Neonatal mass screening for metabolic disorders

The present situation of neonatal mass screening for metabolic disorders in eleven European countries is presented. The only disease screened for on a population wide basis in almost all countries is phenylketonuria. Screening for congenital hypothyroidism has been started in most countries or is under active consideration. A priority list of disorders that should be screened for routinely in all newborns comprises congenital hypothyroidism, hyperphenylalaninaemia, galactosaemia and maple syrup urine disease. Other disorders, like adrenogenital syndrome, cystic fibrosis. Duchenne's muscular dystrophy, histidinaemia, or tyrosinaemia cannot be recommended for mass screening at present because of an unsatisfactory test procedure or lack of effective treatment.     

Follow-up study of a nation-wide neonatal metabolic screening program in Japan

A nationwide neonatal sreening program for phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria, histidinemia and galactosemia was started in Japan in 1977. The total number of infants screened had reached 6,311,754 by March, 1982. A follow-up study revealed the incidence of the disease in Japan: 1/108,823 for PKU; 1/450,840 for hyperphenylalaninemia (HPA); 1/1,577,939 for biopterin deficiency; 1/525,980 for MSUD; 1/1,051,959 for homocystinuria; 1/8,371 for histidinemia, and 1/788,969 for galactosemia type 1. The incidences of PKU, HPA, homocystinuria, and galactosemia (type 1) were found to be markedly low in Japan as compared with those in Caucasian countries. There was no great difference in the incidence of MSUD between both. On the other hand, the incidence of histidinemia was higher in Japan.It was found that most of the patients with PKU, HPA, MSUD, homocystinuria, or galactosemia are developing normally due to the early initiation of dietary treatment. These results clearly indicate that the neonatal mass screening program plays a great role in preventing the occurrence of handicapped children.     

Histidinaemia: a benign metabolic disorder

Histidinaemia is a relatively common inherited metabolic disorder with an incidence similar to phenylketonuria. This paper reports the long term outcome of patients diagnosed by newborn screening in the north west of England. Between 1966 and 1990, 108 infants were diagnosed as having histidinaemia by a regional neonatal screening programme (incidence 1:11,083). A further five children were detected following diagnosis in a sibling. Of the 113, nine were lost to follow up. Infants diagnosed before 1981 (n = 47) were placed on a low histidine diet (225 mg/kg/d) for an average period of 21 months (SD 4.5). All patients were reviewed regularly, Griffiths developmental quotients (DQ) were assessed at 2 and 4 years, and WISC-R intelligence quotients (IQ) at 8, 12, and 18 years. IQ data were converted to standard deviation scores (IQ SDS) to account for increasing IQ norms with time. Neither DQ nor IQ correlated with plasma histidine at diagnosis or with the mean plasma histidine throughout life. Growth was normal in all patients. There was no apparent benefit from a low histidine diet in early childhood. In contrast to other studies, there was no excess of clinical symptoms. On the basis of these findings, histidinaemia is a benign metabolic disorder that does not require treatment.     

Histidinaemia: a benign metabolic disorder.

Histidinaemia is a relatively common inherited metabolic disorder with an incidence similar to phenylketonuria. This paper reports the long term outcome of patients diagnosed by newborn screening in the north west of England. Between 1966 and 1990, 108 infants were diagnosed as having histidinaemia by a regional neonatal screening programme (incidence 1:11,083). A further five children were detected following diagnosis in a sibling. Of the 113, nine were lost to follow up. Infants diagnosed before 1981 (n = 47) were placed on a low histidine diet (225 mg/kg/d) for an average period of 21 months (SD 4.5). All patients were reviewed regularly, Griffiths developmental quotients (DQ) were assessed at 2 and 4 years, and WISC-R intelligence quotients (IQ) at 8, 12, and 18 years. IQ data were converted to standard deviation scores (IQ SDS) to account for increasing IQ norms with time. Neither DQ nor IQ correlated with plasma histidine at diagnosis or with the mean plasma histidine throughout life. Growth was normal in all patients. There was no apparent benefit from a low histidine diet in early childhood. In contrast to other studies, there was no excess of clinical symptoms. On the basis of these findings, histidinaemia is a benign metabolic disorder that does not require treatment.     

SCREENING FOR CONGENITAL HYPOTHYROIDISM

ABSTRACT. Larsson, A., Ljunggren, J. G., Ekman, K., Nilsson, A. and Olin, P. (Departments of Paediatrics and Child Psychiatry, Karolinska Institute, St. Goran's Children's Hospital; the Department of Medicine, St. Göran's Hospital; and the PKU Section of the Department of Bacteriology, National Bacteriological Laboratory, Stockholm, Sweden). Screening for congenital hypothyroidism. I. Laboratory results of a pilot study based on dried blood samples collected for PKU screening. Acta Paediatr Scand, 70:141, 1981. – A pilot study was performed to establish optimal conditions for nation-wide screening for congenital hypothyroidism in Sweden. The levels of T₄ and TSH were determined by automated radioimmunoassay in the dried blood spots, routinely collected for PKU screening on the fifth postnatal day, from all 1979, 2 infants born in the Stockholm area during a 14-month period. To identify safe minimum recall criteria for routine use, infants were recalled if the TSH level was more than 30 mU/l of plasma or–if they were not preterm–the T₄ concentration was less than -2 S.D. of the mean. Altogether 160 infants were recalled. Seven newborns with congenital hypothyroidism were identified, 6 with primary and one with secondary hypothyroidism. Five infants had decreased levels of thyroxine-binding globulin. The results of the follow-up analyses from recalled infants showed that determination of the reverse-T₃ level may be of diagnostic value around the 23rd day of life. The results of the clinical investigation of recalled infants are reported in a subsequent paper and a programme for nation-wide screening for congenital hypothyroidism is proposed.     

Screening for neonatal hyperbilirubinaemia and ABO alloimmunization at the time of testing for phenylketonuria and congenital hypothyreosis

In a population-based study including 2463 infants, serum bilirubin measurements were added to the neonatal screening programme for phenylketonuria and congenital hypothyreosis. This screening programme detected 11/17 (65%) of infants with serum bilirubin levels > 350/μmol l⁻¹, of whom 7 (3 per 1000) were readmitted from home (6 treated with phototherapy). A total of 139 infants (5.6%) received phototherapy. Maternal blood type O occurred significantly more often in term infants treated (30/54; 55.6%) compared with preterm infants treated (32/85; 37.6%) and with blood type O occurrence in the total population of mothers (906/2426; 37.3%) ( p < 0:05). The blood type constellations mother O/infant A or B showed a sensitivity of 64%, specificity 65%, positive predictive value 12% and a negative predictive value of 96% for the requirement of phototherapy for the whole material. Exchange transfusion was not required in any of the infants. No infant developed bilirubin encephalopathy (kernicterus). Adding bilirubin to a neonatal screening programme detects some cases with unexpectedly high bilirubin levels in need of intervention. Routine ABO blood typing of pregnant women, ABO cord blood typing and Coombs' test in infants of mothers with blood type O cannot be recommended because of low positive predictive value for the requirement of intervention (phototherapy) by these tests.     

Experience of Routine Live-birth Screening for Galactosaemia in a British Hospital,with Emphasis on Heterozygote Detection

Results are reported of a screening programme for galactosaemia covering a period of 2½ years and 6415 births. The gene frequency for galactosaemia estimated from the data of the screening programme was 0·002. This conflicted with the known live-birth incidence of at least 1: 50,000 during this same period. 2 of the 4 galactosaemic infants concerned died under circumstances that were preventable had they been screened at birth. The need to screen all sick infants for galactosaemia is emphasized, as is the requirement for reliable information on its incidence in Great Britain. The screening test employed (Beutler and Baluda, 1966a) seemed appropriate for this purpose. It was simple to perform and apparently accurate in galactosaemic infants. Its accuracy in detecting heterozygotes is uncertain. This test should be available in all hospitals receiving sick neonates.     

Screening for inherited metabolic disease in Wales using urine-impregnated filter paper.

Urine specimens from 135 295 infants have been collected on filter papers and tested for 7 abnormal urinary constituents using spot tests and paper chromatography. The method has detected 5 infants with phenylketonuria, 4 with histidinaemia, 5 with cystinuria, 5 with diabetes mellitus, and one with alcaptonuria. Transient abnormalities such as tyrosyluria, generalized aminoaciduria, cystinuria, and glycosuria have been noted. 2 phenylketonuric infants failed to excrete a detectable quantity of o-hydroxyphenlacetic acid at the time of testing. The findings show that the detection of this compound in urine is an unreliable method of screening for phenylketonuria.     

PLACENTAL TRANSFER OF MATERNAL ANTI-RABBIT IgG CAUSING FALSELY ELEVATED TSH LEVELS IN NEONATES

Abstract. Larsson, A., Hedenborg, G. and Carlström, A. (Department of Paediatrics, Karolinska Institute, St. Göran's Children's Hospital, and the PKU Section, Department of Bacteriology, National Bacteriological Laboratory, Stockholm, and the Department of Clinical Chemistry, Karolinska Institute, Danderyd's Hospital, Danderyd, Sweden). Placental transfer of maternal anti-rabbit IgG causing falsely elevated TSH levels in neonates. Acta Paediatr Scand, 70:699,.–Two infants were found to have markedly increased TSH levels, 104 and 154 mU/l of plasma, respectively, in a routine screening programme for congenital hypothyroidism. The recall limit used was 50 mU/l of plasma. On follow-up, both infants were clinically euthyroid and had normal serum T₄ and T₃. The elevated TSH levels were confirmed only with some commercial radioimmunoassay kits–but not with others. Similar results were obtained in TSH assays of samples from their mothers, who had no other biochemical or clinical evidence of thyroid dysfunction. Both mothers had intense contact with rabbits over long periods. The apparent TSH activity was found to be associated with the IgG fraction. It was neutralized by the addition of normal rabbit serum to the samples and was caused by antibodies to rabbit immunoglobulin. The activity was eliminated from the circulation of both infants with a half-life of approximately one month. Apparently, the heterophilic antibodies were of maternal origin and were transferred to the foetus via the placenta. Infants with so-called transient hyperthyrotropinaemia identified in screening programmes have to be reevaluated to exclude false TSH elevations of this type.     

Follow-up study of 16 years neonatal screening for inborn errors of metabolism in West Germany

Capillary blood samples from almost one million neonates from Baden-Württemberg were investigated for inborn errors of metabolism between 1969 and 1984 in our screening centre. Besides 7 patients with maple syrup urine disease (MSUD), 3 with homocystinuria and 18 with galactosaemia, a follow-up of the positive screening results confirmed 94 patients with phenylketonuria (PKU) and 76 with non-PKU hyperphenylalaninaemia (non-PKU HPA). The incidence of PKU is 1: 10 000, and that of HPA in the wider sense (PKU and non-PKU HPA) as obtained by newborn screening before further classification at 6 months 1: 5532.For West Germany as a whole, the number of newly discovered cases with persistent hyperphenylalaninaemia was 1480 in the same period. The subdivision into PKU and non-PKU HPA is not yet possible from this figure. It is strongly suggested that the abnormal results of newborn screening for phenylalanine be designated as hyperphenylalaninaemia (in the wider sense) and that the terms PKU or non-PKU HPA be used only after further differentiation as carried out by us at the age of 6 months.Abbreviations MSUD maple syrup urine disease - PKU phenylketonuria - non-PKU HPA non-PKU hyperphenylalaninaemia     

Screening for congenital hypothyroidism in Turkey

Abstract A pilot study was performed to determine the incidence of congenital hypothyroidism (CH) in Turkey and to build a model for nationwide screening. From December 1991 to December 1992, 30097 newborns were screened for CH using a primary measurement of thyroid stimulating hormone in capillary blood on days 3–5 of life. Samples were obtained in collaboration with the ongoing nationwide phenylketonuria screening programme. Eleven cases of primary CH were detected giving the incidence of 12736. Recall rate was 2.3%. Replacement therapy withl-thyroxine was started after the confirmation of diagnosis. The median age at the initiation of replacement therapy was 23 days (range 7–35 days).Conclusion The incidence of CH is notably higher in Turkey than reported in most other countries. Iodine deficiency and/or dyshormonogenesis might contribute to this high incidence. This result emphasizes the necessity of a nationwide screening programme.     

OMPHALOCELE and GASTROSCHISIS IN SWEDEN 1965–1976

Abstract. Lindham. S. (Department of Paediatric Surgery, Karolinska Hospital, Stockholm, Sweden). Omphalocele and gastroschisis in Sweden 1965–1976. Acta Paediatr Scand, 70:55, 1981.–The present investigation supports the view that omphalocele and gastroschisis are two different congenital malformations. They differ not only anatomically but also regarding the incidence of concomitant malformations, sex ratio and maternal age. There has been a significant increase in the incidence of gastroschisis in Sweden during the period 1965–1976 but no corresponding increase in the incidence of omphalocele. The incidence of abdominal wall defects in stillborn is twenty times higher than in liveborn children.     

Evaluation of the usefulness for neonatal mass screening in light of 35 years personal experience

The results and the significance of neonatal mass-screening programmes for inborn errors of metabolism, conducted by the National Research Institute of Mother and Child (NRIMC), are discussed. As the first in Poland, in 1964, mass-screening for phenylketonuria (PKU) was introduced. The BIA-Guthrie test was used. Other Guthrie tests (GBIA) were applied in homocystinuria, tyrosinemia, histidinemia and leucinosis (Maple Syrup Urine Disease-MSUD). In the middle of the 60. the Beutler and Baluda test was introduced for galactosaemia, as well as the Efron urine test in infant screening for different inborn errors of metabolism. In the middle of the 70., neonatal mass-screening for cystic fibrosis (CF, mucoviscidosis) was started. Meconium tests and the sweat test with ion selective chloride electrode were used. Apart from inborn errors of metabolism, we also introduced a screening programme for neuroblastoma in which vaniline mandelic acid (VMA) in urine was estimated and for congenital hypothyroidism were TSH level was assessed. The results of screening are shown in the tables and in the figures. In our opinion the best clinical results are obtained with screening for congenital hypothyroidism and for PKU, since very early detection and treatment in these diseases prevents severe mental retardation. We therefore consider that both these screening programmes should be treated as obligatory examinations in all neonates. Taking into consideration the fact that there are different types of hyperhenylalaninemias, the principles of differential diagnosis are discussed. Molecular genetic investigations, carried out in the NRIMC Department of Genetics proved to be a very important procedure in the verification of diagnosis of different mutations. The authors also discuss the problem of dietary treatment duration in PKU. In our opinion the hypophenyloalanine diet regimen in girls, should not be discontinued during adolescence, since there is the problem of maternal PKU and the possibility of foetal damage. The results of our own investigations of maternal PKU are discussed. The significance of mass-screening for galactosemia is still under discussion. In our opinion, mass-screening for galactosemia is not useful and we have discontinued it. Selective screening has been started combined with molecular genetic studies in high risk families. In the future, we plan to prepare guidelines on the principles of diagnosis and treatment of galactosemia in children and women in the reproductive age. Mass-screening for cystic fibrosis is also still under discussion. The results of the early screening programmes were not satisfactory and the tests were discontinued. In 1998, after reorganisation of the whole system, CF screening, using tripsin-radioimmune assays, was started again. The new screening programme is combined with molecular genetic investigation of different mutations. It is still too early to assess the importance and success of this CF mass-screening programme. We decided to discontinue the screening for homocystinuria, histidinemia, tyrosinemia, leucinosis and for neuroblastoma, since these programmes did not comply with criteria of mass-screening. In 1997, major reorganisation of screening programmes for inborn errors of metabolism, at NRIMC, was undertaken. The Guthrie test for PKU was changed to a quantitative colorimetric method. The immuno-luminometric method is used for TSH estimation. The whole system is based on complete computer control of all the steps of screening, from blood sampling on filter paper until the final diagnosis. The advantages of this modern system of organisation of the screening programme are discussed.     

Results of a regional cord blood screening programme for detecting neonatal hypothyroidism.

Our regional cord blood screening programme for detecting neonatal hypothyroidism using initial cord blood thyroxine (T4) determinations, with supplemental thyrotropin (TSH), and triiodothyronine resin uptake (T3U) measurements, gave an incidence of thyroid abnormalities of 1/3000 births, with 1/5000 infants having severe primary hypothyroidism. No hypothyroid infant detected in the programme had been suspected clinically before the screening and, in retrospect, only a few babies had any signs of hypothyroidism. Supplemental TSH and T3U determinations were required on 8-12% of the population screened initially with a T4 test to avoid missing affected cases. With an initial T4 and supplementary TSH and T3U testing on cord blood serum, recalls to exclude primary hypothyroidism were reduced to 0.16% of the screened population. The incidence of abnormalities detected in this cord blood screening programme was comparable with that reported by others using neonatal dried blood screening methods, indicating that cord blood screening can be effective provided the appropriate recall criteria and transport conditions are used. Nevertheless, for several practical reasons, neonatal dried blood methods are recommended as the screening test of choice for surveying large populations over extensive geographical areas.     

Hereditary tyrosinaemia. Clinical, enzymatic, and pathological study of an infant with the acute form of the disease.

A clinical, enzymatic, and pathological study of an infant with the acute form of hereditary tyrosinaemia is presented. Treatment with a diet low in methionine, tyrosine, and phenylalanine was unsuccessful. A selection of specific and nonspecific hepatic enzymes, obtained at necropsy within one hour of the infant's death at 9 1/2 weeks, were studied to try to throw light on the basic defect. The major pathological findings were those of a peculiar hepatic fibrosis associated with bile retention and an abnormal grouping of hepatocytes, islet-cell hyperplasia of the pancreas, and dilatation of the proximal renal tubules. Death was precipitated by bronchopneumonia and liver failure. The difficulty in diagnosing the acute form of tyrosinaemia is pointed out, especially in differentiating it from hereditary galactosaemia (transferase deficiency) and hereditary fructosaemia. All three may present with the same clinical symptoms and liver lesions, and the distinction must be made by enzyme studies and by therapeutic trial.     

Chromatographic screening of 70,328 neonates for inborn errors of amino acid metabolism

Between the years 1974 and 1984, amino acid chromatography was performed from dried blood spots and partly from urine of 70 328 neonates. Six cases of phenylketonuria, one histidinaemia, one hyperglycinaemia and three cystinurias were found. Since all these could have been detected by other methods, the regional screening was discontinued in agreement with international recommendations.     

Hypothalamo-pituitary hypothyroidism detected by neonatal screening for congenital hypothyroidism using measurement of thyroid-stimulating hormone and thyroxine

The optimal strategy in neonatal screening for congenital hypothyroidism is still a subject of controversy. In Kanagawa Prefecture in Japan, simultaneous thyroid-stimulating hormone (TSH) and T4/fT4 determination has been used, while the results of our program may provide valuable information. Cumulative findings were analysed to determine the type and frequency of thyroid disorders in infants detected by simultaneous TSH and T4/fT4 determination, and the TSH and T4/fT4 screening strategy was validated. A total of 1284130 neonates were screened between October 1979 and September 1997 and infants followed because of low T4/fT4 without elevated TSH (T4 < 51.5 nmol/L or fT4 < 9 pmol/L and TSH < 15 mU/L) were retrospectively analysed. The first survey was carried out within 6 mo of birth and the second in 1998; 258 infants were diagnosed with congenital hypothyroidism at the first medical evaluation, 15 of them with hypothalamo-pituitary hypothyroidism. However, in the second survey, only 8 children were confirmed as having hypothalamo-pituitary hypothyroidism, therefore the incidence detected by the present strategy was 1/160516. Of 8 children with hypothalamo-pituitary hypothyroidism, mental retardation was prevented in 3 owing to early treatment. CONCLUSIONS: Simultaneous measurement of TSH and T4/fT4 is a useful strategy for detecting hypothalamo-pituitary hypothyroidism, but more studies are needed to show the cost-benefits of using this strategy.     

Hyperphenylalaninaemia of various types among three-quarters of a million neonates tested in a screening programme.

A total of 795 382 infants born in north London was screened for phenylketonuria using the Guthrie test between October 1969 and December 1978. During this period it became recognised that phenylketonuria is not a single disease entity but one that encompasses a number of disorders of differing clinical and biochemical severity. The overall incidence of persistent hyperphenylalaninaemia was of the order of 7 per 100 000 births (or 1 in 15 000) and all the early treated patients made normal developmental progress. During the study there was an appreciable fall in the incidence of uncomplicated transient hyperphenylalaninaemia with or without tyrosinaemia. This reduction coincided with the change in infant feeding practice in the UK which led to lower intakes of protein and phenylalanine. It was concluded that any infant found to have a persistent blood phenylalanine concentration of 240 mumol/1 (4 mg/100 ml) or greater should be followed closely.     

Psychomotor Development of Children with Congenital Hypothyroidism Diagnosed by Neonatal Screening

ABSTRACT. The psychomotor development in 68 children with congenital hypothyroidism diagnosed during the first two years of a nationwide neonatal screening programme in Sweden was assessed during their first three years of life. Replacement therapy with thyroxine was initiated at the age of 15±7 days (mean ± SD). Griffiths tests were performed in 15 patients at the age of 18 months and in 51 patients at 30–47 months. Their developmental quotients did not differ from those of control children, indicating that the psychomotor development in the children with congenital hypothyroidism was normal. In earlier studies of Swedish children with congenital hypothyroidism, diagnosed clinically before the age of three and a half years, the psychomotor development was found to be impaired. In contrast, the patients diagnosed by neonatal screening and given early therapy displayed normal results in Griffiths tests. This indicates that the age at the start of treatment is an important determinant for the prognosis.     

Expanding screening for rare metabolic disease in the newborn: an analysis of costs, effect and ethical consequences for decision-making in Finland

Aim: Currently, the only metabolic disorder that newborns are screened for in Finland is congenital hypothyroidism. A proposal to start a pilot study on screening for other rare metabolic diseases using tandem mass spectrometry prompted a health technology assessment project on the effect and costs of expanded newborn screening programme options. Method: A modelling study using data from current published studies, healthcare registers and expert opinion. Results: The annual running cost of screening 56 000 newborns for the chosen five disorders (congenital adrenal hyperplasia, medium-chain acyl-CoA dehydrogenase deficiency [MCADD], long chain 3-hydroxyacyl-CoA dehydrogenase deficiency [LCHADD], phenylketonuria [PKU] and glutaric aciduria type 1 [GA 1]) was estimated to be €2.5 million or €45 per newborn when starting costs were included. The costs per quality-adjusted life year (QALY) gained are a maximum of €25 500. Prevention of severe handicap in one newborn would reduce the costs to a maximum of €18 000 per QALY gained.
Conclusions: Expanding the Finnish neonatal screening programme would require a new organization. The cost-effectiveness, resources, ethics and equity need to be considered when deciding in favour of or against starting a new screening programme.