Tag Archives: IL-10

Just the Beginning: Mutations in Very Early Onset Inflammatory Bowel Disease

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A recent study (Gastroenterol 2014; 146: 1028-39) indicates that mutations in tetratricopeptide repeat domain 7A (TTC7A) can result in a severe form of very early onset inflammatory bowel disease (VEOIBD).

After identifying a TTC7A heterozygote mutation in an infant by using whole exome sequencing of DNA, the authors subsequently identified 4 additional patients (2 siblings from 2 families) who also had loss of function mutations in VEOIBD.  Thus far, four of the five identified infants have died.

The manuscript has some terrific figures describing endoscopic/histologic characteristics, TTC7A genetic analysis, functional TTC7A enterocyte studies with immunofluorescence, impaired cell adhesion figure, tandem mass spectrometry, and a summary mechanistic figure (figure 6).  Hematopoietic stem cell transplantation has not been effective and might not work due to the enterocyte defect.

This study adds another VEOIBD gene mutation.  Previous mutations have involved in VEOIBD have included IL10RA/B, XIAP, ADAM17, NCF4, and NCF2/RAC2. The specific subtype matters as some defects may respond to stem cell transplantation.

Take-home message: there are a diverse number of pathways that can lead to VEOIBD.  Given the recent availability of whole exome sequencing, more mutations are sure to be identified soon.

Related blog post/link:

IL-10 and early onset IBD | gutsandgrowth In addition to the Toronto group (noted in this blog), a group in Boston with Harland Winter/CJ Moran is also interested in whole exome sequencing for VEOIBD patients.

Causes and Treatment of Very-Early Onset IBD –-this link is to the AGA Journals blog post on the same subject.

IL-10 and early onset IBD

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Among physicians who take care of patients with inflammatory bowel disease (IBD), there is an understanding that the labels “Crohn’s disease” (CD) and “ulcerative colitis” (UC) are imprecise labels.  There may be many subtypes of IBD that are classified as CD or UC.  This is becoming even more clear with advances in genetics which have shown specific genetic defects that predispose to an IBD phenotype.  In fact, more than 100 genetic loci have been uncovered that contribute to IBD, more than any other complex disease (according to editorial in same issue as reference below, pgs 285-87).

Immunodeficiency disorders, like chronic granulomatous disease, are well-recognized as potential mimics for IBD. More recently, IL-10 and IL-10 recpetor genetic mutations have been associated with early-onset IBD phenotypes (Gastroenterol 2012; 143: 347-55.)

In this study, 66 patients whose IBD started before age 5 were investigated for mutatons in the genes encoding IL-10, IL10R1, and IL-10R2.  IL-10R deficiency was confirmed with functional assays of patients’ mononuclear cells.  “Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency.”  In all 16 patients, the phenotype included refractory colitis with perianal disease; symptoms developed in the first three months of life in these 16 patients.  Five of these patients improved after hematopoietic stem cell transplantation with a median followup of 2 years.

Take-home message:

Test patients with infantile IBD for IL-10 and IL-10 receptor deficiency

Contact for IL-10 testing (free):

Karoline Fiedler, Clinical Research Coordinator, IBD Program, Toronto

karoline.fiedler@sickkids.ca

http://www.neopics.com

Crohn’s disease Differential Diagnosis:

  • Tuberculosis
  • Histoplasma
  • Sarcoidosis
  • Amebiasis
  • CMV
  • C. diff
  • Klebsiella oxytoca
  • Actinomycosis
  • Vasculitis (dermatomyositis, Wegener’s, SLE)
  • FMF
  • Allergic colitis
  • Hirschsprung’s
  • Autoimmune enteropathy
  • HIV
  • Chronic granulomatous disease
  • Glycogen storage dz, 1B
  • Hermansky-Pudlak syndrome
  • Wiskott Aldrich syndrome
  • NEMO (NF-kB essential modifier) deficiency
  • Leukocyte adhesion deficiency
  • SCID
  • Behcet’s
  • FELS/hemophagocytic lymphohistiocytosis
  • Typhlitis
  • HSP
  • Solitary rectal ulcer syndrome
  • Early-onset: IL10/IL10R deficiency, XIAP, ADAM17, NCF2 gene variant

Additional references:

  • -Gastroenterol 2012; 143: 347-55.  IL-10 signaling defects and IBD.
  • -Gut 2012; 61: 1028-35.  NCF2 gene variant and IBD.
  • -NEJM 2011; 365: 1502-408.  ADAM17 deletion and IBD.
  • -NEJM 2009; 361: 2033-45.  IL-10 receptor and IBD.
  • -JPGN 2010; 51: 690.  Discusses sarcoid (check angiotensin converting enzyme, CGD, Hermansky Pudlak)
  • -JPGN 2010; 50: 99.  Perianal dz in young children may be due to autoimmune neutropenia. -IBD 2008; 14: 1443.  phagocyte dysfunction.  Also, discusses Hermansky-Pudlak, GSD 1B, chronic granulomatous disease, Chediak-Higashi, leukocyte adhesion deficiency, cylic neutropenia, congenital neutropenia
  • -Clin Gastro & Hep 2009; 7: 1037.  MRI best study for perianal fistulas.
  • -JPGN 2006; 42: 405.  Vasculitis mimicking IBD.
  • -Pediatr 2008; 121:  447.  Consider chronic granulomatous disease -particularly if recurrent.  15-18% of CGD pts with perianal abscess.  Immunocompromised hosts at increased risk along with Crohn’s patients.  However, “vast majority” do not have underlying disease.  Can treat perianal abscess medicaly in otherwise healthy infants. (Peds 2007; 120: e548).  www.pediatrics.org/cgi/content/full/120/3/e548
  • -NEJM 2005; 352: 489-94.
  • -Gold B et al. NEJM 2003; 349 (26): 2541, Table 2

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