Spectrum of patients with hypermethioninemia based on neonatal screening tests over 14 years / 소아과

PURPOSE: The neonatal screening test for homocystinuria primarily measures methionine by using a dried blood specimen. We investigated the incidence and clinical manifestations of homocystinuria, isolated hypermethioninemia, and transient hypermethioninemia among patients with hypermethioninemia on a neonatal screening test. METHODS: We performed a retrospective study of 58 patients transferred to Shoonchunhyang Hospital because of hypermethioninemia on a neonatal screening test between January 1996 and August 2009. We analyzed the level of amino acid from plasma and urine, as well as blood homocysteine. RESULTS: Almost half of the 58 patients were identified as normal. Whereas only 3 (5.1%) patients were identified as having homocystinuria, about 20.7% (12 cases) of the patients had isolated hypermethioninemia. The ages of these two groups at initial detection of hypermethioninemia on plasma amino acid analysis were 50.0+/-22.5 days and 34.9+/-13.5 days, respectively. Both groups were put on diets, and they showed a normal developmental course as a result of early diagnosis and treatment. CONCLUSION: Hypermethioninemia without homocystinuria, referred to as isolated hypermethioninemia, was also detected. Thus, the impact of hypermethioninemia on a neonatal screening test should be carefully evaluated through analysis of amino acid levels from blood and urine, and we need to detect and treat an early stage of isolated hypermethioninemia as well as homocystinuria.

A Cost-Benefit Analysis of Neonatal Screening Tests for Maple Syrup Urine Disease, Homocystinuria, Galactosemia, and Congenital Adrenal Hyperplasia

PURPOSE: Neonatal screening tests are increasingly being used forearly diagnosis of inborn errors of metabolism (IEM) in the hope of avoiding the severe developmental delay, acute illness, and death that may result from these diseases. In this study, a cost-benefit analysis was performed on the neonatal screening of maple syrup urine disease, homocystinuria, galactosemia, and congenital adrenal hyperplasia in Korea. MATERIALS AND METHODS: This study included 1,259,220 Korean newborns born between January 2005 to December 2007, who were screened for maple syrup urine disease, homocystinuria, galactosemia, and congenital adrenal hyperplasia. We calculated and compared the total costs in cases where these four screening tests were implemented, and those where they were not. RESULTS: There were no benefits to screening for maple syrup urine disease or homocystinuria due to their low prevalence for these two tests, the costs exceeded the benefits at benefit:cost ratios of 0.5:1 and 0.6:1, respectively. In contrast, benefits far exceed costs at a ratio of 4.1:1 for galactosemia and 2.9:1 for congenital adrenal hyperplasia. The average benefit:cost ratio for all four tests was 2.0:1. CONCLUSION: Neonatal screening tests for maple syrup urine disease, homocystinuria, galactosemia, and congenital adrenal hyperplasia are financially viable.

Late Detection of Thyroid Dysfunction in NICU Patients / 대한주산의학회잡지

OBJECTIVE: To evaluate the incidence, the time of detection, classification, and risk factors of thyroid dysfunction in very low birth weight (VLBW) and sick infants in order to help with the diagnosis and treatment of thyroid dysfunction in the neonatal intensive care unit (NICU). METHODS: We reviewed the medical records of 78 infants, who were admitted for more than 1 month in the NICU at Chungbuk National University Hospital from July 2004 through June 2006. In these infants, at least to 2 thyroid function tests were performed, a initial screening whthin 2 weeks of age and a repeated thyroid function test after 2 weeks of age. RESULTS: 1) The study infants were divided into 2 groups, VLBW (birth weight or =1,500 g). 2) In the VLBW groups (n=48), 24 infants (50%) showed thyroid dysfunction. Six infants (12.5%) were detected at initial screening test and all had transient hypothyroxinemia. The remaining 18 infants (37.5%) were detected at repeated tests, most commonly detected at 4~8 weeks of age (n=8). Their types of thyroid dysfunction were primary hypothyroidism (PH) with a delayed marked TSH rise (n=3), PH with a delayed mild TSH rise (n= 7), euthyroid sick syndrome (ESS, n=8), and central hypopituitary hypothyroidism (HH, n=1). 3) In the NVLBW groups (n=30), 11 infants (36.7%) showed thyroid dysfunction. Three infants (10%) were detected at initial screening test, while 8 (26.7%) were detected at repeated tests. Their types of thyroid dysfunction were PH (n=5), ESS (n=3), transient hyperthyrotropinemia (n=2), and HH (n=1). 4) Among 35 infants with thyroid dysfunction, 20 infants (57.1%) were treated with thyroxine. CONCLUSION: Thyroid dysfunction was very common in sick infants in the neonatal intensive care unit, especially in the very low birth weight infants. Often, they were not detected at the initial screening test, but detected at later repeated tests. The repeated thyroid function test need to be performed in infants at risk for late detection of thyroid dysfunction after 2~4 weeks of age.

The Long Term Follow up Study of Newborns with TSH Elevation without Low T4 / 대한소아내분비학회지

PURPOSE: In this study, we aimed to find useful methods for diagnosis and treatment of hyperthyrotropinemia in neonates showing normal T4 and elevated TSH levels in neonatal screening test. METHODS: We retrospectively reviewed the medical records of 16 male and 26 female neonates whose T4 were normal and TSH were elevated in the neonatal screening test from 1994 to 2006. The clinical data, including perinatal history, thyroid function test and radionuclide scannig was analysed. RESULTS: Of the forty-two patients, male was 38.1% and female was 61.9%. Mean T4 and TSH level were 8.61+/-1.55 ug/dL, 49.66+/-36.56 uU/mL respectively. At the recheck, when recalled, TSH were normalized in 8 patients (19.1%), still elevated in 34 patients (80.9%). (99m)TC thyroid scan was performed in 36 cases. The results were normal in 18 cases (50.0%), diffuse enlargement in 11 cases (30.5%), ectopic thyroid, poor visualization, hypoplasia respectly in 11.2%, 5.5%, 2.8%. Fourteen patients (33.3%) had histories of povidone use for umbilical care. Of the 42 patients, 27 (64.0%) cases were treated by thyroid hormone, 15 cases (36.0%) were followed up without treatment. Among 15 cases without treatment, 8 patients showed TSH normalization at 1.5 months, 5 patients at 3 months, one patient at 6 months and one patient at 9 months. Among 27 cases with treatment, 18 cases (66.7%) are being treated, 5 cases (18.6%) are being treated more than 3 years, the 3-years treatment was ended in 6 cases (22.2%), follow up loss was 3 cases (11.1%). CONCLUSION: At long term follow up, TSH was normalized in many patients who showed normal T4 and elevated TSH levels in neonatal screening test. Imaging study such as (99m)TC thyroid scanning was helpful to decide whether to treat with thyroid hormone replacement. To predict longer term prognosis of cases without thyroid hormone replacement, long term follow up of large number of patients is needed.

Predictors of Transient Hypothyroidism in Neonatal Screening Test / 대한소아내분비학회지

PURPOSE: Congenital hypothyroidism is detected through the neonatal screening test and treated early from neonatal period. Among these patients, however, transient hypothyroidism is included. In this study, we aimed to evaluate the predicting factors of transient hypothyroidism in neonatal screening test. METHODS: We retrospectively reviewed medical records of 40 male and 31 female neonates diagnosed as congenital hypothyroidism by newborn screening from 1996 to 2003. The untreated cases that revealed slightly decreased levels of thyroid hormone on repeated examination and the cases who showed normalized hormone after 2 years of treatment were regarded as transient hypothyroidism. The results of neonatal screening tests and other clinical features of children with transient hypothyroidism were compared to those of children with permanent form. The time to normalization of thyroid hormone levels in the transient hypothyroidism were also reviewed. RESULTS: Among 71 cases of congenital hypothyroidism, 39 cases (54.9%) were transient and 32 cases (45.1%) were permanent hypothyroidism. There were no significant differences in clinical features between two groups, except lower birth weight in the transient group (transient 2.80+/-0.75 kg, permanent 3.22+/-0.57 kg, P=0.02). Free T4 levels were significantly lower and TSH levels were significantly higher in the permanent form than the transient ones (P<0.01). The estimated cut-off point for distinguishing transient hypothyroidism from permanent form was 2.05 ng/dL (sensitivity 54%, specificity 93%) for free T4 and 34 microIU/mL (sensitivity 72%, specificity 87%) for TSH. CONLCUSION: In this study, transient hypothyroidism could be differentiated from permanent hypothyroidism by TSH and free T4 levels of neonatal screening test. Repeated thyroid function tests are thought to be essential to make a diagnosis of not only transient but also permanent hypothyroidism.

Change of TSH, T4, and Free T4 Concentrations During the 48 Hours of Postnatal Period / 대한소아내분비학회지

PURPOSE: Congenital hypothyroidism is the most common endocrine disease in infant period and if it is not treated in good time it would cause irreversible failure to thrive and mental retardation. For this reason neonatal screening test for diagnosis is critical in early infant. TSH concentrations which were performed to know thyroid functions normally or not increased rapidly at 30 minutes of life and then fell at 48 hours of life so it was considered inappropriate for neonatal screening test because of false positive result. Otherwise free T4 is not variable within 48 hours, and that's why authors proposed free T4 as an applicable way to early discharge neonates for neonatal screening test. METHODS: We have performed this study to obtain normal TSH, T4, and free T4 concentrations in Korean neonates. Total 17 neonates were studied in Soonchunhyang University Hospital from March 2004 to June 2004. 17 samples were performed at 15, 30 minutes, 1, 2, 3, 4, 24, 48 hours of life from 17 neonates who have had no perinatal problem, medication history and mother's illness studied and the results were compared by applying enzyme linked immunosorbent assay. RESULTS: In the early postnatal period, serum TSH concentrations increased rapidly to peak level (mean of 32.06 microIU/mL) at 30 minutes of life and then fell very gradually to mean concentration (mean of 4.18 microIU/mL) at 48 hours of life and serum T4 concentrations shows variable pattern but the mean values of T4 showed normal range of T4 (6.0-19.9 microgram/dL). On the other hand, serum free T4 concentrations increased to peak level (mean of 3.00 microgram/dL) at 24 hours of life and gradually decreased and it was observed that the mean values of free T4 maintained higher than the diagnostic criteria of congenital hypothyroidism (0.85 microgram/dL). CONCLUSION: According to this result, we consider that free T4 is much more applicable way to early discharge neonates for neonatal screening test because of its slim variability.

Reevaluation of the Neonatal Screening Test for Congenital Hypothyroidism / 소아과

PURPOSE: We performed this study to compare the TSH and free T4 levels according to gestational age and birth weight, and to reevaluate the cut-off values in the neonatal screening test for congenital hypothyroidism. METHODS: Total 2,133 neonates(1,749 healthy newborns and 384 sick neonates) were screened in Dankook University Hospital from May 2000 to January 2003. Neonates with abnormal TSH values (higher than 20 microliterU/mL) or abnormal free T4 levels(lower than 1 ng/dL) were recalled to recheck the thyroid function test. At that time, physical examinations and history-taking regarding perinatal problem, medication history, and mother's illness were undertaken. RESULTS: Serum TSH and free T4 values revealed no significant difference according to sex, delivery type, and Apgar score. The free T4 levels showed statistically significant differences, with gestational age or birth weight(P20 microliterU/mL or free T4<1 ng/dL was relatively high, it was impossible to set up new cut-off values without compromising sensitivity. We think studies including a larger study population will be required to change the cut-off values.

Establishment of Cutoff Value in the Neonatal Screening Tests / 대한소아내분비학회지

PURPOSE: This study was undertaken to determine the adequate cutoff value of the neonatal screening test to decrease recall and false-positive rates. METHODS: During the period of January 1999 through December in Asan Medical Center, newborn screening tests for phenylketonuria, congenital hypothyroidism, congenital adrenal hyperplasia, and galactosemia were performed in 3,775, 3,707, 3,783, and 3,806 newborns respectively using commercial ELISA kits. We reviewed and analyzed the recall rate at currently used cutoff values. RESULTS: 1)In neonatal screening test for congenital hypothyroidism, using a current cutoff value, 17 microIU/mL, the recall rate was 0.9% and using a 99.7% cutoff value, 21.3 microIU/mL, the predictive recall rate was 0.4%. There were no significant differences in the other reports that suggest adequate recall rate. 2)In neonatal screening test for phenylketonuria, using a current cutoff value, 3.6 mg/dL, the recall rate was 1.5% which was no significant difference compared with expected presumptive positive rate, 1.44%. 3)In neonatal screening test for congenital adrenal hyperplasia and galactosemia, the recall rate was high when using current cutoff value. But all results were within normal limits in reevaluation. CONCLUSION: The cutoff values of screening test which are currently recommended by manufacturers of commercial kits for congenital hypothyroidism, congenital adrenal hyperplasia and galactosemia, are needed to be reset to decrease the recall rate by false-positive results on the basis of data from an individual newborn screening laboratory.

Re-Evaluation of Neonatal Screening Tests for Inborn Errors of Metabolism with Dried Filter Paper Blood Spots

PURPOSE: There have been high rates of false positive and recall in neonatal screening test using the cut-off points set by the manufacturing company. So, it is necessary to re-evaluate the cut-off values to minimize the false positive rates. METHODS: We collected capillary blood in dry filter paper from 996 healthy neonates on the third day in cases of normal vaginal delivery or the fifth day in cases of Cesarean section. The levels of phenylalanine, galactose, 17-hydroxyprogesterone and branched-chain amino acids were measured using enzyme immunoassay. The results were compared with the original cut-off points set by the manufacturing company. RESULTS: The original cut-off points of four substances were 4.0mg/dL, 7.5mg/dL, 35ng/mL, and 8.0mg/dL, respectively, so that false-positive rates were 0.4, 1.6, 3.93, and 0.001%, respectively. When we set the cut-off point at 99.7 percentile using the data from healthy neonates, they should be 4.0mg/dL, 9.2mg/dL, 54.3ng/mL, and 8.0mg/dL, respectively. CONCLUSION: The false-positive and recall rates were higher in galactosemia and congenital adrenal hyperplasia when using the original cut-off points, suggesting that it would be reasonable to modify the cut-off point at 99.7 percentile after measuring those substances from enough of healthy neonates.

Re-Evaluation of Neonatal Screening Tests for Inborn Errors of Metabolism with Dried Filter Paper Blood Spots

PURPOSE: There have been high rates of false positive and recall in neonatal screening test using the cut-off points set by the manufacturing company. So, it is necessary to re-evaluate the cut-off values to minimize the false positive rates. METHODS: We collected capillary blood in dry filter paper from 996 healthy neonates on the third day in cases of normal vaginal delivery or the fifth day in cases of Cesarean section. The levels of phenylalanine, galactose, 17-hydroxyprogesterone and branched-chain amino acids were measured using enzyme immunoassay. The results were compared with the original cut-off points set by the manufacturing company. RESULTS: The original cut-off points of four substances were 4.0mg/dL, 7.5mg/dL, 35ng/mL, and 8.0mg/dL, respectively, so that false-positive rates were 0.4, 1.6, 3.93, and 0.001%, respectively. When we set the cut-off point at 99.7 percentile using the data from healthy neonates, they should be 4.0mg/dL, 9.2mg/dL, 54.3ng/mL, and 8.0mg/dL, respectively. CONCLUSION: The false-positive and recall rates were higher in galactosemia and congenital adrenal hyperplasia when using the original cut-off points, suggesting that it would be reasonable to modify the cut-off point at 99.7 percentile after measuring those substances from enough of healthy neonates.

A Study on Subtypes of Thyroid Disorders Detected by Neonatal Screening Test / 대한소아내분비학회지

PURPOSE:The project of the neonatal mass screening test for inborn errors of metabolism are just at the beginning in Korea and there was a few reports about the overall incidence and subtypes of congenital hypothyroidism. METHODS:In this study, we analysed the 97 cases of newborns with hyperthyrotropinemia who were detected by neonatal screening test to identify the incidence and early clinical manifestations of each subtypes of congenital hypothyroidism. Thyroid function were measured by thyrotropin(TSH) level, T4, T3, Free T4, Free T3, thyroglobulin, T3 resin uptake, TBII, TBG in serum, thyroid ultrasonography and 99mTc thyroid scan. We reanalysed the thyroid functions 1 week after discontinuance of L-thyroxine treatment for 1 year. RESULTS: 1) The time of neonatal screening test were between 3 and 7 days after birth in 46 cases(47.4%) and 8 and 14 days after birth in 35 cases(36.1%). Two cases (2.1%) were done neonatal screening test at the age of 2 days old. 2) The major cause of thyroid disorders were primary hypothyroidism in 45 cases of the total due to thyroid aplasia(7 cases), thyroid hypoplasia(17 cases), ectopic thyroid gland(12 cases) and dyshormonogenesis(9 cases). Other causes of thyroid disorders were TBG deficiency(11 cases), TBG dysfuction(1 case), transient hyperthyrotropinemia(28 cases) and transient hypothyroidism(12 cases). 3) Serum level of thyrotropin(TSH) at diagnosis were 223.5+/-229.6microU/ml in thyroid aplasia, 41.6+/-42.9microU/ml in thyroid hypoplasia, 52.4+/-55.6microU/ml in ectopic thyroid gland. TSH levels were significantly high in thyroid aplasia. T4 levels in thyroid aplasia are 1.7+/-2.0microg/dl and this is significantly lower than other types of thyroid disorders. T3 levels were within normal range except in thyroid aplasia and TBG deficiency. 4) Prolongation of physiologic jaundice was the most common clinical manifestation(33.3%) in patients with primary hypothyroidism and macroglossia, hypothermia, umbilical hernia and cold skin were the next commom clinical manifestations in order to present. 5) Osseous development was normal in 57 cases(82.6%) out of 69 cases who accomplished roentgenographic examination of knees. Only 12 cases(17.4%) showed retardation of osseous development, but there was no significant differences between types of thyroid disorders. 6) Most of the newborn(93.3%) with primary hypothyroidism started to treatment within 8 weeks of age. 7) Initial dosage of L-thyroxine was 10microg/kg/day and decreased 6 to 12 months after treatment. 8) There was significantly decreased thyroid uptake of 99mTc after 1 year follow-up in 5 cases of dyshormonogenesis. 9) The serum TSH levels returned to normal ranges within 6 month after treatment in transient hypothyroidism and transient hyperthyrotropinemia. CONCLUSIONS:Special attention should be paid to transient hyperthyrotropinemia and transient hypothyroidism because many of the congenital thyroid disorders showed transient type and it is necessary to establish the diagnostic guideline to early detect these transient types of congenital thyroid disorders.