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Elevated Free Thyroxine Levels Detected by a Neonatal Screening System

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Elevated Free Thyroxine Levels Detected by a Neonatal Screening System 0031-3998/09/6603-0312 Vol. 66, No. 3, 2009 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2009 International Pediatric Research Foundation, Inc. Elevated Free Thyroxine Levels Detected by a Neonatal Screening System TOSHIHIRO TAJIMA, WAKAKO JO, KAORI FUJIKURA, MASARU FUKUSHI, AND KENJI FUJIEDA Department of Pediatrics [T.T., W.J.], Hokkaido University School of Medicine, Sapporo, Hokkaido 060-8635, Japan; Sapporo City Institute of Public Health [K.F., M.F.], Sapporo, Hokkaido 003-8505, Japan; Department of Pediatrics [K.F.], Asahikawa Medical College School of Medicine, Asahikawa, Hokkaido 078-8510, Japan ABSTRACT: In Sapporo city of Japan, neonatal screening for of Gs␣ protein McCnune-Albright syndrome has been also congenital hypothyroidism has used the measurement of free thyrox- reported to cause hyperthyroidism in neonatal period (10,11). ine (T4) and thyroid-stimulating hormone (TSH) in the filter-paper LaFranchi et al. (12) have reported the first systematic study blood spot. This system has enabled us to identify hyperthyroxinemic to screen neonatal hyperthyroxinemia using T4 screening in diseases. Filter papers were collected from neonatal infants born at Oregon. According to their study, any case with NGD among Ͼ 4–6 d of age and neonates who showed elevated free T4 ( 4.0 80,884 infants was not detected. Instead, 10 had thyroxine- ng/dL, 4 SD above the mean) were studied. Between January 2000 binding globulin excess, five were thought to be familial and December 2006, 83,232 newborns were screened. Eleven infants demonstrated persistent hyperthyroxinemia. One patient with slightly dysalbuminemic hyperthyroxinemia (FDH), and two had re- elevated free T4 and normal TSH was diagnosed as having familial sistance of thyroid hormone (RTH). After this report, the dysalbuminemic hyperthyroxinemia (FDH). The other two patients study of differential diagnosis of neonatal hyperthyroxinemia with elevated free T4 without suppressed TSH were considered as detected by neonatal screening is scarce (12,13). having resistance of thyroid hormone (RTH), and analysis of thyroid In Sapporo of Japan, neonatal screening for congenital hormone receptor (TR) ␤ gene confirmed the diagnosis. The remain- hypothyroidism has been based on simultaneous TSH and free ing eight patients were diagnosed as having neonatal Graves’ disease T4 measurements and was effective for the identification of (NGD). Seven of eight pregnant women were treated with antithyroid primary and central congenital hypothyroidism (6). As free T4 drug and thus only one unrecognized NGD during pregnancy was measurement could also identify hyperthyroxinemic disorder, detected by screening. Our screening system enables for early aware- we have determined the type of diseases detected by elevated ness of RTH and FDH. Regarding Graves’ disease, the benefit of free T4 in neonatal screening between 2000 and 2006 in elevated free T4 screening is small, because most pregnant women with Graves’ disease were managed. (Pediatr Res 66: 312–316, Sapporo of Japan. 2009) METHODS ongenital hypothyroidism is the most prevalent endocrine A neonatal screening for congenital hypothyroidism and thyroid hormone measurement. In Sapporo of Japan, ϳ10,000 infants were born C disorder in the newborn, with a rather constant world- annually. Almost 100% of these newborns were subjected to neonatal screen- wide incidence of permanent congenital hypothyroidism of ing. The neonatal screening program for congenital hypothyroidism was 1:3000 to 1:4000 newborns (1,2). The main purpose of neo- based on simultaneous TSH and free T4 measurements in dried blood on filter paper specimens. Dried blood samples on filter paper were collected from natal mass screening for congenital hypothyroidism is early neonatal infants born in Sapporo City at 4–6 d of age from maternity and detection and treatment to hypothyroidism. During the past parturition clinics to screening center. Whole blood was drawn by heel prick, three decades, this screening has been very successful with the and TSH and free T4 were then measured from one punched 3.2-mm circle, which corresponded to 3.5 ␮L of whole blood. TSH and free T4 were vast majority of patients with congenital hypothyroidism measured by ELISA kits (Bayer Medical Enzaplate Neo-TSH and Enzplate achieving normal neurologic outcome (1–3). Two methods for N-FT4 kits, Japan). In free T4 measurement, intraassay coefficient variation was 7.6–8.1% and interassay coefficient variation was 9.4–18%. To detect the screening system are now used. Most screening programs infants who were at risk for hyperthyroxinemic disorders, we determined the in Europe and Asia, including Japan, use primary thyroid- upper cutoff values for free T4 as 4.0 ng/dL. This cutoff value represented Ͼ4 stimulating hormone (TSH) screening. Another program is SD above the mean. If infants had free T4 values Ͼ4.0 ng/dL, then second heel puncture was requested. thyroxine (T4) or free T4-based neonatal screening (4–6). T4 In one family of FDH, serum T4, triiodothyronine (T3), free T4, free T3, or free T4 screening enables the detection of hyperthyroxine- and TSH were measured using commercial RIA kits (Dinabot, Matsudo, mia in addition to congenital hypothyroidism. In hyperthyrox- Japan). Serum free T4 and free T3 were also measured by one-step labeled antibody radioassay (Amerlex MAB free T4 and free T3 kits, Trinity Biotech, inemic disorders, neonatal Graves’ disease (NGD) is thought Ireland). to be the most prevalent and the occurrence is estimated as one Gene analysis. DNA analysis of thyroid diseases was approved by the in 10,000 to 50,000 newborn infants (7–9). Activating muta- ethical committee of Hokkaido University School of Medicine, and informed tion of TSH receptor mutations and gain of function mutations consent for DNA analysis was obtained from their parents. To examine the Abbreviations: FDH, Familial dysalbuminemic hyperthyroxinemia; RTH, Received February 9, 2009; accepted April 29, 2009. ␤ Correspondence: Toshihiro Tajima, MD, PhD, Department of Pediatrics, Hokkaido Uni- Resistance of thyroid hormone; TR , Thyroid hormone receptor; TSH, versity School of Medicine, N15, W7, Sapporo, Japan; e-mail: [email protected] Thyroid stimulating hormone; T4, Thyroxine; T3, Triiodothyronine 312 HYPERTHYROXINEMIA AND NEONATAL SCREENING 313 mutation (R218P) in exon 7 of the albumin gene, the endonuclease digestion/ are continuing to follow-up six neonates. They have normal allele-specific primer method was used as described previously (14). For the neuropsychological development. thyroid hormone receptor (TR) ␤ gene analysis, each exon was amplified by PCR according to a previous report (15) and directly sequenced. During this screening period, central hypothyroidism due to maternal Graves’ disease was not observed. RESULTS A case of FDH. The first screening of case 9 with FDH showed mildly elevated free T4 (4.88 ng/dL) and normal TSH From January 2000 to December 2006, a total of 83,232 levels. As mildly elevated free T4 (4.02 ng/dL) at 23 d of age infants were screened. During this period, 28 infants demon- were observed in the second screening test, he was referred to strated elevated free T4 at first screening. Of 28 infants, 11 our hospital at 45 d of age. At the referral, he grew well and infants showed persistent increased free T4, whereas the did not show any sign of hyperthyroidism. Thyroid function of second screening sample of 17 infants decreased to normal case 9 and his family was summarized in Table 3. He revealed levels. Values of the first screening in the 11 infants with the extremely high total T4 and T3 levels (Table 3). Serum persistent hyperthyroxinemia who were subjected to further free T4 and free T3 were also high using T4 and T3 analog evaluation were shown in Table 1. RIA kit (Table 3). By using one labeled antibody radioassay Cases of NGD. Of these 11 infants, eight infants were kit, serum free T4 was normal (1.0 ng/dL) but free T3 was diagnosed as having NGD. Therefore, the estimated incidence elevated (82.3 pg/mL) (Table 3). It is known that the mea- of NGD is one in 10,404 during this period. Thyroid function surements of the free T3 and free T4 concentrations in serum of these patients was summarized in Table 2. Because our city may give spurious results in FDH, especially in assay using had several central hospitals for maternal and neonatal care, iodothyronine analogs that bind to the abnormal albumin mothers of patient 2, 4, 5, and 6 were referred to our city for (16,17). His thyroid binding globulin (TBG) level was within further follow-up and treatment for maternal Graves’ disease the normal range. On the basis of these findings, he was from other district. Among these patients, Graves’ disease of suspected to have FDH. From the interview, his father had only patient 1 was detected by neonatal screening. The mother been treated with antithyoid drug, but he had no symptom and was not known to have Graves’ disease, but after her neo- stopped medication. His father and his elder brother also nates’ diagnosis, she was also diagnosed with Graves’ disease. showed similar results to the infants. Because R216P of the The other patients were closely observed and evaluated peri- albumin gene has been identified in a Japanese FDH family odically after birth and were diagnosed as having NGD. (14), we investigated this mutation. The result of the albumin In patient 2, at gestational age of 27 wk, persistent fetal gene analysis was shown in Figure 1. The infant, his father, tachycardia was identified, and the mother was referred to our and the elder brother had the mutant and normal bands. On the hospital. Maternal thyroid function test revealed maternal other hand, the mother had only normal band. Therefore, we Graves’ disease and fetal thyrotoxycosis was suspected. An- confirmed the diagnosis of FDH in this family. tithyroid drug of propylthiouracil 150 mg/d, via maternal oral Cases of RTH.
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