[CIS PIDD] [cis-pidd] Input please - 8 week male inflammatory condition with absent B cells

Tue Nov 24 08:38:17 EST 2015

Dear Theresa,

severe autoinflammation status since birth and absence of B cells reminds
me of our patient with overlapping clinical symptoms who was finally
diagnosed with SIFD (congenital sideroblastic anemia, B-cell
immunodeficiency, periodic fevers, and developmental delay).
Molecular diagnosis was performed in NIH, I.Aksetijevich, quite recently -
actually our patient was one of the first two cases whos investigation led
to the discovery of the gene - TRNT1, mitochodrial enzyme with a role in
RNA transfer. In our case a verification of sideroblastic nature of anemia
and extremelly high serum levels of IL-6 were helpful in confirmation of
correct diagnosis.
After  very difficult periods of inflammation and other complications stem
cell transplantation was performed, the child, however, died for
complications of transplantation. Some successful transplantations were,
however, reported in the literature.
In our case, however, GIT problems were dominant in the first months,
descriptively characterized as "pseudoobstruction", later he developped
necrotizing enterocolitis - that seems to be missing in your case. On the
other hand inflammation, cytopenias and extreme ferritin levels were very
much the same as you report. We have also tried Anakinra, but had to stop
it for sepsis he had developped (not certain if it was in direct connection
to the treatment).

With regards

Anna

On Tue, Nov 24, 2015 at 10:17 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
wrote:

> Dear CIS Members
>
>
>
> Following our recent success with diagnosing a patient after discussion in
> this group we would value your thoughts on another patient in Melbourne,
> Australia. We are interested in any suggestions regarding diagnosis or
> further investigations.
>
>
>
> This is an 8 week old male who presented soon after birth with an
> inflammatory condition and absence of peripheral B cells (CD19+present in
> marrow)
>
>
>
> Background:
>
> ·         2nd child, non-consanguineous Sudanese parents
>
> ·         Mother:
>
> o   History of latent TB (quantiferon positive).
>
> o   3 weeks prior to delivery,  developed fevers, rash, arthritis,
> splenomegaly & high ferritin, requiring ICU admission post-delivery
>
> §  negative viral studies including CMV, EBV, HBV, HCV & HIV
>
> §  diagnosed with Still’s disease (no BM bx done)
>
> §  treated with steroids. Currently controlled on anakinra
>
> §  similar presentation during previous pregnancy, not as severe, no
> treatment required
>
> ·         19 month old sister – well
>
>
>
> HOPC:
>
> ·         born vaginal breech in poor condition.
>
> o   cooled for HIE
>
> o   LP – PMNs 100, culture negative
>
> §  Commenced IV antibiotics for presumed meningitis
>
> ·         D3 – extubated.
>
> o   Thrombocytopenia (plt 18), requiring platelet transfusion
>
> o   Ferritin 3100
>
> ·         D5 – noted skin vesicle on posterior aspect distal R. leg.
> Spontaneously deroofed.
>
> o   Swollen PIP joints
>
> o   Inguinal & axillary lymphadenopathy
>
> o   Hepatomegaly
>
> ·         D9 – fevers (up to 39 C), ferritin 11,000, transient blanching
> erythematous rash
>
> o   BMA – normocellular, no haemophagocytosis
>
> o   MRI brain: normal
>
> o   Abdominal USS: no hepatosplenomegaly
>
> o   Normal newborn hearing
>
> o   Commenced on 1mg/kg prednisolone x 3/7 then changed dexamethasone
> 10mg/m2
>
>
>
> ·         Fevers settled, however, despite therapy, ferritin elevated to
> 49,360
>
> o   sCD25 22,446 pg/mL
>
> o   anaemia, thrombocytopenia (stable)
>
> o   mildly deranged LFTs
>
> o   normal fibrinogen & lipids
>
> o   Repeat Abdominal USS: multiple splenic abscesses
>
>
>
> Investigations:
>
> -          Absent B cells (performed on 3 separate samples) on peripheral
> blood
>
> o   Normal subsets otherwise, normal naïve T cells
>
> o   BTK no mutation
>
> o   CD19+ present in first bone marrow aspirate
>
> -          Initially normal IgG (4.65 – RR 2.5-12), detectable IgM
> (0.29). undetectable IgA
>
> o   Since, IgG and IgM have risen above normal range.
>
> o   Highest result:
>
> §  IgG 12.4 (2.5-12)
>
> §  IgA 0.12 (0-0.53)
>
> §  IgM 13.6 (0.19-1.93)
>
> o   Protein electrophoresis:
>
> §  Monoclonal IgM (kappa) protein band detected, measuring 5g/L
>
> §  Repeat ~ 2/52 later: Known IgM protein band detected now co-migrating
> with an IgG (kappa) and measuring 6g/L in total.
>
> ·         Also detected IgM (lambda) band measuring 2g/L and an IgG
> (kappa) band measuring 2 g/L
>
>
>
> -          CSF: macrophages & lymphocytes. No haemophagocytosis
>
> -          Leishmaniasis serology negative
>
> -          Viral PCRs negative
>
> o   Blood: CMV/EBV/adeno/ HHV6 negative
>
> o   CSF/mouth/serum: HSV/VZV/CMV PCR negative
>
> o   CSF enterovirus negative
>
> -          Repeat BM – clotted sample but no evidence of haemophagocytosis
>
> -          Heel ulcer biopsy:
>
> o   fat necrosis, collagen necrosis & scarring without any significant
> inflammatory population. ? Non-infectious/non-inflammatory causes such as
> prolonged pressure or attempts at vascular access
>
> o   Negative enterovirus/HSV/mycobacterium PCR
>
> -          Genetics: NLRC4 no mutation identified
>
> -          Normal NK cell degranulation, perforin & SAP/XIAP (performed
> while on 2.5mg/m2 dexamethasone)
>
> -          V:B repertoire: polyclonal T cells
>
>
>
> Progress:
>
> -          Dexamethasone gradually weaned. 3/7 after weaned to 2.5mg/m2,
> developed profuse diarrhoea, poor feeding & irritability with
> thrombocytopenia and elevation in ferritin, sCD25 and LFTs.
>
> -          Dex increased back to 5mg/m2 with subsequent improvement
>
> -          Commenced on anakinra ~ 2mg/kg and Dex weaned to 2.5mg/m2.
>
> o   developed neutropenia and anakinra was held for 3 days (as this was
> thought to be the cause). 3 days after anakinra held, developed new onset
> fevers and became hypotensive & tachycardic, requiring multiple fluid
> boluses.
>
> §  LFT derangement worsened
>
> §  Ferritin elevated from 13000 to 39,000, sCD25 42,000
>
> o   Anakinra recommenced and dexamethasone again increased to 5mg/m2.
> Also covered with IV antibiotics over this time. Subsequent resolution
> within a few days.
>
> -          Dexamethasone since weaned gradually by 1mg/m2 per week.
> Currently on 2mg/m2 oral dexamethasone on same dose of anakinra. Stable
> tolerating full feeds.
>
>
>
>
>
> We have considered looking for known autoinflammatory conditions but the
> presentation is not classical. Therefore we are planning to proceed to WES
> but any further suggestions about diagnosis or further investigation would
> be appreciated!
>
>
>
> Has anyone seen this severity of presentation following maternal illness
> without identifiable cause in the infant?
>
>
>
> Thanks
>
>
>
> Theresa
>
>
>
>
>
> *Dr Theresa Cole BM PGDipPID PhD FRACP*
>
> Paediatric Immunologist Allergist
>
> Department of Allergy & Immunology
>
>
>
> The Royal Children's Hospital Melbourne
>
> 50 Flemington Road Parkville 3052 Victoria
>
> *T*: 03 9345 5701 *F*:03 9345 4848
>
> www.rch.org.au
>
>
>
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-- 
Prof. Anna Sediva, M.D., Ph.D.
Department of Immunology
2nd School of Medicine, Charles University
University Hospital Motol
V Uvalu 84
Prague, 15006
Czech Republic

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