Cognitive and White Matter Microstructure Development in Congenital Hypothyroidism and Familial Thyroid Disorders.

CONTEXT: Children with congenital hypothyroidism (CH) are at risk for suboptimal neurodevelopment. OBJECTIVES: To evaluate neurocognitive function and white matter microstructure in children with permanent or transient CH and to correlate these findings with disease severity. DESIGN, PARTICIPANTS AND METHODS: A retrospective and prospective observational study was conducted in 39 children with permanent or transient CH, and in 39 healthy children. Cognitive function was assessed by Wechsler Intelligence Scale, Fourth Edition, and by other tests; the white matter microstructure was investigated by 3 Tesla magnetic resonance imaging. RESULTS: Children with permanent CH have lower cognitive scores at a median age of 9.5 years than those with transient CH and controls. An IQ score between 71 and 84 was found in 28.6% of permanent CH and of <70 (P = 0.06) in 10.7%. The Processing Speed Index (PSI; P = 0.004), sustained visual attention (P = 0.02), reading speed (P = 0.0001), written calculations (P = 0.002), and numerical knowledge (P = 0.0001) were significantly lower than controls. Children born to mothers with Hashimoto's thyroiditis have significantly lower IQ values (P = 0.02), Working Memory Index (P = 0.03), and PSI (P = 0.02). Significantly lower IQ and Verbal Comprehension Index values were found in children with a family history of thyroid disorders (P = 0.004 and P = 0.009, respectively). In children with permanent CH, significant correlations between abnormalities in white matter microstructural, clinical, and cognitive measures were documented. CONCLUSIONS: These findings indicate that children with CH are at risk of neurocognitive impairment and white matter abnormalities despite timely and adequate treatment. The association between offspring cognitive vulnerability and maternal thyroid disorders requires careful consideration.

Health-Related Quality of Life in Patients With Early-Detected Central Congenital Hypothyroidism.

CONTEXT: Central congenital hypothyroidism (CH) requires lifelong medical treatment. The majority of children with central CH have multiple pituitary hormone deficiencies (MPHD), but in some cases central CH is isolated. Most pituitary hormone deficiencies are associated with impaired health-related quality of life (HRQoL). However, studies on HRQoL in central CH are lacking. OBJECTIVE: To evaluate HRQoL and fatigue in children and young adults with central CH, as well as parent perspectives. DESIGN: Nationwide cross-sectional study comparing HRQoL between early-detected central CH patients and unaffected siblings with the Pediatric Quality of Life inventory (PedsQL™) and PedsQL Multidimensional Fatigue Scale. Participants ≥ 8 years old filled in self-reports; parents of participants aged 3 to 18 years filled in parent reports. Isolated central CH patients, MPHD patients, and siblings were compared using a linear mixed model and Tukey's post hoc test. RESULTS: Eighty-eight patients and 52 siblings participated, yielding 98 self-reports and 115 parent reports. Isolated central CH patients (n = 35) and siblings showed similar scores on all subscales, both in the self-reports and parent reports. For MPHD patients (n = 53), self-reported scores were similar to those of siblings. Parent reported total HRQoL and fatigue scores were significantly poorer in MPHD patients compared with siblings (mean differences -10.2 and -9.4 points; P < 0.01), as were scores for physical functioning, social functioning and general fatigue. CONCLUSION: Self-reported HRQoL scores in isolated central CH and MPHD patients were similar to siblings. However, parents reported significantly lower HRQoL and fatigue scores for MPHD patients, suggesting a difference in perceived limitations between MPHD patients and their parents.

Cognitive outcome in congenital central hypothyroidism: a systematic review with meta-analysis of individual patient data.

Objective: To provide an overview of cognitive and motor outcome, and quality of life (QoL) in patients with congenital central hypothyroidism (CH-C). Design: Systematic review with individual patient data (IPD) meta-analysis. Methods: OVID MEDLINE, EMBASE and PsycInfo were searched from inception to June 11th, 2019. Studies in patients with CH-C, either isolated or with multiple pituitary hormone deficiency (MPHD), were included if CH-C patients could be separated from any additional patient groups. Primary outcomes were full-scale intelligence quotient (FSIQ) and motor outcome; secondary outcome was QoL. Following data-extraction, one-stage IPD meta-analysis was performed, fitting a linear mixed model with FSIQ as dependent variable. Random intercepts were fitted for each study. Results: Six studies measuring FSIQ were eligible for meta-analysis, comprising 30 CH-C patients (20 males; 27 MPHD patients). FSIQ range was wide (64-123). Mean weighted FSIQ was 97 (95% CI: 88-105). Twenty-seven percent had an FSIQ below 85 (≥1 s.d. below norm score), and 10% below 70 (≥2 s.d. below norm score). There was no significant association between FSIQ and sex or age. Age at treatment initiation was available from three studies only, thus impeding a reliable analysis of this parameter. Motor outcome and QoL were each studied in one study; no quantitative analyses could be performed for these outcomes. Conclusion: A wide range in FSIQ scores was observed in CH-C patients. Results should be interpreted with caution, because included patients mainly had MPHD and age at treatment initiation was unknown for the majority of patients.

Relation between Early Over- and Undertreatment and Behavioural Problems in Preadolescent Children with Congenital Hypothyroidism.

OBJECTIVE: Congenital hypothyroidism (CH) per se, when not treated or undertreated, may lead to severe behavioural problems (cretinism), whereas overtreatment of CH seems associated with attention problems. DESIGN AND METHODS: For 55 CH patients, prospectively followed from birth until 11 years, parents rated the Child Behaviour Checklist and teachers the Teacher's Report Form at children's ages 6 and 11 years. We related scores regarding Attention, Delinquency, and Aggression (ADA scores, indicative for attention deficit hyperactivity syndrome, ADHD), and scores regarding Withdrawn, Anxious, Social, and Thought problems (WAST scores, indicative for autism) to the occurrence of over- and undertreatment in five age periods. Over- and undertreatment were defined as free thyroxine (fT4) concentrations above/below the range of the patient's individual fT4 steady state concentration. RESULTS: ADA scores at 6 and 11 years for patients overtreated in the period 1-3 months postnatally were higher than those for patients who were not overtreated. Patients with severe CH undertreated in the period 3-6 months postnatally had higher WAST scores at 6 and 11 years than all other patients. CONCLUSIONS: This is the first study suggesting that permanent ADHD as well as autism in CH patients at ages 6 and 11 years are the result of early overtreatment and undertreatment, respectively.

Parenting styles and coping strategies among patients with early detected and treated congenital hypothyroidism. / Estilos parentales y estrategias de afrontamiento en pacientes con hipotiroidismo congénito detectado y tratado en forma temprana.

INTRODUCTION: Congenital hypothyroidism (CH), as any chronic disease, has an impact on the parent-child relationship and on the child's resources to cope with conflicting situations. OBJECTIVES: To describe parenting styles according to the perception of children with CH and their coping strategies. POPULATION AND METHODS: Children aged 9-10 years who had CH detected by newborn screening and had received adequate treatment and a group without CH (control group). The Argentine Coping Questionnaire, the Argentine Scale for the Perception of Parent Relations, and the comprehension subtest of the Wechsler Intelligence Scale for Children III (WISC III) were used. Results were compared using a multivariate analysis of variance (MANOVA). RESULTS: Sixty children with CH were included; they perceived that their mothers exercised a strict control and that their fathers showed more acceptance. They sought more support and became paralyzed more often in conflicting situations than the 60 children without CH. CONCLUSION: These findings may be associated with a higher level of dependence. They should be taken into consideration in CH care.

INTRODUCCIÓN: El hipotiroidismo congénito (HC) como enfermedad crónica impacta en la vinculación padres-hijo y en recursos del niño para afrontar situaciones conflictivas. OBJETIVOS: Describir estilos parentales desde la percepción del hijo con HC y sus estrategias de afrontamiento. POBLACIÓN Y MÉTODOS: Niños de entre 9 y 10 años con HC detectado por pesquisa neonatal y adecuadamente tratado y un grupo sin HC (grupo control). Se utilizó el cuestionario argentino de afrontamiento y la escala argentina de percepción de la relación con los padres y el subtest comprensión de la Wechsler Intelligence Scale for Children III (WISC III). Se compararon los resultados con el análisis multivariante de la varianza (multivariate analysis of variance; MANOVA, por sus siglas en inglés). RESULTADOS: Se incluyeron 60 niños con HC; percibían a su madre con una modalidad de control estricto y a su padre con más aceptación. Buscaban mayor apoyo y se paralizaban más ante situaciones conflictivas que los 60 niños sin patología. CONCLUSIÓN: Estos hallazgos podrían asociarse a mayor dependencia. Deben considerarse en la atención del HC.

Mean High-Dose l-Thyroxine Treatment Is Efficient and Safe to Achieve a Normal IQ in Young Adult Patients With Congenital Hypothyroidism.

Context: The optimal levothyroxine (LT4) dose to treat congenital hypothyroidism (CH) remains unclear, with debate over whether higher starting doses (>10 µg/kg) are necessary and safe for a normal intelligence quotient (IQ). Objective: To examine psychomotor, metabolic, and quality of life (QoL) outcomes in patients with CH treated with a mean high initial LT4 dose. Design, settings, participants: A cross-sectional cohort study of patients with CH identified in the Berlin newborn screening program from 1979 to 2003; 76 patients with CH (mean age, 18 years; mean initial LT4 dose, 13.5 µg/kg) and 40 siblings completed the study. Main outcome measures: Psychomotor (Wechsler Intelligence Test, CNS Vital Signs), QoL (short form-36 Health Survey), anthropometric (body mass index, height), and metabolic (intima media thickness, laboratory parameters) outcomes were compared with those of healthy siblings. Mean values and percentage of episodes of elevated thyroxine (T4) and tri-jod-thyronin (T3) and suppressed thyrotropin (TSH) before age 2 years were analyzed. A meta-analysis of CH treatment studies was performed. Results: There were no significant differences in IQ, QoL, or other outcome measures in patients with CH compared with controls. Most T4 levels were high before age 2 years and during subsequent testing, but mean T3 and TSH levels remained normal. The meta-analysis showed a significant IQ difference in severe vs mild CH cases only when treatment started with an LT4 dose <10 µg/kg. Conclusions: High initial LT4 dosing was effective and safely achieved optimal cognitive development in patients with CH, including those severely affected. Supranormal T4 values during infancy were not associated with impaired IQ in adolescence.

Vocal Evaluation of Children with Congenital Hypothyroidism.

OBJECTIVE: To evaluate the vocal characteristics of a group of children with congenital hypothyroidism (CH) and the association of these characteristics with the children's clinical, laboratory, and therapeutic profiles. MATHERIAL AND METHODS: Observational, analytical, cross-sectional study including 200 prepubertal children, of whom 100 had CH (study group [SG]) and 100 had no CH (control group [CG]). The following parameters were evaluated: 1) history (identification, complaints, and interfering variables), 2) auditory-perceptual and acoustic evaluation (samples analyzed by a group of specialists, and objectively by a computer program), 3) self-assessment scores in the Pediatric Voice-Related Quality-of-Life (PVRQoL) survey, 4) laryngological evaluation (presence or absence of laryngeal lesions and data regarding glottal closure), and 5) medical records (CH etiology, age at treatment initiation, disease severity at diagnosis, treatment quality, and thyroid function tests on the day of the examination). RESULTS: In the perceptual assessment, 62.6% of the SG children passed, whereas 37.4% failed in the voice screening, but these results were comparable with those in the CG (P = 0.45). Both groups had mean/median acoustic measurements within the normal limits. The mean PVRQoL in the SG (99.3 ± 2.4) and CG (99.5 ± 1.7) were comparable (P = 1.00). Both SG (16.7%) and CG (15%) presented vocal cord lesions (P = 1.00). There was no association between voice/larynx characteristics and endocrinological data. CONCLUSION: Prepubescent children diagnosed with CH during neonatal screening and who have a lifelong history of adequate treatment of CH showed similar vocal and laryngeal characteristics compared with children without CH.

Perinatal hypothyroidism increases play behaviors in juvenile rats.

Thyroid hormones play an instrumental role in the development of the central nervous system. During early development, the fetus is dependent on maternal thyroid hormone production due to the dysfunction of its own thyroid gland. Thus, maternal thyroid dysfunction has been shown to elicit significant abnormalities in neural development, neurochemistry, and behavior in offspring. Previous reports have suggested that human maternal hypothyroidism may increase the chances of having children with autism spectrum disorder and attention-deficit/hyperactivity disorder. However, very few studies have evaluated social behaviors in animal models of perinatal hypothyroidism. To evaluate the possibility that hypothyroidism during development influences the expression one of the most commonly observed non-reproductive social behaviors, juvenile play, we used the validated rat model of perinatal hypothyroidism by methimazole administration (MMI; 0.025% in drinking water) from GD12-PD23. Control animals had regular drinking water. During adolescence (PD33-35), we tested subjects for juvenile play behavior by introducing them to a same-sex, unfamiliar (since weaning) littermate for 30min. Play behaviors and other behaviors (sleep, social contact, locomotion) were then scored. MMI-treated subjects played more than twice as much as control animals, and the increase in some behaviors was particularly dramatic in males. Locomotor and other affiliative social behaviors were unaffected. These data suggest that perinatal hypothyroidism may alter the organization of the neural networks regulating play behaviors, but not other social behaviors. Moreover, this implicates perinatal hypothyroidism as a potential etiological factor in the development of neurobehavioral disorders, particularly those characterized by heightened social interactions and impulsivity.

Evaluation of neurodevelopment of children with congenital hypothyroidism by the Denver Developmental Screening Test.

BACKGROUND: Thyroid hormones are essential for growth and brain development in childhood. Although congenital hypothyroidism (CH) is the most common reason for mental retardation, normal neurological development can be achieved through early and effective treatment. The aim of the present study was to evaluate the neurological development of CH patients aged 24-56 months. METHODS: The study included a total of 116 healthy control subjects and 112 patients aged 24-56 months who were diagnosed with CH during the neonatal period and were being followed up at the Pediatric Endocrinology Department, Keçiören Training and Research Hospital, between 2012 and 2015. Demographics and clinical data of interventions and outcomes were retrieved for each patient. Statistical analysis was performed using an unpaired Student's t-test to compare means and χ2-analysis to compare proportions. RESULTS: There were no significant differences between the CH and control groups with respect to gestational age, birth weight, height standard deviation scores (HSDS) and body weight standard deviation scores (BWSDS) (p>0.05). When the groups were compared according to the Denver Developmental Screening Test (DDST), no significant differences were found in terms of personal-social, fine motor skills, or language development (p=0.325, p=0.087 and p=0.636, respectively). However, a significant difference was found between the two groups with respect to gross motor development and the result of the DDST (p=0.001). No statistical difference was found between the control and patient groups on the day of starting treatment but the number of patients with an abnormal result in the DDST starting treatment at >15 days was found to be significantly higher than the number of patients starting treatment ≤15 days. No associations were found between the DDST results of the CH group and the following factors: initial L-thyroxine (LT4) level, initial LT4 dose and the onset of treatment. CONCLUSIONS: The findings of this study indicate that the DDST results in patients with CH are generally good. Initiating treatment immediately after diagnosis and during the first days of life is absolutely imperative. However, in contrast to timing, we could not find strong evidence for determining the precise optimal dosage of LT4 to initiate treatment in children diagnosed with CH. Both the American Academy of Pediatrics and the European Society for Pediatric Endocrinology recommend 10-15 µg/kg/day as the initial dose.

Individualized treatment to optimize eventual cognitive outcome in congenital hypothyroidism.

BACKGROUND: In congenital hypothyroidism (CH), age-specific reference ranges (asRR) for fT4 and thyrotropine (TSH) are usually used to signal over/under-treatment. We compared the consequences of individual fT4 steady-state concentrations (SSC's) and asRR regarding over-treatment signaling and intelligence quotient at 11 y (IQ11) and the effect of early over-treatment with high L-T4 dosages on IQ11. METHODS: Sixty-one patients (27 severe, 34 mild CH) were psychologically tested at 1.8, 6, and 11 y. Development scores were related to over-treatment in the period 0-24 mo, relative to either individual fT4SSC's or asRR. Three groups were formed, based on severity of over/under-treatment 0-5 mo (severe, mild, and no over/under-treatment). RESULTS: FT4 and TSH asRR missed 41-50% of the over-treatment episodes and consequently 22% of the over-treated patients, classified as such by fT4SSC's. Severe over-treatment 0-5 mo led to lowered IQ11's and to a 5.5-fold higher risk of IQ11 < 85 than other treatment regimes. Under-treatment had no effect on development scores. Initial L-T4 dosages >10 µg/kg resulted in a 3.7-fold higher risk of over-treatment than lower dosages. CONCLUSIONS: Data suggest that asRR, compared to fT4SSC's, signal over-treatment insufficiently. Using fT4SSC's and avoiding over-treatment may optimize cognitive outcome. Lowered IQ11's are usually a late complication of severe early over-treatment.

Effect of Atomoxetine on the Cognitive Functions in Treatment of Attention Deficit Hyperactivity Disorder in Children with Congenital Hypothyroidism: A Pilot Study.

BACKGROUND: With early initiation of thyroxine supplementation, children with congenital hypothyroidism (CH) retain some subtle deficits, such as attention and inhibitory control problems. This study assessed the effects of atomoxetine on cognitive functions in treatment of attention deficit hyperactivity disorder (ADHD) symptoms in children with CH. METHODS: In a 6-month, open-labeled pilot study, 12 children were recruited and received atomoxetine. The measures of efficacy were scores on the Swanson, Nolan and Pelham Teacher and Parent Rating Scale, version IV (SNAP-IV) and Clinical Global Impression-Severity scale (CGI-S). The cognitive functions were evaluated with the Wechsler Intelligence Scale for Chinese Children, Digit Span, Wisconsin Card Sorting Test, and Stroop test. RESULTS: A statistically significant difference was found between the mean CGI-S and SNAP-IV scores before and after treatment (p < 0.01). All the indicators of cognitive functions at the endpoint were improved compared with those at baseline. No serious adverse events were reported. CONCLUSION: Atomoxetine appears to be useful in improving ADHD symptoms, as well as cognitive functions, in children with CH. Larger, randomized, double-blinded, clinical trials are required to replicate these results.

Factors affecting parent-child relationships one year after positive newborn screening for cystic fibrosis or congenital hypothyroidism.

OBJECTIVE: Examine factors that mediate parent-infant relationships 12 months after positive newborn screening (NBS). METHODS: We examined effects of infant diagnosis, parents' perceptions of child vulnerability and child attachment, parental depression and anxiety on parent-infant feeding interactions for 131 mothers and 118 fathers of 131 infants whose NBS and diagnostics confirmed cystic fibrosis (CF, n = 23), congenital hypothyroidism (CH, n = 35), CF carrier status (CF-C, n = 38), or healthy normal NBS (H, n = 35). RESULTS: Separate composite indicator structural equation models for mothers and fathers showed that neonatal diagnosis was not associated with increased anxiety or depression. In comparison with the healthy group, CF group parents reported higher perceptions of child vulnerability (p < .001, p = .002), and CF-C group fathers viewed their children as more attached (p = .021). High maternal perception of child vulnerability was associated with low perceptions of child attachment (p = .001), which was associated with task-oriented feeding behavior (p = .016, p = .029). Parental task-oriented feeding behavior was associated with less positive (p < .001, p < .001) and more negative interactions (p < .001, p = .001) with their infants. High paternal perception of child vulnerability was associated with negative parent interactions (p < .001). High parental affective involvement and verbalization was associated with high infant affective expressiveness, communicative skills, and social responsiveness (mothers' p < .001, fathers' p < .001). High parental negative effect and/or inconsistent and intrusive behavior were associated with infant dysregulation and irritability (mothers, p < .001, fathers, p < .001). CONCLUSION: The severity of conditions identified through NBS can affect parents' perceptions of their child's vulnerability and attachment. Infant feeding problems in the context of chronic health conditions, like CF, could represent signs of more deeply rooted concerns regarding the parent-child relationship that merit additional clinical evaluation.

The role of thyroid hormones for brain development and cognitive function.

Through its actions on regulatory genes that form, grow and sculpt the brain, thyroid hormone (TH) is essential for human brain development. Although much of what we know about these effects is based on research with rodents, recent studies of children exposed to TH insufficiencies during critical stages of early development provide preliminary evidence on how and when the human brain needs TH. This paper reviews some of the major studies from both the rodent research and research on offspring of women with hypothyroidism during pregnancy and children with congenital hypothyroidism (CH) who were assessed using neuropsychological tests and with advanced neuroimaging techniques. The final section will compare findings from children lacking TH due to maternal hypothyroidism and CH conditions, whose loss of TH at different times represents unique time windows for examining TH effects in the human brain.

Children with congenital hypothyroidism have similar neuroradiological abnormal findings as healthy ones.

OBJECTIVE: To assess the neuroradiological findings of children with congenital hypothyroidism (CHT) compared to healthy controls (HC). PATIENTS AND METHODS: Thirty children with CHT, mean age 12.5 ± 1.6 years, 14 (44.8%) males, were compared with 38 HC mean age 11.7 ± 1.7 years, 16 (45.7%) males. Clinical data were collected from medical charts and questionnaires seeking information on family history, birth and perinatal period events, medications, and overall health history. Neurocognitive function was assessed for global intelligence, visual and verbal memory, and executive functioning using standardized tests. Neuroimaging was performed using 1.5 T magnetic resonance imaging and assessed by two pediatric radiologists. RESULTS: Children with CHT had a similar proportion of incidental findings as did the children in the HC group, at 43.3% and 39.5%, respectively, P = 0.69. Abnormalities of the sellar region were reported in 13.3% of CHT group and 7.9% of HC group, P = 0.46. Other incidental findings included cerebellar ectopia, choroidal fissure and pineal cysts, and multiple increased signal intensity foci. Neuroradiological findings were not associated with clinical and neurocognitive abnormalities. CONCLUSION: Neuroimaging of children with CHT demonstrated a similar incidence of structural abnormalities as in the healthy population. There is no association between those findings and neurocognitive function.

Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring.

CONTEXT: Overt hypothyroidism in pregnant women is associated with poorer neurodevelopment in their children. Findings from studies investigating the effect of less severe impairments in the maternal thyroid function on cognitive functioning in offspring are difficult to interpret for a number of reasons, including lack of objective cognitive tests, preschool age at assessment, and small sample sizes. OBJECTIVE: We aimed to assess the effect of the maternal thyroid status in early pregnancy on their offspring's cognitive performance at 5 to 6 years of age. DESIGN AND PARTICIPANTS: This was a prospective study that included the data of 1765 healthy 5- to 6-year-old children from the Amsterdam Born Children and their Development study. Maternal serum free T4 and TSH were obtained at a median gestational age of 90 (interquartile range, 83 to 100) days. MAIN OUTCOME MEASURES: Cognitive performance was tested using a computerized assessment program that measured response speed, response speed stability, visuomotor skills, response selection, and response inhibition. RESULTS: Maternal hypothyroxinemia (ie, maternal free T4 in the lowest 10% of distribution) was associated with a 41.3 (95% confidence interval, 20.3-62.4) ms slower response speed in a simple reaction time task. In this test, it was also associated with a decreased stability in response speed. The relations found persisted after adjustment for family background and perinatal conditions. The effect of hypothyroxinemia on these outcomes was dependent on its interaction with TSH level. CONCLUSIONS: Lower maternal free T4 concentration at the end of the first trimester predicted slower response speed and decreased stability in response speed in offspring at 5 to 6 years of age.

Evaluation of cognitive and motor development in toddlers with congenital hypothyroidism diagnosed by neonatal screening.

OBJECTIVE: The Dutch neonatal congenital hypothyroidism (CH) screening procedure and treatment modality has been adapted several times since its national institution in 1981. These changes enabled us to investigate whether earlier treatment has resulted in improved cognitive and motor outcomes. The present study examined whether the advancement of treatment modality has resulted in improved cognitive and motor outcomes. METHODS: In 95 toddlers with thyroidal CH (CH-T), born in 2002 through 2004 and treated at a median age of 9 days, cognitive and motor outcomes were assessed with the Bayley Scales of Infant Development-II-NL at 1 and 2 years of age. This outcome was also analyzed in relation to treatment variables. RESULTS: The mean mental developmental index (MDI) scores of the severe (initial free thyroxine [FT4] ≤0.4 ng/dL (≤5 pmol/L), moderate (0.4 < initial FT4 ≤ 0.8 ng/dL (5.0 < initial FT4 ≤ 10.0 pmol/L), and mild (initial FT4 > 0.8 ng/dL (>10.0 pmol/l) CH-T groups at 1 year and the moderate and mild CH-T groups at 2 years were similar to the population mean. The mean MDI scores of the total CH-T group and severe CH-T group at 2 years were significantly lower than the population mean (p < .0001). In all 3 severity subgroups, significant lower psychomotor developmental index scores (p < .0001) were observed. No correlations were found between starting day of treatment and developmental outcome. Initial T4 concentration and initial T4 dose were weak predictors for developmental outcome. CONCLUSION: Essentially, comparable with our earlier findings, children with CH, especially those with severe CH, are still at risk for motor and cognitive problems, which are probably due to the consequence of the prenatal hypothyroid state or the thyroid hormone deficiency in early life.

[Effects of early treatment on physical and intelligence development in children with congenital hypothyroidism].

OBJECTIVE: To compare differences in the intelligence and physical developmental levels of children with congenital hypothyroidism (CH) who received initial treatment at different times. METHODS: Forty-nine children with CH diagnosed by neonatal screening between September 2008 and September 2011 were enrolled in this study. According to the timing of initial treatment with thyroid hormone, they were classified into two groups: <1 month and 1 to 3 months of life. At 6 months old, 1 year and 2 years old, their intelligence levels were evaluated by Gessell test. Their physical developmental levels were also measured. Their thyroid functions were examined with fluorescence immunoassay. RESULTS: With treatment, there were no significant differences in thyroid hormones (FT3, FT4 and TSH) between the two groups (P>0.05) at 6 months old, 1 year and 2 years old. However, heights and weights in the <1 month treatment group were significantly higher than in the 1 to 3 months treatment group at all time points (P<0.05). At 6 months old, intelligence developmental levels in the <1 month treatment group were better than the 1 to 3 months treatment group (P<0.05) but significant differences were not noted at 1 and 2 years old (P>0.05). CONCLUSIONS: The timing of initial treatment with thyroid hormone appears to be associated with the intelligence and physical development in children with CH. Treatment starting at less than 1 month of life contributes to improved physical and intelligence development compared with treatment starting at 1 to 3 months of life.

Overgrowth syndromes.

PURPOSE OF REVIEW: Human growth ensues from a complex interplay of physiological factors, in the wider setting of varying genetic traits and environmental influences. Intensive research in these divergent areas, and particularly in the field of genetics, continues to clarify the molecular basis of disorders which result in overgrowth, and it is therefore timely to provide a review of these findings. RECENT FINDINGS: This article provides an overview of the factors which regulate growth, followed by a discussion of the more commonly encountered overgrowth syndromes and their genetic basis as it is understood at the current time. There is also an added focus on recently discovered genetic associations in some conditions, such as Weaver, Perlman and Proteus syndromes. SUMMARY: New discoveries continue to be made regarding the genetic basis for many overgrowth syndromes and the development of a much needed molecular classification system for overgrowth may become possible as the interlinking functions of these genes on growth are unravelled. As there exists a wide spectrum of syndromes, disorders resulting in overgrowth can represent a diagnostic and therapeutic challenge, from those causing prenatal overgrowth with a poor prognosis to less severe genetic aberrations which are identified in later childhood or adult life.

Early levothyroxine treatment on maternal subclinical hypothyroidism improves spatial learning of offspring in rats.

Maternal hypothyroidism has adverse effects on neural development in the offspring. The present study aimed to investigate whether maternal subclinical hypothyroidism impairs spatial learning in the offspring, as well as the efficacy and optimal time of levothyroxine (L-T(4)) treatment in pregnancy. Female adult Wistar rats were randomly divided into six groups (n = 10 per group): control, hypothyroid (H), subclinical hypothyroid (SCH) and SCH treated with L-T(4), starting from the tenth, thirteenth and seventeenth gestational day (GD10, GD13 and GD17), respectively, to restore normal thyroid hormone levels. Spatial learning was assessed on progenies by a water maze test, a field excitatory postsynaptic potential (fEPSP) recording, and an long-term potentiation induction assay. Protein levels of early growth response protein 1 (Egr1), activity-regulated cytoskeleton-associated protein (Arc), Ras-proximate-1 (Rap1), p-extracellular signal-regulated kinase (p-ERK) and brain-derived neurotrophic factor (BDNF) were determined by western blotting. Progenies from the SCH and H groups demonstrated significantly longer mean latency in the water maze test and a lower amplification percentage of the amplitude and slope of the fEPSPs compared to offspring of the control group. L-T(4) treatment for the GD10 and GD13 groups significantly shortened mean latency and increased the amplification percentage of the amplitude and slope of the fEPSPs of the progeny of rats with subclinical hypothyroidism. However, L-T(4) treatment for the GD17 group showed only minimal effects on spatial learning in the offspring. Progenies of SCH and H groups had lower levels of Egr1, Arc, p-ERK and BDNF but higher levels of Rap1 compared to those of the controls. L-T(4) treatment ameliorated these protein expression changes in the progeny of rats with subclinical hypothyroidism. Maternal subclinical hypothyroidism impaired spatial learning in the offspring; L-T(4) treatment in early pregnancy recovered this adverse effect, and the optimal time of treatment should start from early pregnancy (GD10 and GD13).