[CIS-PAGID] 16 yr old boy with difficult to control Autoimmune Enteropathy

[Bodo Grimbacher]

Dear Jane,
Some thoughts:

How are his IgG levels?
Any other autoimmunity/cytopenias?
May he have LRBA deficiency?
Please read attached.

How long did you use anti-TNF? Long enough at sufficient dose?

CMV colitis and other rare infectious agents have been excluded, I suppose?

IL10 and IL10R defects unlikely as he was also fine at times without Tx.

If FoxP3 nl, how about CD25?
Please also consider XIAP (reason below and I know of at least 5 more...)

Best, 
Bodo Grimbacher
Director
CCI, Freiburg, Germany



Genet Med. 
<http://www.ncbi.nlm.nih.gov/pubmed?term=inflammatory%20bowel%20whole%20exo
me#> 2011 Mar;13(3):255-62.

Making a definitive diagnosis: successful clinical application of whole
exome sequencing in a child with intractable inflammatory bowel disease.

Worthey EA 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Worthey%20EA%22%5BAuthor%5D>,
Mayer AN 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Mayer%20AN%22%5BAuthor%5D>,
Syverson GD 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Syverson%20GD%22%5BAuthor%5D>,
Helbling D 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Helbling%20D%22%5BAuthor%5D>,
Bonacci BB 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Bonacci%20BB%22%5BAuthor%5D>,
Decker B 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Decker%20B%22%5BAuthor%5D>,
Serpe JM 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Serpe%20JM%22%5BAuthor%5D>,
Dasu T 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Dasu%20T%22%5BAuthor%5D>,
Tschannen MR 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tschannen%20MR%22%5BAuthor%5D>,
 Veith RL 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Veith%20RL%22%5BAuthor%5D>,
Basehore MJ 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Basehore%20MJ%22%5BAuthor%5D>,B
roeckel U 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Broeckel%20U%22%5BAuthor%5D>,
Tomita-Mitchell A 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tomita-Mitchell%20A%22%5BAuthor
%5D>, Arca MJ 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Arca%20MJ%22%5BAuthor%5D>,
Casper JT 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Casper%20JT%22%5BAuthor%5D>,
Margolis DA 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Margolis%20DA%22%5BAuthor%5D>,
Bick DP 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Bick%20DP%22%5BAuthor%5D>,
Hessner MJ 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hessner%20MJ%22%5BAuthor%5D>,
Routes JM 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Routes%20JM%22%5BAuthor%5D>,
Verbsky JW 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Verbsky%20JW%22%5BAuthor%5D>,
Jacob HJ 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Jacob%20HJ%22%5BAuthor%5D>,
Dimmock DP 
<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Dimmock%20DP%22%5BAuthor%5D>.
SourceHuman and Molecular Genetics Center, The Medical College of
Wisconsin, Milwaukee 53226, USA. eworthey at mcw.edu

Abstract
PURPOSE:We report a male child who presented at 15 months with perianal
abscesses and proctitis, progressing to transmural pancolitis with
colocutaneous fistulae, consistent with a Crohn disease-like illness. The
age and severity of the presentation suggested an underlying immune
defect; however, despite comprehensive clinical evaluation, we were unable
to arrive at a definitive diagnosis, thereby restricting clinical
management.
METHODS:We sought to identify the causative mutation(s) through exome
sequencing to provide the necessary additional information required for
clinical management.
RESULTS:After sequencing, we identified 16,124 variants. Subsequent
analysis identified a novel, hemizygous missense mutation in the X-linked
inhibitor of apoptosis gene, substituting a tyrosine for a highly
conserved and functionally important cysteine. X-linked inhibitor of
apoptosis was not previously associated with Crohn disease but has a
central role in the proinflammatory response and bacterial sensing through
the NOD signaling pathway. The mutation was confirmed by Sanger sequencing
in a licensed clinical laboratory. Functional assays demonstrated an
increased susceptibility to activation-induced cell death and defective
responsiveness to NOD2 ligands, consistent with loss of normal X-linked
inhibitor of apoptosis protein function in apoptosis and NOD2 signaling.
CONCLUSIONS:Based on this medical history, genetic and functional data,
the child was diagnosed as having an X-linked inhibitor of apoptosis
deficiency. Based on this finding, an allogeneic hematopoietic progenitor
cell transplant was performed to prevent the development of
life-threatening hemophagocytic lymphohistiocytosis, in concordance with
the recommended treatment for X-linked inhibitor of apoptosis deficiency.
At >42 days posttransplant, the child was able to eat and drink, and there
has been no recurrence of gastrointestinal disease, suggesting this
mutation also drove the gastrointestinal disease. This report describes
the identification of a novel cause of inflammatory bowel disease. Equally
importantly, it demonstrates the power of exome sequencing to render a
molecular diagnosis in an individual patient in the setting of a novel
disease, after all standard diagnoses were exhausted, and illustrates how
this technology can be used in a clinical setting.









Am 18.05.12 06:55 schrieb "Jane Peake" unter <j.peake at uq.edu.au>:


>

>Hi 

>I would appreciate any thoughts regarding management of this difficult

>case. 

>

>Initial presentation age 9 months with diarrhoea and poor weight gain

>- Duodenal biopsies (on gluten free diet) total absence of villi,

>inflammatory infiltrate

>- Diagnosed as autoimmune enteropathy

>- Good clinical response to steroids; also required period on TPN	

>- Maintained on Cyclosporine - gradually weaned off

>- Off all treatment by ~ 4yrs of age

>

>Relapse 2004 (age 8):

>- Presented with severe watery diarrhoea

>- Partial villous atrophy and inflammatory infiltrate

>- Treated with steroids, then maintained on Tacrolimus with good control

>

>Relapse 2008 (age 12):

>- Over next couple of years treatments tried (and in various

>combinations) sirolimus, pulse methyl prednisolone, azathioprine,

>Tacrolimus, infliximab

>- Currently on azathioprine, tacrolimus, prednisone

>- Over last 4 years TPN dependent, completely intolerant of any oral

>intake including amino acid formulas

>- Still has 2-3 vomits daily and approx 3 loose bowel motions daily

>- Anti-enterocyte Ab - neg; FOXP3 expression normal

>- Only other Hx of note: R renal artery stenosis following investigation

>for hypertension - R nephrectomy 1998

>- No other problems at all

>- Life is miserable for him!!

>

>

>I was considering Rutuximab but am unable to find any literature on the

>use of this in this setting. Any thoughts would be very much appreciated.

>

>Kind regards Jane

>

>

>Dr Jane Peake

>Paediatric Immunologist and Allergist

>Senior Lecturer

>University of Queensland

>level 3 Foundation Building

>Royal Children's Hospital

>Herston Rd, Herston QLD 4029

>Tel (61 7) 33655333 or 36365059

>Fax (61 7) 33655455

>


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