Congenital Hypothyroidism: Screening and Management.

ABSTRACT: Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Prompt diagnosis by newborn screening (NBS) leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet established in all countries globally. Seventy percent of neonates worldwide do not undergo NBS.The initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism.Newborn screening alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.

Congenital Hypothyroidism: Screening and Management.

Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Newborn screening (NBS) for CH should be performed in all infants. Prompt diagnosis by NBS leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet practiced in all countries globally. Seventy percent of neonates worldwide do not undergo NBS. The recommended initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and with free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding the detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth-weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism. NBS alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.

History of the Thyroid.

The history of the thyroid dates from 2697 BCE when the "Yellow Emperor" Hung Ti described the use of seaweed to treat goiter. The English name "thyroid" was coined by Thomas Wharton in 1656 from the Greek word for a shield. Bernard Courtois discovered iodine in 1811 when he noted a residual purplish ash while burning seaweed. Robert Graves is known for his classic 1835 report of "palpitations, goiter, and exophthalmos" in three women, but Caleb Parry observed the same clinical features in 1786. The clinical syndrome we now recognize as hypothyroidism was characterized as "myxoedema" in 1878 by William Ord at St. Thomas Hospital. In 1891, George Murray reported that injection of thyroid extract from sheep led to improvement in symptoms in a woman with myxedema. Thomas Kocher, who reported that patients with goiter who underwent complete thyroidectomy developed cachexia strumipriva, was awarded the Nobel Prize in Physiology and Medicine in 1909. Edward Kendall discovered "thyroxin" on Christmas day in 1914. Studies by David Marine that iodine treatment prevented endemic goiter led to salt iodination, which has largely eradicated endemic cretinism. In 1973, Jean Dussault reported detection of congenital hypothyroidism by screening newborn populations.

Thyroid Function in Preterm/Low Birth Weight Infants: Impact on Diagnosis and Management of Thyroid Dysfunction.

Maternal thyroid hormone crosses the placenta to the fetus beginning in the first trimester, likely playing an important role in fetal development. The fetal thyroid gland begins to produce thyroid hormone in the second trimester, with fetal serum T4 levels gradually rising to term. Full maturation of the hypothalamic-pituitary-thyroid (HPT) axis does not occur until term gestation or the early neonatal period. Postnatal thyroid function in preterm babies is qualitatively similar to term infants, but the TSH surge is reduced, with a corresponding decrease in the rise in T4 and T3 levels. Serum T4 levels are reduced in proportion to the degree of prematurity, representing both loss of the maternal contribution and immaturity of the HPT axis. Other factors, such as neonatal drugs, e.g., dopamine, and non-thyroidal illness syndrome (NTIS) related to co-morbidities contribute to the "hypothyroxinemia of prematurity". Iodine, both deficiency and excess, may impact thyroid function in infants born preterm. Overall, the incidence of permanent congenital hypothyroidism in preterm infants appears to be similar to term infants. However, in newborn screening (NBS) that employ a total T4-reflex TSH test approach, a higher proportion of preterm babies will have a T4 below the cutoff, associated with a non-elevated TSH level. In NBS programs with a primary TSH test combined with serial testing, there is a relatively high incidence of "delayed TSH elevation" in preterm neonates. On follow-up, the majority of these cases have transient hypothyroidism. Preterm/LBW infants have many clinical manifestations that might be ascribed to hypothyroidism. The question then arises whether the hypothyroxinemia of prematurity, with thyroid function tests compatible with either non-thyroidal illness syndrome or central hypothyroidism, is a physiologic or pathologic process. In particular, does hypothyroxinemia contribute to the neurodevelopmental impairment common to preterm infants? Results from multiple studies are mixed, with some randomized controlled trials in the most preterm infants born <28 weeks gestation appearing to show benefit. This review will summarize fetal and neonatal thyroid physiology, thyroid disorders specific to preterm/LBW infants and their impact on NBS for congenital hypothyroidism, examine treatment studies, and finish with comments on unresolved questions and areas of controversy.

Outcome of Newborn Screening for Congenital Adrenal Hyperplasia at Two Time Points.

BACKGROUND/AIMS: Screening newborns for congenital adrenal hyperplasia (CAH) is problematic owing to the dynamic changes in serum 17-hydroxyprogesterone (17-OHP) levels following birth. Our study objectives were to determine the accuracy of screening, severity of CAH, and biochemical and clinical outcomes of cases detected by our program which collects specimens at 2 time periods following birth. METHODS: We reviewed all CAH cases detected in the Northwest Regional Newborn Screening Program from 2003 through 2017. Comparison was made of screening and confirmatory serum 17-OHP, neonatal, maternal, and follow-up auxologic data, steroid treatment doses, and 21-hydroxylase genotype in cases detected on the first versus second test. RESULTS: Out of 164 cases of CAH, 25% were detected on the second screen. Infants detected on the second test had a lower screening 17-OHP (147 vs. 294 ng/mL), lower confirmatory serum 17-OHP (7,772 vs. 14,622 ng/dL), and were more likely to have simple virilizing CAH. There were no identifiable neonatal or maternal factors associated with detection on the second test. 21-Hydroxylase genotypes overlapped in first versus second screen cases. CONCLUSION: Early collection of specimens necessitated by early discharge resulted in milder CAH cases falling below the screening 17-OHP cutoff. In our program 25% of cases were detected on a routine second screen.

Newborn Screening in the US May Miss Mild Persistent Hypothyroidism.

OBJECTIVE: To determine if newborn screening (NBS) programs for congenital hypothyroidism in the US use thyroid-stimulating hormone (TSH) cutoffs that are age adjusted to account for the physiologic 4-fold reduction in TSH concentrations over the first few days of life. STUDY DESIGN: All NBS programs in the US were contacted and asked to provide information on their NBS protocols, TSH cutoffs, and whether these cutoffs were age adjusted. RESULTS: Of 51 NBS programs, 28 request a repeat specimen if the initial eluted serum TSH concentration is mildly increased (between the cutoff and a median upper limit of 50 mU/L), whereas 14 programs perform a routine second screen in all infants. Although these specimens are typically collected between 1 week and 1 month of life, 16 of the 28 programs with a discretionary second test and 8 of 14 programs with a routine second test do not have age-adjusted TSH cutoffs after the first 48 hours of life. CONCLUSIONS: There is variation in NBS practices for screening for congenital hypothyroidism across the US, and many programs do not adjust the TSH cutoff beyond the first 2 days of life. Samples are processed when received from older infants, often to retest borderline initial results. This approach will miss congenital hypothyroidism in infants with persistent mild TSH elevations. We recommend that all NBS programs provide age-adjusted TSH cutoffs, and suggest developing a standard approach to screening for congenital hypothyroidism in the US.

Detecting Congenital Central Hypothyroidism by Newborn Screening: Difficulty in Distinguishing from Congenital Thyroxine-Binding Globulin Deficiency.

BACKGROUND/AIMS: Congenital central hypothyroidism (CH-C) can be detected on newborn screening (NBS) by programs using thyroxine (T4)-reflex thyroid-stimulating hormone (TSH) test approach. CH-C must be distinguished from T4-binding globulin (TBG) deficiency. We sought to determine whether thyroid function tests reliably separate CH-C from TBG deficiency. METHODS: We analyzed NBS and serum free and total T4, T3 resin uptake (T3RU) or TBG, and TSH for infants in the Northwest Regional NBS Program (NWRSP) between the years 2008 and 2015 with either CH-C or TBG deficiency. RESULTS: We discovered a significant overlap in T3RU and TBG levels amongst 21 cases of CH-C and 250 cases of TBG deficiency. Mean serum TBG levels were lower in CH-C cases (20.3 µg/mL, range 14.2-33.3) than what is reported in healthy infants (28.6 µg/mL, range 19.1-44.6). Serum free T4 was lower in CH-C cases than TBG deficiency but did not always differentiate between the two conditions. CONCLUSION: CH-C benefits from detection on NBS but must be distinguished from TBG deficiency. The diagnosis of CH-C rests solely on subnormal serum free T4, but is supported by the demonstration of other pituitary hormone deficiencies. As an overlap exists, serum TBG (or T3RU) levels do not play a role in the diagnosis of CH-C.

Characterization of Thyroid Abnormalities in a Large Cohort of Children with Down Syndrome
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BACKGROUND/AIMS: Thyroid disease is a common comorbidity in individuals with Down syndrome (DS), but historical studies have multiple limitations. We assessed thyroid abnormalities in a large cohort of children with DS. METHODS: Retrospective records review from a single institution. Calculated prevalence of common thyroid abnormalities and associations with common comorbidities. RESULTS: Among 508 patients, 120 (24%) had a thyroid-related diagnosis, the majority having elevated thyrotropin treated with levothyroxine. A Kaplan-Meier estimate projects that 50% have thyroid disorder by adulthood, with 20% of hypothyroidism diagnosed before the age of 6 months. When tested, approximately 50% had positive antithyroid antibodies, though this rate was 100% in overt hypothyroidism. There was no association between congenital or acquired hypothyroidism and common comorbidities. CONCLUSION: Thyroid disease in DS is more common and occurs earlier than in the general population, and is often transient. Thyroid disease is unrelated to gender, obesity, or other comorbidities. Apart from overt hypothyroidism, much of hypothyroidism in DS appears unrelated to autoimmunity; we recommend checking of antithyroid antibodies only in select cases. An additional screen for thyroid disease between the newborn screen and the 6-month well-child visit will detect early cases of hypothyroidism who passed their newborn screen.
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Transient versus Permanent Congenital Hypothyroidism after the Age of 3 Years in Infants Detected on the First versus Second Newborn Screening Test in Oregon, USA.

BACKGROUND/AIMS: The newborn screening (NBS) program in Oregon, USA, collects two routine specimens in all infants. The aim of our study was to determine the incidence of permanent versus transient congenital hypothyroidism (CH) in infants detected on the first versus second screening test. METHODS: Thyroid function was determined in infants after the age of 3 years diagnosed with CH and born in Oregon between 2005 and 2011. Permanent hypothyroidism was defined as a TSH rise >10 mIU/ml after the first year on treatment or a TSH rise >6 mIU/ml with temporary discontinuation of l-thyroxine after the age of 3 years. RESULTS: Of the cases detected on the first test, 72 of 87 (83%) were permanent and 15 of 87 (17%) were transient, while of the cases detected on the second test, 5 of 22 (23%) were permanent and 17 of 22 (77%) were transient (OR 16.3, p < 0.001). There was a female preponderance detected on the first screen versus a male preponderance on the second screen. Blood spot and serum thyroid function tests at diagnosis, before treatment, were not meaningfully different between the two groups. The mean l-thyroxine dose at the age of 3 years was greater on the first screen: 61.2 versus 36.6 µg/day. CONCLUSIONS: Infants detected on the second NBS specimen have a higher incidence of transient CH. © 2016 S. Karger AG, Basel.

Screening for congenital hypothyroidism: a worldwide view of strategies.

Detection by newborn screening (NBS) and treatment of babies with congenital hypothyroidism (CH) has largely eliminated the intellectual disability caused by this disorder. Lowering of the screening TSH cutoff and changes in birth demographics have been associated with an approximate doubling of the incidence of CH, from 1:3500 to 1:1714. The additional cases detected by lowering of the TSH cutoff tend to have milder hypothyroidism, with imaging often demonstrating a eutopic, "gland in-situ", and some cases turn out to have transient CH. Based on our search for current screening programs, approximately 71 percent of babies worldwide are not born in an area with an established NBS program, despite the existence of screening for over five decades in developed countries. Thus, the majority of babies with CH worldwide are not detected and treated early, such that the economic burden of retardation owing to CH remains a significant public health challenge.

Detection of neonates with mild congenital hypothyroidism (primary) or isolated hyperthyrotropinemia: an increasingly common management dilemma.

Anywhere from 10% to 40% of neonates detected by newborn screening programs have mild congenital hypothyroidism (thyroid-stimulating hormone [TSH] 6 to 20 mU/l with borderline low free T4) or isolated hyperthyrotropinemia. The increasing frequency of such cases appears to be chiefly the result of lowering screening TSH cutoffs. In some cases, the etiology is a mild form of dysgenesis or dyshormonogenesis; most cases, however, on imaging have gland in situ of unexplained etiology. Re-evaluation after age 3 years shows some with transient hypothyroidism, a minority with permanent hypothyroidism, while the majority have persistent, mild TSH elevation and normal free T4. There is limited data on neurodevelopmental outcome to guide management. In cases where the TSH is trending down and free T4 is normal, we recommend re-checking serum TSH and free T4 at weekly intervals. If serum TSH does not normalize by 4 weeks of age, we recommend treatment, with re-evaluation after age 2-3 years.

Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein.

CONTEXT: Microcephalic primordial dwarfism (MPD) is a rare, severe form of human growth failure in which growth restriction is evident in utero and continues into postnatal life. Single causative gene defects have been identified in a number of patients with MPD, and all involve genes fundamental to cellular processes including centrosome functions. OBJECTIVE: The objective of the study was to find the genetic etiology of a novel presentation of MPD. DESIGN: The design of the study was whole-exome sequencing performed on two affected sisters in a single family. Molecular and functional studies of a candidate gene were performed using patient-derived primary fibroblasts and a zebrafish morpholino oligonucleotides knockdown model. PATIENTS: Two sisters presented with a novel subtype of MPD, including severe intellectual disabilities. MAIN OUTCOME MEASURES: NIN, encoding Ninein, a centrosomal protein critically involved in asymmetric cell division, was identified as a candidate gene, and functional impacts in fibroblasts and zebrafish were studied. RESULTS: From 34,606 genomic variants, two very rare missense variants in NIN were identified. Both probands were compound heterozygotes. In the zebrafish, ninein knockdown led to specific and novel defects in the specification and morphogenesis of the anterior neuroectoderm, resulting in a deformity of the developing cranium with a small, squared skull highly reminiscent of the human phenotype. CONCLUSION: We identified a novel clinical subtype of MPD in two sisters who have rare variants in NIN. We show, for the first time, that reduction of ninein function in the developing zebrafish leads to specific deficiencies of brain and skull development, offering a developmental basis for the myriad phenotypes in our patients.

Congenital hypothyroidism caused by excess prenatal maternal iodine ingestion.

We report the cases of 3 infants with congenital hypothyroidism detected with the use of our newborn screening program, with evidence supporting excess maternal iodine ingestion (12.5 mg/d) as the etiology. Levels of whole blood iodine extracted from their newborn screening specimens were 10 times above mean control levels. Excess iodine ingestion from nutritional supplements is often unrecognized.

Approach to the diagnosis and treatment of neonatal hypothyroidism.

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-T(4) in the first few weeks of life have a normal or near-normal neurodevelopmental outcome. The recommended starting dose of l-T(4) (10-15 µg/kg · d) is higher on a weight basis than the dose for children and adults. Tailoring the starting l-T(4) dose to the severity of the hypothyroidism will normalize serum T(4) 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 T(4) and TSH should be checked at intervals frequent enough to ensure timely adjustment of l-T(4) dosing and to keep serum free T(4) 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.

Congenital hypothyroidism.

Congenital hypothyroidism (CH) occurs in approximately 1:2,000 to 1:4,000 newborns. The clinical manifestations are often subtle or not present at birth. This likely is due to trans-placental passage of some maternal thyroid hormone, while many infants have some thyroid production of their own. Common symptoms include decreased activity and increased sleep, feeding difficulty, constipation, and prolonged jaundice. On examination, common signs include myxedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Thyroid dysgenesis accounts for 85% of permanent, primary CH, while inborn errors of thyroid hormone biosynthesis (dyshormonogeneses) account for 10-15% of cases. Secondary or central CH may occur with isolated TSH deficiency, but more commonly it is associated with congenital hypopitiutarism. Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In countries with newborn screening programs in place, infants with CH are diagnosed after detection by screening tests. The diagnosis should be confirmed by finding an elevated serum TSH and low T4 or free T4 level. Other diagnostic tests, such as thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination may help pinpoint the underlying etiology, although treatment may be started without these tests. Levothyroxine is the treatment of choice; the recommended starting dose is 10 to 15 mcg/kg/day. The immediate goals of treatment are to rapidly raise the serum T4 above 130 nmol/L (10 ug/dL) and normalize serum TSH levels. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and free T4 should be measured every 1-2 months in the first 6 months of life and every 3-4 months thereafter. In general, the prognosis of infants detected by screening and started on treatment early is excellent, with IQs similar to sibling or classmate controls. Studies show that a lower neurocognitive outcome may occur in those infants started at a later age (> 30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.