[CIS PIDD] [cis-pidd] Severe lymphadenopathy and chronic enteritis

Seppänen Mikko Mikko.Seppanen at hus.fi
Tue Oct 28 11:26:58 EDT 2014 

Agree with Josh, 

our 3rd patient with STAT3 GOF (see Haapaniemi E et al, not yet in PubMed but can be found from Blood First Edition already) does actually nowadays have low level chronic EBV viremia (L Kainulainen, oral communication), though the impact of it to her clinical disease at this stage is questionable. 
Enteropathy and hypogamma found in all our patients, as are otherwise rare organ-specific autoimmune diseases (IPEX-like), while NIH/Josh's cohort resembles ALPS more than ours (but like we have noted ours have features of it as well). So his cohort is more like Your patient

Other alternatives might - thinking of hypogamma + EO-diarrhea- include for example LRBA, IL21/R def? 

Mikko

Mikko Seppänen, Finland

________________________________________
Lähettäjä: Milner, Joshua D. (NIH/NIAID) [E] [jdmilner at niaid.nih.gov]
Lähetetty: 28. lokakuuta 2014 16:50
Vastaanottaja: CIS-PIDD
Aihe: Re: [cis-pidd] Severe lymphadenopathy and chronic enteritis

Pere some elements of this history are consistent with gain-of-function STAT3 mutations just described in Nat Genetics (Flanagan et al), Blood (Haapeniemi et al) and one in press from several groups.
 Several of the patients in our cohort had early-onset chronic autoimmune enteropathy along with lymphoproliferative disease, as well as low antibody levels. We have noticed significant heterogeneity including minimally affected and asymptomatic carriers when probands were substantially affected. EBV viremia has not been a major feature but with the other suspects rule out it should be considered. If it turns out to be GOF STAT3, treatments varied, but steroids were effective many of the enteritis cases. MMF and rituximab were also used. Two patients with bad enteritis were transplanted (one survived). One might also consider anti-IL6 therapy, which was used successfully for a patient with refractory polyarthritis.

Josh


Joshua D. Milner, MD Chief, Genetics and Pathogenesis of Allergy Section
Laboratory of Allergic Diseases, NIAID, NIH
NIH Building 10-CRC Room 5-3950
Bethesda, MD  20892
Lab phone: 301 827 3662
Fax: 301 480 8384
jdmilner at niaid.nih.gov
http://www.niaid.nih.gov/labsandresources/labs/aboutlabs/lad/allergicinflammation/Pages/milner.aspx

From: Pere Soler Palacin <psoler at vhebron.net<mailto:psoler at vhebron.net>>
Reply-To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
Date: Tuesday, October 28, 2014 10:26 AM
To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
Subject: [cis-pidd] Severe lymphadenopathy and chronic enteritis



Dear colleagues, we'd really appreciate your thoughts about this tough case we are currently facing since we are in an impasse and the patient is severely ill. Currently, the main problem is persistent diarrhoea and malnutrition. Any suggestions would be highly appreciated, including possible therapies to improve the enteritis.

He is a 13 year-old male patient with uncontrolled persistent recurrent benign B-cell lymphoproliferation associated with chronic EBV infection since early infancy that needed repeated courses of rituximab with good but transient response and uncontrolled diarrhoea in the last 4 months.

Family history:

Caucasian. No consanguinity. Mother with coeliac disease

Medical history

-Since 18months of age, the patient presents recurrent and severe episodes oflymphadenopathies both peripheral and profound, and splenomegaly with persistent EBV viraemia that did not respond to antiviral therapy (only transient responses were observed) and finally, partially responded to repeated courses of rituximab (see pictures in the attached document). EBV viraemia remains negative since the last course of RTX (2013).

- He has never developed haemophagocytosis.

- Normal liver function throughout all the episodes.

- No persistent fever.

- No other infections.

-       No autoimmune manifestations.

-       No endocrine disorders.



-    Failure to thrive due to persistent diarrhoea with elevated faecal calprotectin. He was on gluten free diet since 8 years of age, and after 9 months of a gluten free diet the intestinal biopsy showed no improvement. Budesonide was no effective (no clinical or pathological improvement). Bowel biopsy (July 2013): A moderate amount of villi with a shortened length were observed. The lamina propria contains an inflamatory cellular infiltrate, predominately lymphoplasmacytic. Using a CD3 immunohistochemical technique a percentage of 27% lymphocytes within the epithelial cells was calculated. These lymphocytes coexpress CD3+ and CD8+.

 - Immunological tests

  *   Undetectable IgA + high IgM + low limit IgG. Periodic IVIG therapy restored IgG levels to normal although high doses needed.
  *   Lymphocyte subsets: CD3: 79.45 (3.58 10E9/L), CD3+CD4+: 12.55 (0.56 10E9/L), CD3+CD8+: 65.68 (2.68 10E9/L), INDEX CD4/CD8 0.19, CD19: 0.88 (0.04 10E9/L), CD56+CD16+: 18.36 (0.83 10E9/L),  TCR alpha/beta on DNT cells: 1%
  *   Proliferation assays: Low proliferation with PHA, normal with anti-CD3.
  *   IgE= 0 UI/ml, Vitamin B12= 583 ng/ml:
  *   FOXP3 and CD25 expression: Normal.
  *   CD40 and CD40L expression: Normal.
  *   Neutrophil burst assay: Normal.
  *   Mild decrease in intracellular SH2DA1.
  *   High perforin expression in CD8+.

 Genetic tests:

  *   No mutations in SAP, XIAP, FAS, ITK and MAGT1 genes.
  *   CD27 expression in CD3+: normal (no assessable in B cells due to several courses of rituximab).
  *   PKCd and Coronin 1 not tested.



 Best regards from BCN,

Pere Soler Palacín, MD, PhD.
Pediatric Infectious Diseases and Immunodeficiencies Unit. Hospital Universitari Vall d'Hebron.
Assistant Professor. Universitat Autònoma de Barcelona.
Pg. de la Vall d'Hebron, 119-129
08035 Barcelona. Spain.
Tel. 0034934893140. Fax 0034934893039.
psoler at vhebron.net<mailto:psoler at vhebron.net>; 34660psp at comb.cat<mailto:34660psp at comb.cat>.
Web: www.upiip.com<http://www.upiip.com/>
My ORCID is: http://orcid.org/0000-0002-0346-5570
LinkedIn <https://www.linkedin.com/nhome/?trk=>



No imprimir aquest correu ajudarà a preservar el medi ambient.
Si vostè no és el destinatari del missatge, o l'ha rebut per error, si us plau notifiqui-ho al remitent i destrueixi el missatge amb tot el seu contingut. Està prohibida la distribució no autoritzada del contingut d'aquest missatge.

No imprimir este correo ayudará a preservar el medio ambiente.
Si usted no es el destinatario del mensaje, o lo ha recibido por error, notifíquelo por favor al remitente y destruya el mensaje con todo su contenido. Está prohibida la distribución no autorizada del contenido de este mensaje.


---

The CIS-PIDD listserv is supported by:

[http://www.clinimmsoc.org/UserFiles/image/cis-pidd-list-logo_v1.jpg]
The science & practice of human immunology

P: +1.414.224.8095
E: info at clinimmsoc.org<mailto:info at clinimmsoc.org>

Not a member of CIS? Please visit www.clinimmsoc.org<https://cis.execinc.com/edibo/Signup> to join!

You are currently subscribed to cis-pidd as: jdmilner at niaid.nih.gov<mailto:jdmilner at niaid.nih.gov>.
To unsubscribe click here: http://lm.clinimmsoc.org/u?id=183824676.04a75971ce63f292890a03511ab41354&n=T&l=cis-pidd&o=45674602

---
The CIS-PIDD listserv is supported by the Clinical Immunology Society
The science & practice of human immunology

P: +1.414.224.8095
E: info at clinimmsoc.org

Not a member of CIS? Please visit www.clinimmsoc.org to join!

You are currently subscribed to cis-pidd as: mikko.seppanen at hus.fi.
To unsubscribe click here: http://lm.clinimmsoc.org/u?id=183824751.2106f30c0050b88ca85ab6b5148641fa&n=T&l=cis-pidd&o=45674720
or send a blank email to leave-45674720-183824751.2106f30c0050b88ca85ab6b5148641fa at lists.clinimmsoc.org

---
The CIS-PIDD listserv is supported by the Clinical Immunology Society
The science & practice of human immunology

P: +1.414.224.8095
E: info at clinimmsoc.org

Not a member of CIS? Please visit www.clinimmsoc.org to join!

You are currently subscribed to cis-pidd as: pagid at list.clinimmsoc.org.
To unsubscribe click here: http://lm.clinimmsoc.org/u?id=183939985.3ea13d40a15475ac00ebbd9cd8a37d6d&n=T&l=cis-pidd&o=45674850
or send a blank email to leave-45674850-183939985.3ea13d40a15475ac00ebbd9cd8a37d6d at lists.clinimmsoc.org

More information about the PAGID mailing list