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Confirmatory Testing Considerations

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Presentation on theme: "Confirmatory Testing Considerations"— Presentation transcript:

1 Confirmatory Testing Considerations
Beth Vogel, MS, CGC Genetic Counselor Newborn screening program Wadsworth center New york state department of health

2 Overview Implementation Short-term follow-up Case review meetings
Diagnostic testing

3 Implementation: Guidance
Partnership with clinicians New York State SCID Consortium 9 external group members National recommendations Newborn Screening Translational Research Network, CLSI Guidelines

4 Implementation: Guidance
Discussion points for NBS and clinician group Minimum standard confirmatory tests Short-term follow-up Diagnostic categories Transplants Algorithm changes Detection of non-SCID disorders

5 Implementation: Education
Target hospitals and primary care providers TREC assay is not well known! Developed educational materials Letter to hospitals Phone consultations NBS and Specialty Care Centers WHAT IS A TREC?!

6 Short-term Follow-up Process
Eight Specialty Care Centers Referral is called to primary care provider and specialty care center (SCC) Diagnostic form completed by clinician

7 Case Review Meetings Identify topics for Consortium conference calls
Unusual cases Identify need for new diagnostic categories Algorithm changes Correlation of laboratory findings and clinical outcomes

8 Case Review Meetings Maintain consistency in case closure Incidence
Algorithm changes Long-term follow-up

9 Diagnostic Categories
From NBSTRN website: SCID Leaky SCID/Omenn syndrome Variant SCID Syndromes with T cell impairment Secondary T cell lymphopenia other than preterm alone Preterm alone

10 SCID Classic phenotype
<300 autologous T cells/μL Emergent treatment required (transplant, gene therapy, enzyme replacement therapy)

11 Leaky SCID/Omenn Syndrome
Low T cell count 3oo to 1500 T cells/μL Requires treatment (transplant, gene therapy, enzyme replacement therapy) Omenn syndrome Erythrodermia, hepatosplenomegaly, eosinophilia, elevated IgE, restricted TCR diversity of T cells

12 Variant SCID Moderately decreased T cell counts
May not require transplant

13 Syndromes with T Cell Impairment
DiGeorge syndrome/22q11.2 deletion syndrome CHARGE syndrome Jacobsen syndrome RAC2 defect DOCK8 deficiency Ataxia telangiectasia VACTERL association Barth syndrome TAR syndrome Down syndrome Ectrodactyly ectodermal dysplasia syndrome Other

14 Secondary T Cell Lymphopenia Other Than Preterm Alone
Birth defects Gastroschisis, intestinal lymphangiectasia, congenital heart defects, cardiac surgery +/- thymectomy Metabolic disorder, degenerative neuromuscular disease

15 Preterm Alone <37 weeks gestation
TREC copy number typically improves over time If TRECs are undetectable, then full work-up warranted regardless of gestational age

16 Idiopathic T-cell Lymphopenia
Non-SCID No congenital anomalies Low T-cells that require clinical monitoring

17 Diagnostic Testing: Complete Blood Count
Lymphocytes T cells = 70% of circulating lymphocytes Proposed as a method to screen for SCID prior to current technologies “ALC (absolute lymphocyte count) <2500/uL in early infancy requires further evaluation” R. Buckley, MD

18 Diagnostic Testing: Flow Cytometry
Evaluation of lymphocyte subpopulations Normal ranges vary by age

19 Diagnostic Testing: Flow Cytometry
CD = Cluster of differentiation

20 Diagnostic Testing: Flow Cytometry
CD Cell Type CD3 T cells CD4 Helper T cells CD8 Suppressor T cells CD19 B cells CD16CD56 NK cells

21 Diagnostic Testing: Flow Cytometry

22 Diagnostic Testing: Lymphocyte Proliferation to Mitogens
Test of T-cell function Less sensitive, but more specific test of T-cell function Culture human peripheral blood mononuclear cells with plant lectin mitogens) phytohemagglutinin (PHA), pokeweed mitogen (PWM), concanavalin (conA) Response highest in newborns and decreases with age

23 Diagnostic Testing: Mitogens

24 Diagnostic Testing: Naïve and Memory T-cell Count
Not typically included as part of standard flow cytometry CD45RA+ = Naive CD45RO+ = Memory

25 Genetic Testing Multiple genes
Mutation info often not needed before transplant May be important if diagnosis is unclear Important for genetic counseling 45% of SCID cases are X-linked (IL2RG-related) Remainder of the cases are recessive

26 Diagnostic Form

27 Diagnostic Form

28 References Hicks MJ, Jones JK, Thies AC, et al: Age-related changes in mitogen-induced lymphocyte function from birth to old age. Am J Clin Pathol 1983;80: Baker M, Grossman W, Laessig R, et al. Development of a routine newborn screening protocol for severe combined immunodeficiency. J Allergy Clin Immunol. 2009; 124: Puck M, et al. Population-based newborn screening for severe combined immunodeficiency: Steps toward implementation. J Allergy Clin Immunol. 2007; 120 (4): Chan K, Puck J. Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol. 2005; 115: Comeau A, Hale J, Pai S, et al. Guidelines for implementation of population-based newborn screening for severe combined immunodeficiency. J Inherit Metab Dis. 2010 pdf Buckley RH. The long quest for neonatal screening for severe combined immunodeficiency. Clinical Reviews in Allergy and Immunology. 2012 Adeli MM and Buckley RH. Why newborn screening for severe combined immunodeficiency is essential: a case report. Pediatrics. 2010; 126(2):e465-e469. Chase NM, Verbsky JW, Routes JM. Newborn screening for SCID: three years of experience. Ann. N.Y. Acad. Sci. 2011; 1238: Buckley RH, Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res. 2011; 49:

29 Thank you Questions?

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