The action of thyroid hormones (thyroxine, T4; triiodothyronine, T3) on brain development and function is gaining renewed interest. It has been known for many years that thyroid hormones are very important in mammalian brain maturation, influencing many aspects related to neural cell migration, differentiation, and signaling. In the last 10 years, genes regulated by thyroid hormones have been identified in the rodent brain, and understanding of the role of thyroid hormone nuclear receptors has been facilitated with the analysis of the phenotype of mutant mice for the different receptor isoforms. The general picture that emerges is that T4 and T3 may enter the brain through specific transporters. T4 is converted to the active hormone, T3, in glial cells, astrocytes, and tanycytes, although the main target cells are neurons and maturing oligodendrocytes. T3, acting through the nuclear receptors, controls the expression of genes involved in myelination, cell differentiation, migration, and signaling. In addition to transducing the T3 signal, the nuclear receptors also have activity in the unliganded state (i.e., as aporeceptors), mainly as repressors of transcription. The physiological meaning of aporreceptor action is not known, but they may play a role in the genesis of the hypothyroid phenotype. Among the questions that remain to be explored in more detail is the role of thyroid hormones and the T3 receptors, both liganded and unliganded, in the fetal brain, especially before onset of fetal thyroid gland function. These questions are relevant for human health and the management of thyroid diseases during pregnancy.

Thyroid Hormones and Brain Development

The adequate functioning of both the maternal and fetal thyroid glands play an important role to ensure that the fetal neuropsycho-intellectual development progresses normally. Three sets of clinical disorders are considered, that may eventually lead to impaired brain development. Firstly, in infants with a defect of glandular ontogenesis (congenital hypothyroidism), the participation of maternal thyroid hormones to the fetal circulating thyroxine environment is normal and, therefore, risk of brain damage results exclusively from the insufficient hormone production by the abnormal fetal thyroid gland. Secondly, when it is only the maternal thyroid gland that is functionally deficient (autoimmune hypothyroidism), the severity and temporal occurrence of maternal underfunction will both drive the resulting consequences for impaired fetal neuronal development. Clinical situations of this type may obviously take place already during early gestation (in women with known but untreated hypothyroidism) or appear only during later gestational stages (in women who have AITD and remain euthyroid during the first half of gestation). Lastly, in conditions with iodine deficiency, both maternal and fetal thyroid functions are affected and, therefore, it is primarily the degree and precocity of the maternal hypothyroxinemia due to iodine deficiency during pregnancy that will drive the potential repercussions for fetal neurological development. In the present review, we summarize available data and develop our present concepts concerning the complex feto-maternal thyroid relationships and the potential impacts of thyroid function abnormalities on the ideal development of the offspring.

The Potential Repercussions of Maternal, Fetal, and Neonatal Hypothyroxinemia on the Progeny

Objective Congenital hypothyroidism (CHT) is a common cause of preventable mental retardation, and the quantification of intellectual disability due to CHT is needed to assess the public health benefit of newborn screening. Design Review of published studies conducted among children born prior to the introduction of newborn screening for CHT and reporting cognitive test scores. Setting Population-based studies. Patients Children with clinically diagnosed CHT. Interventions Thyroid hormone substitution. Main outcome measures Intelligence quotient (IQ) (mean and distribution). Results The prevalence of recognised CHT rose from one in 6500 prior to screening to approximately one in 3000 with screening. In four population-based studies in high-income countries, among children with clinically diagnosed CHT 8–28% were classified as having intellectual disability (defined as an IQ Conclusions Although the prevalence of overt disability among children with CHT in the absence of screening may be less than previously estimated, the preventable burden of intellectual disability due to CHT is substantial and justifies newborn screening. However, changes in existing newborn screening protocols to capture more cases are unlikely to prevent overt cases of disability and should therefore be justified instead by the documentation of other benefits of early detection.

https://adc.bmj.com/content/archdischild/96/4/374.full.pdf

Prevention of intellectual disability through screening for congenital hypothyroidism: how much and at what level?

Objective. To describe intellectual, mo- tor, and school-associated outcome in young adults with early treated congenital hypothyroidism (CH) and to study the association between long-term outcome and CH variables acting at different points in time during early development (CH severity and early L-thyroxine treatment levels (0 - 6 years)). Methods. Neuropsychological tests were adminis- tered to all 49 subjects with CH identified during the first 3 years of the Norwegian neonatal screening program (1979 -1981) at a mean age of 20 years and to 41 sibling control subjects (mean age: 21 years). Results. The CH group attained significantly lower scores than control subjects on intellectual, motor, and school-associated tests (total IQ: 102.4 (standard devia- tion: 13) vs 111.4 (standard deviation: 13)). Twelve (24%) of the 49 CH subjects had not completed senior high school, in contrast to 6% of the control subjects. CH severity (pretreatment serum thyroxine (T4)) correlated primarily with motor tests, whereas early L-thyroxine treatment levels were related to verbal IQ and school- associated tests. In multiple regression analysis, initial L-thyroxine dose ( 0.32) and mean serum T4 level during the second year ( 0.48) predicted Verbal IQ, whereas mean serum T4 level during the second year ( 0.44) predicted Arithmetic. Conclusions. Long-term outcome revealed enduring cognitive and motor deficits in young adults with CH relative to control subjects. Verbal functions and Arith- metic were associated with L-thyroxine treatment vari- ables, suggesting that more optimal treatment might be possible. Motor outcome was associated with CH sever- ity, indicating a prenatal effect. Pediatrics 2003;112:923- 930; congenital hypothyroidism, thyroid hormone, thyrox- ine treatment, adult outcome, intelligence, achievement, motor function.

Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults.

Since the advent of biochemical screening for congenital hypothyroidism, the majority of monozygotic twins reported with thyroid dysgenesis have been discordant, and most were missed on neonatal screening, presumably due to fetal blood mixing. We hypothesized that there may be bias leading to preferential reporting of discordant twins and/or of false negative screening results. Therefore, we performed a systematic search for twins in two congenital hypothyroidism screening centers, Quebec and Brussels, that use a primary TSH approach. In Quebec, 10 pairs of twins were identified, all discordant for congenital hypothyroidism due to thyroid dysgenesis (4 monozygotic and 4 dizygotic pairs) and dyshormonogenesis (2 dizygotic pairs). The 6 pairs identified in the Brussels database were also all discordant for congenital hypothyroidism due to thyroid dysgenesis (1 monozygotic and 3 dizygotic pairs) and dyshormonogenesis (2 dizygotic pairs). The median increase in TSH between screening and diagnosis was 7-fold in the monozygotic twins vs. 2-fold in matched singletons (P = 0.02), suggesting fetal blood mixing between the twins. In summary, discordance for thyroid dysgenesis is the rule in monozygotic twins, and fetal blood mixing may result in delayed or missed diagnoses. We therefore conclude that 1) a second sample for congenital hypothyroidism screening at 14 d of age should be considered for all same-sex twins; and 2) thyroid dysgenesis generally results from epigenetic phenomena, early somatic mutations, or postzygotic stochastic events.

Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology.

Screening programs for congenital hypothyroidism (CH) dramatically improved the neuropsychological prognosis in affected children. However, mild impairments in cognitive performances, poorer motor skills, defective language abilities, and learning problems have been reported in some studies of early-treated CH children. The occurrence of these defects makes neuropsychological follow-up mandatory. The aim of the present study was to identify those neuropsychological functions that are more frequently affected in early-treated CH children and that might require prompt rehabilitation treatment to prevent permanent defects. The study group involved 24 CH children. Levothyroxine (LT4) treatment (initial dose 8-10 microg/kg per day) was started at mean age of 28 days (range 15-45) and was then adjusted with the goal to keep thyrotropin (TSH) and free thyroid hormone levels in the normal range. Cognitive evaluation was performed at 3, 5, and 7 years of age and did not significantly differ from that of controls. Mean neurological scores were lower in children 5 years of age than in controls. Children with severe neonatal hypothyroidism (serum thyroxine [T4] < 2 microg/dL) had significantly lower neurological scores compared to less affected CH children and normal controls. The most affected functions were balance, extremity coordination, fine motricity, quality of movements, associated movements, and head movements. Language disorders were observed in half of CH children at 3 and 5 years of age, but moderately severe defects were restricted to those with severe neonatal hypothyroidism. In conclusion, a problem-oriented, simplified neuropsychological follow-up of early-treated children with CH should not systematically include the frequent repetition of time-consuming and expensive psychometric tests because individual IQ scores are in the normal range of tests in almost all CH children and can be differentiated from those of normal controls only on a population-statistic basis. Selected tests of motor proficiency are indicated at 3 and 5 years of age to detect those defects in motor skills that appear to be more specifically affected in CH children. Language performances are at particular risk in CH children, and should be always checked at 3 and 5 years of age. Children with even mild language disorders or delayed language achievements should be regularly reevaluated at 6-month intervals and, if no spontaneous improvement is observed, they should receive specific rehabilitation treatment. No further motor and language evaluation is warranted in CH children with normal tests at age 5 years.

Neuropsychological follow-up in early-treated congenital hypothyroidism: a problem-oriented approach.

Objective Evaluation of school attainments in children with congenital hypothyroidism (CH) detected by neonatal screening and treated early in life. Patients and methods Text comprehension, mathematics, reading, writing and verbal and spatial memory, as indices of school learning, were evaluated in nineteen 5- to 10-year-old children with CH attending nursery or elementary school. l-Thyroxine substitution (starting dose 8-10 microg/kg body weight per day) was initiated at a mean age of 30+/-10 days of life. The control group included 298 unaffected children matched with the CH children for age and school grade. Thirty per cent of controls were classmates of CH children. Intelligence quotients (IQ), language performances and motor development were evaluated in CH children at age 5 years, and were related to their school attainments. School performances of CH children were also compared with their neonatal serum thyroxine (T4) concentration, and with the social-cultural level of the family. Results Four out of 19 (21%) children with CH, 3 in the nursery and 1 in the elementary school, displayed a generalized learning disorder. Symbol copy, geometric copy, phrase repetition, dictation writing and spontaneous writing were particularly defective in nursery school CH children, while orthographic error recognition was defective in elementary school CH children. School learning disorders in CH children were significantly correlated with a borderline-low IQ, poor language performances and a low social-cultural level of the family, but not with motor skills or neonatal T4 concentration. Conclusion School attainments of early treated CH children were within the normal range in most affected cases. However, about 20% of CH children, most of them attending nursery school, showed a generalized learning disorder. Low IQ scores and poor language performances at age 5 years were associated with defective learning, mainly in CH children living in a poor social-cultural environment. In this subset of CH children, prompt initiation of speech and psychomotor rehabilitation therapy is recommended in order to prevent subsequent school learning disorders.

/pdf/school-attainments-in-children-with-congenital-4pezfxy3qk.pdf

School attainments in children with congenital hypothyroidism detected by neonatal screening and treated early in life

Objective: Neonatal screening for congenital hypothyroidism (CH) prevents the serious neuropsychological features of CH, but the question remains whether intelligence and motor skills of CH children treated early are completely normal. Design: In this report we describe the rare case of two genetically identical twins, only one of whom was affected by CH due to thyroid agenesis. L-Thyroxine (9 μg/kg body weight/day) therapy was initiated at 27 days of age and was adequate throughout the follow-up. Methods: Neuropsychological evaluation was performed on the twins in parallel from 3 months to 8 years of age. Results: The CH twin (NB) did not show major neuromotor impairments but, compared with the unaffected twin (EB), she had a slight delay in postural/motor achievements and in language development that completely disappeared at 8 years of age. On standardised tests of intelligence, NB was indistinguishable from control children but, compared with her twin, she had lower IQ scores in most testing occasions up to 7 years of age (NB = 108 vs EB = 115), School achievements of NB did not significantly differ from those of her classmates but, compared with her twin, she scored worse in writing, mechanical reading, verbal memory, and possibly in arithmetic. Conclusions: Because the twins were genetically and phenotypically identical, were raised in the same environment, and received a similar education, it is concluded that hypothyroidism in utero and in the first neonatal month was responsible for the lower neuropsychological achievements of the CH twin. While foetal hypothyroidism is at present unavoidable, earlier diagnosis and initiation of treatment in neonates with CH are important and highly recommended.

Neuropsychological development in a child with early-treated congenital hypothyroidism as compared with her unaffected identical twin.

BACKGROUND The aim of this paper was to evaluate school learning in early treated CH children in order to investigate whether and how this pathology influences school performance. METHODS Using a sample of 50 early treated CH children who have received regular follow-up at our Institute, 20 subjects attending primary (grade) school or the final year of nursery school for assessment of school learning have been selected. Results were compared with a class/grade matched control group. Evaluations of cognitive, motor and language development, T4 level determined at birth, thyroid disorder and socio-cultural level of the family background were examined in relation to the school performance of each child. RESULTS The evaluations showed that out of 20 CH children, 5 (25%) presented generalized learning disorders. This percentage is higher than in the normal population (3.4%). When learning disorder findings were correlated with data pertaining to motor, speech and cognitive development, socio-cultural level and thyroid disorder, it was found that children with generalized learning difficulties presented more severe motor and speech disorders, a lower intelligence quotient and a lower socio-cultural background than children achieving higher scores in school tests. CONCLUSIONS The conclusion is drawn that early treated CH children of same age have more learning difficulties during nursery school, while they have normal learning performances during primary school.

Ipotiroidismo congenito precocemente trattato: Valutazione dell'apprendimento scolastico

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Neuropsychological follow-up in early-treated congenital hypothyroidism: a problem-oriented approach.

School attainments in children with congenital hypothyroidism detected by neonatal screening and treated early in life

Neuropsychological development in a child with early-treated congenital hypothyroidism as compared with her unaffected identical twin.

Ipotiroidismo congenito precocemente trattato: Valutazione dell'apprendimento scolastico