Juliet Oerton

Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England: prevalence, predictive value and test validity based on 1.5 million screened babies

Background Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare, life-threatening condition. Early diagnosis by screening asymptomatic newborns may improve outcome, but the benefit to newborns identified with variants not encountered clinically is uncertain. Objective To estimate, overall and by ethnic group: screen-positive prevalence and predictive value (PPV); MCADD prevalence; proportion MCADD variants detected of predicted definite or uncertain clinical importance. Setting All births in areas of high ethnic minority prevalence in England. Methods Prospective multicentre pilot screening service; testing at age five to eight days; standardized screening, diagnostic and management protocols; independent expert review of screen-positive cases to assign MCADD diagnosis and predicted clinical importance (definite or uncertain). Results Approximately 1.5 million babies (79% white; 10% Asian) were screened. MCADD was confirmed in 147 of 190 babies with a positive screening result (screen-positive prevalence: 1.20 per 10,000; MCADD prevalence: 0.94 per 10,000; PPV 77% [95% CI 71–83]), comprising 103 (70%) with MCADD variants of definite clinical importance (95 white [95%]; 2 Asian [2%]) and 44 (30%) with variants of uncertain clinical importance (29 white [67%]; 12 Asian [28%]). Conclusion One baby in every 10,000 born in England is diagnosed with MCADD by newborn screening; around 60 babies each year. While the majority of MCADD variants detected are predicted to be of definite clinical importance, this varies according to ethnic group, with variants of uncertain importance most commonly found in Asian babies. These findings provide support for MCADD screening but highlight the need to take account of the ethnic diversity of the population tested at implementation.

Arrest Referral in London Police Stations: characteristics of the first year. A key point of intervention for drug users?

The paper examines the demographic, drug use and offending profile of arrestees in contact with arrest referral (AR) schemes in London, compares these contacts with the arrestee population as a whole, and with drug users presenting to treatment services in the community, and assesses the proportion and characteristics of AR contacts that go on to attend drug-treatment services. Routine monitoring data from AR schemes (April 2000 to March 2001) were analysed and compared with data ( for equivalent time period) on arrestees from the Crime Reporting Information System (CRIS) and data from the National Drug Treatment Monitoring System (NDTMS). AR schemes see about 10% of arrestees in London. Approximately half of those assessed by an AR worker report using heroin (55%) and crack cocaine (49%) with a similar proportion (51%) having no previous contact with drug-treatment services. The large majority (80%) report previous convictions. Of those referred by AR workers (50% of assessments) between 25 and 37% attend a first appointment at a drug-treatment service. Drug users seen by AR workers are younger, more likely to come from ethnic minorities and more likely to be using crack cocaine than those presenting to treatment services in the community. AR is a key point of contact with problem drug users, including those considered under-represented at drug-treatment services. However, to fully assess the effectiveness of AR, further information is required about retention in treatment and its effect on drug use and offending behaviour.

Incidence and clinical features of congenital adrenal hyperplasia in Great Britain

Objectives To estimate the incidence of clinically diagnosed congenital adrenal hyperplasia (CAH), clinical features and age at first presentation. To assess the potential benefit of newborn screening for CAH. Design Active surveillance through the British Paediatric Surveillance Unit of all children aged under 16 years with newly diagnosed CAH, undertaken prospectively between August 2007 and August 2009. Twelve laboratories testing for CAH reported new diagnoses between August 2007 and January 2009. Reporting clinicians completed clinical questionnaires. Setting England, Wales and Scotland. Results 144 children with CAH were reported, of whom 132 (92%) had 21-hydroxylase deficiency. Thirty-six (25%) children were Asian and 62 (43%; 95% CI 35% to 51%) were boys. Incidence of new diagnoses in children ≤16 years was 0.60 (95% CI 0.50 to 0.71) per 100 000. Eighty-six (59%; 36 boys) children were diagnosed in the first year of life (estimated birth prevalence 5.48 (95% CI 4.42 to 6.81) per 100 000), most (77; 89%) of whom presented in the first month of life. Virilised genitalia were found in three-quarters of girls. Twenty-seven newborns first presented with salt-wasting crises, of whom 18 (67%; 16 boys) presented on or after 14 days of age. Conclusions Approximately one child in every 18 000 born in Great Britain has CAH. Similar numbers of boys and girls present clinically in the first year of life, but boys present with more severe manifestations, such as salt-wasting crises. Around 70% of newborns who first present with salt-wasting crisis would be detected earlier through newborn screening.

Ethnicity of children with homozygous c.985A>G medium-chain acyl-CoA dehydrogenase deficiency: findings from screening approximately 1.1 million newborn infants.

Objectives It has been suggested that homozygous c.985A>G medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disease of White ethnic origin but little is known regarding its ethnic distribution. We estimated ethnic-specific homozygous c.985A>G MCADD birth prevalence from a large-scale UK newborn screening study. Methods Homozygous c.985A>G MCADD cases were ascertained in six English newborn screening centres between 1 March 2004 and 28 February 2007 by screening approximately 1.1 million newborns using tandem mass spectrometry analysis of underivatised blood spot samples to quantitate octanoylcarnitine (C8). Follow-up biochemistry and mutation analyses for cases (mean triplicate C8 value ≥0.5 µmol/L) were reviewed to confirm diagnosis. Ethnicity was ascertained from clinician report and denominators from 2001 UK Census estimates of ethnic group of children less than one year. Results Sixty-four infants were c.985A>G MCADD homozygotes (overall prevalence 5.8 per 100,000 live births; 95% CI 4.4–7.2). Sixty (93%) were White, two (3%) were mixed/other and two were of unknown ethnic origin. No Asian or Black homozygotes were identified. Proportions of White, mixed/other, Asian and Black births in screening regions were estimated, yielding homozygous c.985A>G MCADD birth prevalence of 6.9 per 100,000 (95% CI 5.2–8.8) in White, and 95% CI estimates of 0–2.7 per 100,000 in Asian and 0–5.8 in Black populations. The c.985A>G carrier frequency in the White group was estimated at one in 65 (95% CI 1/74, 1/61) under Hardy–Weinberg conditions. Conclusion c.985A>G homozygous MCADD is not found in Black and Asian ethnic groups that have been screened at birth in England. This is consistent with the earlier published observations suggesting that MCADD due to the c.985A>G mutation is a disease of White ethnic origin.

Detection of urinary hexanoylglycine in the diagnosis of MCAD deficiency from newborn screening.

We strongly support Piero Rinaldo_s and Kevin Carpenter_s comments regarding the importance of accurate and reliable identification of urinary hexanoylglycine (HG) as a definitive diagnostic factor for MCAD deficiency (J Inherit Metab Dis 2008;31: 142–145, Notes and Queries in Metab-L). Qualitative organic acid analysis should detect the near normal concentrations of HG seen in some Fnon-crisis_ MCADD (both c.985A>G homozygotes and mild variants) samples. However, data from the ERNDIM EQA scheme with >70 participants demonstrate failure to detect HG around 8 2mol/mmol creatinine in 10–30% of samples. When the UK embarked on pilot screening for MCADD in 2004 the six UKCSNS-MCADD screening centres (Shortland et al 2006) agreed that, after qualitative organic acid assessment of trimethylsilyl derivatives by individual laboratories, all follow-up urine samples from presumptive positive cases (day 5 blood spot octanoylcarnitine >0.5 2mol/L) would have HG quantified by a central laboratory using GC-MS stable-isotope dilution analysis (SID) of methyl esters. To our knowledge, quantitative HG data have not been available in other studies of newborn screening for MCADD. In the two-year pilot period, HG concentrations (2mol/mmol creatinine) were available in 93/105 cases: 6 but in only 1/13 samples below the upper limit of normal (<1.1). Detection of HG failed in 4 samples with concentrations above the normal range (values 1.2, 5.0, 5.5 and 5.9). In view of these findings, for implementation of MCADD screening in the UK (completion due April 2009) the UKCSNS-MCADD recommended that follow up urine samples where HG is not detected on qualitative analysis should have HG quantified by GCMS-SID.

Newborn Screening for Primary Congenital Hypothyroidism: Estimating Test Performance at Different TSH Thresholds.

Abstract Context Active surveillance of primary congenital hypothyroidism (CH) in a multiethnic population with established newborn bloodspot screening. Objective To estimate performance of newborn screening for CH at different test thresholds and calculate incidence of primary CH. Design Prospective surveillance from June 2011 to June 2012 with 3-year follow-up of outcomes. Relative likelihood ratios (rLRs) estimated to compare bloodspot TSH test thresholds of 6 mU/L and 8 mU/L, with the nationally recommended standard of 10 mU/L for a presumptive positive result. Setting UK National Health Service. Patients Clinician notification of children aged <5 years investigated following clinical presentation or presumptive positive screening result. Main Outcome Measure(s) Permanent primary CH status determined by clinician report of continuing T4 requirement at 3-year follow-up. Results A total of 629 newborns (58.3% girls; 58.7% white ethnicity) were investigated following presumptive positive screening result and 21 children (52.4% girls; 52.4% white) after clinical presentation; 432 remained on treatment at 3-year follow-up. Permanent CH incidence was 5.3 (95% CI, 4.8 to 5.8) per 10,000 infants. With use of locally applied thresholds, sensitivity, specificity, and positive predictive value were 96.76%, 99.97%, and 66.88%, respectively. Compared with a TSH threshold of 10 mU/L, positive rLRs for 8 mU/L and 6 mU/L were 1.20 (95% CI, 0.82 to 1.75) and 0.52 (95% CI, 0.38 to 0.72), and negative rLRs were 0.11 (95% CI, 0.03 to 0.36) and 0.11 (95% CI, 0.06 to 0.20), respectively. Conclusions Screening program performance is good, but a TSH threshold of 8 mU/L appears superior to the current national standard (10 mU/L) and requires further evaluation. Further research should explore the implications of transient CH for screening policy.

P09 Initial diagnostic outcome of screening for congenital hypothyroidism after newborn bloodspot screening: a uk surveillance study

Introduction Primary congenital hypothyroidism (CHT) is due to reduced thyroid hormone production. Oral thyroxine therapy commenced soon after birth improves cognitive development and growth. Despite 30 years of newborn screening for CHT in the UK, its success in identifying babies who require lifelong therapy for CHT remains unclear. Aim To determine, through UK-wide active surveillance, the number and characteristics of children aged ≤5 years diagnosed annually with CHT, detected by screening or after clinical manifestations, and to describe clinical management. Results During 13 months of surveillance, 704 children with positive screening results were reported by screening laboratories. Local clinicians completed 643 questionnaires (response rate = 91%). An additional 20 children aged <5 years were notified who were not identified through screening, including three diagnosed prior to screening (2 family history, 1 unwell) and 17 with negative screening tests (10 preterm, 5 unwell, 2 Downs syndrome); screening results were untraceable for 2 children. Of 643 screen positive children, 260 (40%) were boys, 130 (20%) were <37 weeks gestation and most were of white or Asian ethnicity (379[59%] and 133[21%] respectively). Investigations carried out soon after referral demonstrated serum TSH >40 mU/l in 365; in an additional 43 children an abnormal thyroid scan result was associated with serum TSH ≤40 mU/l. Based on the reported initial investigations for 643 children, an expert panel assigned a diagnosis of CHT in 410, excluded CHT in 120 and considered 113 had probable/possible CHT requiring follow-up. The local clinicians commenced 485 children on oral thyroxine, 401 of whom were assigned as having definite CHT by the expert panel. During 12 months of follow up after diagnosis, eleven children died of causes unrelated to CHT. Conclusion Our findings suggest that the predictive value of a positive screening test is at most 81% (523/643) assuming CHT is confirmed in those with possible CHT as an initial diagnosis. Our data suggest that permanent CHT cannot be confirmed at initial diagnostic investigation in a significant proportion of screen positive babies. Follow up of this cohort is continuing to determine outcome by two years of age. Funding Public Health England (NHS Newborn Blood Spot Screening Programme).