This document discusses severe combined immunodeficiency (SCID), a group of genetic disorders caused by mutations that lead to absence of T- and B-cell function. Patients with SCID have very small or absent lymph nodes and spleen and are susceptible to life-threatening infections from a variety of pathogens. While newborn screening has improved early detection, SCID often presents with infections in the first year of life without hematopoietic stem cell transplantation or gene therapy. The document outlines pathogenesis, clinical manifestations, diagnosis, treatment options including stem cell or gene therapy, and genetics of the most common forms of SCID.

1. SEVERE COMBINED
IMMUNODEFICIENCY
Dr.Himanshu S Dave
Dept of Pediatrics
NRCH, New Delhi

2. • Severe combined immunodeficiency (SCID ) is
caused by diverse genetic mutations that lead
to absence of T- and B-cell function.
• Patients with this group of disorders have the
most severe immunodeficiency.

3. PATHOGENESIS
• SCID is caused by mutations in genes crucial
for lymphoid cell development.
• All patients with SCID have very small
thymuses; contain no thymocytes and lack
corticomedullary distinction or Hassall
corpuscles.

4. • The thymic epithelium appears histologically
normal.
• Both the follicular and the paracortical areas
of the spleen are depleted of lymphocytes.
• Lymph nodes, tonsils, adenoids, and Peyer
patches are absent or extremely
underdeveloped.

5. CLINICAL MANIFESTATIONS
• SCID is included in the newborn screening
program in many areas.
• Thus, infants are identified prior to symptoms,
which has dramatically improved the survival of
infants with SCID.
• A few genetic types of SCID are not detected by
newborn screening, and there are a few states
where newborn screening for SCID is not yet
performed.

6. • SCID most often present with infection .
Diarrhea, pneumonia, otitis media, sepsis,
and cutaneous infections are common
presentations.
• Infections with a variety of opportunistic
organisms, either through direct exposure or
immunization, can lead to death.

7. • Potential threats include Candida albicans,
Pneumocystis jiroveci , parainfluenza 3 virus,
adenovirus,RSV, rotavirus vaccine,CMV, EBV,
varicella-zoster virus, measles virus, MMRV
(measles, mumps, rubella, varicella) vaccine,
or bacille Calmette-Guérin (BCG) vaccine.

8. • Affected infants also lack the ability to reject
foreign tissue and are therefore at risk for
severe or fatal graft-versus-host disease
(GVHD) from T lymphocytes in non irradiated
blood products or maternal immuno
competent T cells that crossed the placenta
while the infant was in utero.

9. • This devastating presentation is characterized
by expansion of the allogeneic cells, rash,
hepatosplenomegaly and diarrhea.
• A 3rd presentation is often called Omenn
syndrome , in which a few cells generated in
the infant expand and cause a clinical picture
similar to GVHD.
• The difference in this case is that the cells are
the infant's own cells.

10. • A key feature of SCID is that almost all patients
will have a low lymphocyte count.
• A combination of opportunistic infections and
a persistently low lymphocyte count is an
indication to test for SCID.

11. • The diagnostic strategy both for symptomatic
infants and those detected by newborn
screening is to perform flow cytometry to
quantitate the T, B, and natural killer (NK) cells
in the infant.
• The CD45RA and CD45RO markers can be
helpful to distinguish maternal engraftment
and Omenn syndrome.

12. • T-cell function is also often assessed by
measuring proliferative responses to
stimulation.
• All genetic types of SCID are associated with
profound immunodeficiency.
• A small number have other associated
features or atypical features that are
important to recognize.

13. • Adenosine deaminase (ADA) deficiency can be
associated with pulmonary alveolar
proteinosis and chondro osseous dysplasia.
• Adenylate kinase 2 (AK2) deficiency causes a
picture referred to as reticular dysgenesis
where neutrophils, myeloid cells, and
lymphocytes are all low. This condition is also
often associated with deafness.

14. TREATMENT
• SCID is a true pediatric immunologic
emergency.
• Unless immunologic reconstitution is achieved
through hematopoietic stem cell
transplantation (HSCT ) or gene therapy,
death usually occurs during the 1st yr of life
and almost invariably before 2 yr of age.

15. • HSCT in an infant prior to infection is
associated with a 95% survival rate.
• ADA-deficient SCID and X-linked SCID have
been treated successfully with gene therapy.

16. • ADA-deficient SCID can also be treated with
repeated injections of polyethylene glycol–
modified bovine ADA (PEG-ADA ), although
the immune reconstitution achieved is not as
effective as with stem cell or gene therapy.

17. GENETICS
• The 4 most common types of SCID are:
- The X-linked form, caused by mutations in
CD132
- Autosomal recessive RAG1 and RAG2
deficiencies and
-ADA deficiency.

18. • For X-linked SCID and ADA deficiency, gene
therapy exists, but genetic counseling is the
most compelling reason for genetic
sequencing to identify the gene defect.
• Several specific gene defects are associated
with increased sensitivity to radiation and
chemotherapy, and their early identification
can lead to a better transplant experience.

19. • Sequencing is often done by requesting a SCID
gene panel.
• Hypomorphic mutations in genes most often
associated with SCID can lead to varied
phenotypes. This condition is often referred to
as leaky SCID.

20. THANK YOU