Mystery Case:

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2007 CIS Summer School in Primary
Immunodeficiency Diseases
Mystery Case A 15 year-old Boy with
Recurrent Gram Negative Mycobacterial Septicemia
Brian O. Porter, M.D., Ph.D., M.P.H. Fellow,
Allergy Immunology NIH/NIAID/LIR/CMRS Bethesda,
Maryland
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Initial Presentation
European-American boy -Referred to NIH at 2.5
yrs -Part of kindred study to evaluate
for T cell immunodeficiency -Older brother two
maternal uncles with disseminated MAC
(Mycobacterium avium complex)
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PMH prior to NIH
Gestational Complications -Pregnancy-induced
diabetes -Premature labor at 6 months
Childhood Illnesses -3 wk episode of
diarrhea, cervical LAD, maxillary
sinusitis (CT scan) thymus -Week-long
hospitalization IV fluids, bilateral
antrostomies, Augmentin, negative Bx of
asymmetric cervical LAD
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Clinical Course after NIH
-At 4 yrs Low-grade fevers, purulent rhinorrhea,
otitis media (Augmentin)
-Several months later Recurrent fever
admission for Haemophilus influenzae type B
septicemia (3 wk IV cefprozil)
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Lost to Follow-up
-At 6 yrs Upon returning home from an
appointment at NIH, he was in a car crash which
killed his mother and older brother.
-Destabilized home environment Subsequently
passed from his father to several other relatives
and finally to a childrens group home at 14 yrs.
-Spared from major infections over this period,
behavioral problems surfaced oppositional
defiant disorder (ODD) post-traumatic stress
disorder (PTSD).
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-At 15 yrs Preceded by 8 mon of infections,
including sinusitis, buttock abscess, and two
low-grade FUOs (admitted for IV
antibiotics). -Head CT Chronic sinusitis
ill-defined lesion in right caudate
lobe -Abdominal CT Mesenteric LAD (up to 4cm)
Return to NIH
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Medication Summary
Allergies Urticaria to eggs periorbital
erythema to cow milk at 1 yr (no anaphylaxis) ?
outgrown. No drug or hymenoptera allergies
tape-sensitive.
-Vaccinations Up to date (including 2 doses
Hib vaccine by age 4 yrs).
-At 2.5 yrs Outpatient antibiotics only
-At 15 yrs aripiprazole for behavioral
issues pimecrolimus for eczema benzoyl
peroxide- clindamycin for acne
intranasal fluticasone cetirizine for
allergic rhinitis MVTCa.
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Initial Physical Examination
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Basic Chemistry NML ALB4.4, UricAc3.8, CK66
Coags PT13.6, PTTgt60 Heme PLT326,
Hct38 WBC8.9 N26, L54 M5, E14
(AEC1200)
Immune Work-up At 2.5 years At
15 years ESR32, CH50103, C370 ESR117,
C3109, C429 IgG642 (424-1051) IgG1310
(639-1349) IgM34 (48-168) IgM100 (56-352)
IgA436 (14-106) IgA605 (70-312)
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Diagnostic Studies
Lineage Subsets CD3, CD4, CD8, CD20, CD16,
CD56 all WNL T Cell Proliferation Mitogens
(PHA) and recall antigens all WNL Ab
Responses Protein and polysaccharide antigens
all WNL
Diagnostic study driven by kindred study
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Family Tree
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A Mystery Revealed!
NEMO Mutation
nuc944 A?C E (Glu) 315 A (Ala)
Mutation in Leucine Zipper domain, likely
involved in intramolecular salt bridge.
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A Mystery Revealed!
- Normal NEMO expression (Western flow) in
hematologic non-hematologic lineages. - ?
IL-12 production following CD40/CD40L activation
in DCs monocytes. - ? IFN-? production by
PBMCs to PHA ?-CD3, partially reversed by
exogenous IL-12. - Intact NF-?B signaling to
IL-1ß, TNF-?, and TLR4 (LPS) TLR7/8 (R-848)
ligands.
Selective impairment of CD40L/CD40-dependent DC
monocyte IFN-? production due to reduced IL-12.
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A Mystery Revealed!
Outcome Despite these measures, MAC lesions
increased. Matched unrelated bone marrow
transplantation considered, given progressive
disease poor outcome of disseminated MAC
infection in NEMO deficiency.