Overview of Severe Combined Immunodeficiencies (SCID) in Plain Communities During the Era of

Newborn SCID Screening

Christine Seroogy MD Associate Professor

Department of Pediatrics Division of Allergy, Immunology & Rheumatology

Funding Source:

Objectives •  Newborn Screening for SCID successfully

detects many forms of SCID •  Awareness of SCID forms and T cell

lymphopenias in Plain communities and approach to evaluation (emphasis on RAG1)

•  Curative treatment for SCID early and infection-free leads to better outcomes

•  Ongoing challenges associated with treatment of SCID in newborns/Plain communities

Severe Combined Immunodeficiency (SCID)  

CLINICAL: •  Infections in first year of life •  Failure to thrive

LABORATORY: •  T cells markedly decreased or absent & don’t function •  B cells absent or non-functional •  To date, 20+ genetic mutations associated with SCID

phenotype.

Fatal without immune reconstitution in the first year of life

Common Theme in ALL forms of SCID: Impaired Thymopoiesis

T Cell Receptor Excision Circle (TREC): biomarker of thymic function

Generation of T cell receptor excision circles (TRECs) occur in >70% of all new (naïve) T

cells and can be detected by PCR Ponchel  et  al.  BMC  Biotechnology  2003  

TREC Assay Platform in Newborn Screening Laboratory

Slide  courtesy  of  Dr.  Mei  Baker  

Population Cumulative 2008-2013 birth number SCID SCID

Prevalence

Total WI population 404,836 (average 67,473/year) 9 1 in 44,982

WI Plain Communities 5,280 (average 880/year) 5 1 in 1,056

(estimated)

Wisconsin SCID Statistics Since NBS SCID Screening

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Es>mated  using  vital  records  and  unique  methodology,    Drs.  Angela  Rohan  and  Murray  Katcher,  unpublished  data    

Includes  one  Amish  newborn  

Genetic Mutations Associated with T cell Lymphopenia & NBS SCID Screening in the Plain Communities

Immunologic Diseases Associated with T cell Lymphopenia

CSC (Lancaster Co, PA)

DDC (Northeast

OH) Indiana WI Other

Detected by NBS

SCID Screen

Plain Community

RAG1 SCID/Omenn Syndrome X X X YES Amish

ADA SCID X X YES Amish

IL7Ra SCID X X YES Mennonite

CD3delta SCID X YES Mexican/Low German-Mennonite

Cartilage Hair Hypoplasia X X X Variable Amish

ZAP70 CID X Variable Amish

Ataxia Telangiectasia X Variable Amish/Mennonite

22q11.2 microdeletion X X Variable Amish

Wiskott Aldrich Syndrome X NO Amish

RAG1 CID X Unknown Mennonite

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*  Direct experience, personal communications, expert opinion, and review of medical literature

Initial Management NBS SCID Positive Screen

• Confirmatory testing and continued diagnostic testing for SCID • Protective isolation: where is safest environment? • Antimicrobial prophylaxis • Intravenous gamma globulin • No live vaccines • Irradiated, CMV- blood products • Safety of breastfeeding? • Cure?

Railey et al J. of Ped 2009

Bone Marrow Transplant in the First 3.5 Months Of Life Has Best Outcome in SCID (Dr. Buckley’s data—no conditioning)

Overall  survival  77%,    survival  for  BMT  in    first  3.5  months  is  94%  

Primary Immunodeficiency Treatment Consortium (PIDTC, 25 centers), 240 Infants with Classical Severe Combined

Immunodeficiency Retrospective 2000-2009:  

Pai  S  et  al.  N  Engl  J  Med  2014;371:434-­‐446.  

Age & Infection Status at the time of Bone Marrow Transplant (BMT) Impact Survival

 

Primary Immunodeficiency Treatment Consortium (PIDTC, 25 centers), 240 Infants with Classical Severe Combined

Immunodeficiency Retrospective 2000-2009:    

 

Pai  S  et  al.  N  Engl  J  Med  2014;371:434-­‐446.  

Survival is Highest with Matched Sibling Donor and Reduced in Recipients with Conditioning Regimens

Conclusions

•  Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection.

•  All available graft sources are expected to lead to excellent survival among asymptomatic infants.

•  Questions:

When does conditioning need to be used? What is the minimal amount of conditioning that is required for acceptable engraftment? Is this a one-size fits all or does SCID genotype matter?

PIDTC MultiCenter Classical SCID BMT Conclusions

•  RAG (recombination-activating gene) 1/2 proteins critical for T and B cell development by initiating VDJ recombination process. This leads to a block in early thymopoiesis.

•  Mutations in RAG1/2 initially associated with SCID. More recent studies have demonstrated RAG 1/2 mutations in patients with combined immune deficiencies, autoimmune disease, and granulomatous disease.

Nature  Structural  &  Molecular  Biology  2009  

RAG1

J  Allergy  Clin  Immunol.  2014  Apr;133(4):1099-­‐108.  doi:  10.1016/j.jaci.2013.10.007.  Epub  2013  Nov  28  

T-­‐B-­‐NK+SCID  Omenn  Syndrome  γδ-­‐T  SCID  Leaky  SCID  CID  Unknown      

Muta>on    found    

in  Amish  

Muta>on  found  in  Amish  

RAG Recombination Activity Tends to Correlate with Clinical Phenotype

Omenn Syndrome (OMIM no. 603554)

•  Clinical features: early in life diffuse erythrodermia, hepatosplenomegaly, lymphadenopathy, alopecia, failure to thrive, recurrent infections.

•  Laboratory features: Absence of circulating B cells, infiltration of skin and intestine by activated oligoclonal T lymphocytes, high serum IgE levels, peripheral blood eosinophilia, increased numbers of poorly functional activated circulating T cells.  

Clinical Immunology, Volume 128, Issue 1, 2008, 31 - 38

Omenn Syndrome •  To date, many SCID-associated genes have been

associated with OS. Mutations in RAG1 is the prototype and most studied.

•  Some hypomorphic mutations, including RAG1, can cause either SCID or OS. Thus, suggesting other gene modifiers or environmental triggers necessary for OS phenotype.

T Cell Number & T Cell Function

Classical SCID

Leaky SCID

Omenn Syndrome

Unique Challenges in Plain Communities:

•  Decreased rates of newborn screening •  Increased population prevalence of

hypomorphic RAG1 mutations •  Curative approaches for SCID are expensive •  Opposition to chemotherapy •  Opposition to prolonged hospitalizations •  Poor access to tertiary care centers •  Refusal of therapy for fatal, but curative

disease

General Challenges •  The use of conditioning for bone marrow

transplantation in newborns (1-2 months) is an extremely difficult decision – Tandem transplant? – Antibody depleting regimens (CD45 not

readily available and anti-c-kit in development)

– Lower dose conditioning? (PIDTC trial) – Serotherapy and αβ-­‐T cell depletion?  

Conclusion •  Newborn screening for SCID successfully

detects all forms of SCID (and other clinically actionable T cell lymphopenias).

•  Early screening leads to early treatment in healthy infants resulting is better outcomes.

•  All forms of SCID and some T cell lymphopenias found in Plain Communities are easily amenable to NBS SCID screening (but not all).

•  cmseroogy@wisc.edu