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Premium member Presentation Transcript Newborn Screening: Newborn Screening Dr Dinesh Dharel MD Pediatrics Resident Institute of Medicine Patan Hospital, March 2012Contents: Contents Concept of Newborn Screening Congenital Hypothyroidism and Congenital Adrenal Hyperplasia Inborn Errors of Metabolism Newborn Screening: Past, Present and Future Newborn Screening in Nepal: Possibilities and ChallengesWhat is Newborn Screening?: What is Newborn Screening? Newborn Screening is a system for identifying genetic and other health problems in newborns that leads to overall improvement in the public health NBS tests look for serious developmental, genetic, and metabolic disorders so that important action can be taken during the critical time before symptoms develop.NBS System: NBS SystemComponents of NBS: Components of NBS 1. Education: Professionals, parents and policy makers 2. Screening: Collection activities, Specimen delivery, Laboratory testing and Result reporting 3. Early Follow-up: 4. Diagnosis: 5. Management: Medical mgt, Long term follow-up, Specimen mgt 6. Evaluation:Conditions detected by Newborn Dried Blood Spot Screening: Conditions detected by Newborn Dried Blood Spot Screening Endocrine disorders- CH, CAH Hematological disorders- G6PD Def, SCD Amino acid disorders- PKU, MSUD, Homocystinuria Fatty acid oxidation disorders Organic acid disorders Urea cycle disorders Galactosemia Biotinidase deficiency Cystic Fibrosis Infectious diseases- HIV, ToxoplasmosisNBS Statistics reported in NBS Workshop 2010: NBS Statistics reported in NBS Workshop 2010Incidence of Different Conditions Screened in India and China: Incidence of Different Conditions Screened in India and China S No Condition screened Incidence India Incidence China 1 Congenital Hypothyroidism 1: 1700 1:2020 2 Cong Adrenal Hyperplasia 1:2575 1:12000 3 G6PD Deficiency 1:2200 0.1% 4 Galactosema 1:10300 5 Phenylketouria 1:18300 6 Mapple Syrup Urine Disease 1:10215 7 Tyrosinemia 1:6234NBS for IEM (China 1012): NBS for IEM (China 1012)Prevalence of CH : Prevalence of CH Country Prevalence of CH Year reported Bangladesh 1:2295 2012 Pakistan 1:1442 2012 Sri lanka 1:1595 2012 Philippines 1:3324 2012 Japan 1:7600 2005 USA 1:3044 2005 Australia 1:4151 2005 World 1:3000 2005Criteria for Screening (Wilson and Jungner WHO 1968): Criteria for Screening (Wilson and Jungner WHO 1968) Important health problem Facilities for diagnosis and treatment available Accepted treatment Recognizable latent and early symptomatic state Suitable test or examination Test acceptable to population Natural history of disease adequately understood Agreed policy on whom to treat as patients Cost of case finding balanced in relation to possible expenditure on medical care as a whole Case finding is a continuous processCongenital Hypothyroidism: Congenital HypothyroidismCongenital Hypothyroidism: Congenital Hypothyroidism A treatable deficiency of thyroid hormone Causes physical and mental retardation Manifests itself too late to treat completely Results in unnecessary health, economic and social burdens for family Can be detected shortly after birth by NBS Can be effectively and inexpensively treated If identified and treated early, good outcomeClinical features of Congenital Hypothyroidism: Clinical features of Congenital Hypothyroidism First 2 Postnatal Weeks Beyond Age 1 Month After Age 3 Months Prolonged neonatal jaundice Edema of the eyelids, hands, and feet Gestation >42 wk Birth weight >4 kg Poor feeding Hypothermia Protuberant abdomen Large fontanelles Darkened and mottled skin Stressful, frequent, and labored breathing Failure to gain weight; poor sucking ability Decreased stool frequency Decreased activity and lethargy Umbilical hernia Infrequent and hard stools Dry skin with carotenemia Macroglossia Generalized swelling or myxedema Hoarse cryPowerPoint Presentation: An infant with cretinism - hypotonic posture, coarse facial features, macroglossia, and umbilical hernia.PowerPoint Presentation: The infant shown above - few months after starting thyroid hormone replacement.Age related values: Age related values TSH ( μ U/ml) Cord = <2.5-17.4 1-3days=<2.5-13.3 1-4wk = 0.6-10.0 1-12mth = 0.6-6.3 1-15yrs = 0.6-6.3 16-50yr = 0.2-7.6 FT 4 (ng/dl) 1-10 days = 0.6-2.0 >10days = 0.7-1.7Congenital Adrenal Hyperplasia: Congenital Adrenal Hyperplasia A family of autosomal recessive disorders of cortisol biosynthesis 21-Hydroxylase deficiency, classic form 21-Hydroxylase deficiency, nonclassic form 11β- Hydroxylase deficiency 3β- Hydroxysteroid dehydrogenase deficiency 17α- Hydroxylase/17,20-lyase deficiency Congenital lipoid adrenal hyperplasia P450 oxidoreductase deficiencyClinical Suspicion for CAH: Clinical Suspicion for CAH Depending on the enzymatic step that is deficient, there may be signs, symptoms, and laboratory findings of mineralocorticoid deficiency or excess; incomplete virilization or premature puberty in affected males; and virilization or sexual infantilism in affected females 21-hydroxylase deficiency is often undiagnosed in affected males until they have severe adrenal insufficiency (adrenal crisis)Inborn Errors of Metabolism: Inborn Errors of Metabolism Diverse heterogeneous group of hereditary biochemical disorders with the versatile clinical manifestations mainly in children Usually normal at birth Non specific clinical manifestations, confounding with neonatal sepsis Rapidly progressive, causes irreversible damage early in course. Usually severe & lethal unless early diagnosis and proper therapy promptly initiated. Treatment can often be effective if commenced early and long term outcome may be improved Correct diagnosis helps in genetic counselling.A high index of suspicion for IEM: A high index of suspicion for IEM Parental consanguinity Positive family history of similar illness/death History of clinical deterioration in previously normal neonate Symptoms onset a few days after feeding (refusal to feed, vomiting, lethargy, hypotonia , coma, seizures) Persistent vomiting, hypoglycemia , ketosis, metabolic acidosis FTT, developmental delay or regression Unusual odour particularly during an acute illness Jaundice, visceromegaly , Dysmorphic featuresUnderstanding Metabolic diseases: Understanding Metabolic diseases Garrod’s hypothesis product deficiency substrate excess toxic metabolite A D B C A group of rare genetic disorders usually caused by defects in the enzymes involved in the biochemical pathways that metabolize food components Include disorders of Carbohydrate, Amino acid or fat metabolismFour simple tests for classifying metabolic disorders: Four simple tests for classifying metabolic disorders Acidosis (arterial pH<7.2,SBE>-5) Ketosis (Urinary ketones + ve ) Arterial Lactate (>18 Mg/dl) Ammonia (>80/ µ g/dl) Diagnosis + + + _ _ + + + _ _ _ ± + _ _ _ ± ± + _ Maple syrup urine disease Organic acidurias Lactic acidosis Urea cycle dusorders Non ketotic hyperglycinemia ; Peroxisomal disorderUrine metabolic screen: Urine metabolic screen Disorder Ferric chloride DNPH Reducing substances Nitroprusside MPS spot Test Phenyl ketonuria + + _ _ _ Galactosemia _ _ + _ _ Organic aciduria + + _ _ _ Amino aciduria _ + _ _ _ Homocystinuria _ _ _ + _ Mucopolysaccharidoses _ _ _ _ +Tests for Newborn screening: Tests for Newborn screeningHistory of NBS: History of NBSHistory of NBS: History of NBSTechnologies in Screening Lab: Technologies in Screening Lab Immunoasasys Enzymatic assays Time resolved Fluorometry Isoelectric focussing techniques End Point PCR Tandem Mass Spectrometry Digital MicrofluidicsImmunoassay: Immunoassay Immunoasays are specific protein binding assays that rely on the high specificity and affinity of the recognition reaction between Ag and Ab Competitive Radiaoimmunoassay (RIA) developed in 1960s still applicable for measuring analytes (small Ag) eg TSH Noncompetitive RIAs (IRMA/IFMA) Time resolved Fluorometry allows multi-analyte assays and is easy to apply and non toxicConditions Screened by TMS: Conditions Screened by TMSAlternative Technology for NBS: Alternative Technology for NBSNEPAL IS ON TRACK TO REACH MDG4 : REDUCING CHILD MORTALITY: NEPAL IS ON TRACK TO REACH MDG4 : REDUCING CHILD MORTALITY Mortality Trend and MDG Goal (Under 5, Infant and Neonatal) Sources: EPI/WHO. Black et al, 2008. The Lancet Series on Maternal and Child Under-nutrition.PowerPoint Presentation: Estimated distribution of direct causes of neonatal deaths Lawn JE et al 4 Million neonatal deaths: when? here? why? The Lancet 365, 891 - 900, 2005Where do these deliveries occur? NDHS: Where do these deliveries occur? NDHSCB-NCP Coverage Districts : CB-NCP Coverage DistrictsDeterminants of poor newborn health in developing countries: Determinants of poor newborn health in developing countriesNewborn screening progress in developing countries-overcoming internal barriers. Padilla CD: Newborn screening progress in developing countries-overcoming internal barriers. Padilla CD Newborn screening is an important public health measure aimed at early identification and management of affected newborns thereby lowering infant morbidity and mortality. It is a comprehensive system that must be institutionalized and sustained within public health systems often challenged by economic, political, and cultural considerations. As a result, developing countries face unique challenges in implementing and expanding newborn screening that can be grouped into the following categories: (1) planning, (2) leadership, (3) medical support, (4) technical support, (5) logistical support, (6) education, (7) protocol and policy development, (8) administration, (9) evaluation, and (10) sustainability.NBS Ethical Issues: NBS Ethical Issues Technology has allowed mapping of the human genome and screening for multiple genetic conditions with small drops of blood. Genetictests are being marketed directly to consumers, bypassing the traditional role of the Physician in determining which tests are appropriate for an individual patient. As genetic testing becomes even more widely available and NBS continues to expand, ethical issues must continue to be discussed and debated, including risks of discrimination and stigmatization, respect for autonomy of individuals, privacy rights, and anxiety associated with testing. Physicians will be called to coordinate care of patients who have genetic conditions as well as to counsel families and assist them in the decision- makingprocess .How to start Pilot Project on NBS?: How to start Pilot Project on NBS? It is usually the action(s) of an interested individual or group of individuals that initiates newborn screening pilot studies. In order to initiate a pilot study that can lead to sustainable newborn screening, it is necessary to identify project financing and to: • Decide on condition or conditions about which prevalence information is desired • Identify a project leadership/management team and team leader Ref. Therrell BL, David-Padilla C. Screening of Newborns for Congenital Hypothyroidism. Vienna: IAEA, 2005, pp. 21-41How to start Pilot Project on NBS?: How to start Pilot Project on NBS? Understand the 6 elements of the newborn screening system (education, screening, early follow-up, diagnosis, management and evaluation) • Diagram the system processes and define the responsibilities of each component • Design an education process for health care workers, parents, and policy makers • Develop appropriate screening protocols – pre-analytic, analytic, post-analytic • Plan and develop data collection activities to answer questions of interest • Initiate the pilot project, evaluate the data and plan next stepsConsiderations in developing NBS program: Considerations in developing NBS program • An individual or group that champions NBS • Preliminary screening activities that develop supportive data • Education and influence of policy makers to include NBS as a routine programme in the national health service. • Use of the media and other public relations efforts to boost support and coverage for newborn screening activities. • Creation of a mechanism to fund routine NBS • Development of national coordination for the established programme by the Ministry of Health • Recognition and development of a method for continuous evaluation and improvement.Financing a NBS Program: Financing a NBS Program Financing is always an issue whether in a developing or developed program. Various strategies have been used and should be considered in finding the best local mechanism. Care should be taken to appropriately and accurately cost out the elements of the screening system. Some successful financing models include government support, insurance, fees charged to the parents, donations, grants and fund raising eventsReferences : References Paul A. Levy; Pediatrics in Review, Inborn Errors of Metabolism; 2009;30;131 C D Padilla & B L Therrell (on behalf of the Working Group of the Asia Pacific Society for Human Genetics); Consolidating newborn screening efforts in the Asia Pacific region: Networking and shared education; JCommunityGenet(2012)3:35–45 B L Therrell, C D Padilla; Screening of Newborns for Congenital Hypothyroidism: Guidance for Developing Programmes; IAEA 2005 D.S. Millington; Expanded Newborn Screening by Tandem Mass Spectrometry and Digital Microfluidics: Platforms for Multiplexing Assays Used in Newborn Screening Manila 2012 Nelson Textbook of Pediatrics, 19 th editionPowerPoint Presentation: Thank You You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.