[CIS PIDD] Recurrent HLH like episodes with persistent splenomegaly

[Notarangelo, Luigi]

Do we know anything about T cell function? Specific antibody responses? Diversity of T cell repertoire? All of these are important when considering any leaky SCID. Was a lymph node biopsy ever performed? If so, what were the findings? Any evidence of EBV viremia? Are NKT cell present?



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Luigi D. Notarangelo, MD
Jeffrey Modell Chair of Pediatric Immunology Research
Division of Immunology
Children's Hospital Boston
Professor of Pediatrics and Pathology
Harvard Medical School
Karp Building, Room 10217
1 Blackfan Circle
Boston, MA 02115

Tel: (617)-919-2276
Fax: (617)-730-0709


On Jul 19, 2012, at 1:51 PM, "Joshi, Avni Y., M.D." <Joshi.Avni at mayo.edu<mailto:Joshi.Avni at mayo.edu>> wrote:


Dear Colleagues,

We would appreciate input on this child who have come all the way from India paying out of pocket for a second opinion about the possibility for BMT:

This is a 12 yr old  Asian Indian boy ( non consanguineous) who has a history of recurrent episodes of lymphadenopathy and cytopenias.

He started off about 4 yrs. ago , with an episode of high grade fever, LAD and splenomegaly. Infectious w/up in India was negative, yet was treated for typhoid fever. Things were quiescent for the next two years except that his spleen was still palpable.  Dad, being a surgeon, would examine him, but he was symptomatically doing well. In 2008, he developed some skin lesions  was seen by a dermatologist and were thought to be erythema nodosum and was given prednisone for 20 mg per day.  The spleen size improved significantly while being on prednisone, but his skin lesions did not improve.  Prednisolone was stopped after a month's time, and his skin lesions slowly improved in the next two to three months' time. He had another recurrence of these episodes of high-grade fever with cytopenia, splenomegaly, and lymphadenopathy when he was seen by a hematologist , who diagnosed him to have ALPS.  His double-negative T-cells were in the normal range.  Bone marrow biopsy was normal and was negative for lymphoma, and his lymph node biopsy samples were sent to Oxford which showed there were no B-cells, but  there was increased T cell numbers, mostly CD8s.Coombs testing/antiplatelet antibody testing not done.

High dose steroids did improve his symptoms, and he did well for a year's time until last year when he had recurrence of his splenomegaly, with his spleen reaching into his right iliac fossa.  He was seen by an immunologist and his double-negative T-cells were borderline high.  He was again diagnosed with ALPS, and genetic testing for FAS, Fas-L, and Caspase-8 was sent to Japan and was negative.  He was initially started on mycophenolate mofetil which did not improve his symptomatology.  He was then switched to sirolimus. His counts drop on sirolimus monotherapy but stabilize when Prednisolone was added. He developed varicella on the combination in Dec 2011.

More recently, in April 2012 he was diagnosed with neuropathy.  EMG is suggestive of sensorimotor peripheral neuropathy with features that would suggest a combination of demyelination and axonal loss.   He had recurrence of the skin lesions which were biopsied and showed evidence of occasional histiocytes.

His bone marrow biopsy has shown evidence of hemophagocytosis on and off during these events.
Only significant F/H is a maternal cousin has sensorineural hearing loss.
He is currently on 20mg/d of prednisolone ( close to a year now)and 3mg/d of Sirolimus.

Labs in US:
CBC: mild lymphopenia and thrombocytopenia, no eosinophilia.
TBNK: T ,B and NK cell lymphopenia
ALPS screen: Negative
sIL-2: 1010 ( Normal: 45-1105 U/ml)
NK subsets :Normal and robust expression of perforin and Gran A/ Gran B
SAP and XIAP expression: Normal
Bone/lymphnode/Skin Bx read here: essentially normal, occasion expression of CD1a and S-100 positive Langerhans cells, relative paucity of B cells. No granulomas.(The Bx have been on at least 20mg/d of Prednisolone)

Immunoglobulins:A,M, G and E: Normal, never been on IGIV.
Recent Thymic Emigrant (CD4RTE): Modestly decreased.
Vit B12: Normal
Ferritin: Normal

Would you consider leaky SCID, hypomorphic RAG mutation?
Due to financial constrains, we have not performed any genetic testing yet.
Dad is 9/10 match .
I'd appreciate any thoughts, recommendations or insights.
Would you recommend BMT?

Thank you so much for your time,
Avni


Avni Y Joshi, MD, MSc
Assistant Professor of Pediatrics and Medicine
Pediatric and Adult Allergy / Immunology
Cellular and Molecular Immunology Laboratory
Pager: 507-293-5387
Secretary: 507-538-0127
Fax: 507-284-0727
E-mail: joshi.avni at mayo.edu<mailto:joshi.avni at mayo.edu>
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