Congenital Hypothyroidism and Brain Development: Association With Other Psychiatric Disorders

Thyroid hormones play an important role in brain development, and thyroid hormone insufficiency during the perinatal period results in severe developmental delays. Perinatal thyroid hormone deficiency is clinically known as congenital hypothyroidism, which is caused by dysgenesis of the thyroid gland or low iodine intake. If the disorder is not diagnosed or not treated early, the neuronal architecture is perturbed by thyroid hormone insufficiency, and neuropathological findings, such as abnormal synapse formation, defects in neuronal migration, and impairment of myelination, are observed in the brains of such patients. Furthermore, the expression of psychiatric disorder-related molecules, especially parvalbumin, is significantly decreased by thyroid hormone insufficiency during the perinatal period. Animal experiments using hypothyroidism models display decreased parvalbumin expression and abnormal brain architecture, and these experimental results show reproducibility and stability. These basic studies reinforce the results of epidemiological studies, suggesting the relevance of thyroid dysfunction in psychiatric disorders. In this review, we discuss the disruption of brain function associated with congenital hypothyroidism from the perspective of basic and clinical research.

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Thyroid Gene Mutations in Pregnant and Breastfeeding Women Diagnosed With Transient Congenital Hypothyroidism: Implications for the Offspring’s Health

Frontiers in Endocrinology ◽

10.3389/fendo.2021.679002 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maria C. Opazo ◽

Juan Carlos Rivera ◽

Pablo A. Gonzalez ◽

Susan M. Bueno ◽

Alexis M. Kalergis ◽

...

Keyword(s):

Thyroid Hormone ◽

Thyroid Hormones ◽

Congenital Hypothyroidism ◽

Gene Mutations ◽

Genetic Variations ◽

Hormone Deficiency ◽

Iodide Transport ◽

Transport Defect ◽

Pregnancy And Lactation ◽

Transient Congenital Hypothyroidism

Fetus and infants require appropriate thyroid hormone levels and iodine during pregnancy and lactation. Nature endorses the mother to supply thyroid hormones to the fetus and iodine to the lactating infant. Genetic variations on thyroid proteins that cause dyshormonogenic congenital hypothyroidism could in pregnant and breastfeeding women impair the delivery of thyroid hormones and iodine to the offspring. The review discusses maternal genetic variations in thyroid proteins that, in the context of pregnancy and/or breastfeeding, could trigger thyroid hormone deficiency or iodide transport defect that will affect the proper development of the offspring.

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Relevance of iodine intake as a reputed predisposing factor for thyroid cancer

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302007000500007 ◽

2007 ◽

Vol 51 (5) ◽

pp. 701-712 ◽

Cited By ~ 47

Author(s):

Meyer Knobel ◽

Geraldo Medeiros-Neto

Keyword(s):

Thyroid Cancer ◽

Iodine Deficiency ◽

Animal Experiments ◽

Experimental Studies ◽

Epidemiological Studies ◽

Iodine Intake ◽

Thyroid Cell ◽

Predisposing Factor ◽

Iodine Prophylaxis ◽

Iodine Excess

Iodine is a trace element that is essential for the synthesis of thyroid hormone. Both chronic iodine deficiency and iodine excess have been associated with hypertrophy and hyperplasia of follicular cells, attributed to excessive secretion of TSH. This may be associated to thyroid cancer risk, particularly in women. Experimental studies have documented thyroid cancer induction by elevation of endogenous TSH, although in a small number of animals. Iodine deficiency associated with carcinogenic agents and chemical mutagens will result in a higher incidence of thyroid malignancy. Inadequate low iodine intake will result in increased TSH stimulation, increased thyroid cell responsiveness to TSH, increased thyroid cell EGF-induced proliferation, decreased TGFbeta 1 production and increased angiogenesis, all phenomena related to promotion of tumor growth. Epidemiological studies associating iodine intake and thyroid cancer led to controversial and conflicting results. There is no doubt that introduction of universal iodine prophylaxis in population previously in chronic iodine-deficiency leads to a changing pattern of more prevalent papillary thyroid cancer and declining of follicular thyroid cancer. Also anaplastic thyroid cancer is practically not seen after years of iodine supplementation. Iodine excess has also been indicated as a possible nutritional factor in the prevalence of differentiated thyroid cancer in Iceland, Hawaii and, more recently, in China. In conclusion: available evidence from animal experiments, epidemiological studies and iodine prophylaxis has demonstrated a shift towards a rise in papillary carcinoma, but no clear relationship between overall thyroid cancer incidence and iodine intake.

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Congenital Hypothyroidism

Neonatal Network The Journal of Neonatal Nursing ◽

10.1891/11-t-699 ◽

2021 ◽

Vol 40 (6) ◽

pp. 377-385

Author(s):

Jacqueline Brady ◽

Ashton Cannupp ◽

Jordan Myers ◽

Amy J. Jnah

Keyword(s):

Thyroid Hormone ◽

Congenital Hypothyroidism ◽

Disease Process ◽

The United States ◽

Hormone Deficiency ◽

Hormone Production ◽

Newborn Screen ◽

Neurocognitive Outcomes ◽

Thyroid Development ◽

Overall Mortality

Congenital hypothyroidism (CH) is a disorder of thyroid hormone deficiency which develops secondary to incomplete thyroid development or inadequate thyroid hormone production. State-mandated newborn screening throughout the United States has increased the detection rate of CH, allowing for early intervention. Although the overall mortality rate of CH is low, delayed or omitted treatment can lead to devastating neurocognitive outcomes. As such, CH is regarded as the leading cause of preventable intellectual disability in children. Early identification, facilitated by astute neonatal nursing and medical care, is contingent upon an active working knowledge of the disease process and awareness of the limitations of the newborn screen.

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Cognitive and Behavioral Complications of Congenital Hypothyroidism

Cognitive and Behavioral Abnormalities of Pediatric Diseases ◽

10.1093/oso/9780195342680.003.0016 ◽

2010 ◽

Author(s):

Ruth D. Nass

Keyword(s):

Thyroid Hormone ◽

Thyroid Gland ◽

Brain Development ◽

Congenital Hypothyroidism ◽

Behavioral Problems ◽

Thyroid Stimulating Hormone ◽

Primary Hypothyroidism ◽

Normal Brain ◽

Gene Encoding ◽

Hormone Synthesis

Congenital hypothyroidism (CH) affects approximately 1 in 3,500 newborns. There is a female preponderance. In areas of iodine insufficiency, the incidence is higher, since iodine is a key element in the synthesis of thyroid hormone. Approximately 85% of CH cases are sporadic, whereas 15% are hereditary. Thyroid hormone is essential for normal pre- and postnatal brain development. The importance of in utero thyroid hormone status is demonstrated by the fact that maternal hypothyroidism during pregnancy is known to result in cognitive and motor deficits in the offspring (Forrest 2004; Zoeller and Rovet 2004). Congenital hypothyroidism is already expressed in fetal life; maternal T4, transferred via the placenta, is not sufficient for normal brain development (Forrest 2004; Haddow et al. 1999; Opazo et al. 2008; Pop and Vulsma 2005). Prior to newborn screening, CH that went undiagnosed and untreated for more than 3 months was associated with permanent and significant mental retardation, as well as behavioral problems. Outcome is now significantly better. Children with CH have normal intelligence, although subtle and specific cognitive and behavioral problems occur. Congenital hypothyroidism can be caused by primary hypothyroidism, due to a defect of the thyroid gland, or by central hypothyroidism secondary to defective hypothalamic or pituitary regulation of thyroid hormone. Several types of primary thyroid abnormalities may occur. Thyroid dysgenesis is the result of a missing, ectopic, or hypoplastic gland. Proteins that are crucial for normal thyroid gland development include the thyroid transcription factors PAX8, TTF1, TTF2, FOXE1 and the thyroid stimulating hormone (TSH) receptor gene. Thyroid dyshormonogenesis is generally due to an autosomal recessive genetic defect in any of many stages of thyroid hormone synthesis, secretion and transport (Moreno and Visser 2007). One in 50,000 children has autosomal dominant thyroid hormone resistance (RTH) due to a mutation in the gene encoding for the TRb thyroid receptors (Hauser et al. 1993; Weiss et al. 1993). Iodine deficiency can also cause CH (endemic cretinism) (DeLange et al. 2000). Gaudino and colleagues (2005) determined the etiology of CH in 49 non-athyroid cases.

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Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302004000100009 ◽

2004 ◽

Vol 48 (1) ◽

pp. 70-82 ◽

Cited By ~ 13

Author(s):

Jussara Vono-Toniolo ◽

Peter Kopp

Keyword(s):

Thyroid Hormone ◽

Congenital Hypothyroidism ◽

Early Recognition ◽

Wide Spectrum ◽

Hormone Deficiency ◽

Follicular Cells ◽

Thyroid Dysgenesis ◽

Hormone Synthesis ◽

Screening Programs ◽

Thyroid Follicular Cells

Congenital hypothyroidism affects about 1:3000-1:4000 infants. Screening programs now permit early recognition and treatment, thus avoiding the disastrous consequences of thyroid hormone deficiency on brain development. In about 85%, congenital hypothyroidism is associated with developmental defects referred to as thyroid dysgenesis. They include thyroid (hemi)agenesis, ectopic tissue and thyroid hypoplasia. Thyroid dysgenesis is usually sporadic; in only 2% it occurs in a familial fashion. It can be caused by mutations in transcription factors that are essential for the development and function of thyroid follicular cells. Thyroid hypoplasia can also result from resistance to TSH at the level of the thyrocytes. Defects in the steps required for thyroid hormone synthesis within thyroid follicular cells are referred to as dyshormonogenesis and account for about 10-15% of congenital hypothyroidism. In contrast to thyroid dysgenesis, affected patients typically present with goitrous enlargement of the thyroid. The defects leading to dyshormonogenesis typically display a recessive mode of inheritance. Careful clinical, biochemical and molecular analyses of patients with syndromic and non-syndromic forms of thyroid dysgenesis and dyshormonogenesis have significantly enhanced our understanding of the wide spectrum of pathogenetic mechanisms underlying congenital hypothyroidism and provide unique insights into the (patho)physiology of thyroid development and hormone synthesis.

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Thyroid hormones and brain development

Acta Endocrinologica ◽

10.1530/eje.0.1330390 ◽

1995 ◽

Vol 133 (4) ◽

pp. 390-398 ◽

Cited By ~ 277

Author(s):

Juan Bernal ◽

Jacques Nunez

Keyword(s):

Gene Expression ◽

Cell Differentiation ◽

Thyroid Hormone ◽

Thyroid Hormones ◽

Brain Development ◽

Neuronal Differentiation ◽

Cell Biology ◽

Physiological Role ◽

Hormone Deficiency ◽

Mammalian Brain

Bernal J, Nunez J. Thyroid hormones and brain development. Eur J Endocrinol 1995;133:390–8. ISSN 0804–4643 Thyroid hormone is a major physiological regulator of mammalian brain development. Cell differentiation, migration and gene expression are altered as a consequence of thyroid hormone deficiency or excess. The physiological role of thyroid hormone can perhaps be defined so as to ensure the timed coordination of different developmental events through specific effects on the rate of cell differentiation and gene expression. All triiodothyronine (T3) receptor isoforms are expressed in the brain and their spatial and temporal patterns of expression suggest unique and complementary functions for the different isoforms. Cell biology studies suggest a role for T3 and its receptors in oligodendroglial and neuronal differentiation and the control of cell death. Some of the effects on neuronal differentiation might be due to an action of thyroid hormone on the production of neurotropins and their receptors. In recent years a number of T3-dependent genes have been identified in the rat brain, such as myelin protein-encoding genes or specific neuronal genes, and thyroid hormone-responsive elements have been demonstrated in some of these genes. The identification of the gene network regulated by thyroid hormone during brain development, the elucidation of the mechanism of regulation and the clarification of the physiological roles of the regulated genes remain major goals for future studies. Jacques Nunez, INSERM U282. Hôpital Henri Mondor, 94010 Créteil, France

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A retrospective study of thyroid hormone in Pediatrics: relationships with growth hormone correlation with effects of diabetes in Riyadh, Saudi Arabia

10.5742/mewfm.2021.94157 ◽

2021 ◽

Vol 20 (11) ◽

Author(s):

Faisal Mujeb Alshareef ◽

Abdullah Hamad Alfaris ◽

Nouryah Abdulaziz Alhafez ◽

Alanoud Saleh Albulosh ◽

Abdulaziz Mshaal Aljuhni ◽

...

Keyword(s):

Growth Hormone ◽

Saudi Arabia ◽

Retrospective Study ◽

Thyroid Hormone ◽

Growth Hormone Deficiency ◽

Blood Sugar ◽

Congenital Hypothyroidism ◽

Blood Sugar Level ◽

Hormone Deficiency ◽

Control Group

Background: Inadequate Thyroid Hormone at birth in newborns is known as Congenital Hypothyroidism (CH) and it has a critical role in their growth and brain development. As a result, untreated CH and abnormal GH/IGF1 levels can lead to failure to thrive, osteoporosis, and Diabetic Retinopathies, among other problems. This retrospective study examines the chances of developing growthhormone disruption and Diabetes Mellitus in patients diagnosed with Congenital Hypothyroidism at the Security Forces Hospital in Riyadh, Saudi Arabia. Methodology: A retrospective chart review of growth hormone deficient (GHD) patients was done at the security force hospital in Riyadh, Saudi Arabia. The data was collected from the medical records of the patients. The study included all patients with growth hormone deficiency (GHD) who had complete clinical, diagnostic and treatment data. Result: At the beginning of the research, 287 growth hormone-deficient (GHD) children ranging in age from 1 to 15 years old were evaluated for diabetes. A total of 151 (52.6%) of the 287 patients got levothyroxine therapy, while the remaining 136 (47.4%) did not (control group). Because the p-value <0.05 (t(149) = 1.165, p = 0.246), the mean difference in blood sugar level changes is not statistically significant (t(149) = 1.165, p = 0.246). Conclusion: We found that levothyroxine therapy has no discernible effect on blood sugar level fluctuations in males and females. Key words: Growth hormone deficiency, Kingdom of Saudi Arabia, Diabetes.

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Thyroid disease in newborns, infants, and children

Oxford Textbook of Endocrinology and Diabetes ◽

10.1093/med/9780199235292.003.3273 ◽

2011 ◽

pp. 557-571 ◽

Cited By ~ 1

Author(s):

A.S. Paul van Trotsenburg ◽

Thomas Vulsma

Keyword(s):

Cell Migration ◽

Cell Differentiation ◽

Thyroid Hormone ◽

Young Children ◽

Brain Development ◽

Glial Cell ◽

Congenital Hypothyroidism ◽

Neural Tube ◽

Thyroid Disease ◽

Older Children

There are good reasons to describe congenital hypothyroidism and hyperthyroidism separately from acquired thyroid diseases because the risks of a disturbed thyroid hormone supply in young children are clearly different from the risks in older children or adults. For adequate metabolism, vertebrates with a higher degree of development, or a more complex ontogeny, are highly dependent on thyroid hormone. Nevertheless, humans appear to be able to ‘vegetate’ for years in the absence of this hormone. After resumption of hormone supply the metabolism normalizes again. However, brain development in young children does not. With the exception of the development of the neural tube, thyroid hormone is involved in regulation of later events, such as cell migration and the formation of cortical layers, and in neuronal and glial cell differentiation. Thyroid hormone also controls differentiation of not only neurons and oligodendrocytes, but also astrocytes and microglia (1).

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