Dianne Webster

Newborn screening for congenital adrenal hyperplasia in New Zealand

OBJECTIVE To evaluate the efficacy and efficiency of newborn screening for classic congenital adrenal hyperplasia (CAH) in New Zealand. DESIGN All infants younger than 6 weeks of age identified by newborn screening between December 1984 and December 1993 were included. RESULTS 23 cases of classic CAH (20 salt-losers) were identified. The incidence of classic CAH was 1 in 23,344. Screening identified 3 of 9 virilized female infants whose disease had not been detected clinically. Screening alone identified all 11 male infants. Notification of cases occurred at 11 +/- 3 days of age. There was a delay in treatment of the group identified by screening alone (n = 14) until 13 days of age (range, 4 to 35 days); at that time 11 infants had hyponatremia and 10 had hyperkalemia. Symptoms of vomiting, poor feeding, and shock were common after 10 days of age (2/10, < 10 days, and 8/8, 11 to 16 days of age). CONCLUSIONS Newborn CAH screening is the only method of identifying male infants with classic CAH without a family history of CAH before symptoms develop, as well as a significant portion of overlooked virilized female infants. So that clinical or significant biochemical deterioration can be avoided, pediatrician notification of screening results and treatment should be started before 10 days of age.

Posthumous diagnosis of long QT syndrome from neonatal screening cards

BACKGROUND Molecular autopsy in sudden unexplained death in the young (SUDY) victims cannot usually be performed if tissue suitable for DNA extraction is not retained at autopsy. OBJECTIVE The purpose of this study was to assess the feasibility and clinical value of posthumous genetic testing for long QT syndrome (LQTS) using residual material from the neonatal screening (Guthrie) card in SUDY victims. METHODS Twenty-one cases were investigated up to 13 years after death. Deaths occurred at <1 year in one, 1-18 years in 18, and 19-35 years in two patients. Guthrie cards were 3-39 years old. DNA was extracted, and amplicons corresponding to the coding regions of the LQTS genes 1, 2, 3, 5, and 6 underwent either denaturing high-performance liquid chromatography screening or direct DNA sequencing. RESULTS Adequate DNA was extracted in every case, although repeated purification and amplification was often required. Rare variants were detected in six of 19 cases undergoing diagnostic screening. Four (21%) are considered to be pathological and have been used for family screening: R243C and H455Y in KCNQ1 in 12-year-old and 13-year-old boys, respectively, and Q81H and S621R in KCNH2 in 21-month and 28-year-old females, respectively. Variants of uncertain significance were R1047L in KCNH2 in a 2-year-old girl and S38G in KCNE1 in a 19-month-old boy. Point mutation tests for previously identified familial LQTS mutations revealed a positive result in both cases: E146K in KCNQ1 and exon 6-4del in KCNH2. CONCLUSION Residual material from Guthrie cards collected for newborn metabolic screening can be used as a reliable source of DNA for the posthumous diagnosis of LQTS decades after SUDY, although purification and amplification of DNA is time intensive.

Etiology of Increasing Incidence of Congenital Hypothyroidism in New Zealand from 1993–2010

BACKGROUND Recent reports suggest that the incidence of congenital hypothyroidism (CHT) is increasing in some countries. The etiology of this change is unclear, and it may relate to changes in screening thresholds. We aimed to determine whether the incidence of CHT in New Zealand has changed and whether ethnic-specific rates and the rates of CHT subtypes have also changed. METHODS The New Zealand neonatal TSH-based screening program has prospectively identified cases of CHT using the same assay and screening thresholds since 1993. Thyroid scintiscans are routinely recommended. We retrospectively identified all cases of CHT requiring levothyroxine treatment from 1993-2010 recorded by the national newborn screening program (>99.5% coverage). Among other parameters, ethnic and CHT subtype-specific incidence rates were calculated. RESULTS There were 330 new cases of CHT and 1,053,457 live births registered in New Zealand in the 18-yr period, and 86% of cases had a scintiscan, 67% of which had thyroid dysgenesis (female to male ratio 5.0:1.0) and 33% dyshormonogenesis (0.9:1.0). The overall incidence of CHT rose from 2.6 to 3.6 per 10,000 live births (P < 0.01). The incidence of dyshormonogenesis (P = 0.01) increased but not of dysgenesis (P = 0.13). This was mediated by a 2-fold increase in Asian births and 40% increase in Pacific Island births. Both ethnic groups displayed higher rates of dyshormonogenesis compared with New Zealand Europeans (odds ratio 3.3 and 2.6, respectively). There was no change in the ethnic-specific incidences of CHT. CONCLUSION Although the incidence of congenital hypothyroidism in New Zealand has increased, this is due to changes in the countrys ethnic composition.

A novel therapeutic paradigm to treat congenital hypothyroidism

Objective  To determine the effectiveness of a novel therapeutic paradigm to treat congenital hypothyroidism (CH) incorporating variable initial doses of L‐T4 based on the underlying aetiology and frequent monitoring, up to 2 years of age.

Information and consent for newborn screening: practices and attitudes of service providers

Objectives: To gather information about the practices and attitudes of providers of maternity care with respect to informed consent for newborn screening (NBS). Methods: A questionnaire concerning information provision and parental consent for NBS was sent to all 1036 registered lead maternity carers (LMC) in New Zealand. Results: 93% of LMC in New Zealand report giving parents information concerning NBS, most frequently after delivery (73%) and in the third trimester (60%). The majority (85%) of LMC currently obtain some form of consent (verbal or written) for NBS from parents and consider this to be the ideal approach (94%). Despite this a significant minority of LMC (23%) reported considering that NBS should be mandatory. Of those in our survey who believed that NBS should be mandatory, paradoxically most (89%) still believed that some form of parental consent should be obtained; of those who believed testing should not be mandatory, only a small proportion (10%) would accept parental refusal without question. Conclusions: When the results of this survey are considered in conjunction with existing evidence there appears to be a consensus that good quality information in the prenatal period should be an integral part of any NBS programme. The issue of consent is more complex and there is less agreement on the preferred degree of parental involvement in decisions to allow babies to undergo NBS. A policy that both strongly recommends NBS but also allows parental choice appears to be most consistent with the views of LMC in this survey.

Neurodevelopmental and body composition outcomes in children with congenital hypothyroidism treated with high-dose initial replacement and close monitoring

BACKGROUND Despite newborn screening and early levothyroxine replacement, there are continued reports of mild neurocognitive impairment in children with congenital hypothyroidism (CHT). In Auckland, New Zealand, cases are identified by a neonatal screening program with rapid institution of high-dose levothyroxine replacement (10-15 μg/kg·d), producing prompt normalization of thyroid function. Subsequently, frequent monitoring and dose alterations are performed for 2 years. We aimed to assess whether the Auckland treatment strategy prevents impairment of intellectual and motor development. METHODS This study encompassed all children with CHT born in 1993-2006 in Auckland and their siblings. Neurocognitive assessments included the following: 1) intelligence quotient via Weschler Preschool and Primary Scale of Intelligence III or Weschler Intelligence Scale for Children IV; 2) Movement Assessment Battery for Children; and 3) Beery Developmental Test of Visual-Motor Integration. Body composition was assessed by dual-energy x-ray absorptiometry. RESULTS Forty-four CHT cases and 53 sibling controls aged 9.6 ± 3.9 years were studied. Overall intelligence quotient was similar among CHT cases and controls (95.2 vs 98.6; P = .20), and there were also no differences in motor function. Severity of CHT did not influence outcome, but greater time to normalize free T4 was associated with worse motor balance. There were no differences in anthropometry or body composition between groups. CONCLUSIONS These findings suggest that a strategy of rapidly identifying and treating infants with CHT using high-dose levothyroxine replacement is associated with normal intellectual and motor development. The subtle negative impact on motor function associated with time to normalize free T4 levels is consistent with benefit from rapid initial correction.

Newborn Screening for Congenital Adrenal Hyperplasia in New Zealand, 1994–2013

OBJECTIVE The objective of the study was to evaluate the efficacy of national newborn screening for severe congenital adrenal hyperplasia (CAH) in New Zealand over the past 20 years. METHODS Newborn screening for CAH is performed through the estimation of 17-hydroxyprogesterone by a Delfia immunoassay. CAH cases diagnosed in the newborn period from 1994 to 2013 were identified from Newborn Metabolic Screening Programme records. RESULTS Between 1994 and 2013, 44 neonates (28 females, 16 males) were diagnosed with CAH, giving an incidence of 1:26 727. Almost half (n = 21) of the newborns with CAH were detected solely via screening (not clinically suspected), including 21% of all affected females. Among the group solely ascertained by screening, 17-hydroxyprogesterone sampling occurred at a mean age of 3.3 days (range 2-8 d), the duration from sampling to notification was 5.2 days (0-12 d), and treatment was initiated at 12.0 days (6-122 d). Vomiting was present in 14% of those ascertained by screening, but none had hypotension or collapse at diagnosis. Increasing age at treatment was correlated with a progressive decrease in serum sodium (r = -0.56; P < .0001) and an increase in serum potassium concentrations (r = 0.38; P = .017). Compared with newborns diagnosed by screening alone, those clinically diagnosed were predominantly female (96% vs 29%; P < .0001), notification occurred earlier (4.8 vs 8.5 d; P = .002), and had higher serum sodium (136.8 vs 130.8 mmol/L; P < .0001) and lower serum potassium (5.3 vs 6.0 mmol/L; P = .011) concentrations. CONCLUSIONS Screening alone accounted for nearly 50% cases of CAH detected in the newborn period, including a fifth of affected females, indicating that clinical diagnosis is unreliable in both genders. Symptoms were mild at diagnosis and there were no adrenal crises. This study confirms the benefits of newborn CAH screening.

The Risk of Fatty Acid Oxidation Disorders and Organic Acidemias in Children with Normal Newborn Screening

New Zealand has undertaken expanded newborn screening since 2006. During that period there have been no reported cases of fatty acid oxidation disorders or organic acidemias that have been diagnosed clinically that the screening programme missed. However there may have been patients that presented clinically that were not diagnosed correctly or notified.In order to investigate the false-negative screening rate a case-control study was undertaken whereby the clinical coding data and relevant medical records were reviewed for 150 controls and 525 cases. The cases had normal newborn screening but with key analytes and/or ratios just below the notification level for individual disorders and thus in theory were most at risk of having metabolic disease.Two cases had medical histories suggestive of metabolic disease and thus could represent a false-negative screen. One of these had marginally elevated octanoyl carnitine levels and thus possible medium-chain acyl Co-A dehydrogenase deficiency (MCADD) while the other had elevated isovaleryl carnitine and thus may have been a case of isovaleric acidemia (IVA). However, subsequent molecular analysis revealed that the diagnosis of MCADD and IVA was unlikely.Despite relatively high cut-offs the New Zealand Newborn Metabolic Screening Programme does not appear to have missed any confirmed cases of fatty acid oxidation disorders and organic acidemias in its first 8 years of expanded newborn screening. This would suggest a similar low false-negative screening rate in centres with comparable screening protocols and would indicate that the risk of fatty acid oxidation disorders and classical organic acidemias in children who had normal newborn screening is low.

Evaluation of the revised New Zealand national newborn screening protocol for congenital hypothyroidism.

The aim of this study was to assess the performance of the revised New Zealand (NZ) newborn screening TSH cut‐offs for congenital hypothyroidism (CHT).

Optimizing Bob Guthrie's legacy--storage and use of residual newborn screening specimens.

Screening of newborn babies for congenital metabolic disorders is done in most countries worldwide. The great majority of testing is done using capillary blood collected onto absorbent paper and dried, as introduced by the late Professor Bob Guthrie. Since screening started in the 1960s, it has been the practice of programs to retain test cards after the completion of analysis and result reporting, to allow retrospective analysis of samples collected from infants who subsequently presented with a screened disorder. This investigation of false-negative screens is an essential part of public health screening and has been possible in this case by the stability of analytes and the ease of storage of blood dried on paper. Storage of these samples was begun in good faith by screeners in the healthcare climate of the 1960s in most cases without any policy for term of storage, potential uses, or permission for access. The development of molecular genetics technology (in healthcare and forensics) in the 1980s brought increased use of residual cards for purposes other than newborn screening, such as investigation of genetic disorders in families (e.g., determination of the mutation status of a deceased child known to be affected with such a disorder to allow prenatal diagnosis in a subsequent pregnancy). Law enforcement agencies were also making use of the technology to identify criminals and developing “DNA databases” for the purpose which is separate from newborn screening. Publicity around the forensic use of residual material has led to international concern about the possible uses of this material and compromise of individual privacy. In the United States, the Secretary of Health and Human Services’ Advisory Committee on Heritable Disorders in Newborns and Children has addressed this concern by the development of a report with recommendations for further action. This report has been reviewed by a distinguished team and their reflections published in the article by Therrell et al.1 in this issue of the journal. The recommendations are not contentious or surprising that programs have policies in this area (including disposition of samples after the completion of screening) and that consideration be given to a national policy; that healthcare professionals and families receive education in this area and that consent issues be explored (taking local conventions into account when considering consent for research). Although the report was written for the US context, the principles have international applicability and should be considered by all programs which store samples. The emphasis throughout the discussion on the importance of maintenance of public confidence in the screening program is well placed. Use of residual samples must not be allowed to jeopardize participation of newborns in screening. In Australasia, practices also vary. Storage is between 2 years and indefinite. Information about storage is on all parent information sheets; some Australian programs allow parent access after 2 years either for return of samples to the family or to request destruction. All Australasian parent information sheets mention the possibility of research use of deidentified samples, some give additional information about alternative uses including forensic. A regional policy about storage and use of residual material has been developed by the Joint Newborn Screening Subcommittee of the Human Genetics Society of Australasia and the Royal Australasian College of Physicians Division of Pediatrics.2 In New Zealand, the cards have been stored since introduction of the program in 1969, to investigate false-negative results, and cards have been used for this purpose consistent with our continuous quality improvement culture. Deidentified cards are also used for method improvement and assay control within the laboratory. Cards continue to be stored indefinitely awaiting a Government decision following public consultation. The New Zealand program is bound under the Health and Disability Commissioner Code of Health and Disability Consumers Rights Regulation 19963 to return samples to families on request (this regulation also covers research uses of residual material), and this is done immediately after testing is complete (or later if the request is made later). Approximately 1% of cards are returned to families. New Zealand Ma ori have a strong sense that the body is tapu (sacred or special), and this extends to respect for removed body parts including blood. The request for return of a newborn screening card may, therefore, be made, so that it can be stored or disposed of in a culturally acceptable way. Other requests may be because of confusion between stored cards and Police DNA databases. Some programs in the region offer destruction of the card as an alternative to return to family. After returns to families, the next most common use of residual samples is for family health reasons. They have been commonly used to assess the possibility of inborn errors of metabolism in symptomatic infants before the introduction of expanded newborn screening; to establish whether cytomegalovirus infection was congenital in children with deafness thought to be due to this infection and to identify long qt syndrome in sudden death. In this case, cards up to 39 years old have been used up to 13 years after death.4 Clinicians will appreciate the value of information about the cause of disability or death to families, both to answer the universal “why?” and to inform healthcare for other family members. This aspect of the value of stored cards may have been underestimated in the discussion by Therrell et al.1 and should be included in both family and professional education. A minor use of stored cards is identification of body parts. A Memorandum of Understanding between the Ministry of Health and Police formalizes the process for requesting forensic use of residual material and includes the requirement that all other possible sources of identification have been exhausted and that From the LabPlus, Auckland City Hospital, Auckland, New Zealand.