[CIS PIDD] [cis-pidd] AW: Patient with a gain of function mutation in CARD11 (Benta disease) and acute liver failure despite liver transplantation

Sat Oct 21 11:30:26 EDT 2017

Dear Simon,

My lab has been studying a cohort of ~15 BENTA patients for several years.
To my knowledge we have not seen abnormal liver function in any patients.
AutoAbs/autoimmune sequelae are also rare, likely due to intrinsic B cell
differentiation defects and perhaps impaired T cell help. One patient with
extremely high B cell lymphocytosis after splenectomy (~60-90,000/ul) was
treated with methotrexate for 4 years out of concern for hyperviscosity,
which did reduce his B cell count substantially. Rituximab was also used
successfully in this patient (during acute EBV infection) and at least one
other I know of. My collaborator at NIH, Helen Su, sees many of these
patients regularly in the clinic and may have more insights.

I would be curious to know where the GOF mutation is in CARD11, if you can
divulge?

Best,
Andy

-- 
Andrew L. Snow, Ph.D.
Associate Professor
Department of Pharmacology & Molecular Therapeutics
Uniformed Services University of the Health Sciences
4301 Jones Bridge Rd., Room C-2013
Bethesda, MD 20814

ph: 301-295-3267
andrew.snow at usuhs.edu

On Sat, Oct 21, 2017 at 2:12 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
wrote:

> Dear Simon,
>
>
>
> in *CARD11* GOF we recently had some promising reduction of splenomegaly
> associated with MMF treatment. However, I feel that in this desperate
> situation rapamycine could be an option, because CARD11 is not only
> signaling via NF-kB but as well via the mTORCs. Nevertheless, the
> lymphocyte depletion strategie with ATG and the plasmapheresis already done
> seem more potent to me.
>
>
>
> Best regards, Fabian
>
>
>
>
>
> *Fabian Hauck, MD, PhD*
>
>
>
> Head Immunodeficiency Unit and Immunological Diagnostics Laboratoy
> Pediatrics / Pediatric Hematology and Oncology / Immunology (DGfI)
>
>
>
> *Dr. von Hauner Children’s Hospital*
> Klinikum der Universität München
> Lindwurmstr. 4, 80337 München
>
> Germany
>
>
>
> Tel.: +49 89 4400-53931 <+49%2089%20440053931>
>
> Fax: +49 89 4400-53964
> E-Mail: *fabian.hauck at med.uni-muenchen.de
> <fabian.hauck at med.uni-muenchen.de>*
>
>
>
>
>
> www.klinikum.uni-muenchen.de
>
>
>
> [image: cid:image001.png at 01D088A4.85EC62E0]
>
>
>
> Das Klinikum der Universität München ist eine Anstalt des öffentlichen
> Rechts (AöR)
>
> The Klinikum der Universität München is an Institution under Public Law
>
>
>
>
>
>
>
> *Von:* cis-pidd at lyris.dundee.net [mailto:cis-pidd at lyris.dundee.net] *Im
> Auftrag von *CIS-PIDD
> *Gesendet:* Freitag, 20. Oktober 2017 18:47
> *An:* CIS-PIDD
> *Betreff:* [cis-pidd] Patient with a gain of function mutation in CARD11
> (Benta disease) and acute liver failure despite liver transplantation
>
>
>
> Dear Colleagues,
>
>
>
> Advice and ideas that might help with the following case would be highly
> appreciated:
>
>
>
> A 30 year old woman with a gain of function mutation in Card11 (Benta
> disease) had a increased frequency of upper respiratory infections but was
> until recently otherwise well. She had a greatly increased number of naive
> B cells (1547 cells/µl), reduced switched memory B cells, reduced IgG and
> IgA with normal IgM and normal vaccine responses. She had mild
> thrombocytopenia, a slightly increased spleen and and ALT was mildly
> increased (55 U/l). About 1 1/2 years ago she was started on monthly Ivig
> replacement therapy and tolerated it well and she delivered a healthy child
> last December.  About  8 weeks ago her transaminases started to rise, went
> into the high thousands and within 2 weeks she developed liver failure. The
> cause of the original liver disease is still unclear. She was negative for
> hepatitis A-E, CMV, EBV, HSV, and the result of a biopsy were not very
> helpful: compatible with autoimmunhepatitis or virus hepatitis with a mixed
> infiltrate of B cells, T cells (both without clonality, and no dominance of
> B cells) and histiocytes – EBV in the biopsy was negative. She had taken no
> other medication besides the pill and immunoglobulins and the pathologist
> said the picture would not fit to a toxic liver damage. Under the
> hypothesis of an autoimmunhepatitis she was treated with steroids and in
> the end for a short time with the combination of MMF and steroids but did
> not improve under this therapy.
>
>
>
> She was HU listed and got liver transplanted. She was immunosuppressed
> with the standard protocol of our center with steroids and Tacrolimus (an
> mTor-Inhibitor was discussed but due to concerns about wound healing
> dismissed) . In the first days after transplantation the transaminases and
> INR recovered but on day 6 within hours went sky high again. The transplant
> team claimed that there was no vascular reason for the destruction of the
> transplant. A biopsy revealed again no clear answer to the cause of the
> organ destruction and the pathologist suggested reperfusion injury - which
> the transplant team due to the time course thought was highly unlikely.
> Within a couple of days she lost the transplant - was relisted and got a
> second organ 7 days ago. This time the transplant team was more worried
> about immunactivation/rejection so she was treated with rituximab, several
> times with ATG, got plasmaphareses 6 times and her Immunglobulin–levels
> were monitored more closely and with ivig treatment the level held
> constantly above 8 g/l.  She is covered with antibiotics and antifungals
> and again received Tacrolimus. Now after a period of recovery the
> transaminases start to rise again and the team is afraid to also loose the
> next organ.
>
>
>
> Now we have a patient that is already highly immunosuppressed - might have
> an infection (PCT was high in the last days but decreased slowly) and/or
> again an autoimmune reaction to her transplanted organ.
>
>
>
> Has anybody else experienced liver disease in a patient with Card11
> mutations? Or other NF-Kb activating diseases?  What do you think could be
> done for this patient?
>
>
>
> An mTor inhibitor? High dose ivIG? An NFK-b Inhibitor (Bortezomib?)…. Any
> suggestions?
>
>
>
> BR
>
>
>
> Simon
>
>
>
> Prof. Dr. Simon Rothenfusser
>
> Immundefekt-Ambulanz für Erwachsene („AIDA“)
>
> Medizinische Klinik IV
>
> Klinikum der Ludwigs-Maximilian Universität
>
> Pettenkoferstraße 8a, 80336 München
> <https://maps.google.com/?q=Pettenkoferstra%C3%9Fe+8a,+80336+M%C3%BCnchen&entry=gmail&source=g>
>
>
>
> E-mail: Simon.rothenfusser at med.uni-muenchen.de
>
>
>
>
>
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