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

[João Farela Neves]

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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