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

Tue Feb 14 14:49:35 EST 2017

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>
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 <(240)%20402-5564>
> Robert.Sokolic at fda.hhs.gov
>
> [image: cid:image001.png at 01D1C57E.DFA022A0] <http://www.fda.gov/>
>
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>
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>
> The above transmission is meant solely for the addressee. The information
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> 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]
> *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>
> *Reply-To: *CIS-PIDD <cis-pidd at lyris.dundee.net>
> *Date: *Tuesday, February 14, 2017 at 6:28 AM
> *To: *CIS-PIDD <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 <(215)%20590-1697>
> (f) 267-426-0363 <(267)%20426-0363>
>
>
>
>
>
> On Feb 14, 2017, at 6:06 AM, CIS-PIDD <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
>
> Sent from my iPhone
>
>
> On Feb 14, 2017, at 6:01 AM, CIS-PIDD <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 <+49%20761%2027077300>
> Telefax: +49 (0)761 270-77744 <+49%20761%2027077744>
> stephan.ehl at uniklinik-freiburg.de
>
> www.uniklinik-freiburg.de
> www.uniklinik-freiburg.de/cci
>
>
>
> *Von: *CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
> *Antworten an: *CIS-PIDD <cis-pidd at lyris.dundee.net>
> *Datum: *Dienstag, 14. Februar 2017 um 11:19
> *An: *CIS-PIDD <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 <+39%20392%20716%209114>
>
> email. boaz.palterer at gmail.com
>
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