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

[CIS-PIDD]

Dear Theresa,
although I don't have an answer, I would like to respond because I am concerned with the course and lacking diagnosis of an Austrian patient now 1 year old with exactly the same phenotype. Most strikingly, congenital B cell hypo-/aplasia, hypogamma, recurring fever since neonatal period, duration of 1-3 days, interval of 2-5 days, flares recently linked to recurring parotits and erythematous edema of the scalp, previously sometimes associated with erythema nodosum or periorbital edema or otherwise asymptotic.
Steroids and anakinra are only partially/ moderately successful and, similar to your patient, led to pancytopenia. Other findings were hepatosplenomegaly, no invasive infections yet. Ig-substituion has been paused for 3 months without drop of Ig levels or occurrence of infections.
We also thought of SIFD, but the anemia is more likely due to chronic inflammation. Bone marrow normal; Btk, SAP, XIAP expression were normal, NK degranulation normal, and an ngs-PID panel of >300 genes revealed a variety of heterozygous mutations not really sounding causal. Trnt1 normal. From agamma-PIDs, AIS, to atypical HLH, many differential diagnoses were pursued. I am currently taking metabolic diseases into the DD.
Would appreciate any input.
Thanks for initiating this topic.
Kind regards from Austria,
Markus Seidel

Priv.-Doz. Dr. Markus G. Seidel | Päd. Häm. Onk. | Med. Univ. Graz | Auenbruggerpl. 38, A-8036 Graz, Austria | Tel +4331638512621 | Fax +4331638513717 | Secr +4331638513485 | Bitte keine dringenden Patienteninformationen per Email | sent from my mobile phone | please excuse typos

Am 24.11.2015 um 10:17 schrieb CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>:

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<http://www.rch.org.au>

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