Mystery Case

1
Mystery Case

• Danna Chung, MD
• Allergy and Immunology Fellow
• Mount Sinai Medical Center

2
Initial Presentation

• 2 year old male with bloody diarrhea and fever
• Prior medical history notable for GERD,
  proctocolitis (resolved during infancy), thrush,
  groin candidiasis
• No other infection or fever history
• No family history of immunodeficiency or IBD
• Physical Exam
• Interactive well nourished, well developed boy in
  NAD
• Distended nontender abdomen with normoactive
  bowel sounds
• Papular rash on buttocks but no evidence of
  candidal infection
• Remainder of exam unremarkable

3
Initial Data

• WBC 14.3 (46 neutrophils, 23.5 lymphocytes,
  30.3 monocytes, 0.1 eosinophils)
• Hemoglobin 10.3, Hematocrit 31.7, Platelets 583
• Chemistry panel unremarkable
• Alkaline phosphatase 101, remainder LFTs wnl
• Albumin 2.6 and total protein 5
• ESR 39
• C-ANCA, P-ANCA negative
• Immunoglobulin IgG subclasses normal

4
Imaging

• CXR NAD
• KUB Several distended distal loops of small
  bowel with differential air fluid levels
• Abdominal Ultrasound No abscess or fluid
  collection
• CT Abdomen Thickening of the colonic wall, more
  severely affecting the right colon. No abscesses
  anywhere in abdomen or pelvis. Some mesenteric
  lymph nodes in right lower quadrant.

5
Gastrointestinal Work-Up

• Colonoscopy
• -Rectosigmoid granular with whitish exudate,
  increased friability
• -Descending and transverse colon with nodularity,
  increased friability
• -Ascending with ulcerations, increased friability
• Biopsies
• -Multifocal cryptitis with mucin depletion
• -Focal crypt abscess
• -Multiple ill-defined granulomas
• -Occasional multinucleate giant cells
• -No significant glandular architectural
  distortion
• -No plasmacytosis
• -No CGD characteristic pigment laden macrophages
• Acute colitis with multiple non-necrotizing
  granulomas

Huang JS et al. Clin Gastroenterol Hepatol
20042690-5
6
Microbiology

• Blood cultures negative
• Urine culture no growth at 24hours
• No infectious organisms isolated in stool
• C.difficile toxin negative
• Colonic biopsies negative for AFB and GMS stains
• ASCA IgA antibody 167 Units (Positive in 49
  Crohns Patients)
• ASCA IgG antibody 16.5 Units (Negative)

7
DHR
Patient Unstim
Father Unstim
Patient Stim
Father Stim
8
DHR Mother
Mother Unstim
Mother Stim
9
Genetic Testing CYBB Gene (gp91-phox)
Rae J et al. Am J Hum Genet 199862 1320-31

• Nucleotide change G to C at 389 ? AA substitution
  of arginine 130 to proline
• Arginine 130 in extracellular loop not highly
  conserved in NADPH-oxidase family
• 2 reported other missense mutations in same loop
  known to cause X-CGD
• This specific genetic mutation has not been
  identified in CGD thus far

10
DHR Mother
MOTHER
MOTHER
MOTHER
11
Clinical Course

• Patient was initially treated with broad-spectrum
  antibiotics and steroids with symptom resolution
  
• Based on abnormal neutrophil function, he was
  started on TMP-SMX and itraconazole for
  prophylaxis
• His fevers and bloody stools recurred while on
  sulfasalazine and topical steroids
• Persisted despite restarting high dose systemic
  steroids and adding metronidazole
• Started 6-MP with eventual symptom improvement
  allowing weaning off of steroids

12
Diagnosis Chronic Granulomatous Disease

• This patients DHR consistent with a p47-like
  (AR) CGD profile
• O2- production 12 of normal is somewhat higher
  than is observed in p47 CGD
• His mother appears to be an X-linked carrier with
  12.9 DHR() cells and 87.1 DHR(/-) cells and a
  low-normal O2- production
• Missense mutation (389 G ? C) in gp91phox
  supports X-linked CGD
• Newly identified missense mutation for X-linked
  CGD that may confer more oxidative activity
  leading to presentation of severe colitis?