DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

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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Infants Diagnosed with Athyreosis on Scintigraphy May Have a Gland Present on Ultrasound and Have Transient Congenital Hypothyroidism

Hormone Research in Paediatrics ◽

10.1159/000514989 ◽

2021 ◽

pp. 1-8

Author(s):

Niamh McGrath ◽

Colin Patrick Hawkes ◽

Stephanie Ryan ◽

Philip Mayne ◽

Nuala Murphy

Keyword(s):

Thyroid Gland ◽

Congenital Hypothyroidism ◽

Thyroid Tissue ◽

Thyroid Stimulating Hormone ◽

Thyroid Ultrasound ◽

Free T4 ◽

Median Serum ◽

Thyroid Glands ◽

Rule Out

Scintigraphy using technetium-99m (99mTc) is the gold standard for imaging the thyroid gland in infants with congenital hypothyroidism (CHT) and is the most reliable method of diagnosing an ectopic thyroid gland. One of the limitations of scintigraphy is the possibility that no uptake is detected despite the presence of thyroid tissue, leading to the spurious diagnosis of athyreosis. Thyroid ultrasound is a useful adjunct to detect thyroid tissue in the absence of 99mTc uptake. Aims: We aimed to describe the incidence of sonographically detectable in situ thyroid glands in infants scintigraphically diagnosed with athyreosis using 99mTc and to describe the clinical characteristics and natural history in these infants. Methods: The newborn screening records of all infants diagnosed with CHT between 2007 and 2016 were reviewed. Those diagnosed with CHT and athyreosis confirmed on scintigraphy were invited to attend a thyroid ultrasound. Results: Of the 488 infants diagnosed with CHT during the study period, 18/73 (24.6%) infants with absent uptake on scintigraphy had thyroid tissue visualised on ultrasound (3 hypoplastic thyroid glands and 15 eutopic glands). The median serum thyroid-stimulating hormone (TSH) concentration at diagnosis was significantly lower than that in infants with confirmed athyreosis (no gland on ultrasound and no uptake on scintigraphy) (74 vs. 270 mU/L), and median free T4 concentration at diagnosis was higher (11.9 vs. 3.9 pmol/L). Six of 10 (60%) infants with no uptake on scintigraphy but a eutopic gland on ultrasound had transient CHT. Conclusion: Absent uptake on scintigraphy in infants with CHT does not rule out a eutopic gland, especially in infants with less elevated TSH concentrations. Clinically, adding thyroid ultrasound to the diagnostic evaluation of infants who have athyreosis on scintigraphy may avoid committing some infants with presumed athyreosis to lifelong levothyroxine treatment.

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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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Diagnosis and Management of Central Congenital Hypothyroidism

Frontiers in Endocrinology ◽

10.3389/fendo.2021.686317 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peter Lauffer ◽

Nitash Zwaveling-Soonawala ◽

Jolanda C. Naafs ◽

Anita Boelen ◽

A. S. Paul van Trotsenburg

Keyword(s):

Thyroid Hormone ◽

Thyroid Gland ◽

Congenital Hypothyroidism ◽

Neonatal Period ◽

Neurodevelopmental Outcome ◽

Pituitary Hormone ◽

Feeding Problems ◽

Severe Condition ◽

Diagnosis And Management ◽

Prolonged Jaundice

Central congenital hypothyroidism (CH) is defined as thyroid hormone (TH) deficiency at birth due to insufficient stimulation by the pituitary of the thyroid gland. The incidence of central CH is currently estimated at around 1:13,000. Central CH may occur in isolation, but in the majority of cases (60%) it is part of combined pituitary hormone deficiencies (CPHD). In recent years several novel genetic causes of isolated central CH have been discovered (IGSF1, TBL1X, IRS4), and up to 90% of isolated central CH cases can be genetically explained. For CPHD the etiology usually remains unknown, although pituitary stalk interruption syndrome does seem to be the most common anatomic pituitary malformation associated with CPHD. Recent studies have shown that central CH is a more severe condition than previously thought, and that early detection and treatment leads to good neurodevelopmental outcome. However, in the neonatal period the clinical diagnosis is often missed despite hospital admission because of feeding problems, hypoglycemia and prolonged jaundice. This review provides an update on the etiology and prognosis of central CH, and a practical approach to diagnosis and management of this intriguing condition.

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Thyroiditis in Children

Pediatrics in Review ◽

10.1542/pir.11.6.184 ◽

1989 ◽

Vol 11 (6) ◽

pp. 184-191

Author(s):

Laura K. Bachrach ◽

Thomas P. Foley

Keyword(s):

Thyroid Gland ◽

Sick Child ◽

Treatment Strategies ◽

Disease Process ◽

Feedback System ◽

Diagnostic Techniques ◽

Thyroid Stimulating Hormone ◽

Endocrine Disorders ◽

Asymptomatic Child ◽

Hormone Production

Thyroiditis ranks with diabetes as the most common of the endocrine disorders of childhood. The term encompasses all forms of thyroid gland inflammation and infection, although chronic lymphocytic thynoiditis is overwhelmingly the most frequent. Thyroiditis may appear as a mass in the neck of an asymptomatic child or it may be a painful, erythematous goiter in a sick child. The affected thyroid gland may be small on large, with varying degrees of dysfunction. Most commonly, thyroiditis causes euthyroid function, although the disease process can result in transient or permanent thyroid dysfunction. The causes of thyroiditis in childhood, as well as the less common thyroid disorders in the differential diagnosis of goiter, are listed in Table 1. Thyroid physiology and pathophysiology will be discussed briefly to explain the rationale for diagnostic studies and treatment strategies. The more recent diagnostic techniques and therapeutic controversies regarding thyroiditis will be included. The goal is to provide the clinician with renewed awareness of this most common pediatric problem. THYROID PHYSIOLOGY Thyroid hormone production is regulated by a classical negative feedback system (Fig 1). Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and secretion of thyroid-stimulating hormone (TSH) from the pituitary. TSH, in turn, stimulates production and release of thyroxine (T4) and triiodothyronine (T3).

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Consequences of the Use of Low Blood-spot Thyroid-stimulating Hormone Cut-offs for the Neonatal Screening of Congenital Hypothyroidism

European Endocrinology ◽

10.17925/ee.2009.05.00.64 ◽

2009 ◽

Vol 05 (0) ◽

pp. 64

Author(s):

Luca Persani ◽

Davide Calebiro ◽

◽

Keyword(s):

Congenital Hypothyroidism ◽

Neonatal Screening ◽

Thyroid Stimulating Hormone ◽

Italian Population ◽

Neonatal Hypothyroidism ◽

Lombardy Region ◽

Increased Risk ◽

The Impact ◽

Blood Spot ◽

Stimulating Hormone

The consequences of using low blood-spot thyroid-stimulating hormone (b-TSH) cut-off values for newborn screening of congenital hypothyroidism (CH) are largely unknown. Therefore, the impact on CH epidemiology and classification generated by the introduction in our Italian region of a low b-TSH cut-off during 1999–2005 was retrospectively examined. This work was recently performed in collaboration with the Laboratory for Neonatal Screening and the Principal Follow-up Centre of the Lombardy region. The incidence of CH in this Italian population was 1:1,446 live births, with a predominance of functional over morphogenetic defects. The use of low b-TSH cut-offs allowed the detection of an unsuspected number of children with neonatal hypothyroidism, evolving to mild permanent thyroid dysfunction later in life. Premature birth was associated with a three- to five-fold increased risk of CH with glandin situ.

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Effect of hypophysectomy by partial decapitation and treatment with thiourea on iodine metabolism in the developing chick embryo

Journal of Endocrinology ◽

10.1677/joe.0.0980113 ◽

1983 ◽

Vol 98 (1) ◽

pp. 113-119 ◽

Cited By ~ 2

Author(s):

Nicole Daugèras-Bernard ◽

François Lachiver

Keyword(s):

Thyroid Gland ◽

Chick Embryo ◽

Pituitary Gland ◽

Direct Action ◽

Thyroid Stimulating Hormone ◽

Yolk Sac ◽

Pituitary Hormone ◽

Iodine Metabolism ◽

Tsh Secretion ◽

And Control

The hypothesis of an action of the pituitary gland of the developing chick embryo in the transfer of iodide from the yolk of the egg to the circulation of the embryo, through the yolk sac, was tested. Plasma iodide levels and thyroidal iodine contents were determined in hypophysectomized (by partial decapitation), thiourea-injected and control embryos. From day 11 of incubation these parameters were always lower in the 'hypophysectomized' embryos than in controls, and plasma iodide levels of the thiourea-treated embryos were higher than those of controls. These results indicate a reduced iodide transfer from the yolk to the 'hypophysectomized' embryo, and an increased iodide transfer to the thioureatreated embryo. This occurred in spite of a reduced thyroid hormonal secretion in both series. The pituitary gland could therefore have a direct action (not through the thyroid gland) at the yolk sac level, to augment the transfer of iodide from the yolk in intact embryos from day 11 to the end of incubation. Thyroid-stimulating hormone (TSH) could be the pituitary hormone acting at the yolk sac level, the increased iodide transfer observed in the thiourea-injected embryos being due to a raised TSH secretion responding to the decreased plasma thyroxine levels.

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Primary congenital hypothyroidism: defects in iodine pathways

Acta Endocrinologica ◽

10.1530/eje.0.1490247 ◽

2003 ◽

pp. 247-256 ◽

Cited By ~ 37

Author(s):

JJ de Vijlder

Keyword(s):

Thyroid Hormone ◽

Thyroid Gland ◽

Congenital Hypothyroidism ◽

Primary Hypothyroidism ◽

Special Importance ◽

Hormone Production ◽

Central Hypothyroidism ◽

Hormone Synthesis ◽

Diagnosis And Classification ◽

The Central Nervous System

The thyroid gland is the only source of thyroid hormone production. Thyroid hormone is essential for growth and development, and is of special importance for the development of the central nervous system. It was for that reason that neonatal screening on congenital hypothyroidism was introduced and is now performed in many countries. Defects in thyroid hormone production are caused by several disorders in hormone synthesis and in the development of the thyroid gland (primary hypothyroidism) or of the pituitary gland and hypothalamus (central hypothyroidism).This paper describes defects in the synthesis of thyroid hormone caused by disorders in the synthesis or iodination of thyroglobulin, leakage of iodinated proteins by a stimulated thyroid gland and the presence of abnormal iodoproteins, mainly iodinated albumin, in the thyroid gland and blood circulation. Circulating thyroglobulin and abnormal iodoproteins, as well as the breakdown products of these iodoproteins excreted in urine, are used for etiological diagnosis and classification. Moreover, our finding of an enzyme that catalyses the dehalogenation of iodotyrosines, which is important for iodine recycling and required for economical use of iodine, is also referred to.

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Recent advances in central congenital hypothyroidism

Journal of Endocrinology ◽

10.1530/joe-15-0341 ◽

2015 ◽

Vol 227 (3) ◽

pp. R51-R71 ◽

Cited By ~ 61

Author(s):

Nadia Schoenmakers ◽

Kyriaki S Alatzoglou ◽

V Krishna Chatterjee ◽

Mehul T Dattani

Keyword(s):

Congenital Hypothyroidism ◽

Pituitary Hormone ◽

Central Hypothyroidism ◽

Neonatal Hypothyroidism ◽

Neurodevelopmental Delay ◽

Screening Programs ◽

Pituitary Development ◽

Pituitary Thyroid Axis ◽

Life Threatening ◽

Tsh Deficiency

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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Newborn Screening for Congenital Hypothyroidism: Recommended Guidelines

PEDIATRICS ◽

10.1542/peds.80.5.745 ◽

1987 ◽

Vol 80 (5) ◽

pp. 745-749

Author(s):

◽

Keyword(s):

Newborn Screening ◽

Congenital Hypothyroidism ◽

North American ◽

Screening Method ◽

Developed Countries ◽

Thyroid Stimulating Hormone ◽

Primary Hypothyroidism ◽

Screening Programs ◽

The North ◽

Important Health

During the past decade newborn screening for congenital hypothyroidism has become an important health activity in most developed countries. These screening programs have not only benefited patients and their families but also have produced new information about the epidemiology, pathophysiology, diagnosis, and treatment of thyroid disease in infancy and childhood. During this period of implementation and growth of the screening programs, a variety of issues and questions arose. Some of these have been resolved, and some have not. The point has now been reached where collation of the combined experiences of the North American programs can address these issues. The reader should understand that what follows reflects current opinion and may require changes when the results of the next decade of screening are reviewed. SCREENING METHOD Thyroxine (T4) and Thyroid-Stimulating Hormone (TSH) Most North American programs use a two-tiered laboratory approach. An initial T4 measurement is followed by measurement of TSH in specimens with low T4 values. In addition to detecting infants with primary hypothyroidism (low or low normal T4 level with elevated TSH value; prevalence 1:3,500 to 4,500 newborns), this approach can also identify infants with thyroxine-binding globulin deficiency and some with hypothalamic-pituitary hypothyroidism (low or low normal T4 level with normal TSH value; prevalence 1:5,000 to 10,000 and 1:50,000 to 150,000 newborns, respectively). Programs that quantify T4 values also have the option of identifying newborns with hyperthyroxinemia (1:20,000 to 40,000 newborns). On the other hand, this approach will miss infants who have normal T4 values but elevated TSH values. Such infants are relatively commonplace in European programs where initial screening is done by measurement of TSH.

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Neonatal Hypothyroidism Detected by the Northwest Regional Screening Program

PEDIATRICS ◽

10.1542/peds.63.2.180 ◽

1979 ◽

Vol 63 (2) ◽

pp. 180-191 ◽

Cited By ~ 3

Author(s):

Stephen H. LaFranchi ◽

William H. Murphey ◽

Thomas P. Foley ◽

P. Reed Larsen ◽

Neil R.M. Buist

Keyword(s):

Congenital Hypothyroidism ◽

Screening Program ◽

Clinical Signs ◽

Thyroid Stimulating Hormone ◽

Primary Hypothyroidism ◽

Screening Tests ◽

Serum Samples ◽

Neonatal Hypothyroidism ◽

Serum T4 ◽

Common Etiology

The Northwest Regional Screening Program to detect congenital hypothyroidism in infants born in Oregon, Montana, Alaska, and Idaho (combined birthrate of 69,000/yr) was added to our ongoing screening program in 1975. The program utilizes dried blood filter paper specimens collected routinely in the first few days of life in all four states and again at about 6 weeks of age in Oregon only. The screening tests consist of an initial thyroxine (T4) measurement; a thyroid-stimulating hormone (TSH) determination is performed on those specimens with T4 concentrations in the lowest 3% group. Serum samples obtained by venipuncture are requested for confirmation of the diagnosis. In the first two years of the program, 25 infants with primary hypothyroidism were detected among 110,667 infants screened, a frequency of 1:4,430. Fourteen cases of thyroxine-binding globulin deficiency were also detected, a frequency of 1:7,900. Using the T4 followed by TSH testing approach, the frequency of requests for repeat specimens was 0.4% in Oregon and 0.05% in the other states. The cost per specimen was $1.96. The majority of infants lacked clinical signs or symptoms of hypothyroidism; only one infant was clinically suspected of having hypothyroidism prior to detection. The most common neonatal symptoms were constipation, lethargy, and prolonged jaundice, while the most common physical signs were hypotonia, umbilical hernia, and large fontanels. Thyroid scans showed the most common etiology to be thyroid aplasia, followed by an ectopic gland, hypoplasia, and goitèr. Serum T4 concentrations were lowest in those infants with aplasia, intermediate in infants with an ectopic gland or hypoplasia, and normal in the infant with the goiter. Neonatal hypothyroidism varies in degree and has several different causes; the capacity to secrete thyroid hormone, the duration before hypothyroidism becomes clinically manifest, and possibly the eventual prognosis for intellectual function depend on the nature of the underlying cause. While the mean age at treatment was 59 days, the goal of diagnosing congenital hypothyroidism and treating affected infants by 1 month of age seems realistic.

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