Case of Baby Joeby

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 Joe’s Blood Count Normal RangeRed blood cells 3.1x106/microliter 2.7x106–4.9x106/microliterPlatelets180,000/microliter 150,000–440,000/microliterTotal white blood cells      3500/microliter 6000–17500/microliterNeutrophils 2600/microliter 2000–7500/microliterEosinophils 170/microliter 0–400/microliterMonocytes 300/microliter 200–800/microliterBasophils 10/microliter 0–100/microliterLymphocytes 350/microliter 1000–4000/microliterT cells 2% of total lymphocytes 60–80% of total lymphocytesB cells < 1% of total lymphocytes      15–25% of total lymphocytesNK cells 90% of total lymphocytes 10–20% of total lymphocytes

• 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.

Can Baby Joe Make Antibodies?

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

Common Molecular Defects

• 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

RSSV gene

RSSD gene

RSS

RSS J geneRSS

• 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 EducationAutosomal Recessive Inheritance

  Carrier Mother  Carrier Father S sS SS (normal) Ss (carrier)s Ss (carrier) ss (affected

with disease)

Legend: S (normal gene) s (carrier)

Clinical Questions

In what type of mutation do one or more base pairs on a DNA chain get deleted or inserted?

A.Missense MutationB.Nonsense MutationC.Frameshift MutationD.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 1971-1983Credit: Baylor College of Medicine Photo Archives

ReferencesBonilla, F.A. (2011). Severe combined immunodeficiency (SCID): an overview.

Uptodate. Retrieved 9-22-11 at http://www.uptodate.com/contents/severe- combined-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/severe-combined-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-history- and-classification- of- Pediatric-hiv-infection? Source

=search _result&search=HIV+children&selectedTitle=3%7E150#H18840505.specific-defects? 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/common-variable-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-of- pseudomonas-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-and- clinical- manifestations?source=search_result&search= Digeorge+syndrome+children& selectedTitle=1%7E43#H15.