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

[Sergio Rosenzweig]

Hi Silvia,
Did you check CASP8? We have a couple of patients that share some of the
characteristics of your patient who carry homozygous CASP8 mutations.
Sergio

Sergio D. Rosenzweig, MD, PhD
Chief, Infectious Diseases Susceptibility Unit
Laboratory of Host Defenses, NIAID, NIH
10 Center Dr., Bldg. 10, CRC 5W-3888
Bethesda, MD 20892-1456
Phone (301) 451 8971
Fax (301) 451 7901
Cell (240) 361 7617
Pager 102 10678
srosenzweig at niaid.nih.gov
 
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>>> Sanchez Ramon.Silvia  06/11/12 8:45 AM >>>

Thanks for your prompt reply. Vit B12 was normal-lower limit.
We haven't ruled out CGD. EBV negative, we ddin't think of XIAP.
No other T-cell alterations. Gamma-delta 3%.
CD25 expression normal.
I'll read Bodo's paper
best, Silvia
 
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


 
De: pagid-bounces at list.clinimmsoc.org
[pagid-bounces at list.clinimmsoc.org] En nombre de Dr. Carsten Speckmann
[carsten.speckmann at uniklinik-freiburg.de]
Enviado el: lunes, 11 de junio de 2012 14:11
Para: pagid at list.clinimmsoc.org
Asunto: Re: [CIS PIDD] ALPS versus CVID patient with progressing
lymphoproliferative syndrome



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:<!--P {MARGIN-TOP: 0px;
MARGIN-BOTTOM: 0px}-->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): negatNormal 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 SpeckmannFacharztZentrum fuer Kinderheilkunde und
JugendmedizinCentrum fuer Chronische Immundefizienz - CCI Universitaet
FreiburgMathildenstr. 179106 FreiburgGermanyphone: +49 (0)761-270
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"Este mensaje, o sus anexos, pueden contener información confidencial,
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el presente mensaje o en sus anexos debe estar previamente autorizada
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