[PAGID] Lymphopenia and arthritis

[Brian P Vickery]

...which has made things very interesting this morning. I was unaware of 
this disorder until the path came back, but I have since learned that EV 
is a form of defective host immunity to specific types of cutaneous but 
not genital HPV infections, which leads to persistence and oncogenic 
transformation (involving skin and in some cases solid tumors such as 
lymphomas) in most patients. In the attached reference, Dr. Casanova 
regards EV as a PID and suggests that it may have been the first PID ever 
described, in the 40s. Most affected patients have null mutations in EVER1 
or EVER2 which are transmembrane proteins expressed primarily in the ER of 
keratinocytes and which function in zinc metabolism. 

Various immunologic abnormalities have been described in EV patients over 
the years including expansion of NK cells / LGL and CD4+ T cell 
lymphopenia (both of which my patient has); and some publications have 
made reference to gamma delta expansion. But I am unable to find any 
mention of associated arthritis or autoimmunity. (molecular mimicry?) 

So now my questions are: should we stop the methotrexate, in view of what 
is known about the natural history of EV? Are this child's lymphocyte 
abnormalities secondary to chronic cutaneous viral infections or does zinc 
metabolism or EVER1/2 function play a role in lymphocyte homeostasis as 
well? And does anyone have experience with these patients? 

Scratching my head,
Brian


J Intern Med. 2008 Aug;264(2):115-27. Epub 2008 Jun 9.
Revisiting human primary immunodeficiencies.
Casanova JL, Fieschi C, Zhang SY, Abel L.
Laboratory of Human Genetics of Infectious Diseases, Institut National de 
la Santé et de la Recherche Médicale, Paris, France. casanova at necker.fr
Abstract
Human primary immunodeficiencies (PIDs) are often thought to be confined 
to a few rare, familial, monogenic, recessive traits impairing the 
development or function of one or several leucocyte subsets and resulting 
in multiple, recurrent, opportunistic and fatal infections in infancy. We 
highlight here the rapidly growing number of exceptions to each of these 
conventional qualifications. Indeed, bona fide PIDs include common and 
sporadic illnesses and may present as dominant, or even polygenic traits; 
their pathogenesis may involve non haematopoietic cells, and they may 
result in single episode of illness, with a single or multiple morbid 
phenotypes, some of which may involve infection, in otherwise healthy 
adults. We need to increase awareness of the multitude of clinical 
presentations of human PIDs considerably and rapidly in the medical 
community. Human PIDs should be considered in a wide range of clinical 
situations.
PMID: 18544117 [PubMed - indexed for MEDLINE]

___________________
Brian Vickery, MD
Division of Pediatric Allergy & Immunology
Duke University Medical Center
DUMC Box 2644, Durham NC 27710
919.681.2949

"Email should NOT be used for urgent medical issues. The information in 
this electronic mail is sensitive, protected information intended only for 
the addressee(s). Any other person, including anyone who believes he/she 
might have received it due to an addressing error, is requested to notify 
the sender immediately by return electronic mail, and to delete it without 
further reading or retention. The information is not to be forwarded to or 
shared unless in compliance with Duke Medicine policies on confidentiality 
and/or with the approval of the sender."

----- Forwarded by Brian P Vickery/Pediatrics/mc/Duke on 05/06/2010 01:38 
PM -----



Re: [PAGID] Lymphopenia and arthritis 

Brian P Vickery 
to:
pagid
05/06/2010 09:24 AM




Thanks for your thoughts, Jason. His IgE is normal and he does not have 
palpable nodes, liver, or spleen. We have not imaged his chest or abdomen, 
and he has not had a slit lamp exam, which is a good idea. Because of the 
poor response to Aldara, the dermatologists just biopsied his diffuse, 
salmon-colored macular rash on Monday and indeed the path demonstrates 
epidermodysplasia verruciformis consistent with HPV infection. 

Brian
___________________
Brian Vickery, MD
Division of Pediatric Allergy & Immunology
Duke University Medical Center
DUMC Box 2644, Durham NC 27710
919.681.2949

"Email should NOT be used for urgent medical issues. The information in 
this electronic mail is sensitive, protected information intended only for 
the addressee(s). Any other person, including anyone who believes he/she 
might have received it due to an addressing error, is requested to notify 
the sender immediately by return electronic mail, and to delete it without 
further reading or retention. The information is not to be forwarded to or 
shared unless in compliance with Duke Medicine policies on confidentiality 
and/or with the approval of the sender."






Re: [PAGID] Lymphopenia and arthritis

raas0027 
to:
pagid
05/05/2010 05:20 PM


Sent by:
pagid-bounces at list.clinimmsoc.org
Please respond to pagid






Dear Brian,

Interesting case. Lymphocytopenia, impaired cell-mediated immunity, 
arthropathy (can look like JIA) and osteopenia can all be [variable] 
features of sarcoidosis, which can occur at this age.

Not a perfect fit however (e.g. hx low PTH, growth failure, facies) but 
sarcoidosis is pretty heterogeneous.

What about the following:

IgE?

Hepatosplenomegaly?

Intrathoracic (or other) lymphadenopathy?

Skin or eye changes?

Regards,

Jason



On May 5 2010, Brian P Vickery wrote:


>Dear Colleagues: 

>

>I would appreciate your input regarding the following 9 year old boy with 



>lymphopenia and unusual T cell phenotype, growth failure, osteopenia, and 



>a deforming polyarticular arthritis, which is progressive and disabling, 

>affecting the large joints, producing contractures, and requiring 

>methotrexate and intermittent joint injections. The osteopenia was 

>associated with a low PTH which Endocrine has decided was spurious. 

>

>He has a history of recurrent acute / chronic otitis media requiring four 



>sets of tympanostomy tubes and has been treated for sinusitis clinically 

>many times. There is no history of pneumonia, sepsis, meningitis, chronic 



>diarrhea, oral thrush or opportunistic infection. He has verruca plana 

>which are not responding to imiquimod. 

>

>He is small (< 3 %ile for ht & wt) with fine blonde, almost whitish hair, 



>and a hint of a triangularly shaped face but not otherwise dysmorphic and 



>his intelligence is above average. 

>

>The family history is unremarkable. 

>

>Lab findings: 

>-Normal quantitative immunoglobulins with protective diphtheria & tetanus

>-ALC 1000 - 1500; note these numbers and the phenotype were obtained 

prior 

>to starting MTX

>-Lymphocyte enumeration notable for increased B & NK cells, decreased 

>alpha/beta and increased gamma/delta T cells, and normal RTEs: 

> 

>CD3

>45.8%

>453

>CD4:CD8 

>0.82

>

>Ti alpha/beta

>25.5%

>252

>Ti gamma/delta

>19.0%

>188

>CD16

>20.4%

>202

>CD56

>19.6%

>194

>CD19

>29.5%

>292

>CD20

>31.9%

>316

>CD45RO

>16.9%

>77

>CD45RA

>56.7%

>257

>45RA+/62L+

>27.2%

>123

>

>-Impaired proliferation to PHA (44,000), and ConA (12,000), and 

borderline 

>response to PWM (44,000)

>-No 22q11 deletion

>-RMRP sequencing normal

>-46XY with normal Affymetrix SNP 6.0 microarray

>-Sweat chloride normal with negative CFTR mutation screen

>-IGF-1 and IGFBP-3 low

>-RF neg, HLAB27 neg, ANA 1:160, speckled pattern

>

>I would be grateful for any diagnostic or therapeutic suggestions. 

>

>Best regards, 

>Brian 

>___________________

>Brian Vickery, MD

>Division of Pediatric Allergy & Immunology

>Duke University Medical Center

>DUMC Box 2644, Durham NC 27710

>919.681.2949

>

>"Email should NOT be used for urgent medical issues. The information in 

>this electronic mail is sensitive, protected information intended only 

for 

>the addressee(s). Any other person, including anyone who believes he/she 

>might have received it due to an addressing error, is requested to notify 



>the sender immediately by return electronic mail, and to delete it 

without 

>further reading or retention. The information is not to be forwarded to 

or 

>shared unless in compliance with Duke Medicine policies on 

confidentiality 

>and/or with the approval of the sender."

>


-- 
Jason Raasch, MD

Midwest Immunology Clinic
15700 37th Ave N
Suite 110
Plymouth, MN 55446

(Phone) 763.577.0008
(FAX)   763.5770192


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