[CIS PIDD] [MARKETING][cis-pidd] Refractory thrombocytopaenia, splenomegaly and high IgM
CIS-PIDD
cis-pidd at lists.clinimmsoc.org
Mon Feb 29 01:47:58 EST 2016
Hi Michael,
In our experience, splenomegaly already at the time of first episode of ITP/AIHA often points to a developing PID,.
My first thoughts:
Besides classic ALPS genes, I would definitely consider:
- PIK3CD/PIK3R1: she has high IgM, lymphadenopathy and splenomegaly, progressive B cell loss, sMBs are rather low (IgG2?)
- STAT3 GOF and LRBA are options among the less classical ALPS-like diseases as well, maybe even CTLA4
- could even be “normal” CVID in the making…
I would thus initially choose an mTOR inhibitor, if PIK3CD, also P110δ inhibitors (GS--‐1101, IC87114), if LRBA / CTLA4, CTLA4-Ig fusion protein might eventually reverse the tide?
Hope this helps,
Mikko
oyl Mikko Seppänen
Harvinaissairauksien yksikkö (HAKE), HUS
Mikko Seppänen, MD, PhD, Associate professor
Specialist in Internal Medicine and Infectious Diseases
Head, Rare Disease Center, Helsinki University Hospital (HUH)
Children’s Hospital, P.O.Box 280
FI-00029 HUS
FINLAND
&
Senior Consultant (PIDD)
Adult Immunodeficiency Unit
Inflammation Center, HUH
phone +358 9 47180201
GSM +358 50 4279606
fax +358 9 47174703
Lähettäjä: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Lähetetty: 29. helmikuuta 2016 5:42
Vastaanottaja: CIS-PIDD
Aihe: [MARKETING][cis-pidd] Refractory thrombocytopaenia, splenomegaly and high IgM
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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