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

[Verbsky, James]

You would have to postulate some defect in promoter/enhancer preventing expression.  There are labs that will do the protein expression, and at least you can rule in out completely..not sure its ever been described.

From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of João
Sent: Thursday, April 12, 2012 4:41 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

Thanks for your replies.

Protein expression was not done, do you think it's worth it?

As for RAG, it has to be excluded, I agree.

I thought We could exclude cd27 deficiency based on the fact that he has 15% of cd19 +cd27+. Should We screen it, anyway?

Thanks again

João

Enviado do meu iPad

No dia 12/04/2012, às 21:44, Dewton Vasconcelos <dmvascon at usp.br<mailto:dmvascon at usp.br>> escreveu:
Dear João, good afternoon

Besides SAP and XIAP, certainly my first thoughts too, ITK and CD27 gene mutations are possible too.

Sometimes CVID patients lose the response to polysaccharide earlier and protein response a long time later. AID and UNG?
I am really afraid of non-caseous granulomatous lymphadenitis, as "sarcoid" lesions may be lymphomas.

Best regards,

Dewton Vasconcelos
University of São Paulo School of Medicine


João Farela Neves wrote:
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




<dmvascon.vcf>
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