Case Presentation

1
Case Presentation

• Matthew Greenhawt, MD
• University of Michigan Health Systems
• Division of Allergy and Clinical Immunology

2
Case History

• The Patient is a 6 year old male
• --He developed hematochesia at 5d, continuing
  intermittently for 12 weeks, which improved with
  maternal milk elimination
• --At 9 mo visit, failure to thrive noted,
  Hemoglobin 6.9 mg/dl
• --Brief response to elemental formula that was
  complicated by recurrent FUO and continued
  hematochesia
• --Admitted to a regional childrens hospital for
  comprehensive work-up at 1 year of age

3
Work-Up

• Exam
• --pale, hypopigmented skin
• --conical teeth
• --dry skin with reduced ability to perspire
• --mild motor delay with normal language
• History of recurring boils
• Father, paternal GM, paternal aunt, paternal
  cousin with similar skin/teeth findings
• Serology low Igs, absent titers despite
  vaccination.
• PST positive to wheat, milk, banana, corn
• Endoscopy both gastric and duodenal
  eosinophilia as well as a hepatic flexure ulcer.
  

4
Differential Diagnosis

• Inflammatory Bowel Disease
• Transient Hypogammaglobulinemia of Infancy
• CVID
• NEMO
• Chediak Higashi
• Eosinophilic Gastrointestinal Disease

5
Case History

• Despite low IgG of unknown origin, IVIg not
  started because of lack of documented infections.
  
• Gastrostomy tube placed for continuous elemental
  feeds
• Begun on Imuran/prednisone for presumed Crohns
  disease
• Over next 2 years, required ileostomy, sub-total
  colectomy, and TPN

6
Case History

• Allergy/Immunology evaluation in 2004 for
  persistence of immunologic abnormalities
• NEMO considered, but felt to be unlikely.
• --Infectious history only significant for
  MSSA septic knee
• IVIg deferred despite low immunoglobulin.
• Patient was then lost to follow up for 3 years.

7
Case History

• TPN and prednisone discontinued in early 2006 as
  his Crohns improved
• Over next 12 months developed an episode of s.
  pneumonia sepsis and 3 episodes of pneumonia
• Imuran discontinued in March 2007 after his
  repeat colonoscopy was normal.
• Re-evaluated by our division in April secondary
  to recent infections and started on IVIg.

8
Laboratory Studies

• December 2006 studies
• --normal B/T/NK cells via flow cytometry
• --Absent PCV-7, tetanus, polio, diphtheria, H.
  flu, HBV titers despite routine series
• Lowest absolute levels (2004)
• IgG 297 (G1 250, G2 21, G3 13, G4 11)
• IgA lt6
• IgM 41
• Levels at 1st dose
• IgG 439 (G2 28, G3 8)
• IgM 44
• IgA 63

• Lymphocytosis present both pre- and post- steroid
  therapy
• Persistent anemia since 2002, but normal
  platelets
• Normal IKBKG
• Negative Prometheus panels
• Wt 25th percentile, Ht 15th percentile presently

9
Treatment

• Developed aseptic meningitis after 1st IVIg dose.
  CSF WBC 1,685/ml3 with 88 PMN.
• Subsequently tolerating Gammagard S/D
• No infections since beginning therapy
• Strong paternal history and negative IKBKG argues
  against X-linked ED.
• Possible atypical AD-ED
• --His ability to remain in the sun to tan
  despite poor sweat production and absent
  hypotrichosis are inconsistent with diagnosis of
  ectodermal dysplasia.
• --Affected paternal family member genetic
  evaluation pending.

10
NF?B Essential Modulator

• NF?B Essential Modulator (IKK?) is regulatory
  subunit of inhibitor of NF?B (I?B)purely
  structural support
• I?B regulates phosphorylation, ubiquination, and
  proteosomal degradation of NF?B to allow its
  dimeric release to initiate transcription
• Mutated IKK? prevents IKK complex phosphorylation
  of I?B signalsome, so no proteosomal degradation
  occurs and no NF?B dimers are releasedno
  transcription

Orange JS, Geha RS. J. Clin Invest. 112983-985.

• Common pathway for TNF family receptors TLRs,
  B/T cell receptors, NK receptors
• Defective signaling imparts variable degree of
  immunodeficiency

Bal E. et al Hum Mutat 28(7) 703-9, 2007. Uzel
G. Curr Opin Allergy Immunol 5513-8, 2005.
Courtois et al. J Clin Invest 1121108-1115
2003. Orange JS et al. J Allergy Clin Immunol
113 725-33, 2004.
11
Ectodermal Dysplasia with Immunodeficiency

• Inherited defect in expression of TNF family
  proteins
• Ectodysplasin (X)
• EDAR (AD,AR)
• EDARDD (AR)
• Inability to properly assemble the IKK kinase,
  preventing NF-?B dimerization
• Clinical manifestations
• Hypotrichois
• Anodontia/Hypodontia
• Anhydrosis/Dyshydrosis
• Pale skin
• Depressed nasal bridge
• Frontal bossing
• .

• Immune defects include
• Hypogammaglobulinemia
• Elevated IgM
• Impaired CD40-mediated signaling
• Absent innate immunity
• Poor titers to carbohydrate antigens
• NK cell defects
• Susceptibility to encapsulated organisms,
  gram negative sepsis, mycobacterium, viruses, PCP

Bal E. et al Hum Mutat 28(7) 703-709, 2007 Uzel
G Curr Opin Allergy Immunol 5513-518, 2005
Courtois et al. J Clin Invest 1121108-1115
2003 Orange JS et al. J Allergy Clin Immunol 113
725-33, 2004
12
Ectodermal Dysplasia with Immunodeficiency
Uzel G. Curr Opin Allergy Immunol 5513-518,
2005.

• EctodysplasinED1 mutation in X linked form
• Ectodysplasin A receptorEDAR mutation in AR and
  AD form, clinically indistinguishable
• EDAR associated Death DomainEDARADD mutation in
  AR form, recently discovered AD form in same
  protein
• In pathway, EDA binds and activates EDAR, which
  then uses EDARDD to help interact with the IKK
  complex to activate NF-?B

Bal E. et al HumMutat 28(7) 703-709, 2007 .
Uzel.G Curr Opin Allergy Immunol 5513-518,
2005. Courtois et al. J Clin Invest
1121108-1115 2003.. Orange JS et al. J Allergy
Clin Immunol 113 725-33, 2004.
13
Uncertain Diagnosis, Correct Treatment

• Based on available present information, most
  compatible diagnosis is CVID with mild ED
• AD-ED with ID from NF-?B pathway mutation not
  completely ruled out
• Infection free x 5 mo on IVIg
• Treatment in 2001 or 2004 could have been
  beneficial to prevent potential complications
• Fortunately, few complications have arisen
  despite delayed treatment