All neonates with a positive NBS require evaluation and confirmatory testing Those with NBS positive for a condition that may result in decompensation in the neonatal period require emergent evaluation even if they appear to be asymptomatic Most neonates with a positive NBS will have a false-positive result Evaluation should include history and physical examination, and IEM-specific routine laboratory tests to reveal clinical manifestation or confirm absence of findings Confirmatory NBS tests should be sent even if routine laboratory tests are normal Evaluation, management, and disposition should be in consultation with an IEM specialist Management should include correction of any metabolic derangements, assuring adequate hydration and avoidance of potentially toxic substances even in asymptomatic patients Goals of Treatment Treatment goal is to confirm NBS and to prevent symptoms and metabolic derangements of IEM Current Understanding The Advisory Committee on Heritable Disorders in Newborns and Children, as of July 2018, recommends that states screen for a core panel of 35 conditions, 24 of which are IEMs, and an additional 26 conditions that are considered secondary targets on the basis of more mild symptoms and/or absence of treatment options, of which 24 are IEMs Most, but not all states, now screen for core conditions, and at least some of the secondary targets (http://genes-r-us.uthscsa.edu/nbsdisorders.pdf ) For every true-positive NBS, there are 12 to 60 false positives To minimize the number of falsenegative NBS results, cutoff values have been deliberately set low with a national goal of an overall 0.3% false-positive rate and a 20% positive predictive value False positives also occur because of maternal IEM, which, in some cases is undiagnosed Even in the asymptomatic neonate, a false positive cannot be assumed Evaluation should include history, physical examination, and routine laboratory tests to reveal clinical manifestations of disease or confirm absence of manifestations The IEMs most likely to cause acute decompensation in neonates include certain forms of tyrosinemia, organic acidemias, urea cycle defects, galactosemia, and, less commonly, biotinidase deficiency Manifestations and treatment of these conditions are detailed in the section of this chapter on known IEMs, and for congenital adrenal hyperplasia in Chapter 89 Endocrine Emergencies Evaluation and management of neonates with positive NBS should be in consultation with a metabolic specialist, or endocrinologist in the case of congenital adrenal hyperplasia, and guided by American College of Medical Genetics NBS condition specific ACTion sheets and confirmatory algorithms, which provide an overview of the condition and information about potential clinical manifestations, and appropriate routine and confirmatory laboratory tests (http://www.ncbi.nlm.nih.gov/books/NBK55827/ ) The New England Consortium website includes descriptions of some of the diseases in their acute illness protocols (http://newenglandconsortium.org/for-professionals/acute-illness-protocols/ ) Descriptions of specific IEMs can also be found in texts referenced at the end of this chapter and on various websites, including the National Center for Biotechnology Information’s “Online Mendelian Inheritance in Man” website (http://www.ncbi.nlm.nih.gov/omim ) Clinical Considerations Triage Triage should be based on symptoms Patients with even subtle symptoms should be expedited for care Assessment History should focus on details of pregnancy and delivery, including gestational age, complications, medications, exposures, route of delivery, Apgar scores, and complications; medications; family history of affected relatives, stillbirths, SIDS; and postnatal history, including fever, lethargy, feeding, vomiting, diarrhea, jaundice, abnormal movements, and abnormal odors History may be unremarkable Examination should take note of level of activity, vital signs, temperature, weight, height, head circumference, dysmorphic features, skin color, fontanelle, red reflex, cataracts, heart sounds, perfusion, respiratory distress, abdominal distention, bowel sounds, hepatomegaly, splenomegaly, ambiguous genitalia, cryptorchidism, suck, grasp, Moro, deep tendon reflexes, tone, symmetry, and seizures Physical examination may be normal Confirmatory testing is required for all neonates with a positive screen Laboratory evaluation should be disease specific Routine tests may include electrolytes, BUN, creatinine, glucose, ammonia, AST, ALT, bilirubin, PT, PTT, CBC, differential, platelets, and blood gas Concurrent evaluation for infection should be guided by history and examination Appropriate tests for confirmation of the NBS condition for which the patient is positive should be sent, even if all routine laboratory tests are normal In some cases, further testing is limited, at least initially, to repeat NBS, which may include measurement of standard NBS analytes, as well as additional analytes, while in other cases, specialized tests including enzyme assays and/or molecular tests are indicated Management Specifics of management depend not only on the condition for which the patient screened positive but also on the likely variant(s) of that condition, the concentration of the metabolite on NBS interpreted in the context of age at the time of screening, and other factors that could modify test results Cardiopulmonary abnormalities and metabolic derangements must be corrected Dietary modification, vitamin cofactors, and/or medication may be appropriate and, in many cases, can prevent clinical manifestations Consultation with a specialist is indicated Patients with any abnormality should, in most cases, be admitted to the hospital For patients who are discharged, a plan for very close follow-up and genetic counseling, even though confirmatory testing may rule out true disease, should be established SUMMARY Collectively IEMs are not rare, and clinical manifestations are often nonspecific Therefore, a high index of suspicion is essential for diagnosis A few routine tests will serve as an informative screen for most IEMs Evaluation and treatment of patients with known IEM should be disease specific All neonates with positive NBS, even if asymptomatic, require evaluation and confirmatory testing, and if at risk for acute decompensation emergent initiation of treatment Rapid initiation of appropriate treatment for patients with suspected or known IEM or positive NBS may not only be lifesaving but is also critical for optimizing long-term outcome Suggested Readings and Key References ACMG Newborn Screening Work Group Metabolic disorders Newborn screening ACT sheets and confirmatory algorithms Available at https://www.acmg.net/ACMG/Medical-Genetics-PracticeResources/ACT_Sheets_and_Algorithms.aspx Accessed March 9, 2019 Acute Illness Protocols New England Consortium of metabolic programs at Children’s Hospital Boston Available at https://newenglandconsortium.org/for-professionals/acute-illness-protocols/ Accessed March 9, 2019 Advisory Committee on Heritable Disorders in Newborns and Children Recommended uniform screening panel Available at https://www.hrsa.gov/advisory-committees/heritabledisorders/rusp/index.html Accessed April 4, 2019 Bahi-Buisson N, Dulac O Epilepsy in inborn errors of metabolism Handb Clin Neurol 2013;111:533– 541 Blau N, Duran M, Gibson KM, et al., eds Physicians’ Guide to the Laboratory Diagnosis of Metabolic Diseases 2nd ed Heidelberg, Germany: Springer; 2002 Cakir B, Teksam M, Kosehan D, et al Inborn errors of metabolism presenting in childhood J Neuroimaging 2011;21(2):e117–e133 Review Erratum in: J Neuroimaging 2011;21(3):306 Ficicioglu C, An Haack K Failure to thrive: when to suspect inborn errors of metabolism Pediatrics 2009;124(3):972–979 Ghaziuddin M, Al-Owain M Autism spectrum disorders and inborn errors of metabolism: an update Pediatr Neurol 2013;49(4):232–236 Hoffman GF, Nyhan WL, Zschocke J Inherited Metabolic Diseases Philadelphia, PA: Lippincott Williams & Wilkins; 2010 Krishna SH, McKinney AM, Lucato LT Congenital genetic inborn errors of metabolism presenting as an adult or persisting into adulthood: neuroimaging in the more common or recognizable disorders Semin Ultrasound CT MR 2014;35(2):160–191 Levy PA Inborn errors of metabolism: part 1: overview Pediatr Rev 2009;30(4):131–137 Levy PA Inborn errors of metabolism: part 2: specific disorders Pediatr Rev 2009;30(4):e22–e28 Mak CM, Lee HC, Chan AY, et al Inborn errors of metabolism and expanded newborn screening: review and update Crit Rev Clin Lab Sci 2013;50(6):142–162 McKusik VA OMIM online Mendelian inheritance in man [database online] Available at http://www.ncbi.nlm.nih.gov/omim Accessed January 30, 2009 National Newborn Screening and Genetics Resource Center United States table of newborn screening tests performed by state What is Newborn Screening? Available at https://www.babysfirsttest.org/ Accessed March 26, 2020 Nia S Psychiatric signs and symptoms in treatable inborn errors of metabolism J Neurol 2014;261(Suppl 2):559–568 Ozben T Expanded newborn screening and confirmatory follow-up testing for inborn errors of metabolism detected by tandem mass spectrometry Clin Chem Lab Med 2013;51(1):157–176 Pagon RA Gene tests Available at http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests Accessed March 11, 2019 Parvaneh N, Quartier P, Rostami P, et al Inborn errors of metabolism underlying primary immunodeficiencies J ClinImmunol 2014;34(7):753–771 Rahman S, Footitt EJ, Varadkar S, et al Inborn errors of metabolism causing epilepsy Dev Med Child Neurol 2013;55(1):23–36 Sahoo S, Franzson L, Jonsson JJ, et al A compendium of inborn errors of metabolism mapped onto the human metabolic network Mol Biosyst 2012;8(10):2545–2558 Saudubray JM, Van den Berghe G, Walter JH, eds Inborn Metabolic Diseases: Diagnosis and Treatment 5th ed Heidelberg, Germany: Springer MedizinVerlag; 2012 Sun A, Lam C, Wong DA Expanded newborn screening for inborn errors of metabolism: overview and outcomes Adv Pediatr 2012;59(1):209–245 Vockley J, Chapman KA, Arnold GL Development of clinical guidelines for inborn errors of metabolism: commentary Mol Genet Metab 2013;108(4):203–205 Weinstein DA, Butte AJ, Raymond K High incidence of unrecognized metabolic and endocrinologic disorders in acutely ill children with previously unrecognized hypoglycemia Pediatr Res 2001;49:88A Weismiller DG Expanded newborn screening: information and resources for the family physician Am Fam Physician 2017;95(11):703–709 Wolf NI, García-Cazorla A, Hoffmann GF Epilepsy and inborn errors of metabolism in children J Inherit Metab Dis 2009;32(5):609–617 Zand DJ, Brown KM, Lichter-Konecki U, et al Effectiveness of a clinical pathway for the emergency treatment of patients with inborn errors of metabolism Pediatrics 2008;122(6):1191–1195 CHAPTER 96 ■ NEONATAL EMERGENCIES NICKIE NIFORATOS ANDESCAVAGE, DEENA BERKOWITZ INTRODUCTION AND INITIAL ASSESSMENT Goals of Emergency Care The neonate is in a fragile state of transition to extrauterine life Newborns have limited ability to maintain temperature and glucose and they have limited cardiopulmonary reserves to compensate for dehydration, sepsis, or other stressors Newborns may exhibit apnea, rather than tachypnea, in response to hypoxia They are immunocompromised and are unable to communicate subjective findings Every clinical finding is likely to be more subtle in the neonate than in the older infant Therefore, the goals of emergency care are to triage and treat neonates urgently until serious disease has been ruled out, while maintaining body temperature and serum glucose KEY POINTS Newborns have very little reserve to compensate when acute illnesses occur Tachypnea may be the only presenting sign of congestive heart failure Hypothermia, rather than fever, may be a neonate’s response to sepsis Weight loss is the most sensitive sign of dehydration in the newborn A loss greater than 10% of birth weight during the first 10 to 14 days of life should be thoroughly investigated Careful attention must be paid to maintenance of temperature and glucose in the ED RELATED CHAPTERS ... Lichter-Konecki U, et al Effectiveness of a clinical pathway for the emergency treatment of patients with inborn errors of metabolism Pediatrics 2008;122(6):1191–1195 CHAPTER 96 ■ NEONATAL EMERGENCIES... 2011;21(3):306 Ficicioglu C, An Haack K Failure to thrive: when to suspect inborn errors of metabolism Pediatrics 2009;124(3):972–979 Ghaziuddin M, Al-Owain M Autism spectrum disorders and inborn errors... EMERGENCIES NICKIE NIFORATOS ANDESCAVAGE, DEENA BERKOWITZ INTRODUCTION AND INITIAL ASSESSMENT Goals of Emergency Care The neonate is in a fragile state of transition to extrauterine life Newborns have