A case of Primary Immunodeficiency in association with aniridia

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A case of Primary Immunodeficiency in association
with aniridia

• Ottavia Delmonte, MD
• Department of Pediatrics
• Division of Immunology and Infectious Disease
• University of Turin, Italy

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Initial Presentation

• 11 week old male with
• Fever (102.4º), increased work of breathing (Sat
  87)
• Worsening red rash on entire body
• Evaluated in the Emergency Room
• CXR increased heart size
• ECHO pericardial effusion
• Labs elevated WBC, normal Hb and PLT
• Pericardial effusion drain Purulent fluid
• Blood and pericardial fluid culture
  Achromobacter xylosoxidans (Gram Negative
  Bacillus)

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History

• Family History
• No history of recurrent or unusual infections
• No consanguinity (Western European descent)
• No history of immune defects or unexplained
  childhood deaths in family
• Mother known to be HIV negative during pregnancy
• Former 42 week infant (Birth Weight 10-25 )
• Initial rule out sepsis after birth (unknown
  reason, 48h abx)
• Since birth Rash, seborrheic dermatitis,
  feeding difficulties, intermittent diarrhea,
  aniridia
• Immunizations 2 mo vaccines (24h before fever)

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Physical exam

• VS Wt 4.05 kg (lt 5) Sats 99 ¼ L O2 Other
  vitals stable
• Head Severe seborrheic dermatitis with paucity
  of hair
• HEENT Aniridia, TMs clear, OP clear, tonsils not
  visualized
• Neck Supple, no lymphadenopathy
• CV 2/6 holosystolic murmur at LUSB Healing
  surgical scar on chest
• Resp Clear to auscultation bilaterally, no
  wheezes, no retractions
• Abd Soft, non-tender, mildly distended, no
  organomegaly
• Extremities WWP with brisk cap refill
• Skin Diffusely erythematous with severe peeling
  throughout entire skin. No edema, however skin
  appears to be stretched out

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(No Transcript)
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What is the differential diagnosis at this point?
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• WBC 81,970 cells/µL (15 N, 73 L, 8
  E, 2 B)
• Hemoglobin / Hematocrit 9.1
  g/dL / 30
• Platelet Count 263 x 10³/µL
• IgG 41 mg/dL
• IgA 9 mg/dL
• IgM 8 mg/dL
• IgE 196 mg/dL
• Absolute Lymphocyte Count
  59,840 cells/µL
• CD3 50,226 cells/µL
• CD4 18,737 cells/µL
• CD8 36,142 cells/µL
• CD19 37 cells/µL
• CD 16/CD56 1,107 cells/µL
• Lymphocyte Proliferation (Mitogens)
  Unresponsive
• FISH for Maternal Engraftment
  Negative
• KARYOTYPE
  Normal 46, XY

L A B S
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Now what is the differential diagnosis?
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Lymphocyte Spectratyping
Control
Patient
Molecular Characterization
Patient DNA First Allele ? 2
missense mutations in RAG1 ? 1 missense mutation
in RAG2 Second Allele
? deletion from 11p12 to 11p14.1( 9.5 MB)
Maternal DNA Same 3 missense mutations
RAG1/RAG2 Paternal DNA RAG1 and
RAG2 sequencing normal
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Omenn Syndrome and Aniridia

• OS is Autosomal Recessive, due to oligoclonal T
  cells infiltrating skin, gut, lymph nodes, liver
  and spleen.
• Hypomorphic mutation of the RAG genes.
• Mutations of Artemis (DCLRE1), IL2rG, RMRP
  and IL7RA genes may also result in the OS
  phenotype.
• RAG1 and RAG2 are located on chromosome 11p13 in
  close proximity to the PAX6 gene.
• PAX6 encodes a transcription regulatory protein.
  PAX6 is essential for the development of tissues
  in the eye (iris, lens, and neuroretina),
  pancreas and brain.
• Heterozygous PAX6 mutations often cause aniridia.

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Schematic representation of chromosome 11p with
deletion and RAG1/RAG2 gene mutations
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Treatment

• Cyclosporine
• Improvement in Skin Condition (within 4-5 days)
• Improvement in Lymphocytosis
• ALC 46,000 ? 19,000 ? 11,000
• Continued loose stools and difficulty tolerating
  feeds
• Continued Eosinophilia (14)
• Solumedrol
• BMT Matched unrelated donor
• Normalization of CD3 Lymphocytes
• Vigorous T-cell proliferation to mitogens
• Improved diversity of T-cell repertoire
• Normalization of CD19 Lymphocytes (No IVIG)
• Good Antibody Response to immunizations

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Summary and Conclusions-1

• First report of OS arising from a combination of
  a mutation and big deletion (9.5 Mb).
• Novel clinical presentation of aniridia in
  association with OS.
• First report of this combination of three RAG
  mutations in cis.
• First report of mutations of both the RAG1 and
  RAG2 genes.
• Contiguous deletion includes the WT1 gene.
• Microdeletion 11p13 is responsible of WAGR
  syndrome (Wilms tumor susceptibility, Aniridia,
  Genitourinary abnormalities, and mental
  Retardation), that occurs when both PAX6 and WT1
  deleted. WT1 deletion confers to the patient a
  high risk of Wilms tumor and genitourinary
  malformation.

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Summary and Conclusions-2

• As deletions in this region are not uncommon,
  this case underscores the importance of testing
  for large deletions to assess the risk of WT1
  deletion in patients presenting with OS-related
  immunodeficiency in whom genetic analysis does
  not clearly identify the expected inheritance of
  both maternal and paternal loss-of-function RAG
  alleles.
• Screening for immunodeficiency among patients
  with aniridia due to deletion is also an
  important consideration. However, the coincident
  inheritance of a RAG1 or RAG2 mutation would be
  the only way that Omenn syndrome would appear in
  conjunction with the Wilms tumor risk.