An Infant with Recurrent Oral Ulcers

1
An Infant with Recurrent Oral Ulcers

• By Soma Jyonouchi, MD
• CIS 2008

2
Case

• 10 mo male infant presents with history of
  recurrent mouth ulcers for 3 months.
• - 1-2 ulcers Q2 weks
• - wound culture normal flora
• - Dentist thought trauma from teething
• 2 small abscesses on the back that were popped by
  the pediatrician (MSSA cultured)
• History of 1 ear infection
• No other infectious history. No recurrent
  fevers.
• Robust weight gain, no hospitalizations or
  surgeries.
• No diarrhea, no eczema
• Fully immunized
• No medications.

3
Case

• Family History No consangnuity. No PID. No
  early deaths. 2 healthy older siblings (1 sister
  and 1 brother)
• Social History no daycare.
• Outside allergist sent an immune screen and found
  ANC 0 and an IgG of 30. Titers pending.
• Patient sent to CHOP for further evaluation.
• Exam in ER Afebrile, normal vitals.
• - happy, well-nourished, 2mm ulcer inside
  lower lip
• - Tonsils present, lungs clear, no HSM. no
  skin lesions.

4
Differential Diagnosis?

• Malignancy
• Congenital causes of neutropenia
• - Cyclic neutropenia
• - Kostmanns Syndrome
• - Shwachman Syndrome pancreatic insuff, /-
  skeletal abnl
• Autoimmune neutropenia
• Viral infection (parv B19, EBV, CMV)
• Drug induced
• PRIMARY IMMUNE DEFICIENCIES WITH NEUTROPENIA
• X-Linked Agammaglobulinemia (XLA)
• Hyper IgM
• IgA deficiency
• Wiskot Aldrich Syndrome (WAS)
• Chediak-Higashi Syndrome
• Dyskeratosis Congenita
• Reticular Dysgenesis

5
Workup

• What labs would you send?
• - CBC with diff, smear
• - Complete metabolic panel, LDH, Uric Acid
• - IgG, IgM, IgA
• - Antibody Titers
• - Lymphocyte Panel
• - Bone marrow biopsy

6
Results

• 11.8 gt 10 lt 570 N 0, L 90, M 5, E 5
  MPV gt 8
• ANC 0 ALC 10620
• IgG 31, IgA 8, IgM 184
• Diptheria and Tetanus Ab undetectable
• 2 pneumococcal serotypes positive (1, 9V)
• Bone Marrow - Normocellular marrow with marked
  left shift in myeloid maturation, with most forms
  in the promyelocyte stage
• Flow CD3 9111 cells/ul
• CD 56 613 cells/ul
• CD4 8024 cells/ul
• CD8 1122 cells/ul
• CD45 RA 7423 cells/ul
• CD 45 RO 705 cells/ul
• CD 20 1804 cells/ul

7
Results

• B-Cell Panel
• - CD19/CD40 1989 cells/uL
• - CD19/IgD/IgM 1796 cells/uL (naïve
  B-cells)
• - CD19/CD27/IgD- 4 cells/uL (switched
  memory)
• - CD19/CD27/IgM- 4 cells/uL (switched
  memory)
• CD40L by flow cytometry absent
• Mutation analysis confirmed X-linked HIGM
• - deletion of adenine and cytosine at
  position 460/461
• - frameshift mutation

8
X-Linked Hyper IgM

• T-cell ligand defect leads to defective
  stimulatory signaling.
• CD40L on T-cells interacts with CD40 receptor on
  B-cells, macrophages, and dendritic cells.
• - B-cell proliferation, CSR, SHM
• - Activation of macrophages and dendritic
  cells
• 
  

9
X-Linked Hyper IgM

• Recurrent respiratory infections with pyogenic
  bacteria.
• Opportunistic infections PCP (Why?)
• Low IgG, IgA, IgE
• IgM normal or elevated
• Absent specific IgG antibody responses
• Low switched memory B-cells
• T-cell subsets and mitogens normal
• Defective Th1 response w/ decreased IFN-Gamma
  secretion and failure of APCs to make IL-12
• gt50 of patients have intermittent or chronic
  neutropenia
• - arrest at the myelocyte-promyelocyte stage
• Autoimmunity common AHA, thrombocytopenia,
  autoimmune hepatitis, inflammatory bowel disease.
  
• Hodgkins lymphoma, malignancies of the liver and
  GI tract.

10
How would you treat this patient?

• Option 1
• - Monthly IVIG
• - Bactrim prophylaxis for PCP
• - GCSF for neutropenia
• - Other antibiotic prophylaxis
• Option 2
• - Bone marrow transplant
• - Haploidentical vs. full HLA match
• Median survival of patients who do not receive
  BMT is less than 25 years
• - PCP - infancy
• - GI malignancy - adult

Levy et al. 1997
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References

• Levy, J. Clinical Spectrum of X-linked Hyper IgM
  syndrome. J. Pediatrics. 1997131 47-54.
• Winkelstein J, Marino M, Ochs H, et al. The
  X-linked Hyper-IgM Syndrome Clinical and
  Immunologic Features of 79 Patients. Medicine.
  2003 82(6) 373-384.
• Notarangelo L, Gaetana L, Peron S, and Durandy A.
  Defects of Class-switch Recombination. JACI.
  2006 117855-64.
• Cham B, Bonilla MA, and Winkelstein J.
  Neutropenia Associated with Primary
  Immunodeficiiency Syndromes. Semin Hematol.
  200239(2) 107-112.
• Scholl PR, O Gorman MRG, Pachman LM, et al.
  Correction of neutropenia abd hypogammaglobulinemi
  a in X-linked hyper-IgM syndrome by allogenic
  bone marrow transplantation. Bone Marrow
  Transplantation. 1998 22 1215-1218.
• Gennery AR et al. Treatment of CD40 ligand
  deficiency by hematopoietic stem cell
  transplantation a survey of the European
  Experience 1993-2002. Blood. 2004 103
  1152-1157.