[CIS PIDD] ALPS versus CVID patient with progressing lymphoproliferative syndrome

[Bodo Grimbacher]

I agree re LRBA and would accept this patient for testing.
Please send me an Email to:
b.grimbacher at ucl.ac.uk
if interested.
Yours, Bodo

Am 11.06.12 14:11 schrieb "Dr. Carsten Speckmann" unter
<carsten.speckmann at uniklinik-freiburg.de>:


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>    To me the disease sounds "too aggressive" for ALPS.

>    I would not overinterpret the DNT count. Biomarker prolife? (e.g.

>    Vitamin B12 elevated?)

>    Did you rule out XIAP (e.g. by flow) and CGD (by DHR) in this boy

>    with Crohn`s disease?

>    He has B lymphopenia. Besides CD8 Lymphopenia any other T cell

>    abnormalities / signs for CID?

>    low naives, impaired proliferation, g/d TCR expansion? -  RAG?

>    Radiosensitivity? (see Rohr et al. 2010 "Chronic inflammatory bowel

>    disease as key manifestation of atypical ARTEMIS deficiency")

>    CD25 expression?

>    Bodo Grimbacher very recently described LRBA deficiency - a PID with

>    childhood onset hypogamma (and in some with severe enteropathy)

>    - if none of the other DD seem likely (WB screening is available).

>    

>    Carsten

>    

>    Am 11.06.12 13:46, schrieb Sanchez Ramon.Silvia:

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>      Dear colleagues,

>       

>      we are taking care of a 15-yo boy followed by Digestive

>            Dept. since 2007 for Crohn disease (biopsy not conclusive),

>            and axillary polyadenopathies. Past medical history of

>            atopic dermatitis and chronic migraines, negative for

>            recurrent infections. He was referred in 2011 to us due to

>            splenomegaly, multiple laterocervical adenopathies and

>            hypogammaglobulinemia (IgG: 343 mg/dL; IgA 30 mg/dL and IgM:

>            28.6 mg/dL). He was clinically well.

>            At that time he showed lymphopenia B of 3%, with low

>            switched-memory B cells of 3%; very low CD8+ T lymphocytes

>            of 3%. Low baseline Ab titers to TT and pneumococcal Ag (he

>            was on steroids 56 mg po/d for IBD). His WBC have been

>            stable around 2000-2500/uL with moderate neutropenia of

>            600-700/uL; Lymphos 3,300/μL. The remaining series are

>            normal (Hb: 12.8 g/dL Hematocrit 37.1 %; platelets: 135

>            10E3/μL ).

>            

>            Normal expression of ZAP70 on T lymphocytes; normal HLA

>            class I and II; IL-2, IL-7 and  IFNγ receptors expression.

>            Noted to have 6% double negative T cells (CD3+CD4-CD8-)

>            alpha-beta; Gamma-delta cells 3%.  No other features of

>            ALPS. He was given IVIg replacement therapy, with suspicion

>            of CVID (TACI mutation was negative) versus ALPS.

>      

>            Other investigations

>            Coeliac disease screening: negative. Other autoantibodies

>            (ANA, ENA, ANCA): negative. Normal complement. Normal TSH,

>            T4L. Direct Coombs negative.

>            

>            Normal serum biochemistries. Ferritin, vit.B12, folate: all

>            normal.

>            Extensive viral/bacterial investigations, including:

>            Serologies to CMV, EBV, toxoplasma, HB, HC, HIV1-2,

>            bartonella, parvovirus negative. Repeated negative PCR for

>            CMV and VEB.

>             

>            In the last months the latero-cervical enlarged lymph nodes

>            with approx 5 cm diameter, and splenomegaly (of 15 cm).

>            Several cervical lymph nodes biopsies have shown lymphoid

>            hyperplasia suggesting unspecific lymphoproliferative

>            disorder, with high proliferative rate (Ki67), without

>            necrosis areas or granulomas, without evidence of malignity

>            and EBV (IHC and ISH) negative. There is a predominance of

>            CD4 T cells, disperse B cells of probable follicular origin

>            (CD20/CD79a/Bcl6+) and TFh (PD1+) cells. No Reed-Sternberg

>            cells or non-haematopoietic neoplastic cells. PCR study: IgH

>            gene: (FR1/JH): polyclonal (FR2/JH): polyclonal (FR3/JH):

>            polyclonal. TCR-gamma (VJ-A) gene: polyclonal (VJ-B):

>            polyclonal.

>             

>            Bone marrow biopsy: normocellular BM parenchyma (3/5),

>            without madurative changes. Multifocal mature

>            lymphohistiocytic aggregates and interstitial lymphocytosis

>            of predominantly CD4+ T cells (IHC). No blast cell

>            aggregates, parasites, fungi, viral cytopathic inclusions,

>            siderosis, mielofibrosis (except on the lymphohistiocytic

>            nodules), or bone alterations were observed. No

>            non-haematopoietic neoplastic infiltrates were observed.

>            

>            Cervical ultrasound: bilateral intraparotideal,

>            yugulodigastric and laterocervical adenopathies, more

>            evident at the right side.

>             Thoracoabdominal CT: Thoracic and abdominopelvic

>            adenopathies, some of them of 4.5 and 3.2 cm diameter,

>            bilateral lung nodules and hepatosplenomegaly.

>            PET-scan: multiple bilateral laterocervical, thoracic,

>            abdominopelvic lymphadenopathies, and  multiple bone and

>            bilateral lung nodules compatible with the diagnosis of

>            lymphoproliferative syndrome.

>             

>            Given the suspected ALP syndrome with multiple

>            lymphadenopathies, therapy with Sirolimus (3.7 mg/24 h po

>            after initial charge dosis) was started in Jan 2012. He

>            showed a significant improvement of adenopathies and

>            recovery of neutropenia, with no secondary effects.

>            He started with lumbalgia in January 2012. MRI disclosed a

>            vertebral L4 body lesion with extension to intervertebral

>            foramina L3-L4 and L4-L5. Biopsies showed non-caseating

>            granulomas. PCR panfungal: negative. Parasites and

>            mycobacteria: negative. PCR Universal 16S rARN negative. PCR

>            Bartonella sp. neg. PCR Aspergillus sp. neg. PCR Panfungal

>            negative. PCR CMV <100 copies/mL. Hemocultures,

>            coprocultures x3, nasopharyngeal cultures all negatives.

>            Negative quantiferon. At the Oncohematology Unit the patient

>            was then given one cycle of chemotherapy, with COP

>            (ciclophosphamide 400 mg/m2 1 dosis, vincristine 1.5mg/m2

>            and prednisone 60 mg/m2 X7 days.

>            

>            Despite of this, a new MRI shows paravertebral and epidural

>            mass with soft-tissue extension and increased signal in T1

>            and turbo stir. New sacral and lumbar bone lesions. The

>            radiological image suggests progression of the

>            lymphoproliferative disorder versus metastatic lesions.

>             

>            He’s on prophylactic Bactrim, IVIg and sirolimus, and

>            tapering doses of prednisone. Currently ongoing: study of

>            caspase 8 and 10, and Fas/FasL mutations.

>            

>            We are concerned about the clinical course of this young

>            patient and on the best management for him, since we still

>            have no definitive diagnosis.

>            

>            1. What other treatment possibilities? Thoughts on

>            chemotherapy?

>            2. What other tests or diagnoses would you consider?

>            

>            Thanks so much in advance for your help.

>            

>            Best regards,

>            

>            Dra. Dolores Gurbindo, Section of Immunopediatrics

>            Dra. Silvia Sánchez-Ramón, Unit of Clinical

>            Immunology

>            

>          Silvia

>            SÁNCHEZ-RAMÓN, MD, PhD

>            Unidad de Inmunología Clínica

>            Departamento de Inmunología

>            Hospital General Universitario Gregorio Marañón

>            Calle Doctor Esquerdo, 46

>            E- 28007 - Madrid, Spain

>            Tel: +34 914265181

>            FAX: +34 915868018

>            E-mail: ssanchez.hgugm at salud.madrid.org

>      

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>      

>    

>

>    

>    

>    -- 

>Dr. med. Carsten Speckmann

>Facharzt

>Zentrum fuer Kinderheilkunde und Jugendmedizin

>Centrum fuer Chronische Immundefizienz - CCI

>Universitaet Freiburg

>Mathildenstr. 1

>79106 Freiburg

>Germany

>

>phone: +49 (0)761-270 43010

>mail: carsten.speckmann at uniklinik-freiburg.de

>web: www.cci.uniklinik-freiburg.de <http://www.cci.uniklinik-freiburg.de>

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