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

[CIS-PIDD]

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
Telefax: +49 (0)761 270-77744
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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