Congenital Hypothyroidism: Etiologies, Diagnosis, and Management

Transcription

1 THYROID Volume 9, Number 7, 1999 Mary Ann Liebert, Inc. Congenital Hypothyroidism: Etiologies, Diagnosis, and Management STEPHEN LaFRANCHI ABSTRACT Congenital hypothyroidism is a common preventable cause of mental retardation. The overall incidence is approximately 1:4000; females are affected about twice as often as males. Approximately 85% of cases are sporadic, while 15% are hereditary. The most common sporadic etiology is thyroid dysgenesis, with ectopic glands more common than aplasia or hypoplasia. While the pathogenesis of dysgenesis is largely unknown, some cases are now discovered to be the result of mutations in the transcription factors PAX-8 and TTF-2. Loss of function mutations in the thyrotropin (TSH) receptor have been demonstrated to cause some familial forms of athyreosis. The most common hereditary etiology is the inborn errors of thyroxine (T4) synthesis. Recent mutations have been described in the genes coding for the sodium/iodide symporter, thyroid peroxidase (TPO), and thyroglobulin. Transplacental passage of a maternal thyrotropin receptor blocking antibody (TRB-Ab) causes a transient form of familial congenital hypothyroidism. The vast majority of infants are now diagnosed after detection through newborn screening programs using a primary T^backup TSH or primary TSH test. Screening test results must be confirmed by serum thyroid function tests. Thyroid scintigraphy, using 99mTc or 123I, is the most accurate diagnostic test to detect thyroid dysgenesis or one of the inborn errors of T4 synthesis. Thyroid sonography is nearly as accurate, but it may miss some cases of ectopic glands. If maternal antibody-mediated hypothyroidism is suspected, measurement of maternal and/or neonatal TRB-Ab will confirm the diagnosis. The goals of treatment are to raise the serum T4 as rapidly as possible into the normal range, adjust the levothyroxine dose with growth to keep the serum T4 (or free T4) in the upper half of the normal range and the TSH normal, and maintain normal growth and development while avoiding overtreatment. An initial starting dose of fig/kg per day is recommended; this dose will decrease on a weight basis over time. Serum T4 (or free T4) and TSH should be monitored every 1-2 months in the first year of life and every 2-3 months in the second and third years. INTRODUCTION Congenital hypothyroidism, which occurs in approxis one of the most ing delayed to beyond 6 months of age the mean IQ dropped to 54 (range 25-80). Thus, there is urgency in making the diagnosis and starting treatment. For these reasons, screen- newborns for hypothyroidism was added to existing screening programs in the mid-1970s (3). Much has been discovered about congenital hypothyroidism since the de- velopment of newborn screening programs. This article re- views what has been learned about the etiology of con- genital hypothyroidism, and presents an approach to its imately 1:3000 to 1:4000 newborns, common preventable causes of mental retardation. The majority of cases are sporadic, so generally it is not possible to identify high-risk pregnancies (1). Most affected babies lack specific clinical features, so that only 5% are diagnosed by physical examination after birth. There is an inverse relationship between the age treatment is started and psychometric outcome. Before the development of newborn screening programs, Klein et al. (2) from Pittsburgh Children's Hospital reported that if treatment was started diagnosis and management, ETIOLOGIES between birth and 3 months, the mean IQ was 89 (range ); if treatment was started between 3 and 6 months, The overall incidence of permanent congenital hypothythe mean IQ was 71 (range 35-96), while if treatment was roidism approximates 1:4000; if transient cases are in- Department of Pediatrics, Division of Endocrinology, Oregon Health Sciences University, Portland, Oregon. 735

2 736 LaFRANCHI eluded, it approximates 1:3000. The major etiologies and their incidence are shown in Table 1. Approximately 85% of cases are sporadic, and are usually the result of thyroid dysgenesis. Approximately 15% of cases are hereditary, the result of one of the inborn errors of thyroxine (T4) synthesis or maternal antibody-mediated hypothyroidism. Screening programs that follow-up infants with persistently low T4 concentrations may detect infants with central (hypothalamic or pituitary) hypothyroidism, which occurs in approximately 1:25,000 to 1:100,000 newborns. Thyroid dysgenesis Thyroid dysgenesis, either aplasia, hypoplasia, or an ectopic thyroid gland, is the most common etiology of congenital hypothyroidism, accounting for approximately 85% of cases. Thyroid ectopia accounts for approximately two-thirds of cases worldwide (1). The pathogenesis of thyroid dysgenesis is largely unknown. The fact that there appears to be some ethnic variation in the prevalence suggests a role for genetic predisposing factors. Congential hypothyroidism occurs in approximately 1:4000 white infants, as compared to 1:2000 Hispanic infants (4) and 1:32,000 black infants. Most screening programs also report a female preponderance, with a 2:1 female-to-male ratio. The significance of this sex ratio is unknown. A recent report from Gagne et al. (5) in Montreal reported such a ratio in infants detected with ectopic glands (41 females, 15 boys), but in the infants with athyreosis, the ratio was more even (5 females, 7 males). Gagne et al. (5) speculated that different genetic and nongenetic mechanisms for athyreosis and ectopic glands are likely. Loss of function mutations in the thyrotropin (TSH) receptor are now recognized as a cause of athyreosis, although it is an uncommon explanation. In the case report by Gagne et al. (5), they found a total of 8 pedigrees of this autosomal recessive disorder in the literature up to Their case had no uptake with technetium-99m, but sonography demonstrated a hypoplastic gland in the normal location. This led to the conclusion that TSH was not critical for thyroid gland migration, but it was important for growth and function. With the discovery of transcription factors, which play a role in thyroid gland embryogenesis, there was an interest in whether mutations in the genes coding for these factors might play a role in thyroid dysgenesis. The transcription factors TTF-1, TTF-2, and PAX-8 are important for thyroid gland morphogenesis and differentiation. They also bind to the promoters of thyroglobulin and thyroid peroxidase (TPO) and so regulate thyroid hormone production. Lapi et al. (6) examined 61 infants with congenital hypothyroidism and thyroid dysgenesis and failed to find any with TTF-1 gene mutations. However, Clifton-Bligh et al. (7) report 2 siblings with thyroid agenesis, cleft palate, and choanal atresia associated wtih a missense mutation in the gene coding for TTF- 2. Macchia et al. (8), in a study of 145 infants with thyroid dysgenesis, found 3 infants with mutations in the PAX-8 gene. Two patients were sporadic while 1 had familial dysgenesis. Two mutations, resulting in s top codon, led to thyroid ectopia and hypoplasia, while the other mutation, resulting in a single base change, was present in an infant with thyroid hypoplasia (8). Because most cases of thyroid dysgenesis do not appear to be hereditary, it is perhaps not surprising that these autosomal recessive conditions were not found more commonly. Inborn errors of T4 synthesis Inborn errors of T4 synthesis are the next most common cause of congenital hypothyroidism, accounting for approximately 10% of cases. Hereditary defects in virtually all of the steps of thyroid hormone synthesis, secretion, and action have been described (Table 2). Mutations in the newly identified sodium/iodide symporter have been shown to cause iodide trapping defects (9). The most common inborn error is a defect in TPO activity leading to imparied oxidation and organification of iodide to iodine, thus interfering with binding to thyroglobulin. All of the inborn errors are autosomal recessive except for defects in thyroid hormone receptor action that are autosomal dominant in inheritance. An interesting new finding is the genetic abnormality in Pendred's syndrome, a condition characterized by congenital goiter and sensorineural deafness. Individuals with Pendred's syndrome tend to have subclinical hypothyroidism, with an elevated serum TSH but a normal T4 concentration. The gene in Pendred's syndrome, located on chromosome 7, may code for a sulfate transport protein, aptly named "pendrin." Mutations resulting in an abnormal sulfate transport protein cause defective iodine binding to thyroglobulin and cochlear malformations (10). Maternal antibody-mediated congenital hypothyrodism Maternal antibody-mediated congenital hypothyroidism, resulting from transplacental passage of a thyrotropin receptor blocking antibody (TRB-Ab), accounts for approximately 5% of congenital hypothyroidism. This condition Table 1. Congenital Hypothyroidism: Etiologies and Incidence Congenital hypothyroidism (overall) Thyroid dysgenesis Inborn errors of thyroxine synthesis Maternal antibody-mediated congenital hypothyroidism Central (hypothalamic-pituitary) hypothyroidism 1:3000-1:4000 1:4500 1:30,000 1:25,000-1:100,000 1:25,000-1:100,000 Table 2. Inborn Errors of Thyroxine Synthesis Iodide trapping defects: sodium/iodide symporter mutations Oxidation and organification defect: TPO mutations Coupling defect: TPO mutations Abnormal Tg: Tg gene mutations Defective proteolysis and secretion of T4 Deiodinase defect: deiodinase gene mutations TPO, thyroid peroxidase; Tg, thyroglobulin; T4, thyroxine.

3 CONGENITAL HYPOTHYROIDISM 737 is characterized by maternal autoimmune thyroid disease (AITD), more than 1 affected infant born to the mother, goiter in the infant, and a transient course with hypothyroidism resolving over 3 to 6 months as the maternal antibody is degraded. While maternal AITD may be characterized by antithyrogloblin and anti-tpo antibodies, only TRB-Ab is pathogenetic in congenital hypothyroidism. In a study of 788 infants with suspected congenital hypothyroidism out of a screening population of 1,614,166 in New York, Brown et al. (11) reported 9 mothers and infants positive for TRB-Ab. All of the neonates had transient hypothyroidism. In 7 mothers followed over time, all had TRB-Ab concentrations persisting for more than 7 years. Three of the 9 mothers had more than 1 affected infant. Central (hypothalamic or pituitary) hypothyroidism It is the objective of screening programs to detect infants with primary congenital hypothyroidism. Those programs that use a primary T4 screening test and follow-up infants with persistently low T4 concentrations (approximately 10% of screening programs in the United States) have the potential to detect infants with congenital hypothalamicpituitary hypothyroidism. While the incidence varies from 1:25,000 to 1:100,000, in Oregon where we make a concerted effort to learn about all such cases, the incidence is 1:29,000 (12). In a report of 10 years' screening experience in the United States northwest, Hanna et al. (12) reported that of a total of 19 infants, 8 were detected by the newborn screening test. Another 7 were diagnosed by clinical symptoms and signs of congenital hypopituitarism before a screening test was obtained, and 4, who were diagnosed outside of the neonatal period, in retrospect had abnormally low screening T4 concentrations that were not followed up. (12). The most common clinical features included hypoglycemia (74%), micropenis and undescended testes in males (71%), and prolonged jaundice (44%). Of the 19 infants, 7 were associated with the syndrome of septo-optic dysplasia, 5 had a cleft lip and/or palate or midfacial hypoplasia, 1 had holoprosencephaly, and 1 had neurofibromatosis, while 4 did not have a recognizable congential syndrome (12). DIAGNOSIS By and large, congenital hypothyroidism is now diagnosed after detection through newborn screening programs. Tests for hypothyroidism were added to existing screening programs in the mid-1970s (3). Currently, all 50 states in the United States, Puerto Rico, Canada, Western European countries, Israel, Japan, Australia, and New Zealand have well-established screening programs. Programs are underway in Latin and South America, eastern Europe, and other countries in Asia and Africa. Approximately 4 million infants are screened in the United States, leading to the detection of 1000 to 1333 infants with hypothyroidism annually; approximately 24 million infants are screened worldwide, with 6000 to 8000 cases of hypothyroidism detected each year. Different screening strategies have evolved to detect congential hypothyroidism. All screening programs perform tests on blood eluted from filter paper samples obtained by heel prick. The most common screening approach in North America is an initial T4 measurement, with a TSH determination on infants with a T4 below a selected cutoff, eg, below the 10th percentile. Other screening programs, for example in Japan, use a primary TSH test; some programs in the United States and Canada are switching to this screening strategy. There are advantages and disadvantages to each screening approach. Programs with a primary T4 test have the potential to detect infants with delayed TSH rise and with central, hypothalamic-pituitary hypothyroidism, while those with an initial TSH test may detect infants with subclinical hypothyroidism. Some programs have experimented with combined T4-TSH testing. Results from these programs show that each approach will miss a small number of affected infants (13). Approximately 10% of programs in the United States collect 2 routine screening specimens, for example the first at age 2 to 5 days and a second at age 2 to 6 weeks of age. Results from these programs show that about 10% of infants are detected only as a result of collection of the second routine specimen (14). This seems to be especially true of preterm infants with congenital hypothyroidism who are more likely to have a delayed TSH rise, perhaps due to immaturity of the pituitary-thyroid feedback mechanism (15). Infants with abnormal screening test results, generally a filter paper T4 less than 10%, and TSH greater than 20 mu/l, should undergo confirmation of the diagnosis by measurement of a free T4 (or T4 and T3 resin uptake) and TSH on a venipuncture serum sample. It should be remembered that the normal serum T4 range is higher in infancy, and test results need to be compared to age-related norms. Once the diagnosis of congenital hypothyroidism is confirmed, some clinicians recommend further diagnostic testing to determine the underlying etiology, while others believe these tests to not alter management and so should be considered optional. Tests to determine the underlying etiology are useful in infants with borderline thyroid function test results, in determining whether some cases are likely to be transient versus permanent, and, in infants proven to have a hereditary form of congenital hypothyroidism, these results guide counseling regarding future pregnancies. Tests commonly used to determine the underlying cause of congenital hypothyroidism are presented in Table 3. As thyroid dysgenesis is the most common etiology, thyroid scintigraphy, using technetium-99m or 123I, is the most informative diagnostic test (16). Thyroid sonography is useful in demonstrating enlarged or absent glands; it is less accurate than scintigraphy in showing ectopic glands (17). Thyroid scintigraphy also is not perfect; some infants who have no demonstrable uptake have serum thyroglobulin concentrations in the normal range, indicative of some as demon- functioning thyroid tissue (18). Large glands, strated by scintigraphy or sonography, may represent inborn errors of T4 synthesis or maternal antibody-mediated thyroid disease. More specialized tests, such as perchlorate discharge, measurement of serum, salivary, and urinary radioiodine, and measurement of serum T4 precursors, such as diiodothyronine, may be necessary to delineate specific inborn errors. If suspicion is raised for one of these, tests for specific gene mutations of the suspected error, as for

4 738 LaFRANCHI Table 3. Diagnostic Studies to Evaluate Congenital Hypothyroidism A. Required to confirm diagnosis 1. Free T4 (or T4 and T3 resin uptake) 2. TSH B. Optional tests to determine underlying etiology 1. Imaging studies: will determine location and size a. Scintigraphy (99mTc or 123I) b. Sonography 2. Function studies a. 123I uptake b. Serum thyroglobulin 3. Suspect inborn error of T4 synthesis a. 123I uptake and perchlorate discharge b. Serum/salivary/urine iodine studies 4. Suspect autoimmune thyroid disease a. Maternal and neonatal serum TRB-Ab determination 5. Suspect iodine exposure (or deficiency) a. Urinary iodine measurement 6. Ancillary tests to assess degree of fetal hypothroidism a. Radiograph of knee for skeletal maturation T4, thyroxine; T3, triiodothyronine; TSH, thyrotropin; TRB-Ab, thyrotropin receptor blocking antibody. the sodium/iodide symporter, TPO, or thyroglobulin may be diagnostic. If maternal AITD is present, this raises the possibility of antibody-mediated congenital hypothyroidism. This can be confirmed by determination of TRB-Ab in mother and baby, using an in vitro bioassay that measures the ability of the antibody to inhibit cyclic adenosine monophosphate (AMP) production, by TSH (19). By scintigraphy, such newborns appear to have aplasia, but some functioning thyroid tissue may be found in the normal location by sonography. It transplacental passage of a TRB-Ab is confirmed, one can predict that the hypothyroidism will be transient, resolving over 3 to 6 months as the maternal TRB-Ab is excreted by the infant (20). If the maternal TRB- Ab is discovered during pregnancy, one needs to consider the possible effect on fetal thyroid function with potential untoward effects on the developing fetal central nervous Table 4. Correlation of IQ with Fetal Hypothyroidism Risk Factors Table 5. Recommended Levothyroxine Treatment Dose Age Initial starting dose 0 to 3 months 3 to 6 months 6 to 12 months 1 to 3 years 3 to 10 years LT4, levothyroxine. LT4 (figlkglday) 10 to 15 8 to 12 7 to 10 6 to 8 4 to 6 3 to 5 system (CNS). One could consider performing fetal sonography to look for a goiter or umbilical cord sampling to assess fetal serum thyroid function. The information gained from cord sampling must be weighed against the potential harmful effects, which include hemorrhage and/or hematomas of the cord, isoimmunization of an Rh-negative mother, and approximately a 5% risk of initiating premature labor. If there is a history of iodine exposure, as may occur with use of topical iodine-containing antiseptics, for example painting the umbilical stump, this can be confirmed by measurement of a urinary iodine concentration. While most large areas of endemic iodine deficiency do not yet carry out newborn screening, if there is suspicion of this it can also be assessed by obtaining a urinary iodine measurement. Term infants generally excrete more than 40 fig of iodine daily. Ancillary tests may be carried out to try and assess the onset and severity of fetal hypothyroidism. These tests may correlate with psychometric outome, and so they may serve some prognostic value. The best example, is a radiograph of the knee to assess skeletal maturation. The Quebec Screening Network used the initial screening T4 concentration and bone surface area determined by radiograph of the knee to divide infants into a more severely affected cohort (T4 < 2 /ug/dl and bone surface area <0.05 cm2) and a less severely affected cohort (T4 > 2 figldl and bone surface >0.05 cm2). Serial IQ measurements up to 12 years of age are presented in Table 4; in general, the more severely affected children's IQ ranged from 12 to 16 points lower (21). The Quebec investigators concluded that the most severely affected infants had a reduction in IQ despite early detection and treatment. Age 3 years 5 years 7 years 12 years IQ High risk T4 <2 fig/dl bone surface <0.05 cm2 Range 91 (61-120) (60-109) (49-98) (55-123) Modified from Glorieux J et al. (21). T4, thyroxine. IQ Low risk T4 <2 figldl bone surface >0.05 cm2 Range (81-140) (84-105) (75-124) (84-124) Screening program Quebec Toronto Toronto New England Denmark Table 6. Time Course of Thyroid Function with Initial Levothyroxine Starting Dose LT4 dose (figlkglday) 6 7 to 9 8 to to 17 Time to Serum T4> 10 figldl (days) 45 to Modified from Fisher and Foley (23) and Heyerdahl et al. (24). LT4, levothyroxine, T4, thyroxine.

5 CONGENITAL HYPOTHYROIDISM 739 Table 7. Effect of Levothyroxine Treatment Dose on IQ and Behavior Low dose High dose p value Initial starting dose (jug/kg/day) T4 at 3 months (Mg/dL) WISC-R IQ Full scale Verbal Performance Child behavior checklist Internalizing problems Social problems Attention problems NS Modified from Rovet and Ehrlich (25). T4, thyroxine; WISC-R, Wechsler Intelligence Scale for Children- Revised. MANAGEMENT Levothyroxine is the treatment of choice. Triiodothyronine (T3) is not indicated, because studies in young animals show that it is the circulating T4 entering brain cells and being converted to T3 that binds to nuclear thyroid hormone receptor (22). The goals of treatment are to raise the serum T4 into the normal range as rapidly as possible, adjust the levothyroxine dose with growth to keep the T4 or free T4 and TSH in the normal range, and to maintain normal growth and development while avoiding overtreatment. The recommended initial levothyroxine dose is fig/kg per day (Table 5). It is important to raise the serum T4 as rapidly as possible into the desirable range so as to minimize exposure of the neonatal brain to further hypothyroidism. With the historical experience of screening programs choosing gradually increasing initial levothyroxine treatment doses, it has become clear that a starting dose of figlkg per day will raise the serum T4 to more than 10 figldl by 7 days (23,24) (Table 6). A study from the Ontario screening program compared 2 groups of infants, one started on an average initial levothyroxine dose of 6.4 figlkg per day versus one started on 9.0 figlkg per day (Table 7). At 3 months of age, the serum T4 concentration was 11.7 ig/dl in the lower dose group versus 13.1 pgldl in the higher dose group. The full scale and verbal IQs were approximately 7 points higher in the group of infants started on the higher dose (25). Infants treated with the higher dose did manifest some features suggestive of overtreatment, including problems with attention span, although these tended to disappear over time. The aim of treatment is to keep the T4 in the upper half of the normal range, approximately figldl ( nmol/l) or the free T4 in the ng/dl (18-30 pmol/l) range, with the TSH suppressed into the normal range. It is important to monitor frequently serum T4 or free T4 and TSH during the first 3 years of life to ensure optimal therapy; recommended monitoring intervals from the American Academy of Pediatrics are shown in Table 8 (26). In general, thyroid function tests should be checked every 1 to 2 months in the first year and every 2 to 3 months in the second and third year of life. It is also important to check thyroid function after a change in dose and any time there is a concern about treatment compliance. The New England Congenital Hypothyroidism Collaborative compared outcome in a group of 18 infants judged to have received inadequate treatment in the first 3 years of life, based on an average levothyroxine dose of less than 5 figlkg per day and known compliance problems. Compared to a group judged to receive adequate levothyroxine replacement, the mean serum T4 concentration was lower, 8.6 versus 11.2 fig/dl, and the average IQ was 18 points lower in the group judged to receive inadequate treatment, 87 ± 5 versus 105 ± 2 (27). The above studies emphasize the importance of selecting the proper starting dose of levothyroxine and frequent monitoring to ensure optimal treatment over the first 3 years of life. It is equally important to avoid overtreatment. Adverse effects reported with overtreatment include premature cranial suture fusion, acceleration of growth and skeletal maturation, and problems with temperament and behavior. All screening programs identify infants with transient forms of congenital hypothyroidism. In cases where it is not clear that the disorder is permanent, it is recommended that the diagnosis be reevaluated at 3 years of age (26). Hypothyroidism is permanent if studies for an underlying etiology show a disorder such as thyroid ectopia or an inborn error of T4 synthesis, or if there has been a secondary rise in serum TSH to more than 20 mu/l after 6 months of age, as for example when an infant outgrows the levothyroxine dose. In the case of failure to take up a radionuclide, one must remember that this is not always diagnostic of athyreosis, as this finding is also seen with transplacental passage of maternal TRB-Ab. If thyroid sonography also confirms absence of thyroid tissue, then the diagnosis of aplasia is confirmed. In all other cases, after 3 years of age levothyroxine should be discontinued for 30 days and serum T4 or free T4 and TSH measured. Cases of equivocal thyroid function require careful follow-up and periodic retesting. Table 8. American Academy of Pediatrics Recommendations for Follow-up Monitoring of Serum T4 (or Free T4) and TSH in Infants with Congenital Hypothyroidism Initiation of treatment: 2 and 4 weeks later First year: every 1 to 2 months Second and third year: every 2 to 3 months Thereafter: every 3 to 12 months until growth and puberty complete Goals: Serum T4 (or free T4) in the upper half of the normal range (10-16 figldl) and TSH suppressed (<10 mu/l) Prevent overtreament Clinical evaluation at less frequent intervals Modified from Rovet and Ehrlich (25). T4, thyroxine; WISC-R, Wechsler Intelligence Scale for Children- Revised.

6 740 LaFRANCHI REFERENCES 1. Fisher DA 1983 Second international conference on neonatal thyroid screening: Progress report. J Pediatr 102: Klein AH, Meltzer S, Kenny FM 1972 Improved prognosis in congenital hypothyroidism treated before age three months. J Pediatr 81: Dussault JH, Coulombe P, Laberge C, Letarte J, Guyda H, Khoury K 1975 Preliminary report on a mass screening program for neonatal hypothyroidism. J Pediatr 86: Penny R, Hoffman P, Barton L 1989 Congenital hypothyroidism in Spanish-surnamed infants in Southern California: Increased incidence and clustering of occurrence. Am J Dis Child 143: Gagne N, Parma J, Deal C, Vassart G, Van Vliet G 1998 Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: Are athyreosis and ectopic thyroid distinct entities? J Clin Endocrinol Metab 83: Lapi P, Macchia PE, Chiovato L, Biffali E, Moschini L, Larizza D, Baserga M, Pinchera A, Fenzi G, Di Lauro R 1997 Mutations in the gene encoding thyroid transcriptional factor-1 (TTF-1) are not a frequent cause of congenital hypothyroidism (CH) with thyroid dysgenesis. Thyroid 7: Clifton-Bligh RJ, Wentworth JM, Heinz P, Crisp MS, John R, Lazarus JH, Ludgate M, Chatterjee VK 1998 Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 19:399^ Macchia PE, Lapi L, Krude H, Pirro MT, Missero C, Chiovato M, Souabni A, Baserga A, Tassi V, Pinchera GF, Fenzi M, Gruters A, Busslinger M, Di Lauro R 1998 PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 19: Pohlenz J, Rosenthal IM, Weiss RE, Jhiang SM, Burant C, Refetoff S 1998 Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site. J Clin Invest 101: Everett LA, Glasser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazami E, Nassir E, Baxemanis AD, Sheffield VC, Green ED 1997 Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 17: Brown RS, Bellasario RL, Botero D, Fournier L, Abrams CAL, Cowger ML, David R, Fort P, Richman RA 1996 Incidence of transient congenital hypothyroidism due to maternal thyrotropin antibodies in over one million babies. J Clin Endocrinol Metab 81: Hanna DE, Krainz PL, Skeels MR, Miyahira RS, Sesser DE, LaFranchi SH 1986 Detection of congenital hypopituitary hypothyroidism: Ten year experience in the Northwest Regional Screening Program. J Pediatr 109: Dussault DH, Morisette J 1983 Higher sensitivity of primary thyrotropin in screening for congenital hypothyroidism: A myth? J Clin Endocrinol Metab 56: LaFranchi SH, Hanna CE, Krainz PL, Skeels MR, Miyahira RS, Sesser DE 1985 Screening for congenital hypothyroidism with specimen collection at two time periods: Results of the Northwest Regional Screening Program. J Pediatr 76: Hunter MK, Mandel SH, Sesser DE, Miyahira RS, Rien L, Skeels MR, LaFranchi SH 1998 Follow-up of newborns with low T4 and "non-elevated" TSH concentrations: Results of the 20 year experience in the Northwest Regional Newborn Screening Program. J Pediatr 132: Muir A, Daneman D, Daneman A, Ehrlich R 1988 Thyroid scanning, ultrasound, and serum thyroglobulin in determining the origin of congenital hypothyroidism. Am J Dis Child 142: Takashima S, Nomura N, Tanaka H, Itoh Y, Miki K, Harada T 1995 Congenital hypothyroidism: Assessment with ultrasound. Am J Neuroradiol 16: Mitchell ML, Hermos RG 1995 Measurement of thyroglobulin in newborn screening specimens from normal and hypothyroid infants. Clin Endocrinol 42: Zakarija M, McKenzie JM, Eidson MS 1990 Transient neonatal hypothyroidism: Characterization of maternal antibodies to the thyrotropin receptor. J Clin Endocrinol Metab 70: Pacaud D, Huot C, Gattereau A, Brown RS, Glorieux J, Dussault JH, Van Vliet G 1995 Outcome in three siblings with antibody-mediated transient congenital hypothyroidism. J Pediatr 127: Glorieux J, Dussault J, Van Vliet G 1992 Intellectual development at age 12 years of children with congenital hypothyroidism diagnosed by newborn screening. J Pediatr 121: Ruiz de Ona C, Obregon MJ, Escobar del Rey F, Morreale de Escobar G 1988 Development changes in rat brain 5'-deiodinase and thyroid hormone during the fetal period: The effects of fetal hypothyroidism and maternal thyroid hormones. Pediatr Res 24: Fisher DA, Foley BL 1989 Early treatment of congenital hypothyroidism. Pediatrics 83: Heyerdahl S, Dase BF, Lie SO 1991 Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment. J Pediatr 118: Rovet JF, Ehrlich RM 1995 Long-term effects of I-thyroxine therapy for congenital hypothyroidism. J Pediatr 126: LaFranchi SH, Dussault JH, Fisher DA, Foley TP Jr, Mitchell ML (American Academy of Pediatrics) 1993 Newborn screening for congenital hypothyroidism: Recommended guidelines. Pediatrics 91: New England Congenital Hypothyroidism Collaborative 1984 Characteristics of infantile hypothyroidism discovered on neonatal screening. J Pediatr 104: Address reprint requests to: Stephen LaFranchi, M.D. Department of Pediatrics (CDW-5) Oregon Health Sciences University 3181 S.W. Sam Jackson Park Road Portland, OR lafrancs@ohsu.edu