[CIS PIDD] [cis-pidd] Heterozygous RAG1 mutation, isolated CD4 lymphopenia, warts and bone marrow hypoplasia

Wed Feb 15 02:59:16 EST 2017

Dear Boaz,

interesting case! The hypoplastic marrow with lymphocyte infiltrations sounds like an immune mediated process (autoimmunity against the marrow?). We sometimes see that in a post transplant setting as a sort of GvHD or in late onset leukopenia/neutropenia. Although the differential with MDS might be very tricky. Did the patient get osteomedullary biopsy? Any other hints from history when he was younger (ITP/other signs of autoimmunity beyond thyroditis/infections…)? 
I agree with Rob that the marrow should be investigated more closely to understand if it is a primary or secondary problem. I wonder if a trial of immunesuppression will help, however it sounds tricky given his CD4penia and recurrent warts.
I will be happy to discuss more if you like.

Best 
Eleonora 

——————————————————————————————————————
Eleonora Gambineri, MD
Researcher/Assistant Professor

Department of "NEUROFARBA": Section of Child's Health
University of Florence 

Department of Haematology-Oncology: BMT Unit
"Anna Meyer" Children's Hospital

Viale Gaetano Pieraccini,24
50139 FIRENZE
ITALY
Tel +39 055 5662405 (office)/055 5662738(BMT ward)
Fax +39 055 4221012
e-mail: eleonora.gambineri at unifi.it; e.gambineri at meyer.it
——————————————————————————————————————

> On 14 Feb 2017, at 22:04, CIS-PIDD <cis-pidd at lists.clinimmsoc.org> wrote:
> 
> The marrow description sounds dysplastic. In order to formally meet criteria for MDS in the WHO 2008 categorization, at least 10% of cells need to be dysplastic. The report clearly says that this is not the case for the erythroid series, and does not mention if this is or is not the case for the myeloid series. The recent revision of the WHO categorization does not discuss this 10% threshold, so this may not be that helpful. Of more concern is the finding of micromegakaryocytes, which is rare in cases of non-clonal cytopenia (leukemia  <>(2015) 66 – 75). Even if he has MDS, his revised prognostic score would be low and not indicate transplant, although that score was calculated from more typical MDS patients with a median age of 71. The prognosis and management for a young man with a similar score are less well-defined.
>  
> The marrow description is similar to a picture that Fabio Candotti and I described a few years ago in ADA-SCID, in that it is hypoplastic for age, micromegakaryocytes are found and there is dysgranulopoiesis (Blood, 2011 Sep 8; 118(10): 2688–2694). Another clue in that setting is frequent tri-lobed eosinophils. Normal eos can have three lobes, but they are relatively more frequent in smears from patient with ADA deficiency. Also, autoimmune thyroid disease is one of the more common autoimmunities in ADA deficiency. The presentation is clearly not classic for ADA-SCID, but it is also not classic for RAG deficiency. The assay for ADA deficiency is cheap in the USA, where it is done by Mike Hershfield at Duke. The groups at Great Ormond Street in the UK and at San Raffaele in Milan also have used this assay.
>  
> I agree that the upfront mortality of transplant in the setting of mild disease is daunting, but that this patient’s hematologic picture is likely to progress.  These considerations would not change even if he has ADA deficiency or RAG deficiency, because of the atypical presentation. I think that it is worth pursuing those diagnoses, but ultimately the decision to transplant will rest on the clinical progression of his hematologic disease, as Kate and Gigi noted. Clinically, the best thing for him may be close hematology follow-up with frequent review of peripheral blood and marrow smears. If over the next several years, the patient can be more definitely said to have MDS, then that would inform the transplant decision. If his abnormal marrow is very stable for a few years, then it might be reasonable to evaluate it less frequently.
>  
>  
>  
>  
>  
>  
> --
> Rob Sokolic, MD
> Medical Officer      
> 
> Center for Biologics Evaluation and Research
> Office of Tissues and Advanced Therapies
> U.S. Food and Drug Administration
> Tel: 240-402-5564
> Robert.Sokolic at fda.hhs.gov <mailto:Robert.Sokolic at fda.hhs.gov>
> <image001.png> <http://www.fda.gov/>
> 
> <image002.jpg> <https://www.facebook.com/FDA>  <image003.jpg> <https://twitter.com/US_FDA>  <image004.jpg> <http://www.youtube.com/user/USFoodandDrugAdmin>  <image005.jpg> <http://www.flickr.com/photos/fdaphotos/>  <image006.jpg> <http://www.fda.gov/AboutFDA/ContactFDA/StayInformed/RSSFeeds/default.htm>
>  
> The above transmission is meant solely for the addressee. The information contained in this message may be of a private, medical, privileged or industrial nature, and may not be communicated beyond the initial recipient. If you are not the intended recipient of this message or the agent of such recipient, please destroy all physical copies of this message, delete all electronic copies and notify the sender of the error.
>  
> This communication does not constitute a written advisory opinion under 21 CFR 10.85, but rather is an informal communication under 21 CFR 10.85(k) which represents my best judgment at this time, but does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed. 
>  
>  
> From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org <mailto:cis-pidd at lists.clinimmsoc.org>] 
> Sent: Tuesday, February 14, 2017 2:50 PM
> To: CIS-PIDD
> Subject: Re: [cis-pidd] Heterozygous RAG1 mutation, isolated CD4 lymphopenia, warts and bone marrow hypoplasia
>  
> Thanks everybody for your precious inputs
>  
> Regarding the warts: I will definitely look into topical cidofovir... looks very promising!
>  
> Bone marrow biopsy: Hypocellular (20-30% cellularity), hyperplastic erythroid line with diserythropoiesis phenomena, dysplasia in <10% of elements. maturation delay of granulopoiesis with prevalence of hyposegmented forms (cd34+ blasts <5%). Micromegakaryocytes. Normal hemosiderin deposits, normal reticular fibers. Presence of lymphoid infiltrates of small T and B lymphocytes.
> Traditional cytogenetics and MDS FISH panel are both negative. 
>  
> BMT: we already typed him, as GATA2 suspicion was high. At this point he has been in follow-up for two years by the hematology dept. and the progression seems very slow. We hoped a genetic diagnosis could hint to prognosis (and thus help regarding BMT choice and timing). However balancing BMT indication between
> - late-onset and clinically mild disease at this time, BMT risks and...
> - losing the windows of opportunity due to severe infections or hematological disease progression
> is daunting!
>  
> I'll keep you posted,
> Kind regards,
> Boaz
>  
>  
> On Tue, Feb 14, 2017 at 2:57 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org <mailto:cis-pidd at lists.clinimmsoc.org>> wrote:
> Agree with Kate that his marrow will likely get worse over time. Would at least type patient and potential donors. Any signs of dysplasia in bone marrow? Would send MDS FISH panel and conventional cytogenetics if not done with molecular studies. <>
> R
>  
>  
> --
> Rob Sokolic, MD
> Medical Officer      
> 
> Center for Biologics Evaluation and Research
> Office of Tissues and Advanced Therapies
> U.S. Food and Drug Administration
> Tel: 240-402-5564 <tel:(240)%20402-5564>
> Robert.Sokolic at fda.hhs.gov <mailto:Robert.Sokolic at fda.hhs.gov>
> <image001.png> <http://www.fda.gov/>
> 
> <image002.jpg> <https://www.facebook.com/FDA>  <image003.jpg> <https://twitter.com/US_FDA>  <image004.jpg> <http://www.youtube.com/user/USFoodandDrugAdmin>  <image005.jpg> <http://www.flickr.com/photos/fdaphotos/>  <image006.jpg> <http://www.fda.gov/AboutFDA/ContactFDA/StayInformed/RSSFeeds/default.htm>
>  
> The above transmission is meant solely for the addressee. The information contained in this message may be of a private, medical, privileged or industrial nature, and may not be communicated beyond the initial recipient. If you are not the intended recipient of this message or the agent of such recipient, please destroy all physical copies of this message, delete all electronic copies and notify the sender of the error.
>  
> This communication does not constitute a written advisory opinion under 21 CFR 10.85, but rather is an informal communication under 21 CFR 10.85(k) which represents my best judgment at this time, but does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed. 
>  
>  
> From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org <mailto:cis-pidd at lists.clinimmsoc.org>] 
> Sent: Tuesday, February 14, 2017 6:32 AM
> To: CIS-PIDD
> Subject: Re: [cis-pidd] Heterozygous RAG1 mutation, isolated CD4 lymphopenia, warts and bone marrow hypoplasia
>  
> Agree, but if recombination activity of that mutant is 100%, then you rule out RAG as a problem. We have found several cases where RAG genetic variants have been published and attributed a disease causing effect, whereas in fact they behave absolutely like wild-type RAG1 9and indeed several of these are reported at relatively high frequency in ExAC).
>  
> I also agree with Kate that sometimes you don't find a gene, and yet a decision must be taken!
>  
> Gigi Notarangelo
>  
> From: CIS-PIDD <cis-pidd at lists.clinimmsoc.org <mailto:cis-pidd at lists.clinimmsoc.org>>
> Reply-To: CIS-PIDD <cis-pidd at lyris.dundee.net <mailto:cis-pidd at lyris.dundee.net>>
> Date: Tuesday, February 14, 2017 at 6:28 AM
> To: CIS-PIDD <cis-pidd at lyris.dundee.net <mailto:cis-pidd at lyris.dundee.net>>
> Subject: Re: [cis-pidd] Heterozygous RAG1 mutation, isolated CD4 lymphopenia, warts and bone marrow hypoplasia
>  
> Even with RAG functional testing, it still leaves the fact that this is heterozygous so there must be an enhancer/regulatory/splice site defect on the other allele for this to be meaningful.
>  
>  
> I guess the question is about management and one possible answer would be BMT.  At 23y, his window of opportunity will only get smaller.
>  
> I wanted to post to just get on my soapbox to say that you don’t always need a gene.  We know WES misses a fair bit and while BMT may or may not be the right answer for this specific patient, I want to just say that we shouldn’t let our gene search and desire for mutations and other technical aspects let us delay therapy.  I know that wasn’t what was intended in the responses but it seemed like a good opportunity to say this important message again.
>  
> For warts specifically- we LOVE topical cidofovir.  Every expensive and often need to partner with other therapies but we LOVE it.
>  
> Kate
>  
>  
>  
> Kate Sullivan, MD PhD
> Wallace Chair 
> Chief of Allergy Immunology
> ARC 1216 CHOP
> 3615 Civic Center Blvd.
> Philadelphia, PA 19104
> (p) 215-590-1697 <tel:(215)%20590-1697>
> (f) 267-426-0363 <tel:(267)%20426-0363>
>  
> 
>  
> On Feb 14, 2017, at 6:06 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org <mailto:cis-pidd at lists.clinimmsoc.org>> wrote:
>  
> We have tested (and extensively published) on the recombination activity of more than 90 RAG1 genetic variants. Send me the specifics of the mutation and I may be able to tell you whether it is functionally relevant. No patient samples are needed for this.
>  
> Luigi D Notarangelo
> Laboratory of Host Defenses
> National Institute of Allergy and Infectious Diseases
> National Institutes of Health
> Bldg 10 CRC, room 5-3950
> 10 Center Drive
> Bethesda, MD 20817
> USA
> Luigi.notarangelo2 at nih.gov <mailto:Luigi.notarangelo2 at nih.gov>
> 
> Sent from my iPhone
> 
> On Feb 14, 2017, at 6:01 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org <mailto:cis-pidd at lists.clinimmsoc.org>> wrote:
> 
> Dear Boaz, 
>  
> Ad 3: Please contact Klaus Schwarz (cc), he will need fibroblasts to perform the assay. 
>  
> Best wishes, St.
>  
>  
> UNIVERSITÄTSKLINIKUM FREIBURG
> Sektion Pädiatrische Immunologie (CCI)
> Zentrum für Kinder- und Jugendmedizin
>  
> Prof. Dr. Stephan Ehl
> Medizinischer Direktor CCI
>  
> Breisacher Straße 115 · 79106 Freiburg
> Telefon: +49 (0)761 270-77300 <tel:+49%20761%2027077300>
> Telefax: +49 (0)761 270-77744 <tel:+49%20761%2027077744>
> stephan.ehl at uniklinik-freiburg.de <mailto:stephan.ehl at uniklinik-freiburg.de>
>  
> www.uniklinik-freiburg.de <http://www.uniklinik-freiburg.de/>
> www.uniklinik-freiburg.de/cci <http://www.uniklinik-freiburg.de/cci>
>  
> Von: CIS-PIDD <cis-pidd at lists.clinimmsoc.org <mailto:cis-pidd at lists.clinimmsoc.org>>
> Antworten an: CIS-PIDD <cis-pidd at lyris.dundee.net <mailto:cis-pidd at lyris.dundee.net>>
> Datum: Dienstag, 14. Februar 2017 um 11:19
> An: CIS-PIDD <cis-pidd at lyris.dundee.net <mailto:cis-pidd at lyris.dundee.net>>
> Betreff: [cis-pidd] Heterozygous RAG1 mutation, isolated CD4 lymphopenia, warts and bone marrow hypoplasia
>  
> Dear all, 
>  
> We are evaluating a 23yo male with idiopathic CD4 lymphopenia (~150-200 T CD4) clinically he presented with:
> - generalized verrucosis (since age 16)
> - slowly progressive signs of bone marrow hypoplasia: macrocytic anemia (Hb ~11, MCV 100), thrombocytopenia (Plt ~100.000), normal neutrophils. Hypoplastic bone marrow, with lymphoid infiltrates. No molecular abnormalities in the BM. 
> - autoimmune thyroiditis
> - vitiligo (as Koebner phenomenon around the warts)
> - otherwise healthy, without history of infections in spite of the lymphopenia
>  
> Normal Ig, with slightly elevated IgE
> IgM 0.6 g/L
> IgA 1.05 g/L
> IgG 10.2 g/L
> IgE 394
>  
> Lymphopenia, mainly CD4 with reduced naive compartment, inverted CD4/8 ratio and elevated T g/d lymphocytes. 
> Lymphocytes 820
> T CD4 170
> T CD8 326
> T GD 159
> B 60
> NK 28
> T CD4 Naive (CD45RA+/CCR7+) 4.9%
> T CD4 TEM (CD45RA-/CCR7-) 67.5 %
> T CD4 TCM (CD45RA-/CCR7+) 24 %
> T CD4 TEMRA (CD45RA+/CCR7-) 3.50%
>  
> Reduced TREC, normal KREC
>  
> High titer ANA antibodies (>1:640, SP pattern), + anti-Pm/Scl antibodies
> Anti-TPO antibodies and anti-TG antibodies
>  
> WES found an unreported heterozygous RAG1 mutation, in an highly conserved area of the Zn binding domain, predicted to be damaging. 
>  
> My questions:
>  
> 1) How to manage the warts? They are resistant to topical therapies and relapse after surgical excision. Furthermore an high risk HPV strain was isolated, rising serious concerns about cancerous evolution. Interferon was proposed as an option, but we are worried about autoimmune manifestations. Does anyone have any experiences? 
>  
> 2) Have you ever seen this bone marrow picture with RAG mutations?
>  
> 3) Is there someone (possibly in Italy or Europe) who can evaluate the recombinase activity, to confirm the mutation relevance?
>  
> Sorry for the lenghty email, and thanks in advance,
> Kind regards,
>  
> Dr. Boaz Palterer
> Dept. of Clinical and Experimental Medicine
> Allergology and Clinical Immunology
> University of Florence, Italy
> cell. +39 3927169114 <tel:+39%20392%20716%209114>
> email. boaz.palterer at gmail.com <mailto:boaz.palterer at gmail.com>
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