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

[Dr. Carsten Speckmann]

  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

>

>

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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


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