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Congenital hypothyroidism: insights into pathogenesis and treatment
Christine E Cherella1, Ari J Wassner1
1Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 USA.
Insights
Congenital hypothyroidism (CH) affects 1 in 2000 newborns. Research is ongoing to understand the neurodevelopmental risks of mild CH and its genetic causes, particularly involving the hypothalamic-pituitary-thyroid axis.
Area of Science:
- Endocrinology
- Genetics
- Pediatrics
Background:
- Congenital hypothyroidism (CH) is a condition present at birth affecting thyroid hormone production.
- Newborn screening has reduced severe intellectual disability from CH, but increased detection of milder forms raises questions about risks and treatment.
- The incidence of CH appears to be rising, yet the causes remain largely unknown.
Purpose of the Study:
- To review current understanding of congenital hypothyroidism, focusing on neurodevelopmental risks in mild cases.
- To explore recent advancements in identifying genetic causes of CH and their implications for the hypothalamic-pituitary-thyroid axis.
- To highlight areas needing further research for optimal management of infants with CH.
Main Methods:
- Literature review of recent studies on congenital hypothyroidism.
- Analysis of genetic research identifying novel genes and pathways involved in CH.
- Synthesis of evidence regarding neurodevelopmental outcomes and treatment efficacy in mild CH.
Main Results:
- Conflicting evidence exists on neurodevelopmental risks associated with mild CH, necessitating further investigation.
- Genetic research has identified new genes, such as *IGSF1*, impacting the hypothalamic-pituitary-thyroid axis and contributing to CH.
- Increasing evidence suggests polygenic inheritance, involving combinations of rare variants, may underlie a significant portion of primary CH.
Conclusions:
- Optimal management strategies for infants with mild CH require further definition.
- Understanding the genetic underpinnings of CH is crucial for elucidating thyroid axis development and function.
- Continued research is essential to address the rising incidence and complex etiology of congenital hypothyroidism.
Abstract:
Congenital hypothyroidism occurs in approximately 1 in 2000 newborns and can have devastating neurodevelopmental consequences if not detected and treated promptly. While newborn screening has virtually eradicated intellectual disability due to severe congenital hypothyroidism in the developed world, more stringent screening strategies have resulted in increased detection of mild congenital hypothyroidism. Recent studies provide conflicting evidence about the potential neurodevelopmental risks posed by mild congenital hypothyroidism, highlighting the need for additional research to further define what risks these patients face and whether they are likely to benefit from treatment. Moreover, while the apparent incidence of congenital hypothyroidism has increased in recent decades, the underlying cause remains obscure in most cases. However, ongoing research into genetic causes of congenital hypothyroidism continues to shed new light on the development and physiology of the hypothalamic-pituitary-thyroid axis. The identification of IGSF1 as a cause of central congenital hypothyroidism has uncovered potential new regulatory pathways in both pituitary thyrotropes and gonadotropes, while mounting evidence suggests that a significant proportion of primary congenital hypothyroidism may be caused by combinations of rare genetic variants in multiple genes involved in thyroid development and function. Much remains to be learned about the origins of this common disorder and about the optimal management of less severely-affected infants.