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
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)
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)
Physical exam
• VS: Wt = 4.05 kg (< 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”
What is the differential
diagnosis at this point?
• 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
L • IgA: 9 mg/dL
• IgM: 8 mg/dL
A • IgE: 196 mg/dL
B • Absolute Lymphocyte Count: 59,840 cells/µL
S • 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
Now what is the
differential diagnosis?
Lymphocyte Spectratyping
Control Patient
Molecular Characterization
Chromosome 11
Short arm Patient DNA:
11p15
First Allele:
● 2 missense mutations in RAG1
11p14
● 1 missense mutation in RAG2
Second Allele:
RAG 2 11p13
● deletion from 11p12 to 11p14.1( 9.5 MB)
RAG 1
11p12
Maternal DNA: Same 3 missense mutations RAG1/RAG2
11p11
Paternal DNA: RAG1 and RAG2 sequencing: normal
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.
Schematic representation of
chromosome 11p with deletion and
RAG1/RAG2 gene mutations
11p12 11p13 11p14.1 11p14.2 11p14.3
M
P
40M 35M 30M 25M
cen tel
Met502Val Met1006Val Met435Val
RAG2 RAG1 WT1 PAX6
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
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.
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.