Introduction
The Early Origins of Newborn Screening
Phenylketonuria: Discovery, Treatment, and Screening
Recognition of the Important Role of Screening in Population Health
1 | The condition sought should be an important health problem. |
2 | There should be an accepted treatment for patients with recognized disease. |
3 | Facilities for diagnosis and treatment should be available. |
4 | There should be a recognizable latent or early symptomatic stage. |
5 | There should be a suitable test or examination. |
6 | The test should be acceptable to the population. |
7 | The natural history of the condition, including development from latent to declared disease, should be adequately understood. |
8 | There should be an agreed policy on whom to treat as patients. |
9 | The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole. |
10 | Case-finding should be a continuing process and not a “once and for all” project. |
Beyond PKU: Expansion of Newborn Screening Programs
Newborn Screening Methodologies
Newborn Screening Programs Worldwide
Amino acid disorders |
Phenylketonuria |
Maple syrup urine disease |
Homocystinuria |
Citrullinemia type I |
Argininsuccinic aciduria |
Tyrosinemia I |
Other secondary conditions (argininemia, citrullinemia type II, hypermethioninemia, benign hyperphenylalaninemia, biopterin defects, tyrosinemia type II and III) |
Organic acid disorders |
Methylmalonic acidemia (with or without homocystinuria) |
Glutaric acidemia type I |
Propionic acidemia |
3-Methylcrotonyl-glycinuria |
3-Hydroxy-3-methyl glutaric aciduria |
Holocarboxylase synthase deficiency |
β-Ketothiolase deficiency |
Isovaleric acidemia |
Other secondary conditions (malonic acidemia, isobutyrylglycinuria, 2-methylbutyrylglycinuria, 3-methylglutaconic acidurias, 2-methyl-3-hydroxybutyric acidurias) |
Fatty acid β-oxidation disorders |
Medium-chain acyl-CoA deficiency |
Very long-chain acyl-CoA dehydrogenase deficiency |
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency |
Trifunctional protein deficiency |
Carnitine transport defect |
Carnitine palmitoyltransferase I deficiency |
Carnitine palmitoyltransferase II deficiency |
Carnitine acylcarnitine translocase deficiency |
Glutaric acidemia type II |
Other secondary conditions (short-chain acyl-CoA dehydrogenase deficiency, medium-short-chain K-3-hydroxyacyl-CoA dehydrogenase deficiency, medium-chain ketoacyl-CoA thiolase deficiency, 2,4-dienoyl-CoA reductase deficiency) |
Lysosomal storage disorders |
Krabbe’s disease |
Pompe’s disease |
Fabry disease |
Gaucher disease |
Niemann pick disease |
Mucopolysaccharidosis I |
Mucopolysaccharidosis II |
Other lysosomal disorders |
Other |
Congenital hypothyroidism |
Human immunodeficiency virus (HIV) |
Toxoplasmosis |
Severe combined immunodeficiency (SCID) |
X-linked adrenoleukodystrophy |
Glucose-6-phosphate-dehydrogenase (G6PD) deficiency |
Hemoglobinopathies |
Sickle cell disease |
Congenital adrenal hyperplasia |
Classic galactosemia |
Biotinidase deficiency |
Cystic fibrosis |
Duchenne muscular dystrophy |
Galactokinase deficiency |
Galactoepimerase deficiency |
Point of care testing |
Hearing loss |
Congenital heart disease |
Proposed future conditions |
Fragile X syndrome |
Ornithine transcarbamylase deficiency |
Wilson disease |
Guanidinoacetate methyltransferase deficiency |
Primary Immunodeficiency Diseases
History of Newborn Screening for Primary Immunodeficiency Diseases
Screening for Severe Combined Immunodeficiency (SCID)
Low TREC levels | Low KREC levels |
Severe combined immunodeficiency* 22q deletion syndrome Combined immunodeficiency Ataxia telangiectasia DOCK 8 deficiency EDA-ID Trisomy 21 Trisomy 18 Kabuki syndrome CHARGE syndrome Noonan syndrome Jacobsen syndrome Nijmegen breakage syndrome** Fryns syndrome Schimke immuno-osseous dysplasia Cartilage hair hypoplasia CLOVES ECC Rac2 defect Renpenning syndrome TAR Other cytogenetic abnormalities - Including 6p deletion, ring chromosome 14, ring chromosome 17, chromosome 17p duplication, 14q microdeletion | Severe combined immunodeficiency (T-B-)** X-linked agammaglobulinemia (XLA) XLA-like disorders Nijmegen breakage syndrome** |
Secondary causes | |
Prematurity Congenital cardiac disease Chylothorax Multiple congenital anomalies Gastrointestinal anomalies - Including gastroschisis Third space losses Vascular leakage Hydrops Neonatal leukemia Maternal autoimmune disease Maternal HIV infection Maternal immunosuppression Other maternal medications -Including ritodrine | Maternal immunosuppression Other maternal medications - Including ritodrine |
Screening for Congenital B Cell Deficiency Disorders
Concurrent Screening for Severe Forms of Primary Immunodeficiency Manifested by T and B Cell Lymphopenia
Region | Screening period | Screening strategy | Number of newborns screened | Primary immunodeficiency cases identified | References |
---|---|---|---|---|---|
USA (10 states + Navajo region) | January 2008–July 2013 (5.5 years) | TREC | 3,030,083 | SCID (n = 52) - Typical SCID (n = 42) - IL2RG (n = 9) - IL7RA (n = 6) - ADA (n = 5) - RAG1 (n = 4) - JAK3 (n = 3) - DCLRE1C (n = 1) - RAG2 (n = 1) - CD3D (n = 1) - TC7A (n = 1) - Pallister-Killian syndrome; tetrasomy 12p (n = 1) - Molecular defect unknown (n = 6) - Genetic testing incomplete (n = 4) - Leaky SCID (n = 10) - RAG1 (n = 4) - RMRP (n = 2) - IL2RG (n = 1) - DCLRE1C (n = 1) - Molecular defect unknown (n = 2) | Kwan et al. 2014 [27] |
Taiwan | 2010–2017 (78 months) | TREC | 920,398 | SCID (n = 7) - IL2RG (n = 3) - RAG1 (n = 1) - Molecular defect unknown (n = 3) SCID variant, molecular defect unknown (n = 8) EDA-HT (n = 1) | Chien et al. 2017 [28] |
Sweden (Stockholm county) | 15 November 2013–14 November (3 years) | TREC/KREC | 89,462 | SCID (n = 2) - Artemis deficiency) (n = 1) - ADA deficiency (n = 1) Ataxia telangiectasia (n = 1) CID, molecular defect unknown (n = 2) | Barbaro et al. 2016 [29] Zetterström et al. 2017 [30] |
Israel | 1 October 2015–30 April 2017 (18 months) | TREC | 290,864 | SCID (n = 13) - Typical SCID (n = 10) - DCLRE1C (n = 3) - IL7RA (n = 2) - RMRP (n = 1) - Ligase 4 deficiency (n = 1) - Complete DiGeorge Syndrome (n = 1) - Molecular defect unknown (n = 2) - Leaky SCID (n = 3) - DCLRE1C (n = 2) - MHC2 deficiency/RFX5 (n = 1) Undefined PID (n = 6) | Rechavi et al. 2017 [39] Rechavi et al. (personal communation) |