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

[Verbsky, James]

Sorry again. I meant to type perforin on the first email

Sent from my iPhone

On May 18, 2012, at 8:31 PM, "Verbsky, James" <jverbsky at mcw.edu> wrote:


> Sorry. Typing on phone a problem. I meant to say primary enteritis is in my opinion a treg defect. We need an assay to assess function. Always thought we would find ctla4 or other treg defect in these patients. For xiap you can stim wih mdp to check nod function. 

> 

> Sent from my iPhone

> 

> On May 18, 2012, at 4:52 PM, "Bodo Grimbacher" <bodo.grimbacher at uniklinik-freiburg.de> wrote:

> 

>> 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

>>> 

>> 

>> <LRBA_deficiency_preprint_main.pdf>