[CIS-PAGID] 5 YO Male with systemic granulomatosis and hypogammaglobulinemia

[João Farela Neves]

Lymphoma is surely one of our main concerns. We have biopsied a deep
abdominal lymph node 3 months ago but we're thinking about doing
another one. We'll try to convince our surgeons to biopsy the lung,
too.

As for Mycobacteria infection... It is always diifult to rule out, but
we have negative results for PCR and culture for both BK and atypical
mycobacteria in the BAL, Bone marrow, gastric sample and lymph node.
Quantiferon is also negative.

Thanks again.

João Farela Neves

2012/4/13, Kobrynski, Lisa <lkobryn at emory.edu>:

> I have a very similar patient - a girl who presented with massive

> splenomegaly, anemia, pulmonary granulomas and agammaglobulinemia.  Biopsies

> showed non-caseating granulomas.  She had infection with atypical

> mycobacteria.

>

> She also has an increase in activated T cells with an inverted CD4/CD8

> ratio.  We have not identified a genetic defect - but presume that this

> represents a CVID phenotype with sarcoid-like granulomas.  The granulomas

> have been responsive to systemic steroids, however it would be important to

> be sure that there is no underlying infection with any mycobacteria

> species.

>

>

>

>

>

> Lisa Kobrynski, MD, MPH

> Associate Professor of Pediatrics

> Section, Allergy/Immunology

> ________________________________

> From: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org]

> on behalf of João Farela Neves [jpfn13 at gmail.com]

> Sent: Thursday, April 12, 2012 3:43 PM

> To: pagid at list.clinimmsoc.org

> Cc: pagid at list.clinimmsoc.org

> Subject: Re: [CIS-PAGID] 5 YO Male with systemic granulomatosis and

> hypogammaglobulinemia

>

> Sequence

>

> Enviado do meu iPhone

>

> No dia 12/04/2012, às 20:37, "Verbsky, James"

> <jverbsky at mcw.edu<mailto:jverbsky at mcw.edu>> escreveu:

>

> You mentioned SAP and xIAP as normal..was this by protein or sequence??

>

> From:

> pagid-bounces at list.clinimmsoc.org<mailto:pagid-bounces at list.clinimmsoc.org>

> [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of João Farela Neves

> Sent: Thursday, April 12, 2012 7:02 AM

> To: pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>

> Subject: [CIS-PAGID] 5 YO Male with systemic granulomatosis and

> hypogammaglobulinemia

>

> Hello all,

>

> Hope you can help me with this one!

> 6 YO boy

> Non-consanguineous parents. No premature deaths or miscarriages.

> 4 YO brother has recurrent otitis media and has

>

> •         complete IgA deficiency (undetectable IgA, normal IgG and IgM with

> conserved responses to proteic and polysaccharide antigens).

>

> •         EBV infection at the age of 2, now has VCA IgM negative with EA

> IgM neg, VCA IgG pos but has not formed EBNA IgG Antibodies nor have the VCA

> IgG titres raised.

> Pregnancy Ok, Newborn period Ok

> Our patient was healthy until the age of 5, when he was hospitalized because

> of intermittent fever lasting for 3 weeks, hepatosplenomegaly + abdominal

> lymphadenopathies + pancytopenia. No other complaints. Examination was

> normal, excluding the hepatosplenomegaly (normal skin, eyes, bone, joints,

> hair, heart)

> Extensive investigation was performed (I describe the most relevant

> results):

> EBV VCA IgM neg, VCA IgG pos, EBNA Neg. Viral load negative.

> CMV, Parvorirus B19 IgG, Enterovirus, HIV and all other vírus Neg.

> Bacteria: BK neg (quantiferon, Mantoux, direct, cultural and PCR for BK in

> gastric lavage sample); Bartonella, Brucella, Coxiella, Francisella,

> Borrelia, etc all negative. Coprocultures neg

> Leishmania: Neg in Bone marrow sample and negative serology.

> Bone marrow: 3 lineage hypercellularity. All infectious agents were negative

> in the BM.

> Abdominal Lymph node excisional biopsy: “non-caseous granulomatous

> lymphadenitis”. PCR for EBV was positive. All other agentes were negative.

>

>

>

> The pancytopenia and hepatomegaly resolved without treatment.

>

> Despite from that, he stood with a heterogeneous, nodulary, huge

> splenomegaly (more than 14 cm) and generalized lymphadenopathies. Further

> investigations:

>

>

>

> Thoracic CT scan: nodules (granulomas) in both lungs.

>

> BAL: Normal. All agentes were negative. Attending immunophenotyping.

>

> Ophtalmologic observation: Normal

>

> Coombs test positive in the first hospitalization. It is now negative.

> Platelet Coombs: Neg

>

> ANA 1/80; AntiDsDNA, AntiB2GP1 IgG/IgM, ACA IgG/IgM negative

>

> ACE: Very high (granuloatous disease) : 188 (superior limit 68)

>

> Lizosime very high 5,39 (0,96- 1,71)

>

> Oxidative burst Normal.

>

> XIAP and SAP Normal

> Immunophenotyping:

> CD3+ %

>

> 76 (1892)

>

> CD3+CD4+ %

>

> 42 (1040)

>

> CD4CD45 RA

>

> 39 (408)

>

> CD4CD45RO

>

> 35 (670)

>

> CD3+CD8+ %

>

> 27 (655)

>

> CD8CD45RA

>

> 75 (493)

>

> CD3HLADR+

>

> 47 (893)

>

> CD4HLADR+

>

> 37 (389)

>

> CD8HLADR+

>

> 56 (367)

>

> CD19+ %

>

> 8 (212)

>

> CD19 CD27+

>

> 15 (31)

>

> CD19CD27-IgD+IgM+

>

> 84 (178)

>

> CD19CD27+IgD+/MZL

>

> 14 (29)

>

> CD19CD27+IgG+ (switch)

>

> 1 (2)

>

> CD19CD38++IgMhigh

>

> 4 (9)

>

> Linf NK % (valor absoluto)

>

> 14 (357)

>

> TCRαβCD4-CD8-

>

> 1,2

>

>

>

>

> 3/11/11

>

> 03/01/12

>

> March 2012

>

> IgG

>

> 4.75

>

> 4.11

>

> 3.4

>

> IgG1

>

> 3.43

>

> 3.16

>

>

>

> IgG2

>

>

>

> 0.20

>

>

>

> IgG3

>

> 0.38

>

> <0.12

>

>

>

> IgG4

>

> 0.005

>

> 0.006

>

>

>

> IgA

>

> <0.24

>

> <0.24

>

> <0.2

>

> IgM

>

> 0.29

>

> 0.30

>

> 0.27

>

> C3

>

> N

>

>

>

>

>

> C4

>

> N

>

>

>

>

>

> CH100

>

> N

>

>

>

>

>

> IgE

>

>

>

> 2.9

>

>

>

> Diphteria

>

> 0.01

>

> 0.01

>

> 5 (upon revaccination

>

> Tétanus

>

> 0.05

>

> 0.05

>

> 5 (upon revaccination

>

>

> He is now 8 months after the first hospitalization. In brief:

> Systemic granulomatous disease with deep lymph nodes, lung and spleen

> involvement. Major splenomegaly.

> Thrombocytopenia secondary to the hypersplenism

> Hypogammaglobulinemia (IgA, IgM and IgG) with conserved responses to proteic

> Ag. We attend results demanded to exclude 2ary hypogamma: urinary and

> enteric loss. No medication.

>

> Regarding possible differential:

>

>

>   *    CGD excluded

>   *   ALPS: alfabeta Double negatives abd IL10/Fas-l/B12 Normal.

>   *   CVID: It is, no doubt, a strong possibility… but the conserved

> response to vaccines and lack of infections surprise me,

>   *   XLP seems to me the most straightforward diafnosis: EBV in the lymph

> node, hypogamma after EBV infection, some auto-immune features (Coombs pos

> anti erythrocyte), EBV serology  with lack of EBNA, along with the “family

> pattern”: brother  with lack of IgA and same serology to EBV. But SAP and

> XIAP are both negative… ITK? We’ve just asked for its sequencing.

>   *   Other HLH? We attend results for NK and CD8 cytotoxicity, perforin

> expression, sCD25.  Ferritin, TG , fibrinogen, etc are normal

>   *   Leaky SCID? Seems odd… but he does have 34% of naïf T cells.

> Proliferation assyas are pending. Should we sequence the genes of leaky

> scid, namely RAG?

>   *   Sarcoidosis? We aim to sequence NOD/CARD if everything else come out

> normal..

>

>          Look  forward for your help,

>

>        João Farela Neves,

>

>        Primary Immunodeficiencies Unit,

>

>        Hospital Dona Estefânia,

>

>         Lisbon, Portugal

>

>

>

>

>

> ________________________________

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