Recent advances in central congenital hypothyroidism

Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR,IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic–pituitary–thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed.

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Role of the Thyrotropin-Releasing Hormone Stimulation Test in Diagnosis of Congenital Central Hypothyroidism in Infants

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2656 ◽

2008 ◽

Vol 93 (2) ◽

pp. 410-419 ◽

Cited By ~ 43

Author(s):

David A. van Tijn ◽

Jan J. M. de Vijlder ◽

Thomas Vulsma

Keyword(s):

Congenital Hypothyroidism ◽

System Development ◽

Nervous System Development ◽

Pituitary Hormone ◽

Trh Test ◽

Central Hypothyroidism ◽

Cerebral Magnetic Resonance Imaging ◽

Young Infants ◽

Type 3 ◽

Tsh Deficiency

Abstract 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.

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Approach to the Diagnosis and Treatment of Neonatal Hypothyroidism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-1175 ◽

2011 ◽

Vol 96 (10) ◽

pp. 2959-2967 ◽

Cited By ~ 84

Author(s):

Stephen H. LaFranchi

Keyword(s):

Newborn Screening ◽

Congenital Hypothyroidism ◽

Neurodevelopmental Outcome ◽

Diagnosis And Treatment ◽

Thyroid Function Tests ◽

Free T4 ◽

Neonatal Hypothyroidism ◽

Serum Free ◽

Screening Programs ◽

Diagnostic Studies

Abstract Congenital hypothyroidism, occurring in 1:3000 newborns, is one of the most common preventable causes of mental retardation. Neurodevelopmental outcome is inversely related to the age of diagnosis and treatment. Infants detected through newborn screening programs and started on l-T4 in the first few weeks of life have a normal or near-normal neurodevelopmental outcome. The recommended starting dose of l-T4 (10–15 μg/kg · d) is higher on a weight basis than the dose for children and adults. Tailoring the starting l-T4 dose to the severity of the hypothyroidism will normalize serum T4 and TSH as rapidly as possible. It is important to obtain confirmatory serum thyroid function tests before treatment is started. Further diagnostic studies, such as radionuclide uptake and scan and ultrasonography, may be performed to determine the underlying cause of hypothyroidism. Because results from these tests generally do not alter the initial treatment decision, however, these diagnostic studies are rarely indicated. The developing brain has a critical dependence on thyroid hormone for the first 2–3 yr of life; thus, monitoring occurs at more frequent intervals than in older children and adults. Serum free T4 and TSH should be checked at intervals frequent enough to ensure timely adjustment of l-T4 dosing and to keep serum free T4 and TSH levels in target ranges. Given the success of early detection and treatment of neonates with congenital hypothyroidism, a public health mandate should be to develop similar programs for the 75% of babies worldwide who are born in areas without newborn screening programs.

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A Newborn Falsely Suspected of Congenital Hypothyroidism due to Mutated Thyroxine-Binding Globulin with Low Binding Affinity

Hormone Research in Paediatrics ◽

10.1159/000516691 ◽

2021 ◽

pp. 1-5

Author(s):

Rutger C.C. Hengeveld ◽

Monique Albersen ◽

Michael A.H. Hadders ◽

Ilse Hellinga ◽

Hennie Bikker ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Neonatal Screening ◽

Screening Program ◽

Sequencing Analysis ◽

Free T4 ◽

Gene Encoding ◽

Central Hypothyroidism ◽

Thyroxine Binding Globulin ◽

Screening Programs ◽

Dna Sequencing Analysis

Introduction: Neonatal screening programs for congenital hypothyroidism (CH) have been implemented worldwide to facilitate early diagnosis and treatment. The Dutch neonatal CH screening is primarily based on the measurement of thyroxine (T4). When T4 is low, an additional thyroxine-binding globulin (TBG) measurement is performed to reduce the number of false-positive screening results due to harmless TBG deficiency. Here, we present a case of a rare functional TBG deficiency leading to a false suspicion of CH. Case Presentation: Neonatal screening in this patient revealed a decreased T4, normal TSH, and normal TBG concentration, suggesting central CH. However, free T4 was normal. DNA sequencing analysis revealed a novel, hemizygous mutation (c.139G>A) in SERPINA7, the gene encoding TBG, resulting in the substitution of the conserved amino acid alanine to threonine at position 27. Crystal structure analyses showed that this substitution has a detrimental effect on binding of T4 to TBG. Conclusions: The novel SERPINA7 variant in this patient led to a false suspicion of central hypothyroidism in the Dutch T4-based neonatal screening program. It is important to recognize patients with such TBG defects to prevent unnecessary additional testing and treatment.

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DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

Acta Endocrinologica ◽

10.1530/eje-18-0383 ◽

2018 ◽

Vol 179 (6) ◽

pp. R297-R317 ◽

Cited By ~ 21

Author(s):

C Peters ◽

A S P van Trotsenburg ◽

N Schoenmakers

Keyword(s):

Thyroid Gland ◽

Congenital Hypothyroidism ◽

Epidemiological Data ◽

Developed Countries ◽

Thyroid Stimulating Hormone ◽

Pituitary Hormone ◽

Hormone Production ◽

Neonatal Hypothyroidism ◽

Developmental Abnormalities ◽

Delayed Treatment

Congenital hypothyroidism (CH) may be primary, due to a defect affecting the thyroid gland itself, or central, due to impaired thyroid-stimulating hormone (TSH)-mediated stimulation of the thyroid gland as a result of hypothalamic or pituitary pathology. Primary CH is the most common neonatal endocrine disorder, traditionally subdivided into thyroid dysgenesis (TD), referring to a spectrum of thyroid developmental abnormalities, and dyshormonogenesis, where a defective molecular pathway for thyroid hormonogenesis results in failure of hormone production by a structurally intact gland. Delayed treatment of neonatal hypothyroidism may result in profound neurodevelopmental delay; therefore, CH is screened for in developed countries to facilitate prompt diagnosis. Central congenital hypothyroidism (CCH) is a rarer entity which may occur in isolation, or (more frequently) in association with additional pituitary hormone deficits. CCH is most commonly defined biochemically by failure of appropriate TSH elevation despite subnormal thyroid hormone levels and will therefore evade diagnosis in primary, TSH-based CH-screening programmes. This review will discuss recent genetic aetiological advances in CH and summarize epidemiological data and clinical diagnostic challenges, focussing on primary CH and isolated CCH.

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Neonatal Detection of Congenital Hypothyroidism of Central Origin

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-2444 ◽

2005 ◽

Vol 90 (6) ◽

pp. 3350-3359 ◽

Cited By ~ 73

Author(s):

David A. van Tijn ◽

Jan J. M. de Vijlder ◽

Bernard Verbeeten ◽

Paul H. Verkerk ◽

Thomas Vulsma

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Congenital Hypothyroidism ◽

Neonatal Screening ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Resonance Imaging ◽

Pituitary Hormone Deficiency ◽

Screening Programs ◽

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 T4-TSH-based neonatal CH screening protocol extended with T4 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.

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Newborn Screening for Congenital Hypothyroidism in Japan

International Journal of Neonatal Screening ◽

10.3390/ijns7030034 ◽

2021 ◽

Vol 7 (3) ◽

pp. 34

Author(s):

Kanshi Minamitani

Keyword(s):

Birth Weight ◽

Low Birth Weight ◽

Newborn Screening ◽

Congenital Hypothyroidism ◽

Failure To Thrive ◽

Thyroid Stimulating Hormone ◽

Low Birth Weight Infants ◽

Term Infants ◽

Screening Programs ◽

Screening Strategies

Congenital hypothyroidism (CH) is the most common preventable cause of intellectual impairment or failure to thrive by early identification and treatment. In Japan, newborn screening programs for CH were introduced in 1979, and the clinical guidelines for newborn screening of CH were developed in 1998, revised in 2014, and are currently undergoing further revision. Newborn screening strategies are designed to detect the elevated levels of thyroid stimulating hormone (TSH) in most areas of Japan, although TSH and free thyroxine (FT4) are often measured simultaneously in some areas. Since 1987, in order not to observe the delayed rise in TSH, additional rescreening of premature neonates and low birth weight infants (<2000 g) at four weeks of life or when their body weight reaches 2500 g has been recommended, despite a normal initial newborn screening. Recently, the actual incidence of CH has doubled to approximately 1:2500 in Japan as in other countries. This increasing incidence is speculated to be mainly due to an increase in the number of mildly affected patients detected by the generalized lowering of TSH screening cutoffs and an increase in the number of preterm or low birth weight neonates at a higher risk of having CH than term infants.

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Current and future perspective of newborn screening: an Indian scenario

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2015-0009 ◽

2016 ◽

Vol 29 (1) ◽

Cited By ~ 11

Author(s):

Gurjit Kaur ◽

Kiran Thakur ◽

Sandeep Kataria ◽

Teg Rabab Singh ◽

Bir Singh Chavan ◽

...

Keyword(s):

Health Care ◽

Congenital Adrenal Hyperplasia ◽

Newborn Screening ◽

Health Care System ◽

Congenital Hypothyroidism ◽

G6pd Deficiency ◽

Metabolic Disorders ◽

Adrenal Hyperplasia ◽

Screening Programs ◽

Care System

AbstractNewborn screening comprises a paramount public health program seeking timely detection, diagnosis, and intervention for genetic disorders that may otherwise produce serious clinical consequences. Today newborn screening is part of the health care system of developed countries, whereas in India, newborn screening is still in the toddler stage.We searched PubMed with the keywords newborn screening for metabolic disorders, newborn screening in India, and congenital disorder in neonates, and selected publications that seem appropriate.In India, in spite of the high birth rate and high frequency of metabolic disorders, newborn screening programs are not part of the health care system. At Union Territory, Chandigarh in 2007, newborn screening was initiated and is currently ongoing for three disorders, that is, congenital hypothyroidism, congenital adrenal hyperplasia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Prevalence of these disorders is found to be 1:1400 for congenital hypothyroidism, 1:6334 for congenital adrenal hyperplasia, and 1:80 for G6PD deficiency.Mandatory newborn screening for congenital hypothyroidism should be implemented in India, and other disorders can be added in the screening panel on the basis of region-wise prevalence. The objective of this review is to provide insight toward present scenario of newborn screening in India along with recommendations to combat the hurdles in the pathway of mandatory newborn screening.

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Should Screening Programs Be Perfect?

PEDIATRICS ◽

10.1542/peds.71.2.301 ◽

1983 ◽

Vol 71 (2) ◽

pp. 301-301

Author(s):

PHILIP R. WYATT

Keyword(s):

United States ◽

Health Care ◽

Early Detection ◽

New England ◽

Health Care System ◽

The United States ◽

Neonatal Hypothyroidism ◽

Screening Programs ◽

Care System

To the Editor.— The report of the New England Regional Screening Program1 on neonatal hypothyroidism is a stunning illustration of the vulnerability of screening programs. It is unfortunate that this experience will probably be used as an argument to minimize the input of screening programs in the health care system in the United States. The report illustrates that, in addition to the 2% of the screened population that eluded the program, 14 infants with hypothyroidism escaped the full benefits of early detection and treatment.

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Newborn Screening for Congenital Hypothyroidism: Recommended Guidelines

PEDIATRICS ◽

10.1542/peds.91.6.1203 ◽

1993 ◽

Vol 91 (6) ◽

pp. 1203-1209

Author(s):

Keyword(s):

Thyroid Hormone ◽

Newborn Screening ◽

Congenital Hypothyroidism ◽

Placental Transfer ◽

Fetal Brain ◽

Iodothyronine Deiodinase ◽

Screening Programs ◽

Organ Systems ◽

Fetal Hypothyroidism ◽

Maternal Thyroid

Congenital hypothyroidism (CH) represents one of the most common preventable causes of mental retardation. The fetal hypothalamic-pituitary-thyroid axis begins to function by midgestation and is mature in the term infant at delivery. If fetal hypothyroidism develops, untoward effects may be demonstrated in certain organ systems, including the central nervous system and skeleton. However, most infants with CH appear normal at birth. Recent data suggest that the hypothyroid fetus is protected to a certain extent by placental transfer of maternal thyroid hormone; serum thyroxine (T4) levels in the cord blood of athyroid fetuses approximate one third of maternal levels.1 In addition, studies in animal models of hypothyroidism demonstrate increased levels of brain iodothyronine deiodinase, the enzyme which converts T4 to triiodothyronine (T3). In the hypothyroid fetus, this increased enzyme acting on T4 of maternal origin is sufficient to produce near normal fetal brain T3 concentrations.2 Thus, it appears that early detection and treatment of congenital hypothyroidism should have the potential to completely reverse the effects of fetal hypothyroidism in all but the most severe cases, for example, athyreotic infants born to mothers with thyroid problems resulting in inadequate placental transfer of maternal thyroid hormone. Since the development of pilot screening programs for CH in Quebec and Pittsburgh in 1974,3 newborn screening for CH has become routine in essentially all developed countries of the world and is under development in Eastern Europe, South America, Asia, and Africa. In North America it is estimated that more than 5 million newborns are screened, with approximately 1400 infants with congenital hypothyroidism detected annually.

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APPROACH TO THE PATIENT Fetal and neonatal thyroid dysfunction

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab747 ◽

2021 ◽

Author(s):

Juliane Léger ◽

Clemence Delcour ◽

Jean-Claude Carel

Keyword(s):

Developed Countries ◽

Antithyroid Drugs ◽

Pituitary Hormone ◽

Rare Disorders ◽

Neonatal Hypothyroidism ◽

Thyrotropin Receptor Antibodies ◽

Neonatal Hyperthyroidism ◽

History Of ◽

Receptor Antibodies

Abstract Fetal and neonatal dysfunctions include rare serious disorders involving abnormal thyroid function during the second half of gestation, which may persist throughout life, as for most congenital thyroid disorders, or be transient, resolving in the first few weeks of life, as in autoimmune hyperthyroidism or hypothyroidism and some cases of congenital hypothyroidism (CH) with the thyroid gland in situ. Primary CH is diagnosed by neonatal screening, which has been implemented for 40 years in developed countries and should be introduced worldwide, as early treatment prevents irreversible neurodevelopmental delay.Central CH is a rarer entity occurring mostly in association with multiple pituitary hormone deficiencies. Other rare disorders impair the action of thyroid hormones. Neonatal Grave’s disease (GD) results from the passage of thyrotropin receptor antibodies (TRAb) across the placenta, from mother to fetus. It may affect the fetuses and neonates of mothers with a history of current or past GD, but hyperthyroidism develops only in those with high levels of stimulatory TRAb activity. The presence of antibodies predominantly blocking TSH receptors may result in transient hypothyroidism, possibly followed by neonatal hyperthyroidism, depending on the balance between the antibodies present. Antithyroid drugs taken by the mother cross the placenta, treating potential fetal hyperthyroidism,but they may also cause transient fetal and neonatal hypothyroidism. Early diagnosis and treatment are key to optimizing the child’s prognosis. This review focuses on the diagnosis and management of these patients during the fetal and neonatal periods. It includes the description of a case of fetal and neonatal autoimmune hyperthyroidism.

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