1

© The Children's Mercy Hospital, 2017

Ibrahim Ahmed, MDJennifer Gannon, MD

Ram Kalpatthi, MDElizabeth Simpson, MD

September 27, 2017

Newborn Screening: 2017 Best Practices Conflict of Interest

Elizabeth Simpson, MD: No conflict of interest

Ram Kalpathi, MD: No conflict of interest

Ibrahim Ahmed, MD: No conflict of interest

Jennifer Gannon, MD: No conflict of interest

2

© The Children's Mercy Hospital, 2017 3 © The Children's Mercy Hospital, 2017

Elizabeth Simpson, MDProfessor of Pediatrics

Medical Director of Routine Newborn Services

Truman Medical Center at Hospital Hill

September 27, 2017

Newborn Screening: 2017 Best Practices

More than 12,000 NB (1/800 Screens) are diagnosed with conditions that can cause extreme disability or death if not

treated quickly

© The Children's Mercy Hospital, 2017

Sources: GAO analysis of information from the Advisory Committee on Heritable Disorders in Newborns and Children and selected states. GAO-17-196

Advisory Committee's Newborn Screening Time-Frame Goals and Barriers Identified by States

2

Federal Goals

Goal to have 95% of results reported to pediatricians within five days of birth for babies with the most time-sensitive conditions.

States to have 95% of samples reach their state lab within 24 hours of being collected.

7

Sources: GAO analysis of information from the Advisory Committee on Heritable Disorders in Newborns and Children and selected states. GAO-17-196

Delay in NB Screening Results is Serious Business

8Ellen Gabler , Milwaukee Journal Sentinel Published 7:35 p.m. CT Dec. 17, 2016

State by State Statistics

9Deadly Delays, Journal Sentinel 11/16/2013

The Embarrassing News!

10

Deadly Delays, Journal Sentinel 11/16/2013

11 12

3

© The Children's Mercy Hospital, 2017

Ram Kalpatthi, MDAssociate Professor of Pediatrics

Division of Pediatric Hem/Onc/BMT Children's Mercy Kansas City

UMKC School of Medicine

September 27, 2017

NBS 2017 Best Practice: Hemoglobinopathies Outline

Introduction History of Screening Purpose of screening Methods used in screening Overview of abnormal hemoglobins & diseases Follow up of an abnormal screen Special note on sickle cell trait

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15

Hemoglobin Development

Hemoglobin Tetromers Newborns Adults

Hb F α2 γ2 70-80% 1-2%

Hb Aα2 β2 20-30% >95%

Hb A2α2 δ2 ~1% <3.5%

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What are “Normal” Hemoglobins

17

What are Some “Abnormal” Hemoglobins

HbS HbC HbE HbH Hb Barts

18

Abnormal Hemoglobins

Hb S (mutation in β6 Glutamic acid Valine) – Occurs in approximately 8% of African-Americans– In other populations that migrated from near Mediterranean sea

Hb C (mutation in β6 Glutamic acid Lysine) – Occurs in 2-3% of African Americans– Significant clinical condition when double heterozygote with HbS

Hb E (mutation in β26 Glutamic acid Lysine) – Most common abnormal Hb in the world– Occurs in >15% of people of Southeast Asian descent– Significant clinical condition when double heterozygote with β0 thalassemia

4

19

Abnormal Hemoglobins

Hb H (β4 tetramers)– 15-20% in HbH disease– HbH causes hemolysis and Heinz bodies in the erothrocytes

Hb Barts (γ4 tetramers) – 100% in hydrops fetalis– 15-25% in HbH disease– Increased in carries of α thalassemia trait at birth

Approximately 100,000 SCD patients in USA Approximately 2000 babies with SCD per year Infection was the most common cause of death in patients SCD Penicillin prophylaxis in 1986 resulted in dramatic decrease in infection

related mortality Universal NBS for SCD initiated in 1987. Currently all 50 states and the District of Columbia perform NBS for

SCD Other disorders such as α and β thalassemias are increasingly identified

20

History of NBS

Identify infants with homozygous SCD and begin penicillin prophylaxis

Identifies infants with other hemoglobinopathieswhom require follow-up

Identifies infants with hemoglobin traits whose families should receive counseling

21

Purpose of Screening Methodologies

Isoelectric focusing (IEF) High Performance Liquid Chromatography (HPLC) Cellulose Acetate Electrophoresis (Alkaline) Citrate Agar Electrophoresis (Acid) Capillary Zone Electrophoresis Molecular methods

22

23

Isoelectric Focusing (IEP)

24

Isoelectric Focusing (IEP)

5

25

Missouri Newborn Hemoglobinopathy Screening Results

2013 2014 2015 2016

Total specimens 91218 91425 91650 92118

FS 14 18 24 17

FSC 11 11 13 6

FSA 1 5 5 5

F only - - - -

FAS 1038 993 1071 1114

Slightly elevated Bart’s 12 8 12 3

Highly elevated Bart’s - - 2 1

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Sickle Hemoglobinopathies

HemoglobinopathyEstimated % of

US patientsNBS

patternClinical severity

Hematological Studies

Hb MCV HbA2 HbF

Hb SS 65 FS Severe 6-8 N or ↑ < 3.5% <25%

Hb SC 25 FSC Mild 9-11 ↓ NA <10%

Sickle β+ thalassemia 8 FSA Mild 9-11 ↓ > 3.5% <25%

Sickle β0 thalassemia 2 FS Severe 6-9 ↓ > 3.5% < 25%

HbS-HPFH < 1 FS Mild >11 N or↑ < 2.5% >25%

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Alpha Thalassemia

28

Alpha Thalassemia

29

Beta Thalassemia

Classification Genotype Clinical Severity Comments

β thalassemia minor or trait

β/β+ , β/β0 MildAsymptomatic

Mild microcytic anemia

β thalassemia intermedia

β+ β+, β+/β0 Moderate Moderate anemia with Hb usually >7

Intermittent blood transfusionsRisk of iron overload

β thalassemia major β0/β0, β+/β+ Severe

Severe anemia early in lifeLifelong blood transfusions

Risk of iron overloadHSCT is curative

Other hemoglobinopathies

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Hemoglobinopathy DefectClinical Severity

Comments

HbE/β0 thalassemia βE/β0 Moderate to severe

Usually β thalassemia intermedia phenotype, Southeast Asian

HbCC βc/βc AsymptomaticUsually no anemia but microcytosis is present.

Occasionally mild anemia present. African origin

HbEE βE/βE MildMild microcytic anemia. Southeast Asian,

Southern Chinese

6

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NBS Pattern & Interpretation

NBS pattern Interpretation Comments

FA Normal None

Fβ thalassemia major

PrematurityRepeat testing, education, genetic counseling, confirmatory testing and hematology referral

AF Likely post-blood transfusion Repeat testing 3-4 months after the last transfusion

FSHbSS disease

Sickle β0 thalassemiaSickle HPFH

Confirmatory testing, education, genetic testing, and hematology referral

FSASickle β+ thalassemia, SCD with

transfusion

Confirmatory testing, education, genetic testing, and hematology referral. Repeat testing in 3-4 months if

transfused

FAS Sickle cell trait Education and genetic counseling

32

NBS Pattern & Interpretation

NBS pattern Interpretation Comments

FSC HbSC diseaseConfirmatory testing, education, genetic counseling,

and hematology referral

FCHb C disease

Hb Cβ+ thalassemiaConfirmatory testing, education, genetic counseling,

and hematology referral

FEHb E disease

Hb Eβ+ thalassemiaConfirmatory testing, education, genetic counseling,

and hematology referral

FA+ variant Hb variant traitConfirmatory testing, education, genetic counseling,

and hematology referral if needed

FA Bart’s

Silent α thalassemia carrierα thalassemia trait

HbH diseaseHbH Constant Spring disease

Hydrops fetalis

If Bart’s <10%, patient will need education and genetic counseling

If Bart’s >10%, patient will need further testing for evaluation of HbH disease and hematology referral

1 in 12 African-Americans carry SCT Affects 8% of African-Americans, 0.5% Hispanics & 0.2% Caucasians Mostly asymptomatic with normal life expectancy Complications that can occur in individuals with SCT

– Decreased urine concentration– Hematuria (papillary necrosis)– Increased risk of DVT– Increased risk of renal medullary carcinoma– Risk of sudden death

33

Sickle Cell Trait (SCT)

Certain factors can predispose individuals with SCT to have symptoms– High altitude (flying, mountain climbing)– Increased pressure (Scuba diving)– Hypoxemia (when exercising intensely, training for athletic

competitions, military boot camp)– Dehydration

34

Sickle Cell Trait (SCT)

• Relatively recent death…freshman defensive back Dale Lloyd at Rice in 2006

• Collapsed after running 16 sprints of 100 yards each• Cause of death was acute rhabdomyolysis• Parents sued Rice and the NCAA• This triggered the NCAA to take a closer look at this issue• 2010: NCAA issued new mandate for SCT screening

35

NCAA and SCT

• Identifying SCT particularly important in athletes.• High training expectations, intense workouts can make them more

susceptible to having symptoms from SCT.• Despite newborn screening, many athletes do not know their Sickle

Cell status. • Student Health is an ideal setting to provide screening and

education for SCT SCT is not a contraindication to participate in competitive sports

36

Athletes and SCT

7

© The Children's Mercy Hospital, 2017 © The Children's Mercy Hospital, 2017

Ibrahim Ahmed, MDDivision of Pediatric Hem/Onc/BMT

Children's Mercy Kansas CityAssociate Professor of Pediatrics

UMKC School of Medicine

September 27, 2017

NBS 2017 best practice: What's the BMT role?

Objectives

What is Blood and Marrow Transplant? Overview of BMT role in SCID Overview of BMT role in metabolic

disorders

39

MO/KS Newborn Screening Disorders Tested

Biotinidase Deficiency (BIOT) Classical Galactosemia (GALT) Congenital Adrenal Hyperplasia (CAH) Congenital Primary Hypothyroidism (CH) Cystic Fibrosis (CF) Severe Combined Immunodeficiency (SCID) ** Amino Acid Disorders Fatty Acid Disorders Organic Acid Disorders Hemoglobinopathies: Sickle cell disease & Beta-thalassemia Lysosomal Storage Disorders: Fabry (GLA); Gaucher (GBA); Hurler/MPS-I (IDUA);Krabbe

(GALC) ** ; Pompe (GAA) Point of Care Screening: Critical Congenital Heart Defects (CCHD) Hearing

** Currently conducting statewide pilot/implementation testinghttp://health.mo.gov/lab/newborn/pdf/MissouriDisorderList.pdf

40

Allogeneic Blood and Marrow Transplntation

41

BMT

Leukemia and Lymphoma

Rescue Marrow (Auto-HCT)

Marrow Failure Syndromes

Severe Aplastic Anemia

Metabolic Syndromes(Enzyme replacement)

Rescue for SCID and other PIDs

Hemoglobinopathies

ALL, AML, MDS, JMML, CML, HL*

FA, CT, DK

SCID,

Hurler Syndrome (MPS-I)

SCDThalassemia Major

High risk CNS cancer, NB, HL (R), NHL (R),

ES (R), WT (R)WAS, Bare cell syndrome, …

Time Health status Benefit/Risk ratio Expectations and Outcome

42

Allogeneic Blood and Marrow Transplntation

8

Severe Combined Immune Deficiency

Disturbed cellular and humoral immunity that may lead to early death from overwhelming infections

43https://www-uptodate-com.ezproxy.cmh.edu/contents/image?imageKey=ALLRG%2F77023&topicKey=ALLRG%2F3912&source=see_link

RAG1/RAG2 (T-B-NK+)Artemis DNA-PKcs

X-SCID (T-B+NK-)JAK3 deficiency

ADA (10-15%)Reticular dysgenesisMTHFD1(T-B-NK-)

CD45 deficiencyCD3 pathway deficiencies(T-B+NK+)

SCID: Presentation & Diagnosis

Family History Healthy child and +ve NBS

– T cell receptor excision circle (TREC) assay

Omenn Syndrome: – Autoimmunity (Erythroderma, Alopacia, HSM, lymphadenopathy)

Present at few months of age with:– Life threattening infections (viral/PJP/bacterial)/complications– Failure to thrive / diarrhea

44

45Cutoff: TREC <95 copies/punch

Cost: € 1.83 / sample +

Cost: € 1.15 / sample +

Personelcost: € 0.8 /

sample

Date of download: 9/4/2017Copyright © 2014 American Medical Association. All rights

reserved.

From: Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States

JAMA. 2014;312(7):729-738. doi:10.1001/jama.2014.9132

Date of download: 9/4/2017Copyright © 2014 American Medical Association. All rights

reserved.

From: Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States

JAMA. 2014;312(7):729-738. doi:10.1001/jama.2014.9132

Classification of Conditions With Low T-Cell Receptor Excision Circles and Low T-Cell Numbers Found by Newborn Screening

48Dorsey et al, J ALLERGY CLIN IMMUNOL; MARCH 2017

9

Protection / Isolation

Intravenous immunoglobulin (IVIG) and Abx/PJP prophylaxis

Confirmatory work-up

Blood and marrow transplant => produce normally functioning T cells and probably B cells

49

Management and Treatment

50Pai et al. N ENGL J MED 371;5 NEJM.ORG JULY 31, 2014

Severe Combined Immune Deficiency

TREC in NBS stands for:a. The Real State Councilb. T cell Receptor Excision Circlec. Transdisciplinary Research on Energetics and

Cancerd. Translating Research in Elder Care

51

Q Hurler Syndrome (MPS-IH)

Incidence 1:100.000

AR

Lysosomal storage disease, due to α-L-iduronidaseinsufficiency => dermatan and heparan sulfate substrates accumulation

52Journal of Pediatric Orthopaedics, 24(1), January/February 2004

Multisystem disease: Coarse facial features, corneal clouding, hepatosplenomegaly, cardiorespiratory failure, progressive intellectual deterioration, sensorineural hearing loss, and a generalized characteristic skeletal dysplasia

Most untreated patients die of complications related to brain damage or cardiopulmonary failure in the first decade of life

53

MPS-IH: Clinical Course

If there is a suitable donor, HCT is recommended Rx for patients <2 years of age with severe MPS I (Hurler)

The progressive replacement of enzyme-deficient hematopoietic cells with donor-derived enzyme-competent cells in vascular and extravascular compartments of the body

54

Hurler Syndrome (MPS-IH)

10

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Mieke Aldenhoven et al. Blood 2015;125:2164-2172©2015 by American Society of Hematology

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Mieke Aldenhoven et al. Blood 2015;125:2164-2172©2015 by American Society of Hematology

Importance in predicting the risk for most prevalent and severe orthopedic complications: – the leukocyte IDUA level obtained post-HCT – age at HCT– follow-up age – follow-up center

57

Hurler Syndrome (MPS-IH)

Mieke Aldenhoven et al. Blood 2015;125:2164-2172

The long-term prognosis of patients with MPS-IH receiving HCT can be improved by:– reducing the age at HCT through earlier diagnosis, – using exclusively noncarrier donors – achieving complete donor chimerism

58Blood, 125(13), 2164-2172

Hurler Syndrome (MPS-IH)

© The Children's Mercy Hospital, 2017 © The Children's Mercy Hospital, 2017

Managing Abnormal Newborn ScreensJennifer Gannon, MD, FAAP, FACMG

Clinical Biochemical GeneticistDivision of Clinical Genetics

Children’s Mercy Kansas CityClinical Assistant Professor, UMKC School of Medicine

NBS 2017 Best Practice

11

Learning Objective

Describe experiences of PCPs and families Know what educational resources are available Incorporate practical information about

evaluating abnormal NBS into daily care of patients.

61

Disclosing NBS Results

62

PCP Experience

63

Pediatrics, 2006:118;1836-1841

Pediatricians’ Reported Barriers Percent agreed

CF CH Sickle Cell

PKU MCAD

Not competent to discuss 13.2 8.8 8.8 22.6 75.0

Uncertain what confirmatory test 20.8 5.6 6.3 39.2 67.7

No convenient laboratory 10.1 2.1 3.5 13.7 17.2

Uncertain how to interpret 15.7 7.0 7.7 30.3 49.5

Uncertain who to refer to if confirmed 4.4 2.1 1.4 7.4 17.2

PCP Experience of NBS Disclosure

64

Clinical Pediatrics 2015;54:67-75

Difficulties with being first point of contact: Management of result

Content of conversation

Addressing parents’ questions

Managing parental anxiety

PCPs recommendations to state NBS labs: Fax communication alone might not be enough

Providing handout for PCP to share with family

Training on “breaking bad news” or handout with common questions

Effect of false positive NBS result

Families with FP for IEM vs. normal result – Mothers had higher scores on Parental Stress Index and Parent-

Child Dysfunction subscale (Waisbren et al, 2003)

FP for MCAD deficiency– Infants with FP had more visits to PCP and >2x as many

hospitalizations in first year of life vs. infants with normal NBS (Karaceper et al, 2016)

65

Parents’ Experiences

203 parents, positive NBS CF or CH– Infants confirmed as TP or carrier

Self-described reactions varied– “Very scary” to “not too concerned”– Significant emotional stress, fear of child dying– Guilt– Rollercoaster of emotions

66http://cdn-img.essence.com/sites/default/files/images/em

Salm N, Yetter E, Tluczek A. J Child Health Care. 2012;16:367-381.

12

Parents’ Recommendations: Themes

Knowledgeable

Known to family

Effective communicator

Calm, reassuring

Answer and encourage questions

Make sure parents understand

Be honest

Be sensitive

Use simple language, don’t overwhelm

Characteristics in PCP PCP approach to disclosure

67Salm N, Yetter E, Tluczek A. J Child Health Care. 2012;16:367-381.Baby-healthguru.com-jpg

ACT SHEET

ACMG

Actions to take

Diagnostic evaluation

Clinical considerations

Additional resources

68https://www.ncbi.nlm.nih.gov/books/NBK55827/

Algorithm

Analyte(s) flagged

Confirmatory labs

Interpretation of results

Next steps

69https://www.acmg.net/docs/ACT%20Sheets/Algorithms/Visio-C8_%20C6_C10.pdf Accessed 06/24/2017

Educational Materials

Baby’s First Test– Conditions by State– Links to State NBS Brochures

STAR-G Genetics Home Reference

70

Opportunity for QI Projects

71

Practical Considerations

72

13

Notification of Treatment Center

Kansas – Lab does not notify Missouri – Lab does notify

– Exception: SCID – PCP must contact Immunology at treatment center

Contacting treatment center recommended

73http://randommization.com/2013/08/02/the-element-of-confusion-tee/

When contacting family:

Who in your practice contacts family? How will you provide information, answer

questions? Evaluate wellness of infant

– If infant is ill, diagnostic testing is warranted

74

Appropriate Reasons to Repeat NBS

Reasons states ask for a repeat:– Unsatisfactory sample– Screen performed too early (<24 hrs)– Infant too young for test (LSDs)– History of transfusion (Hb, GALT)– “Low risk” result for certain conditions

75

http://www.ggc.org/images/DSB_Sample_Collection__Requirements.pdfhttp://i.dailymail.co.uk/i/pix/2010/10/18/article-1321698-0BAA9B22000005DC-712_468x484.jpghttp://livesstar.com/wp-content/uploads/2017/02/prematurity-for-child_2.jpg

Repeat Screens

Don’t repeat unless asked to Repeating NBS = betting that it will be

normal

76

Risks of Repeating Screen on a Referral

77

Delay of diagnosis Delay of treatment Missed diagnosis One analyte = multiple conditions

– Additional tests to differentiate

Repeat NBS = entire screen

Summary

Evaluation of abnormal NBS stressful for everyone Workup algorithms are available Educational materials are available NBS allows for prompt initiation of evaluation and

treatment

78

14

Acknowledgements

Bryce Heese, MD

Uttam Garg, PhD

Emily Barr, RD

Hilary Boorstein, PhD

Randi Hanson, MS CGC

Nikki Lewis, RN

Kelly Neuburger, MSW

Meghan Strenk, MS, CGC

Kasey Rowzer, RD

Tarine Weihe, RD

Missouri Department of Health and Senior Services NBS Lab

Kansas Department of Health and Environment NBS Lab

Patients and Families

79 80

© The Children's Mercy Hospital, 2017

Elizabeth Simpson, MDProfessor of Pediatrics

Medical Director of Routine Newborn Services

Truman Medical Center at Hospital Hill

September 27, 2017

Newborn Screening: 2017 Best Practices Just getting the results is not the end of the problem

82

A Journal Sentinel Special ReportThe price of being wrongNewborn screening saves babies, but lives can be shattered when state labs ignore science and common sense.By Ellen Gabler of the Milwaukee Journal Sentinel 12/9/2016

In Summary, What We Did at TMC

Big QI Project Designated only certain collection hours Hired a courier for weekends State of MO passed a law to improve

turnaround time but didn’t fund it

83

Action Steps for Your Practice?

84

15

Examine Your Existing Process

Designate someone at your hospital and in your office to help follow up on screens Periodically re-evaluate how you are doing Be sure to reach out if you have problems

85

Don’t forget Hearing Screens

1-6/1000 with Real Loss Repeat Screen at 1 month Diagnose by 3 months Amplify by 6 months OAE is not enough

86

Resources/References

87

• ACTion Sheets and Algorithms: https://www.ncbi.nlm.nih.gov/books/NBK55827/

• Advisory Committee on Heritable Disorders in Newborns and Children: https://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/index.html

• Baby’s First Test: http://www.babysfirsttest.org/

• STAR-G: http:// www.newbornscreening.info

• Genetics Home Reference: https://ghr.nlm.nih.gov/

• Davis TC, Humiston SG, Arnold CL, et al. Recommendations for effective newborn screening communication: results of focus groups with parents, providers, and experts. Pediatrics. 2006;117(5 pt 2):S326-S340.

• Farrell MH, Christopher SA, Tluczek A, et al. Improving communication between doctors and parents after newborn screening. WMJ. 2011;110:221-227.

• Finan C, Nasr SZ, Rothwell E, Tarini B. Primary care providers’ experiences notifying parents of cystic fibrosis newborn screening results. Clin Pediatr (Phila). 2015;54:67-75.

• Gennaccaro M, Waisbren SE, Marsden D. The knowledge gap in expanded newborn screening: survey results from paediatriciansin Massachusetts. J Inherit Metab Dis. 2005;28:819-824.

• Gurian EA, Kinnamon DD, Henry JJ, Waisbren SE. Expanded newborn screening for biochemical disorders: the effect of a false-positive result. Pediatrics. 2006;117:1915-1921.

Resources/References

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• Gurian EA, Kinnamon DD, Henry JJ, Waisbren SE. Expanded newborn screening for biochemical disorders: the effect of a false-positive result. Pediatrics. 2006;117:1915-1921.

• Hinton CF, Neuspiel DR, Gubernick S et al. Improving Newborn Screening Follow-up in Pediatric Practices: Quality Improvement Innovation Network. Pediatrics. 2012;130:e669-e675.

• Kemper AR, Uren RL, Moseley KL, Clark SJ. Primary care physicians’ attitudes regarding follow-up care for children with positivenewborn screening results. Pediatrics. 2006;118:1836-1841.

• Salm N, Yetter E, Tluczek A. Informing parents about positive newborn screening results: parents’ recommendations. J Child Health Care. 2012;16:367-381.

• Tluczek A, Koscik RL, Farrell PM, Rock MJ. Psychosocial risk associated with newborn screening for cystic fibrosis: parents’ experience while awaiting the sweat-test appointment. Pediatrics. 2005;115:1692-1703.

• Tluczek A, Orland KM, Cavanaugh L. Psychosocial consequences of false-positive newborn screens for cystic fibrosis. QualHealth Res. 2011;21:174-186.

• Waisbren SE, Albers S, Amato S et al. Effect of expanded newborn screening for biochemical genetic disorders on child outcomes and parental stress. JAMA. 2003;290:2564-2572.

Hemoglobinopathies: Current practices for screening, confirmation and follow-up, CDC 2015

Chandrakasan S, Kamat D. An overview of hemoglobinopathies and the interpretation of newborn screening results. Pediatr Ann. 2013;42:502-8

Hoppe CC. Newborn screening for non-sickling Hemoglobinopathies. Hematology Am SocHematol Educ Program. 2009:19-25

https://www.cdc.gov/ncbddd/sicklecell/index.html

http://health.mo.gov/living/families/genetics/newbornscreening/factsheets.php

Naik RP, Haywood C. Sickle cell trait diagnosis: clinical and social implications. Hematology Am Soc Hematol Educ Program. 2015;2015:160-7

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References

http://health.mo.gov/lab/newborn/ Accessed 09/01/2017 Uptodate: << https://www-uptodate-com.ezproxy.cmh.edu/contents/image?imageKey=ALLRG%2F77023&topicKey=ALLRG%2F3912&source=see_link>> Accessed

09/01/17 Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, Baker M, Ballow M, Bartoshesky LE, Bonagura VR, Bonilla FA, Brokopp C, Brooks E,

Caggana M, Celestin J, Church JA, Comeau AM, Connelly JA, Cowan MJ, Cunningham-Rundles C, Dasu T, Dave N, De La Morena MT, Duffner U, Fong C, Forbes L, Freedenberg D, Gelfand EW, Hale JE, Hanson IC, Hay BN, Hu D, Infante A, Johnson D, Kapoor N, Kay DM, Kohn DB, Lee R, Lehman H, Lin Z, Lorey F, Abdel-Mageed A, Manning A, McGhee S, Moore TB, Naides SJ, Notarangelo LD, Orange JS, Pai S, Porteus M, Rodriguez R, Romberg N, Routes J, Ruehle M, Rubenstein A, Saavedra-Matiz CA, Scott G, Scott PM, Secord E, Seroogy C, Shearer WT, Siegel S, Silvers SK, Stiehm ER, Sugerman RW, Sullivan JL, Tanksley S, Tierce ML, Verbsky J, Vogel B, Walker R, Walkovich K, Walter JE, Wasserman RL, Watson MS, Weinberg GA, Weiner LB, Wood H, Yates AB, Puck JM. Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States. JAMA. 2014;312(7):729–738. doi:10.1001/jama.2014.9132

Laura Tagliaferri , Joachim B. Kunz , Margit Happich , Susanna Esposito , Thomas Bruckner , Daniel Hübschmann , Jürgen G. Okun , Georg F. Hoffmann , AnsgarSchulz , Judit Kappe , Carsten Speckmann , Martina U. Muckenthaler , Andreas E. Kulozik. Newborn screening for severe combined immunodeficiency using a novel and simplified method to measure T-cell excision circles (TREC). Clinical Immunology 175 (2017) 51–55

Dorsey, Morna J., MD, MMSc; Dvorak, Christopher C., MD; Cowan, Morton J., MD; Puck, Jennifer M., MD. Treatment of infants identified as having severe combined immunodeficiency by means of newborn screening. J Allergy Clin Immunol. 2017 Mar;139(3):733-742. doi: 10.1016/j.jaci.2017.01.005.

Weisstein JS, Delgado E, Steinbach LS, Hart K, Packman S. Musculoskeletal manifestations of Hurler syndrome: long-term follow-up after bone marrow transplantation. J Pediatr Orthop. 2004 Jan-Feb;24(1):97-101.

Aldenhoven, M., Wynn, R. F., Orchard, P. J., O’Meara, A., Veys, P., Fischer, A., Valayannopoulos, V., Neven, B., Rovelli, A., Prasad, V. K., Tolar, J., Allewelt, H., Jones, S. A., Parini, R., Renard, M., Bordon, V., Wulffraat, N. M., de Koning, T. J., Shapiro, E. G., Kurtzberg, J., & Boelens, J. J. (2015). Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood, 125(13), 2164-2172. Accessed September 05, 2017. https://doi.org/10.1182/blood-2014-11-608075.

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References

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Of Course, Our Babies are Worth It!

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Thank you