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Case of Baby Joe
by
Susan Paran,Charmaine Pierce,Michelle Rensel,Lauren Sutton
and Naomi Winterheld
At birth, Baby Joe appeared to be a
normal, healthy baby boy.
•Parents healthy.
•At four weeks of age, Joe developed an
otitis media, then recurrent ear infections.
•Starting at three months of age, Joe had
four bouts of diarrhea which persisted for
3–5 days each time.
• Joe also was not gaining weight as
rapidly as was expected during this time
and was diagnosed with “failure to
thrive.”
•At four months old, he developed another
ear infection. Cultures revealed
Pseudomonas aeroginosa, an
opportunistic infection
•Joe also had a urinary tract infection
Nature or Nurture?
• The underlying cause of Joe’s health problems is genetic.
Although we still have to consider :
• His Environment:
Siblings, Daycare, Pets, etc.
• His Anatomy:
Shortened or narrow Eustachian tubes
• Failure To Thrive? Inflammatory process affecting absorption of
nutrients resulting in malnutrition
No lymph nodes could be palpated in Joe’s neck or armpits. His heart, lungs,
liver, and spleen were of normal size. Suspecting a problem with Joe’s immune
system, Joanne ordered a complete blood count (CBC). The CBC revealed the
following results:
Cell Type
Red blood cells
Platelets
Total white blood cells
Neutrophils
Eosinophils
Monocytes
Basophils
Lymphocytes
T cells
B cells
NK cells
Joe’s Blood Count
Normal Range
3.1x106/microliter
2.7x106–4.9x106/microliter
180,000/microliter
150,000–440,000/microliter
3500/microliter
6000–17500/microliter
2600/microliter
2000–7500/microliter
170/microliter
0–400/microliter
300/microliter
200–800/microliter
10/microliter
0–100/microliter
350/microliter
1000–4000/microliter
2% of total lymphocytes
60–80% of total lymphocytes
< 1% of total lymphocytes
15–25% of total lymphocytes
90% of total lymphocytes
10–20% of total lymphocytes
Can Baby Joe Make
Antibodies?
• Baby Joe’s B cells account for <1% of the total
lymphocyte in his body.
• Antibodies are produced by the plasma cell.
• We need to have normal B cells that are a precursor
to plasma cells in order to have normal antibody
levels.
How do these data explain Baby Joe’s
symptoms?
• Recurrent Infections
– ↓ Total WBCs and lack of B cells and T cells
• Inability to palpate lymph nodes & normal size spleen and
liver
– Lack of lymphocytes
• Chronic Diarrhea
-Related to his recurrent infections/ IgA deficiency
Differential Diagnoses
• Digeorge Syndrome
• HIV
• Common Variable Immunodeficiency (CVID)
Can likely rule out above disorders, but not:
• Severe Combined Immunodeficiency (SCID)
Clinical Manifestations of SCID:
• 3 most common Clinical Manifestations:
– Severe, recurrent infections
– Chronic diarrhea
– Failure to thrive
• Absence of palpable lymphoid tissue
• T Cell deficiency
• B Cells can be decreased or normal
• NK cells increased or normal
• Recurrent Fevers
• Opportunistic Infections
• Usually fatal within the first year of life unless underlying deficit is
corrected
•
•
•
•
•
•
X-Linked (T-B+NK-) – cause of approx. 46% of SCID cases
- mutation on gene affecting various interleukin molecules (cytokines)
ADA Deficiency (T-B-NK-) – cause of approximately 17% of cases
- toxic metabolites buildup causing lymphocytic death
IL-7Rα (T-B+NK+) – cause of approx. 10% of cases
- responsible for T-Cell maturation
Jak3 Deficiency (T-B+NK-) – cause of approx. 7% of cases
- enzyme that communicates cytokine information to the nucleus
RAG-1 or RAG-2 Deficiency (T-B-NK+) – cause of approx. 3% of cases
- gene that encodes proteins necessary for antigen receptor arrangement
Artemis Deficiency (T-B-NK+) – cause of approx. 1% of cases
- DNA repair factor; repairs DNA after RAG makes its’ cuts
Types of Mutations
• Missense Mutation
• Nonsense Mutation
• Silent Mutation
• Frameshift Mutation
Frame shift Mutation
A sample of Baby Joe’s DNA was sent for sequence analysis, which
revealed mutations in both copies of his RAG gene. The mutations in both
genes were frame shift mutations, which resulted in a complete lack of
expression of functional RAG protein.
• Recombinase-Activating Gene (RAG-1 or RAG-2)
• Antigen Receptor Site Formation
Somatic Recombination
RSS
V gene
RSS
D gene
RSS
RSS
J gene
RSS
• Recombinase enzyme produced by RAG-1 and RAG-2 cleave the V, D, & J
genes at the Recombination Signal Sequences (RSS)
• The recombined V, D, & J genes make up B and T cell receptors
• The formation of receptors is essential for lymphocyte maturation
Stages of Hematopoiesis
Treatment Options
• IVIG Transfusion
• Hematopoietic Stem Cell Transplants/BMT
• Gene Therapy
IVIG Transfusions
• Healthy effective antibodies pooled from
multiple donors.
• Usually given every 3-4 weeks.
• Expensive!!!
Hematopoietic Stem Cell or BM Transplant
• Bone Marrow Transplant (BMT) is the widely
used cure.
• Abnormal lymphocytes replaced by
immunocompetent cells.
• Success rates 90% or higher with close HLA
matched donor.
– Haploidentical match (from parent) with 78% success
rate.
• BMT for SCID doesn’t require preparative
chemotherapy.
Bone Marrow Transplant Cont.
• T Cell depleted donor cells decrease chance of
Graft Versus Host Disease (GVHD).
• May not generate normal B Cell function.
• Higher success rates when performed early in
life.
Umbilical Cord Blood
• Umbilical cord blood stem cell transplantation
has several advantages.
– More readily available vs. obtaining bone marrow
– Lower risk of viral infection transmission
– NO risk to donor
– Lower risk for GVHD
Gene Therapy
• Not currently a viable option unless a failure
with BMT
Epidemiology
• Incidence of SCID is estimated to be 1:50,000 to 1:
500,000 live births
• About half of all cases of SCID are X-linked
• Other cases, like RAG-deficiency in Joe, are
autosomal recessive
(Bonilla, 2011)
Parental Education
• Neither parents, caregivers, nor patient should receive
live vaccines
• Encourage parents to join a support group
• Keep child away from large crowds and areas where
infection is likely.
• Have child wear a mask if you bring into public places
• Any small illness acquired by a child with SCID merits
medical attention
• Frequent hand washing is essential
• Limited Contact with Relatives
Parental Education
Autosomal Recessive Inheritance
Carrier Father
Carrier Mother
S
S
s
SS (normal)
Ss (carrier)
Legend:
S (normal gene)
s (carrier)
s
Ss (carrier)
ss (affected
with disease)
Clinical Questions
In what type of mutation do one or more base pairs on
a DNA chain get deleted or inserted?
A. Missense Mutation
B. Nonsense Mutation
C.Frameshift Mutation
D.Silent Mutation
What is/are the most common clinical
manifestation(s) of SCID?
•
•
•
•
•
A. Chronic Diarrhea
B. Failure to Thrive
C. High WBC count
D. Recurrent Infections
E. Only A, B, D
True or False?
If both your parents carry an autosomal recessive
mutation, you have a 25% chance of developing the
disease associated with the mutation
Higher survival rates are seen in stem cell transplants
with Haploidentical matches from a parent donor when
compared to that of the HLA match of a sibling.
• True or False?
What advantages would umbilical cord blood stem cell
transplantation offer in comparison to BMT?
a) No chance for Graft versus host disease
b) No risk to donor
c) No HLA markers on umbilical cord blood stem cells so
universally transferrable
D) Can be transplanted at birth to avoid risk associated with
acquired disease
David Vetter 1971-1983
Credit: Baylor College of Medicine Photo Archives
References
Bonilla, F.A. (2011). Severe combined immunodeficiency (SCID): an overview.
Uptodate. Retrieved 9-22-11 at http://www.uptodate.com/contents/severecombined-immunodeficiency-scid-an overview?source= search_ result&search
=Scid& selected Title=1%7E94.
Bonilla, F.A. (2011). Severe combined immunodeficiency (SCID): specific defects.
Uptodate. Retrieved 9-20-11 at http://www.uptodate.com/contents/severecombined-immunodeficiency-scid-specificdefects?
Source=search_result&search=scid&selectedTitle=2%7E94.
Buckley, R. (2004). Molecular Defects in Human Severe Combined Immunodeficiency
and Approaches to Immune Reconstitution. Annual Reviews of Immunology,
22, 625-655. doi:10.1146/annurev.immunol.22012703.104614
References
DiPiro, J., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G, Posey, L.M (2005).
Pharmacotherapy: A Pathophysiologic Approach. (6th ed.) New York:McGraw
Hill.
Gillepsie, S.L. (2011). Natural history and classification of pediatric HIV infection.
Uptodate. Retrieved 9-22-11 at http://www.uptodate.com/contents/natural- historyand-classification- of- Pediatric-hiv-infection? Source =search
_result&search=HIV+children&selectedTitle=3%7E150#H18840505.specificdefects? Source =search_result&search=Scid&selectedTitle=2%7E94.
Hogan, M.B. & Wilson, N.W. (2011). Common variable immunodeficiency in children.
Uptodate. Retrieved 9-22-11 at http://www.uptodate.com/contents/commonvariable-immunodeficiency-in children source= search_ result &search =
CVID&selectedTitle=4%7E52.
McCance, K., Huether, S., Brashers, V., Rote, N. (2010). Pathophysiology: The
Biological Basis for Disease in Adults and Children. (6th ed.) Maryland Heights,
MO: Mosby Elsevier
References
O’Donovan, D.J. (2011). Urinary tract infections in newborns. Uptodate. Retrieved 9-21-11 at
http://www.uptodate.com/contents/urinary-tract-infections-in-newborns?source
=search_result&search=child +uti+clinical+manifestations&selectedTitle=5%7E150.
Ramphal, R. (2011). Epidemiology of pseudomonas aeuroginosa infection. Uptodate. Retrieved
9-22-11 at http://www.uptodate.com/contents/epidemiology-and-pathogenesis-ofpseudomonas-aeruginosa-infection?source=search_result&search=pseudomonas
+aeroginosa&selectedTitle= 2%7E150.
Seroogy, C.M. (2011). DiGeorge syndrome: pathogenesis, epidemiology and clinical
manifestations. Uptodate. Retrieved 9-20-11 at
http://www.uptodate.com/contents/digeorge-syndrome-pathogenesis-epidemiology-andclinical- manifestations?source=search_result&search= Digeorge+syndrome+children&
selectedTitle=1%7E43#H15.