Nationwide neonatal screening for congenital adrenal hyperplasia in sweden: a 26-year longitudinal prospective population-based study.

IMPORTANCE: Recent reports have questioned the rationale for neonatal screening for congenital adrenal hyperplasia (CAH) owing to low sensitivity in salt-wasting forms and a high rate of recall (ie, a positive finding resulting in a visit to a pediatrician and a second test) in preterm infants. OBJECTIVE: To determine the efficiency of the neonatal screening program for CAH in Sweden over time. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal prospective population-based study in Sweden. We assessed neonatal screening for CAH from January 1, 1986, through December 31, 2011, when 2 737 932 infants (99.8%) underwent testing. The CYP21A2 genotype was investigated in 219 cases with true-positive findings (94.8%). We investigated the screening outcomes for 231 patients who had true-positive findings, 43 with late diagnosis, and 1497 infants with false-positive findings. MAIN OUTCOMES AND MEASURES: Sensitivity of the screening for salt-wasting CAH. The most important secondary outcome measures were the positive predictive values and recall rates for full-term and preterm infants and sensitivity for milder forms of CAH. RESULTS: A total of 143 patients with salt-wasting CAH were identified; none were missed. The sensitivity was lower for milder forms of the disorder (P = .04), including 79.7% for simple virilizing forms and 32.4% for nonclassic forms. The positive predictive value was higher in full-term (25.1%) than preterm (1.4%) infants and correlated with gestational age (r = 0.98; P < .001). The recall rate in full-term infants (0.03%) was lower than that in preterm infants (0.57%) (P < .001). An analysis of previously reported results from other screening programs revealed that the sensitivity of the screening was negatively correlated with the duration of follow-up (P = .03). CONCLUSIONS AND RELEVANCE: Screening for CAH was highly effective in detecting the salt-wasting form and thereby reducing mortality. Additional late-onset cases of CAH were detected in childhood and adolescence, reducing the sensitivity for milder forms. The positive predictive value was high despite a low recall rate in full-term infants. Further improvements are necessary to increase the effectiveness of screening among preterm infants.

Galactosemia screening with low false-positive recall rate: the Swedish experience.

Newborn screening was implemented in the 1960s with screening for phenylketonuria (PKU). In the same decade, it became possible to screen for classical galactosemia, a rare autosomal recessive inherited disorder, which is potentially life threatening if not treated. While newborn screening for PKU has become almost universal, galactosemia is included only in a minority of European newborn screening programs. The major arguments why galactosemia is excluded from newborn screening programs are that the disease can be diagnosed clinically, there is a high rate of false positives and long-term complications are common despite early diagnosis.Here, we report how we have decreased the number of false-positive galactosemia recalls to less than 0.01%, using a two-tier test strategy. All samples are tested with the Beutler blood spot test, a method that measures galactose-1-phosphate uridyltransferase activity. Samples with less than ≤15% activity are tested for galactose with a galactose dehydrogenase test (the rapid GAL-DH test), which catalyzes the oxidation of galactose and the reduction of NAD(+) to NADH that is estimated visually by fluorescence under UV-light. Both tests are semiquantitative.With this strategy, screening for galactosemia is inexpensive, does not demand a heavy workload, and has a low false-positive re-call rate. The incidence of classical galactosemia in Sweden is 1/100,000, which is lower than the reported incidence in other European countries. Despite this, newborn screening for galactosemia has never been questioned. Concise sentence: Screening for galactosemia using well-established methods to reduce the false-positive rate.

Profound biotinidase deficiency: a rare disease among native Swedes.

Biotinidase deficiency is an autosomal recessive metabolic disorder included in many newborn screening programmes. Prior to the introduction of screening for biotinidase deficiency in Sweden in 2002, the disorder was almost unknown, with only one case diagnosed clinically. Biotinidase activity was measured in dried blood spots with a semiquantitative method using biotin-6-amidoquinoline as substrate. The cutoff value was set at 25% (later lowered to 20%) of the mean activity of all samples measured on that day. The disorder was confirmed by quantitative determination of biotinidase activity in plasma and DNA analyses. Over a period of 6 years, 13 patients were identified among 637,452 screened newborns and 5,068 adoptive/immigrant children. None of the patients had clinical symptoms at the time of diagnosis. Six patients had profound biotinidase deficiency, with an activity of 0-5% of normal in plasma. Four of these patients were born to parents who were first cousins of Middle Eastern or African origin. Eighteen gene alterations were identified, nine of which have not previously been described: seven mutations p.L83S (c.248T > C), p.R148H (c.443G > A), p.N202I (c.605A > T), p.I255T (c.764T > C), p.N402S (c.1205A > G), p.L405P (c.1214T > C), p.G445R (c.1333G > A) and two silent mutations p.L71L (c.211C > T) and p.L215L (c.645C > T). The predicted severity of the novel mutations was analyzed by sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), predicting p.L83S, p.L405P and p.G445R as severe mutations. Due to the high rate of immigrants since 1990 from non-Nordic countries, the incidence of biotinidase deficiency is similar to that found in many other Western countries.

Congenital CMV infection: prevalence in newborns and the impact on hearing deficit.

Congenital cytomegalovirus (CMV) infection is asymptomatic in 90% of infected newborns but approximately 10-20% of these infants are at risk of developing sequelae later, mostly hearing deficit. The aims of the study were to investigate the prevalence of congenital CMV infection in a Swedish population of newborns and investigate the relative risk of hearing deficit in newborns with congenital CMV infection. The dried blood spot (DBS) samples of 6060 newborns in southern Stockholm during 12 months (October 2003-June 2004; August 2004-October 2004) were analysed for CMV DNA by TaqMan based real-time PCR. Hearing deficit was assessed by otoacoustic emission (OAE) within a newborn screening programme. 12 infants out of 6060 or 0.2% (95% CI 0.1-0.3%) had congenital CMV infection. One boy among the 12 infected infants had unilateral hearing loss, indicating that the risk of hearing loss is greatly increased (about 20 times) in CMV infected infants. No child developed ocular complications such as chorioretinopathy during 3 y of follow-up. Congenital CMV has an impact on child health but can easily be overlooked due to lack of signs in the neonatal period. Surveillance for congenital CMV is important in addition to programmes for prevention and treatment.