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

[Kumar, Ashish]

The lack of NKT cells is not universal in these disorders. See this publication

http://www.ncbi.nlm.nih.gov/pubmed/19398375

-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Seppänen Mikko
Sent: Tuesday, June 12, 2012 1:17 AM
To: 'pagid at list.clinimmsoc.org'
Subject: Re: [CIS PIDD] ALPS versus CVID patient with progressing lymphoproliferative syndrome

Dear Silvia,

great consultation, great replies, just a small hint: considering SH2D1A-, XIAP- and ITK-mutations, possibly all(?) of them lack NKT cells, these in turn would be quite easy to check. Has anyone seen any of these with any NKTs?

This clinical presentation is quite a "common" scenario in children and in young adult CVIDs-patients in Finland as well, and as one can see from replies, it is getting more and more complex genetically and therapeutically, really would call for a comprehensive review of the subject in the literature?? 

mikko

__________________________________________________
Mikko Seppänen, MD, PhD, Docent (Associate professor/Senior Lecturer) Specialist in Internal Medicine and Infectious Diseases Senior Consultant, Physician in charge (PIDD) EM(E)A Expert, PIDDs and Intravenous Immunoglobulin Therapy

Immunodeficiency Unit
Division of Infectious Diseases
Department of Medicine
Helsinki University Central Hospital
Hospital District of Helsinki and Uusimaa Aurora Hospital, Ward 4-2 and Outpatient Clinic P.O.Box 348
FI-00029 HUS, Helsinki
FINLAND
phone +358 9 47175923, fax +358 9 47175945 _________________________________________


-----Alkuperäinen viesti-----
Lähettäjä: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] Puolesta Sanchez Ramon.Silvia
Lähetetty: 11. kesäkuuta 2012 17:47
Vastaanottaja: pagid at list.clinimmsoc.org
Aihe: Re: [CIS PIDD] ALPS versus CVID patient with progressing lymphoproliferative syndrome

Thanks Sergio,
We are still waiting results of CASP8.
Also XIAP as proposed by Carsten and Ashish is a good idea.
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 Sergio Rosenzweig [srosenzweig at garrahan.gov.ar] Enviado el: lunes, 11 de junio de 2012 15:24
Para: pagid at list.clinimmsoc.org
Asunto: Re: [CIS PIDD] ALPS versus CVID patient with progressing lymphoproliferative syndrome

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:

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<mailto:ssanchez.hgugm at salud.madrid.org>

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"Este mensaje, o sus anexos, pueden contener información confidencial, en especial datos de carácter personal, y se dirigen exclusivamente al destinatario del mismo que está obligado al secreto profesional respecto de la información y los datos contenidos en el mensaje. Si usted lo ha recibido por error, por favor, comuníquenoslo por este medio y proceda a destruirlo o borrarlo, y en todo caso absténgase de utilizar, reproducir, alterar, archivar o comunicar a terceros el presente mensaje y/o ficheros anexos, pudiendo incurrir, en caso de llevar a cabo tales acciones, en responsabilidades legales. En cualquier caso, la reproducción o comunicación a terceros de la información contenida en el presente mensaje o en sus anexos debe estar previamente autorizada por el emisor. El emisor no garantiza la integridad, rapidez o seguridad del presente correo, ni se responsabiliza de posibles perjuicios derivados de la captura, incorporaciones de virus o cualesquiera otras manipulaciones efectuadas por terceros."

"Este mensaje, o sus anexos, pueden contener información confidencial, en especial datos de carácter personal, y se dirigen exclusivamente al destinatario del mismo que está obligado al secreto profesional respecto de la información y los datos contenidos en el mensaje. Si usted lo ha recibido por error, por favor, comuníquenoslo por este medio y proceda a destruirlo o borrarlo, y en todo caso absténgase de utilizar, reproducir, alterar, archivar o comunicar a terceros el presente mensaje y/o ficheros anexos, pudiendo incurrir, en caso de llevar a cabo tales acciones, en responsabilidades legales. En cualquier caso, la reproducción o comunicación a terceros de la información contenida en el presente mensaje o en sus anexos debe estar previamente autorizada por el emisor. El emisor no garantiza la integridad, rapidez o seguridad del presente correo, ni se responsabiliza de posibles perjuicios derivados de la captura, incorporaciones de virus o cualesquiera otras manipulaciones efectuadas por terceros."