[CIS PIDD] [MARKETING]Re: [cis-pidd] Refractory thrombocytopaenia, splenomegaly and high IgM
CIS-PIDD
cis-pidd at lists.clinimmsoc.org
Mon Feb 29 05:02:15 EST 2016
Just a note:
Stephan and I seem to agree on a potential diagnosis: APDS type I= PIK3CD (APDS type II = PIK3R1).
Especially if naïve T cells low and TEM, TEMRA hi, these would support together with the progressive loss of B cells.
However the ddg is broad, like Markus notes:
" any (pseudo-)hyper-IgM and alps/cvid-like syndrome"
Let us know what - if anything - you eventually find.
ATB,
Mikko
-----Alkuperäinen viesti-----
Lähettäjä: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Lähetetty: 29. helmikuuta 2016 11:43
Vastaanottaja: CIS-PIDD
Aihe: [MARKETING]Re: [cis-pidd] Refractory thrombocytopaenia, splenomegaly and high IgM
Thank you all for your replies.
Markus, she has metabolically active axillary, para-aortic, external iliac and inguinofemoral lymph nodes on PET scan although the nodes were not enlarged, and appearance on PET scan were stable when repeated 1 month later. We have not measured alphe-fetoprotein or checked for cold agglutinins (she has had a negative direct Coombs test). She has responded to varicella and rubella vaccination, pneumococcal IgG2 antibodies are 7mg/L (has not been vaccinated since receiving her primary course of pneumococcal conjugate vaccine as an infant), tetanus antibodies pending. There was occasional haemophagocytosis seen in lymph node but not in bone marrow, and ferritin is at the lower end of normal range. We haven't investigated for leishmaniasis, and I'll ask the family specifically about history of malignancy.
Clinically there are no signs of autoimmunity or inflammation and the only significant abnormalities on examination are the large spleen and bruising. ESR remains high with normal CRP. The patient feels very well and would have continued playing football regularly if the haematologists had not recommended she stop while her platelet count is so low.
Mikko, the genetic testing available locally will allow us to include your helpful suggestions, and I'll check her IgG subclasses.
Stephan, we haven't assessed naive/memory and T cell activation yet but it is planned for this week when she returns for a repeat PET scan.
Kind regards,
Michael
On 29/02/2016, CIS-PIDD <cis-pidd at lists.clinimmsoc.org> wrote:
> Naive CD4? APDS?
> SE
>
>
>
> Beste Grüße
>
> Prof. Dr. Stephan Ehl
> Medizinischer Direktor
>
> UNIVERSITÄTSKLINIKUM FREIBURG
> CCI - Center for Chronic Immunodeficiency
>
> Breisacher Str. 117 - 2. OG, 79106 Freiburg i. Brsg., Germany
> phone: +49(0)761.270-77300
> Sekretariat +49(0)761.270-77550 fax +49(0)761.270-77600
> e-mail:
> stephan.ehl at uniklinik-freiburg.de<mailto:stephan.ehl at uniklinik-freibur
> g.de>
>
> Von: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
> Gesendet: Montag, 29. Februar 2016 09:40
> An: CIS-PIDD
> Betreff: Re: [cis-pidd] Refractory thrombocytopaenia, splenomegaly and
> high IgM
>
> Dear Michael, another idea,
> Was leishmania infection and hemophagocytosis excluded? Probably she
> would be more ill, though. Did you check ferritin and sIL2R?
>
> Univ.-Prof. 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 29.02.2016 um 04:42 schrieb CIS-PIDD
> <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>:
>
> Dear all,
>
>
>
> We are seeing a patient in Perth, Western Australia, together with our
> haematology colleagues who has refractory thrombocytopaenia and
> splenomegaly. She is a 10 year old girl, no significant past medical
> history prior to this episode. Dad (part Japanese and born in
> Australia), mum (Romanian) and a 7 year old brother are all well. No
> family history of autoimmune, lymphoproliferative or immunodeficiency
> diseases. She has received routine childhood vaccinations without adverse reactions.
>
>
>
> She had a systemic illness in September 2015 lasting 5 days with high
> fevers and generalised aches. About 1-2 weeks later, Mum noticed
> increased bruising with blood tests confirming thrombocytopaenia
> (platelet count 2 x 10^9/L).
>
>
>
> On initial review in November 2015, the patient felt well with no
> weight loss, fevers or sweats. She had petechiae and ecchymoses with
> marked firm splenomegaly ~10cm below costal margin.
>
>
>
> Initial investigations
>
> Full blood picture - normocytic anaemia (Hb 10g/dL), mild neutropaenia
> 1.1 x 10^9/L, lymphocytes 1.9 x 10^9, a few atypical lymphocytes on
> blood film suggestive of viral infection
>
> Ferritin 39mcg/L (normal 20-100), transferrin saturation slightly low
> at 10%. Normal Vitamin B12 (540pmol/L)
>
> Normal UEC, liver function and LDH
>
> EBV and CMV IgG and IgM negative
>
> IgG 10.6, IgA 0.5, IgM 16.3 g/L, no paraprotein
>
> C3 is slightly low at 0.69g/L, normal C4 0.29g/L
>
> ESR 70mm/hr, CRP normal
>
> Raised lambda > kappa serum free light chains (ratio of kappa:lambda
> borderline low).
>
> Negative ANA, dsDNA, lupus anticoagulant, rheumatoid factor.
>
> Weak positive IgM anti-cardiolipin, moderate IgA B2GPI; negative IgG
> aCL and B2GPI.
>
>
>
>
>
> Lympohcyte immunophenotyping on 2 occasions:
>
>
>
> CD3 (T cells) 84 82 % (58-76)
> *
>
> CD4 (CD4+ T cells) 54 53 % (30-52)
> *
>
> CD8 (CD8+ T cells) 24 23 % (18-40)
>
>
>
> CD4/8 Ratio 2.25 2.30 (0.70-2.60)
>
>
>
> CD19 (B cells) 9 5 % (11-27)
> *
>
> CD16/56 (NK cells) 7 13 % (5-19)
>
>
>
> CD3 Absolute Count 1008 1558 x10 ^6 /L (900-2500)
>
> CD4 Absolute Count 648 1007 x10 ^6 /L (500-1400)
>
> CD8 Absolute Count 288 437 x10 ^6 /L (400-1300)
> *
>
> CD19 Absolute Count 108 95 x10 ^6 /L (200-500)
> *
>
> CD16/56 Absolute Count 72 228 x10 ^6 /L (100-500)
>
>
>
> GATED ON CD19+ B CELLS:
>
>
>
> Naive B (IgD+CD27-) 89.4 %
> (49.0-100.0)
>
> MZL Mem B (IgD+CD27+) 9.2 % (2.0-28.0)
>
> CD27+ Sw Mem B (IgD-CD27+) 1.1 % (1.0-43.0)
>
> CD27- Sw Mem B (IgD-CD27-) 0.3 % (3.0-10.0)
>
>
>
>
>
> Bone marrow was hypercellular with increased numbers of
> morphologically normal megakaryocytes and normal haemopoiesis. There
> was no evidence of infiltration. Cytogenetics: normal (X;X).
>
>
>
> Treated with high dose IVIg (2g/kg) with no response.
>
>
>
> PET scan (December 2015): diffuse moderate metabolic activity in
> spleen associated with some lymphadenopathy.
>
> Axillary lymph node excision: Reactive hyperplasia. No evidence of
> lymphoma or Castleman's disease.
>
> No clonal B or aberrant T cell population on flow cytometry of the node.
>
>
>
> Received IV methylprednisolone x 3 doses in January 2015 with no rise
> in platelet count.
>
>
>
> Repeat lymphocyte immunophenotyping in January and February 2016,
> including TCR studies on double negative T cells
>
>
>
> Lymphocytes 2.3 1.7 x10 ^9 /L (1.5-7.0)
>
>
>
> CD3 (T cells) 84 82 % (58-76)
> *
>
> CD4 (CD4+ T cells) 55 57 % (30-52)
> *
>
> CD8 (CD8+ T cells) 23 19 % (18-40)
>
>
>
> CD4/8 Ratio 2.39 2.95 (0.70-2.60)
> *
>
>
>
> CD19 (B cells) 6 5 % (11-27)
> *
>
> CD16/56 (NK cells) 10 12 % (5-19)
>
>
>
> CD3 Absolute Count 1932 1394 x10 ^6 /L (900-2500)
>
> CD4 Absolute Count 1265 952 x10 ^6 /L (500-1400)
>
> CD8 Absolute Count 529 323 x10 ^6 /L (400-1300)
> *
>
> CD19 Absolute Count 138 85 x10 ^6 /L (200-500)
> *
>
> CD16/56 Absolute Count 230 204 x10 ^6 /L (100-500)
>
>
>
> CD3+CD4-CD8- T-cells = 7.7%
>
> TCR as a % of CD3+ cells:
>
> CD3+CD4-CD8-TCR Alpha/Beta =4.6%
>
> CD3+CD4-CD8-TCR Gamma/Delta=2.9%
>
> TCR as a % of Lymphocytes:
>
> CD3+CD4-CD8-TCR Alpha/Beta =3.5%
>
> CD3+CD4-CD8-TCR Gamma/Delta=2.2%
>
>
>
>
>
> The patient remains well, aside from thrombocytopaenia and bruising.
> Her spleen is still enlarged, IgM now 21.8 g/L, platelets remain low
> (3 x 10^9/L). EBV and CMV IgM and IgG were negative in both November
> and February. HHV6 IgG was positive with negative IgM in November, and
> on repeat in February HHV6 IgM and IgG were both positive.
>
>
>
> We will arrange sequencing of FAS, FASL, FADD, CASP8 and CASP10
> (despite the normal vitamin B12), and were planning a trial of
> sirolimus in advance of a definitive diagnosis based on the
> encouraging results from recent publications in ALPS and other refractory cytopaenias.
>
>
>
> I'd appreciate any recommendations the group may have on further
> investigations or treatment options, particularly if you would suggest
> considering an alternative to sirolimus?
>
>
>
> Kind regards,
>
> Michael
>
>
>
>
>
> Michael O'Sullivan | Consultant | Immunology
>
> Fiona Stanley Hospital
>
> Level 1, Pathology, 102-118 Murdoch Drive, MURDOCH WA 6150
>
> T: (08) 6152 8006<tel:%2808%29%206152%208006> | F: (08) 6152
> 8051<tel:%2808%29%206152%208051>
>
>
>
> Princess Margaret Hospital
>
> Roberts Road, SUBIACO WA 6008
>
> T: (08) 9340 8310<tel:%2808%29%209340%208310> | F: (08) 9380
> 6246<tel:%2808%29%209380%206246>
>
> E:
> michael.o'sullivan at health.wa.gov.au<mailto:first.last at health.wa.gov.au
> >
>
> www.health.wa.gov.au<http://www.health.wa.gov.au/>
>
> Delivering a Healthy WA
>
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