[CIS PIDD] [cis-pidd] CTLA4 haploinsufficiency?

[CIS-PIDD]

Dear all,

I’m considering CTLA4 haploinsufficiency diagnosis on a patient and would like your thoughts on some specific questions.

She’s an 8yo girl who carries a diagnosis of recurrent HLH/MAS, has been followed by Rheumatology and Hematology before.  In Feb 2015 presented meeting 8/8 criteria for HLH, and genetic panel for HLH genes (Cincinnati) was negative.  She has been since treated with steroids (prednisone) and cyclosporine with “flares” (headaches and neural symptoms) when immunosuppression is attempted to be weaned.  Just recently admitted with headaches, vomiting, fatigue, abdominal discomfort.  On brain MRI multiple enhancing cerebellar lesions, also in brainstem.  Chest CT with multiple pulmonary nodules.  She has not had any other autoimmune complications, no cytopenias, no endocrine or liver involvement.  Brain biopsy showed:
> 
> - Extensive, highly reactive mixed histiocytic and lymphocytic (T-cell predominant) infiltration
> - Erythrophagocytosis/macrophage activation syndrome like features noted (see Microscopic Description)
> - PCR-based T-cell gene rearrangement studies pending

Some T and B cell lymphopenia but pretty mild (off steroids for 3mo, off cyclosporine for 1 month).  Normal vaccine responses to tetanus and diphtheria.  Immunoglobulins OK, with IgG in the high 500s/low 600s.  Multiple infectious studies sent from peripheral blood, and stained brain biopsy, all negative thus far.  Tons of CD3/CD4 positivity on brain biopsy.

My questions to you:

- Does this smell like CDTLA4 haploinsufficiency to you? Other differential diagnosis (outside of infectious)?

- Do you think is worth it to look at pulmonary tissue, and pursue biopsy? my guess is that same process there? she had BM biopsy done, with some HLH evidence, need to ask for CD3 staining.  On Science and Nature Med papers the staining for tissue involved CD3/CD4/CD8/CD138; other markers you’d look at on tissue?

- Are there other immune functional/phenotypic testing you would do? we can look at Tregs phenotype and attempt suppression assay, but as you know, not commercially available.  B cell phenotype with abnormal CD21 for these patients, and could pursue B cell phenotype at Mayo, but all of that suggestive;  genetic testing for Cincinnati for CTLA4/LRBA sent

Thanks for your time.

Elena Hsieh, MD
Assistant Professor
Allergy and Immunology 
University of Colorado Denver
Children’s Hospital Colorado
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