[CIS PIDD] LPD in a patient with an uncharacterized immune deficiency

[Rohan Ameratunga (ADHB)]

Dear Angela,

We have reported a 55 yr female with follciular NHL who was a carrier for SH2D1A- presumably as a result of age related lyonisation.  Perhaps this could happen at a younger age with extreme lyonisation.

Regards

Rohan Ameratunga
Adult and paediatric immunologist
Auckland
New Zealand 
________________________________________
From: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org] On Behalf Of Cowan, Mort [mcowan at peds.ucsf.edu]
Sent: Wednesday, July 25, 2012 7:58 AM
To: pagid at list.clinimmsoc.org
Cc: Wes Miller; krueg456 at umn.edu
Subject: Re: [CIS PIDD] LPD in a patient with an uncharacterized immune deficiency

Phenotyping c/w T-B-NK+ with leakiness. You might check Artemis or RAG. EBV lymphomas have been reported by Paris group in leaky Artemis SCID patients.   mort

Morton J. Cowan, M.D.
Professor of Pediatrics
Chief, Allergy, Immunology, and Blood and Marrow Transplant Division
UCSF Children's Hospital, Room M659
505 Parnassus Ave
San Francisco, CA 94143-1278

Phone: 415-476-2188
FAX: 415-502-4867

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-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of smith719 at umn.edu
Sent: Tuesday, July 24, 2012 9:30 AM
To: PAGID list
Cc: krueg456 at umn.edu; Wes Miller
Subject: [CIS PIDD] LPD in a patient with an uncharacterized immune deficiency

Dear all

I am seeing a 5 year old girl from Saudi Arabia with an underlying diagnosis of a "combined immune deficiency" and sickle cell disease who was referred to me for stem cell transplant. She came with 5 pages of medical records so we have essentially had to start from scratch. During her evaluations, we discovered a lymphoproliferative process so my questions are both diagnostic with regard to her underlying immune deficiency and therapeutic with regard to her LPD.

Her referral letter indicated low T, B and NK cell numbers as well as moderate to severe reduction in T cell proliferation to PHA, but normal immune globulin levels and "adequate" pneumococcal titers. She has never received IVIG. She was born full-term after a normal pregnancy and weighed 3.5kg at birth. She had no issues until approximately 1.5 years of age when she started to develop frequent sino-pulmonary infections. She is hospitalized every 1-2 months for these infections and requires IV antibiotics. She has never been admitted to the ICU, been intubated or required surgical intervention. She has been maintained on bactrim prophylaxis. Per parents, she has had all recommended vaccinations with no adverse reactions. No history of autoimmune pathology.

Despite the diagnosis if sickle cell disease, she has never required any transfusions and her hemoglobin generally runs around 9. Evaluations here revealed that she has concurrent HPFH so this is essentially a non-issue with regard to her need for transplant.

Despite the frequent infections and hospitalizations, she has been growing and developing normally. She is at the 25th percentile for weight and height.
She
was attending kindergarten back home and according to her parents, her teachers had some concerns about her ability to concentrate, but otherwise she is on track with her peers.

Her family history is only significant for consanguinity. Her parents are first cousins and their parents are also related. There is no family history of immune deficiency or early childhood deaths. Her parents both have sickle cell trait. She has a 3 year old sister who is healthy and is an HLA match.
Her
sister's counts are normal, she has normal lymphocyte subsets and hemoglobin electrophoresis.

Upon arrival to the US, the patient was febrile and was admitted for evaluation. During this evaluation she was noted to have pan-sinusitis with bilateral otomastoiditis, bibasilar pneumonia (nodular in appearance) and extensive mediastinal lymphadenopathy. Despite this, she clinically looked well. She has no organomegaly and no palpable lymphadenopathy with the exception of shotty cervical nodes. Morphologically, she has somewhat widely spaced eyes and low set ears, but no other obvious stigmata. Her work-up thus far is as follows:

White blood cell count of 2.7 with an ANC of 1.6 and an ALC of 0.4.
Lymphocyte
subsets: Absolute CD3 count 353, absolute CD4 count 118, absolute 8 count 163, absolute CD19 count 27, absolute CD16/56 count 526. Her CD4-CD8 ratio was 0.72.
IgG level 1270, IgA 199, IgM 524 and IgE less than 2. IgG1 973 (306-945),
IgG2
184 (61-345), IgG3 199 (10-122), IgG4 <1 (2-113.

CH50 of 79 (normal 60-144)

Lymphocyte antigen and mitogen proliferation tests were done, though there were insufficient numbers of isolated lymphocytes to validate the assay. Results were reported anyway which showed absent lymphocyte responses to Candida and tetanus, low lymphocyte responses to PHA and concanavalin A, and normal lymphocyte responses to pokeweed mitogen. Repeat tests are in process.

Thymopoiesis panel: TREC copies relative to CD3 T cell count = 289 copies per million CD3 T cells. Her absolute CD4 RTE level was 8.1 cells/mcL. T cell receptor repertoire testing is pending.

Her B-cell subset immunophenotyping is remarkable for significantly decreased class switched memory B cells relative to both total B cells and total memory B cell pool. The percent total CD27+ memory B cells appear normal due to relative expansion of the proportion of marginal zone B cells. The frequency of plasmablasts is also substantially decreased. All other B-cell subsets appear to be quantitatively normal.

Isohemagglutinin titers show an anti-A IgM of 512 and an anti-B IgM of 1024.

Rubeola antibody of 259 (positive and suggests previous exposure and probable immunity). Tetanus titer of 0.06 (protective, but greater than 0.15 is desirable). Diphtheria antibody of 0.06 (protective, but greater than 0.1 is desirable). Pneumococcal titers are low except for type 23F.

NK cell activity is normal.

HIV 1 and 2 antibodies are negative. All other infectious disease testing also negative with exception of BAL tests below.

Echocardiogram reveals normal intracardiac anatomy with good ventricular contractility and ejection fraction of 65% to 70%.

Chromosome analysis for DiGeorge syndrome is pending. Comparative genomic hybridization (CGH) is also pending.

A bronchoscopy was performed that revealed 42,000 copies/mL of EBV and 4000 copies/mL of CMV, but was otherwise negative. She was started on IV antibiotics and ganciclovir while a lymph node and lung biopsy were arranged.

Though we were expecting infection, her lung biopsy revealed a high grade, EBV positive diffuse large B cell (CD20+) lymphoma. The surgeon decided the lymph node biopsy wasn't needed so this was not done. She will be getting bilateral bone marrow biopsies and an LP today and a PET CT soon for further staging. She has also developed a lip lesion of unclear etiology that will be biopsied today.

Any thoughts on diagnosisof her immune deficiency and treatment for her LPD are greatly appreciated.

The most pressing question at this point is how we should treat her DLBCL.
Given that it is CD20+, we will definitely use rituximab. Would aggressive chemotherapy (CHOP, EPOCH, other) also be recommended based on the lung based lesions and pathology alone? Any other thoughts on treatment strategies?

Any thoughts on the diagnosis of her underlying immune deficiency? Her main issue seems to be one of thymic output. Given the LPD diagnosis, we are considering Nijmegen breakage syndrome.

Thanks in advance for your help.

Angie

--
Angela R. Smith, MD, MS
Assistant Professor
Pediatric Blood and Marrow Transplantation
420 Delaware Street SE
MMC 484
Minneapolis, MN 55455
Phone: 612-626-2778
Fax: 612-626-2815