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

Wed Mar 29 21:47:35 EDT 2017

For the sake of completeness, I would also consider bone marrow failure
syndromes.  Have you done telomeres?  Cincinnati and Blueprint genetics
have good inherited bone marrow failure syndrome panels with some PID
overlap and includes TERT, TERC etc.  I'm sure there are similar panels
available somewhere in Europe.

He could be an evolving MDS.  I have a couple of patients who have normal
cytogenetics and only mildly dysplastic marrows that I am just following
for now.  They don't have the low CD4 counts or autoimmune features
though.  Chances are he will declare himself over time.

Regarding transplant and MDS, we frequently transplant young patients with
MDS but generally only those with a definitive diagnosis of MDS and usually
RAEB 1 or 2 subtypes as we know they are going to progress to AML.

Jen

Jennifer Grossman  MD, FRCPC
Hematologist
Division of Hematology and Hematologic Malignancies
Alberta Health Services, Calgary Zone
Rm 681 Foothills Medical Centre
1403- 29th Street NW
Calgary, Alberta  T2N 2T9
Phone: 403-944-1564   Fax: 403-944-2102

On Wed, Feb 15, 2017 at 1:38 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
wrote:

> Dear Boaz (and Colleagues),
>
> Do you know if the WES was done in an unbiased manner? I ask because the
> commercial labs and even some academic ones use algorithms to select
> genetic variants, which rely on a priori knowledge of diseases and the
> genes involved. This has led to many cases being missed. You all might
> recall a discussion on this forum 2-3 years ago regarding a couple CVID
> patients who developed marrow failure caused by lymphoid aggregates in
> their bone marrows. We had one such patient who we finally transplanted and
> she is doing great. We performed trio-WES and it came back negative. In
> fact, the genetic counselor wrote in the result that the condition is
> likely acquired, not germline (the patient was 24). After last year's CIS
> meeting and prompted by a positive result in a similar patient, I asked our
> genetics lab to go back look at CECR1 (ADA2) in our index patient and they
> found her to be compound-heterozygous for 2 previously described mutations.
>
> Ashish
> Ashish Kumar, MD, PhD
> Associate Professor of Pediatrics
> Director, Langerhans Cell Histiocytosis Center
> Director, Pediatric Hematology/Oncology Fellowship Program
> Cincinnati Children's
> 3333 Burnet Avenue, , Cincinnati, OH 45229
>
>
>
>
> -----Original Message-----
> From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
> Sent: Wednesday, February 15, 2017 3:45 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
>
> Dr. Palterer:
>
> With the autoimmune thyroiditis and marrow suppression, I would suggest it
> may be worth it to check serology and blood PCR's for parvovirus B19.  If
> positive, IVIG may buy some time.  Would not explain the flipped CD4:CD8
> ratio, though ...
>
> I agree with Dr. Sullivan on topical cidofovir for the cutaneous
> verrucosis.
>
>   - Karl
>
> Karl O. A. Yu, M.D., Ph.D., F.A.A.P.
> Section of Infectious Diseases  |  Department of Pediatrics  |  Comer
> Children's Hospital  |  University of Chicago
> 5841 S Maryland Ave,  MC 6054,  Chicago  IL  60637 Office phone:
> 773-702-9281  |  Pager: 773-702-6800 x1744  |  Fax: 773-702-1196
>
> ________________________________________
> From: CIS-PIDD [cis-pidd at lists.clinimmsoc.org]
> Sent: Wednesday, February 15, 2017 1:59 AM
> To: CIS-PIDD
> Subject: Re: [cis-pidd] Heterozygous RAG1 mutation, isolated CD4
> lymphopenia, warts and bone marrow hypoplasia
>
> 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<mailto:eleonora.gambineri at unifi.it>;
> e.gambineri at meyer.it<mailto:e.gambineri at meyer.it>
> --------------------------------------
>
> On 14 Feb 2017, at 22:04, CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:
> 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><https://urldefense.proofpoint.com/v2/
> url?u=http-3A__www.fda.gov_&d=DwIF-g&c=P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_
> iO9LJTHr-vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_
> EYgZpKSuu_6rZc&s=-oEE_sytL20CJYcmnFJtzv1BXNVPh2ecu2xmKMRCxgY&e= >
>
> <image002.jpg><https://urldefense.proofpoint.com/v2/
> url?u=https-3A__www.facebook.com_FDA&d=DwIF-g&c=
> P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=
> kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_EYgZpKSuu_6rZc&s=
> 6rylGT6680buUfaLFCFHDfyCkboBV-9Z1eR0tygqqlo&e= >  <image003.jpg><https://
> urldefense.proofpoint.com/v2/url?u=https-3A__twitter.com_
> US-5FFDA&d=DwIF-g&c=P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-
> vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_
> EYgZpKSuu_6rZc&s=f0sqLC3v01f0SkZpMTjnLw-1DpFME-8RypIh9EYmIrs&e= >
> <image004.jpg><https://urldefense.proofpoint.com/v2/
> url?u=http-3A__www.youtube.com_user_USFoodandDrugAdmin&d=DwIF-g&c=
> P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=
> kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_EYgZpKSuu_6rZc&s=
> 0FzloRNN4zCYyNzz0UK62vOT9rdXkuW3k3OEsUBb9uk&e= >  <image005.jpg><https://
> urldefense.proofpoint.com/v2/url?u=http-3A__www.flickr.com_
> photos_fdaphotos_&d=DwIF-g&c=P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-
> vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_
> EYgZpKSuu_6rZc&s=QHXN3ykzAOKHdQHr2hZ1ikYRkWp-c4K_lKPr9bpKDbk&e= >
> <image006.jpg><https://urldefense.proofpoint.com/v2/
> url?u=http-3A__www.fda.gov_AboutFDA_ContactFDA_
> StayInformed_RSSFeeds_default.htm&d=DwIF-g&c=
> P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=
> kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_EYgZpKSuu_6rZc&s=iJq0ybzOkZcrJdm_-O8PwLKWB_
> u345RKla7jiEwdj4A&e= >
>
> 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]
> 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><https://urldefense.proofpoint.com/v2/
> url?u=http-3A__www.fda.gov_&d=DwIF-g&c=P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_
> iO9LJTHr-vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_
> EYgZpKSuu_6rZc&s=-oEE_sytL20CJYcmnFJtzv1BXNVPh2ecu2xmKMRCxgY&e= >
>
> <image002.jpg><https://urldefense.proofpoint.com/v2/
> url?u=https-3A__www.facebook.com_FDA&d=DwIF-g&c=
> P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=
> kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_EYgZpKSuu_6rZc&s=
> 6rylGT6680buUfaLFCFHDfyCkboBV-9Z1eR0tygqqlo&e= >  <image003.jpg><https://
> urldefense.proofpoint.com/v2/url?u=https-3A__twitter.com_
> US-5FFDA&d=DwIF-g&c=P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-
> vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_
> EYgZpKSuu_6rZc&s=f0sqLC3v01f0SkZpMTjnLw-1DpFME-8RypIh9EYmIrs&e= >
> <image004.jpg><https://urldefense.proofpoint.com/v2/
> url?u=http-3A__www.youtube.com_user_USFoodandDrugAdmin&d=DwIF-g&c=
> P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=
> kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_EYgZpKSuu_6rZc&s=
> 0FzloRNN4zCYyNzz0UK62vOT9rdXkuW3k3OEsUBb9uk&e= >  <image005.jpg><https://
> urldefense.proofpoint.com/v2/url?u=http-3A__www.flickr.com_
> photos_fdaphotos_&d=DwIF-g&c=P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-
> vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_
> EYgZpKSuu_6rZc&s=QHXN3ykzAOKHdQHr2hZ1ikYRkWp-c4K_lKPr9bpKDbk&e= >
> <image006.jpg><https://urldefense.proofpoint.com/v2/
> url?u=http-3A__www.fda.gov_AboutFDA_ContactFDA_
> StayInformed_RSSFeeds_default.htm&d=DwIF-g&c=
> P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=
> kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_EYgZpKSuu_6rZc&s=iJq0ybzOkZcrJdm_-O8PwLKWB_
> u345RKla7jiEwdj4A&e= >
>
> 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<https://urldefense.proofpoint.com/
> v2/url?u=http-3A__www.uniklinik-2Dfreiburg.de_&d=DwIF-g&c=
> P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=
> kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_EYgZpKSuu_6rZc&s=ThBrqtFvWOPUYlc5l94ZHyUCU7-
> 8HbO1HrLXLdrk75c&e= > www.uniklinik-freiburg.de/cci<
> https://urldefense.proofpoint.com/v2/url?u=http-3A__www.
> uniklinik-2Dfreiburg.de_cci&d=DwIF-g&c=P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_
> iO9LJTHr-vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_
> EYgZpKSuu_6rZc&s=Jx6hOcROOGbKNnoERL3LpVqA18G2VwBv_KPilUsDy5o&e= >
>
> 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>
> ---
>
> ---
> You are currently subscribed to cis-pidd as: ashish.kumar at cchmc.org.
> To unsubscribe click here: https://urldefense.proofpoint.
> com/v2/url?u=http-3A__cts.dundee.net_u-3Fid-3D96396410.
> 80d0426a8f030c7d59f25e5e3c6ac047-26n-3DT-26l-3Dcis-2Dpidd-
> 26o-3D4193677&d=DwIF-g&c=P0c35rBvlN7D8BNx7kSJTg&r=7_Xi_iO9LJTHr-
> vy99jYOfSlhgVB29ez3xj6iG4Kpn0&m=kDDLZTy36ZKzhLuYP8p9AkpeUmeZ_
> EYgZpKSuu_6rZc&s=k0mR0UE73iZHxNkHhOu48bxP51X663PDzSiXf4B6_Nk&e=
> or send a blank email to leave-4193677-96396410.
> 80d0426a8f030c7d59f25e5e3c6ac047 at lyris.dundee.net
>
>
> ---
> You are currently subscribed to cis-pidd as: jkgrossman2 at gmail.com.
> To unsubscribe click here: http://cts.dundee.net/u?id=96396675.
> 7bddb5dbb2a8f30f1e32a0eda2e295ac&n=T&l=cis-pidd&o=4195000
> or send a blank email to leave-4195000-96396675.
> 7bddb5dbb2a8f30f1e32a0eda2e295ac at lyris.dundee.net
>

---
You are currently subscribed to cis-pidd as: pagid at list.clinimmsoc.org.
To unsubscribe click here: http://cts.dundee.net/u?id=96396833.5a9591ccd1e327fe6bc4d1543298c482&n=T&l=cis-pidd&o=4294796
or send a blank email to leave-4294796-96396833.5a9591ccd1e327fe6bc4d1543298c482 at lyris.dundee.net
-------------- next part --------------
An HTML attachment was scrubbed...
URL: <https://pairlist7.pair.net/pipermail/pagid/attachments/20170329/606961a3/attachment-0001.html>