Severe Combined Immunodeficiency Introduction Benjamin L Wright MD
Severe Combined Immunodeficiency Introduction Benjamin L. Wright, MD
Disclosures • I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity.
Objectives • • • Discuss the pathogenesis of SCID. Provide an overview of the molecular defects. Discuss clinical presentation Explain the implications of newborn screening. Review treatment strategies. Address outcomes of treatment.
Severe Combined Immunodeficiency (SCID) A fatal syndrome of diverse genetic origin, characterized by absence of T and B cell (and sometimes NK cell) functions.
Blood Components
The Factory
The School House
School House Lessons • Recognize self • Recognize non-self
TRECs
Newborn Screening for SCID
Flow Cytometry
Mutations in at Least 13 Different Genes: SCID Lymphocyte Phenotypes Lymphocyte Profile Molecular Defect T- B+ NK- c-deficient, Jak 3 -deficient T- B+ NK+ IL-7 Ra-deficient, CD 3 -deficient, CD 45 -deficient T- B- NK- ADA-deficient T- B- NK+ RAG 1/RAG 2 -deficient, Artemis-deficient, Ligase 4 deficient, DNA-PKcs, Cernunos
T cell receptor
Clinical Presentation • Common infections – otitis media – pneumonia • Opportunistic infections: – thrush – P. jiroveci, fungus, mycobacteria. • Chronic diarrhea • Failure to thrive
Absent thymic shadow
Oral thrush
Positive Screens: Referral • Referral to an immunologist • Reason: the TREC test picks up other T cell lymphopenic conditions in addition to SCID, many of which do not require a transplant. • No need to hospitalize positively screened newborn but parents should implement reverse precautions at home.
Diagnostic Evaluation • CBC with differential • Flow cytometry to assess lymphocyte subsets • T cell proliferation to mitogens • Genetic testing
Management • Transfusion precautions (CMV-, irradiated) • Antibiotic prophylaxis (bactrim/pentamidine for PJP) • Avoid live viral vaccines • IVIG • Contact precautions
Treatment • Hematopoietic stem cell transplant (bone marrow, cord blood, peripheral blood) • Gene therapy
Thymus growth after transplant
SCID Cases reported from Transplant Centers Predicted Incidence 1 per CD 45, FOXN 1, CD 3 D, 100, 000 CD 3 E, Reticular dysgenesis, congenital abnormalities, ~1% each SCID Cases found in 11 States by Newborn Screening Average Incidence: 52 cases in 3 Million Infants, 1. 715 per 100, 000, or 1/58, 000 Survival 92% Unknown 3% RAG 2 1% RMRP 1% TTC 7 A 1% IL 2 RG 19% Unknown/unspecified 23% JAK 3 7% IL 2 RG 50% ADA 14% Chromosome abnormality 2% TTC 7 A 2% RAG 1 15% CD 3 D 2% DCLRE 1 C 2% RAG 2 2% IL 7 R 10% RAG 1 1% Combined estimates from published series (Duke, European, PIDTC) ADA 10% IL 7 R 11% Kwan et al. , JAMA 312: 729 -738, 2014
Other conditions detected by TREC screening • Multisystem syndromes with variable T cell deficiency – 57% Di. George/chromosome 22 q 11. 2 deletion – 15% Trisomy 21 – 3% Ataxia telangiectasia – 2% CHARGE syndrome
Other conditions detected by TREC screening • Secondary T lymphopenia – 25% Congenital cardiac anomalies – 38% Other congenital anomalies – 13% Vascular leakage, third spacing hydrops – 3% Neonatal leukemia
Other conditions detected by TREC screening • Extreme preterm birth alone—T cells become normal over time. • “Variant SCID” or Idiopathic T lymphopenia – Low T cells and TRECs, – low naïve CD 45 RA T cells – no maternal engraftment – impaired T cell or antibody responses, – no known gene defect
T cell deficiencies with normal TREC levels • Zap 70 • MHC class II deficiency • X-linked Hyper Ig. M • Wiskott Aldrich Syndrome • HIV/AIDS
NBS in AZ for SCID • Estimated prevalence of SCID in US is 1: 58, 000 • 85, 352 births in AZ, 1, 296 births in the Navajo Nation. • 1. 47 babies/yr born with SCID in AZ • 0. 48 babies/yr born with SCID in the Navajo Nation alone. • Estimated total babies born in AZ with SCID – 1. 95/yr
NBS in AZ for SCID • 11. 75 babies/yr with other causes of T cell lymphopenia in AZ • 36 referrals/yr for confirmatory testing
- Slides: 40