Combined immunodeficiency with dysmorphic features

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Combined immunodeficiency with dysmorphic features

• Nancy Wasserbauer, DO
• Clinical Immunology Summer School 2008

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23 yo white female patient

• Referred to immunology by hematology for
  recurrent infections and low immunoglobulins.
• Past history of ITP.
• Has long PMHx since birth.
• Decreased fetal movement at 6 mos., 40 wk, 3
  7oz, FTT, feeding delay, dysmorphic features,
  single kidney, d/cd from NICU without unifying
  diagnosis.

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• Recurrent OM, sinusitis, pneumonia since 6 mos.
  old. No abscess, thrush or skin infections.
• In last one year 2 pneumonias, 5-6 acute
  sinusitis, vaginal yeast infection, UTI, inguinal
  folliculitis, shingles.
• Other recent history includes idiopathic
  tachycardia, seizure disorder, developmental
  delay, allergic rhinitis, asthma, scoliosis, bee
  sting anaphylaxis.

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• Surgical hx
• PETs since 6 mos. old
• TA
• Appendectomy
• Sinus sx.
• Strabismus sx.

• Family hx
• nonconsanguinous parentage
• Father deceased, hx not known
• Mother allergic rhinitis, asthma, depression
• 2 half sisters allergic rhinitis and asthma

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Physical Exam

• HT50 for 9yo, WT87 for 9 yo.
• Gen dysmorphic/pale
• HEENT small head, high forehead, upslanting
  palpebral fissures, R TM w/perforation, L TM with
  PET, thick white nasal mucous, teeth wnl, heavy
  jaw, maxillary hypoplasia, tented secondary
  palate.

• CV Tachycardic 110
• Chest Pectus carinatum, scoliosis, CTA b/l
• Abdprotruberant, palpable spleen and liver
• Lymph no significant adenopathy.
• Neuro/Musc Apparent developmental delay,
  tightened achilles.

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Laboratory

• WBC 2.2 X10 9/L
• Hgb 12 g/dL
• PLT 54 X 10 9/L (MPV is high)
• N 76.9
• L 15.5
• M 5.2
• Eo 2.0
• ANC-1692
• ALC-341
• Normal chemistry and liver function
• HIV 12 negative by PCR

• IgM-14 mg/dL(50-300)
• IgA-lt7 mg/dL(70-390)
• IgG-125 mg/dL(700-1600)
• IgG1-87 mg/dL(422-1292)
• IgG2-lt18 mg/dL(117-747)
• IgG3-7 mg/dL(41-129)
• IgG4-lt2 mg/dL(0-29)
• 12 serotype pneumococcal antibody panel pre and
  post prevnar and pneumovax ALL lt0.2

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Laboratory

• Influenza A (0.89) and B (1.03) Ab (equivocal)
• Mycoplasma Ab titer 0.15 (0-0.90)
• RSV Ab titer 164 (gt14)
• Tetanus Ab titer 0.16 (gt0.10)
• Anergic by skin test
• Lymphocyte proliferative responses
• Lectins -
• Low/normal response to PHA and CON A
• Normal response to PWM
• Specific antigens-
• Decreased response to Candida, tetanus,MMR
• Normal proliferation to Streptolysin O.

• CD3-291 (1174-2102)
• CD4-25 (42-56)
• CD8-196 (192-695)
• CD4/CD8-0.4 (1.4-3.2)
• CD19-24 (162-410)
• CD56-16 (58-328)
• ADA and PNP are WNL
• TCR Vß decreased at 48 vs. 69 in normal control
• Normal chromosomes, FISH and microarray
• Normal HLA typing
• Negative for anti-lymphocyte antibodies
• Granulocyte Ab 4/04.

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Imaging

• January 2006 MRI of head No focal gyral
  asymmetry. White matter volume loss r/t ischemic
  or inflammatory change.
• Nov. 2006 CT head and sinus Skeletal dysplasia
  based on thickened bony appearance, inflammatory
  changes left maxillary and ethmoid air cells
  without focal abnormality.

• February 2007 CT chest 2-3 para-aortic nodes and
  6 mm opacity at posterior RUL.
• February 2007 abdominal/pelvic US Enlarged
  spleen, no masses.
• August 2008 follow-up CT chest pending.

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Assessment

• 23 year old white female with dysmorphic
  features, developmental delay, seizures, single
  kidney, ITP
• Hypogammaglobulinemia
• No response to pneumovax/prevnar
• low CD3, CD4, CD19, CD56
• low normal CD8
• Decreased response to Tetanus, Candida, MMR,
• Low normal response to PHA, ConA
• Normal response to PWM, Streptolysin O

• Anergic by skin testing
• Negative HIV
• Normal HLA
• Normal ADA, PNP
• Normal chromosomes, FISH and microarray
• Decreased Vß expression

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Differential Diagnosis

• Common Variable Immune Deficiency
• Leaky SCID
• Immunodeficiency-centromeric instability-Facial
  anomalies (ICF)

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Plan

• The patient started intravenous infusion of
  immunoglobulin at a dose of 400mg/kg/month in
  December 2007. Since this time there has been a
  dramatic decrease in the incidence of her
  infections. Her serum IgG level prior to the
  third infusion was 470mg/dL (700-1600). Her ITP
  is stable and is followed by hematology/oncology
  service.

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Plan

• Established an EBV cell line
• TACI and BAFF receptors.
• Flow cytometry to further characterize this
  patients B and T cells.
• Naïve and memory T-cells
• B-cell subpopulations
• Would like to look at TRECs.
• Would like to look at Lyonization of the X
  chromosome.
• May consider DNA methyltransferase 3 B gene
  (mutation in ICF), but less likely with normal
  karyotype.

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Thank You!!

• Dr. Mark Ballow
• Dr. Julian Ambrus Jr.
• Dr. Karen Nadeau

• Cheryl Allen, BS
• Gary Rich, BA
• Alicia Lieberman, MS

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