs worldwide.

The effect of thyroxine treatment started in the neonatal period on development and growth of two-year-old Down syndrome children: a randomized clinical trial.

CONTEXT: Young Down syndrome children appear to have a mild form of congenital hypothyroidism that is rarely detected by neonatal screening and usually left untreated. OBJECTIVE: To investigate the effects of thyroxine treatment on development and growth of young Down syndrome children. DESIGN, SETTING, AND PARTICIPANTS: Single-center, randomized, double-blind, 24-month trial (enrollment June 1999 to August 2001) with nationwide recruitment, comparing thyroxine administration with placebo in 196 Down syndrome neonates. INTERVENTION: Neonates were randomly assigned to treatment for 2 yr with either thyroxine (n = 99; initial dose 8 microg/kg) or placebo (n = 97). Daily thyroxine doses were adjusted at regular intervals to maintain plasma TSH in its normal and free T(4) concentrations in its high-normal range. Placebo dose adjustments mirrored those of thyroxine. MAIN OUTCOME MEASURES: The primary outcome was mental and motor development at age 24 months, assessed with the Bayley Scales of Infant Development II. RESULTS: At age 24 months, the developmental testing results of 90 thyroxine-, and 91 placebo-treated children were available for analysis. The thyroxine-treated children had a 0.7-month smaller delay in motor developmental age (95% confidence interval, -1.4 to 0), corresponding to a difference of seven motor developmental index points. The mental developmental age delay was also 0.7 month smaller in the thyroxine group (95% confidence interval, -1.5 to 0.2), but lacked statistical significance. Thyroxine-treated children had greater gains in length (1.1 cm; 95% confidence interval, 0.2 to 2.0) and weight (378 g; 95% confidence interval 55 to 701). CONCLUSIONS: The data of our study provide evidence to support the hypothesis that thyroxine treatment may improve development and growth of young Down syndrome children. Thyroxine treatment should be considered in Down syndrome neonates to maximize their early development and growth.

An investigation of impulsivity in children with early-treated congenital hypothyroidism.

The main feature of congenital hypothyroidism (CH) is a total or partial absence of thyroid hormone, caused by a developmental disorder of the thyroid gland. Introduction of neonatal thyroid screening allows early treatment with replacement hormone. As a result the prognosis of CH has greatly improved but neuropsychological problems do still occur. Claims that early-treated CH is associated with impulsivity were tested with a memory search task comprising 2 response probability conditions: a baseline condition in which "yes" and "no" responses were equally probable and a response bias condition in which the probability of a "no" response was raised to 70%. Impulsivity was defined as the ability to stop and change a response set and was assessed from the amount of inaccurate "no" responses made. Comparisons were made between 47 children with early-treated CH and 35 controls at the age of 7.5 years. Children with early-treated CH were notably slow and variable in their overall task performance but, most important, did not show signs of poor impulse control. Suggested short-term memory problems in these children could not be confirmed. Performance could not be attributed to early disease-related factors or lowered intelligence.