[CIS PIDD] [cis-pidd] XLP and rituximab
CIS-PIDD
cis-pidd at lists.clinimmsoc.org
Fri Oct 20 10:30:44 EDT 2017
Dear colleagues,
We are the group caring for the patient Dr Verbsky mentioned -- 30 year old male patient who was referred to us for refractory IBD and problems with infections while immunosuppression was being attempt for it. He too was discovered via WES with a variant of unknown significance- but with follow up lack of XIAP expression and functional assay -- confirmed this was a pathogenic mutation. We are now dealing with what to do with him clinically. As Dr. Verbsky mentioned, he is EBV naive and no history of HLH. Per our GI dept, if he fails this last ustekinumab then likely we are facing the BMT work up route. We wanted to get some more opinions or experience with the issue of whether to put such a patient on rituximab (plus IGG in his case with history of infections with suppression) because of this issue if EBV?
Thank you
Shefali Samant, MD
Allergy/Immunology, faculty
Kaiser Permanente Southern California
Los Angeles Medical Center
1515 N Vermont Ave
Los Angeles, CA 90027
shefali.a.samant at kp.org
> On Oct 19, 2017, at 7:11 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org> wrote:
>
> Dear Dr Vinh,
>
> I agree with Michael Albert and James Verbsky: beside expression, it is essential to evaluate for XIAP function.
> In our cohort, we report on the variable disease spectrum (e.g. early onset XLP vs. later-onset Crohn vs. asymptomatic carriers: all in the same family). https://www.ncbi.nlm.nih.gov/pubmed/23973892
> In our supplemental data, we also show the limitation of protein expression assays: in our ongoing investigations we see that up to 10% of patients show normal protein expression, but do have impaired protein function) and may develop full disease. We also find the L18MDP test very helpful for the evaluation of XIAP function:
> https://www.ncbi.nlm.nih.gov/pubmed/24611904
> I think the problem with XIAP (as for many other rare PIDs) is our lack of longterm prospective naturally history data…(some of our reported asymptomatic carriers are still healthy, while other developed active disease over the years).
>
> BW Carsten
> --
> PD Dr. Carsten Speckmann
> Oberarzt
>
> UNIVERSITÄTSKLINIKUM FREIBURG
> Centrum für Chronische Immundefizienz
> Zentrum für Kinder- und Jugendmedizin
> Pädiatrische Hämatologie und Onkologie
>
> Mathildenstrasse 1 · 79106 Freiburg · Germany
> Telefon: +49 (0)761 270 43010
> Telefax: +49 (0)761 270 45990
> carsten.speckmann at uniklinik-freiburg.de
>
> https://www.uniklinik-freiburg.de/cci/
> https://www.uniklinik-freiburg.de/paed-haematologie.html
>
>
> Von: cis-pidd at lyris.dundee.net [mailto:cis-pidd at lyris.dundee.net] Im Auftrag von CIS-PIDD
> Gesendet: Donnerstag, 19. Oktober 2017 15:19
> An: CIS-PIDD
> Betreff: Re: [cis-pidd] XLP on screening
>
> Dear All:
>
> Thank you for your comments thus far; they have been insightful and stimulating.
>
> As suggested by all, protein detection will be performed (this is being organized as a send-out to a lab in the US).
> Presuming that the genetics analysis is correct, as Mikko reiterated, this is predicted to be a hemizygous stop-gain mutation in exon 2, and thus a profoundly truncated protein. Nonetheless, I will also recommend them to assess protein function.
> We will pursue the fecal studies and further phenotypic evaluation of the pedigree (I think this latter has already been done, but will ensure this, focusing on the broad presentations of XIAP deficiency).
>
> However, should the obvious occur (i.e. no resulting functional protein), I am intrigued by Dr. Albert's assessment of risk. When you say that he is "not very likely to have a fatal first disease manifestation", would you be able to send me any numbers/references on that risk? This is going to be important for discussions with family regarding management options (i.e. watch and wait vs. HSCT).
> As a corollary, Mikko: on a brief search, I could not find any reports on a genotype-phenotype, or more relevantly, cellular phenotype-clinical phenotype correlation of XIAP mutations. The reports I did find are the typical ones, of mutation identification in the context of active or recently-treated HLH, rather than as in this case, i.e. incidental finding.
>
> I think this also highlights the need that, for PIDs with broad manifestations, biomarkers (either genomics or proteomic, or other) are needed, to provide more precise care.
>
> Thanks again. Please continue to send your inputs, as I am collating them for the referring team.
>
> Best,
> Don
>
>
>
>
>
>
>
>
>
> Donald C. Vinh, MD, FRCP(C)
> Director, Infectious Disease Susceptibility Program
> Lilian Wilkins Associate Professor, FRQS Clinician-Scientist
> Dept of Medicine (Division of Infectious Diseases; Division of Allergy & Clinical Immunology)
> Dept of Medical Microbiology; Dept of Human Genetics
>
> McGill University Health Centre - Research Institute
> 1001 Decarie Blvd; Block E; Rm EM3-3230 (Mail Drop: EM3-3211)
> Montreal, Quebec, Canada H4A 3J1
>
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>
>
> From: cis-pidd at lyris.dundee.net <cis-pidd at lyris.dundee.net> on behalf of CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
> Sent: October 19, 2017 8:20 AM
> To: CIS-PIDD
> Subject: AW: [cis-pidd] XLP on screening
>
> This really is an interesting one. I would definitely also do the XIAP expression (which can be normal in some affected individuals) plus functional testing. And I would test calprotectin in his stool to screen for gut inflammation, which may still be subclinical.
> And I would screen the male relatives on the maternal side. There may be other asymptomatic or not quite so asymptomatic individuals. There may be uncles or cousins with “Crohns disease” or “severe acne” or unexplained splenomegaly or funny autoimmunity…
> As for HSCT, I am close to Elies position. But in a three year old, I would also feel fine to maybe wait a little. He is not very likely to have a fatal first disease manifestation especially if he is seen by a doctor every time he develops a fever, so if he develops gut disease, he’d still be a good HSCT candidate. Enough time to get to know the family and their perspective, look for the best donor….
> BR
> Michael
>
> _______________________________________________
>
> Prof. Dr. med. Michael Albert
> Oberarzt
> Abteilung für Pädiatrische Hämatologie/Onkologie
> Leiter der Stammzelltransplantation
> Dr. von Haunersches Kinderspital der LMU
> Lindwurmstr.4
> 80337 München
> Tel: 089 4400 52785
> Fax: 089 4400 54819
>
>
> Michael Albert, MD
> Professor
> Department of Pediatric Hematology/Oncology
> Head SCT Program
> Dr. von Haunersches Children's Hospital
> Lindwurmstr.4
> 80337 Munich
> Germany
> Tel: +49 89 4400 52785
> Fax: +49 89 4400 54819
>
>
>
>
> Von: cis-pidd at lyris.dundee.net [mailto:cis-pidd at lyris.dundee.net] Im Auftrag von CIS-PIDD
> Gesendet: Donnerstag, 19. Oktober 2017 03:43
> An: CIS-PIDD
> Betreff: Re: [cis-pidd] XLP on screening
>
> Hi
>
> if I got it correctly, this boy has an early truncating mutation in a large X-encoded gene (54.000+ bp gene with 9 exons)..... not much function at all to be expected??? And he is still EBV neg at age 3.
>
> Like Don and Kate, I am worried, symptoms yet or not.
>
> Don, you probably went through the literature, previous reports on early truncating mutations and disease course when EBV hits?
>
> ATB
>
> Mikko
>
> Oyl Mikko Seppänen
> Harvinaissairauksien yksikkö (HAKE)
>
> Head, Rare Disease Center,
> Helsinki University Hospital (HUH)
> FINLAND
>
> phone +358 947180201
> GSM +358 50 4279606
> fax +358 9 47174703
>
> CIS-PIDD <cis-pidd at lists.clinimmsoc.org> kirjoitti 19.10.2017 kello 1.29:
> Hmmm….very interesting debate indeed. I would not be so affirmative on the rule of non transplanting an asymptomatic child. There are many other situations (HLH for example) in which we transplant asymptomatic patients when discovered by screening for an index case as sibling for example.
> I agree with XiAP expression as well as MAIT counts, and if these tests appeared to be abnormal, I would go for a transplant. If the tests are normal…. well I don’t know but you would not need to push me very hard to transplant.
> Elie
>
>
> Elie Haddad, MD, PhD,
> Professor of Pediatrics, University of Montreal,
> Head, Pediatric Immunology and Rheumatology Division,
> e-mail: elie.haddad at umontreal.ca
>
>
>
>
>
> Le 2017-10-18 à 18:14, CIS-PIDD <cis-pidd at lists.clinimmsoc.org> a écrit :
>
> Burkitt like lymphoma and SH2D1A mutation make sense for transplant, but an asymptomatic child with an unknown XIAP variant doesn't. Even if it was a known pathologic mutation, I don't think we would recommend transplant yet. You could look for XIAP protein expression by flow and if normal, unlikely this is pathologic. This is a bit hard to comprehend or rather explain, but we need to stick to the science - these assays should not be used as screening tools.
> Ashish
> Ashish Kumar, MD, PhD
> Associate Professor
> Director, Pediatric Hematology-oncology fellowship program
> Director, Langerhans cell histiocytosis center
> Cincinnati Children's Hospital Medical Center
>
> On Oct 18, 2017, at 4:53 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org> wrote:
> We just had a scarily similar case…
>
> Patient had WES for developmental delay. He came into the seen when the (in his case SH2D1A) mutation was found. Upon arrival- he had adenopathy and it turned out to be a Burkitts like lymphoma.
>
> I think they can do bad things in unpredictable ways and a three year old is more resilient for a transplant than an older kiddo/adult.
>
>
> Kate
> Sullivan, Kathleen MD PhD
> Wallace Chair
> Chief of Allergy Immunology
> ARC 1216 CHOP
> 3615 Civic Center Blvd.
> Philadelphia, PA 19104
> (p) 215-590-1697
> (f) 267-426-0363
> sullivank at email.chop.edu
>
>
>
> On Oct 18, 2017, at 4:47 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org> wrote:
>
> Dear All:
>
> I was consulted on the following case and would appreciate your input:
>
> A 3 year old male, with a family history of Adams-Olivier syndrome, underwent screening when he was a newborn by whole-genome sequencing in what appears to be an accredited diagnostic laboratory in the U.S. (I do not have further details... I think he was screened because of the potential neuro-developmental delays associated with this disorder; he did not have any of the associated malformations).
>
> While he did not have any mutations in genes associated with the targeted syndrome, he was found to have a variant in XIAP (NM_001167; c.340C>T; p.Gln114*). This is obviously predicted to be deleterious.
>
> He is asymptomatic, including no GI symptoms.
> He has been treated with IVIG, as prophylaxis against EBV. He has no hypo/dys-gammaglobulinemia (prior to starting IVIG at around 2 years of age).
>
> Given the broad presentations of XIAP deficiency, what recommendations would you make? Specifically, would you recommend going to HSCT ASAP?
>
> Thanks,
> Don
>
>
>
>
>
> Donald C. Vinh, MD, FRCP(C)
> Director, Infectious Disease Susceptibility Program
> Lilian Wilkins Associate Professor, FRQS Clinician-Scientist
> Dept of Medicine (Division of Infectious Diseases; Division of Allergy & Clinical Immunology)
> Dept of Medical Microbiology; Dept of Human Genetics
>
> McGill University Health Centre - Research Institute
> 1001 Decarie Blvd; Block E; Rm EM3-3230 (Mail Drop: EM3-3211)
> Montreal, Quebec, Canada H4A 3J1
>
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