Case presentation June 2015 Amit Assa, M.D Disclosure Some - - PowerPoint PPT Presentation

Case presentation

June 2015

Amit Assa, M.D

Disclosure

Some constipation from time to time

Based on a true story…

12 months old boy with 4 weeks of rectal bleeding

• 9 months of 5-8 soft-watery stools
• Dropping percentiles….(25% to 3%)
• Normal diet (previously, no response to diary

withdrawal)

Case History

• Pregnancy and delivery: Term, BW 3300, no

complications

• At 2 months: Bi-lateral cervical lymphadenitis (fever,

CRP, ESR)

• Aspiration from lymph node: Serratia Marcescens
• Resolution under Resprim and Cefuroxime
• Bone marrow tap- normal
• Infectious serologies for EBV, CMV, HIV: Negative
• Immunoglobulins- Normal
• CBC- normal (WBC 20,000-30,000, normal differential)
• No other infectious events
• Normal development

PE+ Labs.

• CBC- leukocytosis
• Hb- 8.5, MCV- 64, RDW-18
• CRP- 3 mg/dl
• ESR- 74
• Albumin- 3.6
• Stool cultures, O&P, CDT- negative

No peri-anal findings

What is the probable diagnosis?:

• a. Very early-onset IBD
• b. Some kind of immune deficiency
• c. Milk protein allergy
• d. A pediatric gastroenterologist’s problem- I don’t

care

What is the probable diagnosis?:

• a. Very early-onset IBD
• b. Some kind of immune deficiency

VEO-IBD

Disease onset < 6Y 4-10% of pediatric IBD Colonic predominance, 20% IBD-U1 No clear evidence of enhanced aggressiveness/ complications2 Family Hx DD with immune deficiency syndromes (SCID, CVID, hyper IgM syn. ...)

1Prenzel et al. JCC 2009 2Benchimol et al. Gastroenterology 2014

Group Classification Age range ( y ) Pediatric-onset IBD Montreal A1 Younger than 17 EOIBD Paris A1a Younger than 10 VEOIBD Younger than 6 Infantile (and toddler) onset IBD Younger than 2 Neonatal IBD First 28 days of age Uhlig et al. Gastroenterology 2014

Specific IBD-like Immune deficiency syndromes

Chronic Granulomatous disease Wiskott-Aldrich syndrome Immune dysregulation-Polyendocrinopathy- Enteropathy-X linked (IPEX) syndrome Glycogen Storage Disease type 1b NEMO deficiency Hermansky-Pudlak Syndrome

nuclear factor κB essential modulator protein (X-linked)

Overlap between IBD and IBD-like Immune deficiency syndromes

Approximately 50 monogenic disorders

 Granulocyte dysfunction: defects in oxidative burst (including SNPs in P40phox and P67phox)1,2  Apoptosis defects: Mutations in X-linked inhibitor of apoptosis protein gene (XIAP). Associated with EBV driven HLH  Epithelial barrier defects: ADAM17 deficiency  T and B cell defects

1Rioux et al. Nat Genet 2007 2Muise et al. Gut 2012

Overlap between IBD and IBD-like Immune deficiency syndromes

IL-10 defects (IL-10, IL-10RA, IL-10RB)

• Infantile colonic IBD
• Severe peri-anal involvement
• Refractoriness to conventional therapies
• Risk for intestinal B-cell lymphomas
• 100% penetrance
• Treatment: HSCT

Uhlig et al. Gastroenterology 2014

So, what do we most probably have here?

Polygenic IBD Monogenic IBD ( IL10 pathway…) Chronic Granulomatous disease Wiskott-Aldrich syndrome Immune dysregulation-Polyendocrinopathy-Enteropathy- X linked (IPEX) syndrome Glycogen Storage Disease type 1b Hermansky-Pudlak Syndrome

So, what do we most probably have here?

Polygenic IBD Monogenic IBD ( IL10 pathway…) Chronic Granulomatous disease Wiskott-Aldrich syndrome Immune dysregulation-Polyendocrinopathy-Enteropathy- X linked (IPEX) syndrome Glycogen Storage Disease type 1b Hermansky-Pudlak Syndrome

Back to the patient

Colonoscopy NBT NOBI Absence of P91, CYBB mutation, mother and sister are carriers

Chronic Granulomatous Disease

1:200,000 live births1 Defects in the phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (phox) complex Genetic mutations in all 5 components of the complex

• Rec. infections (lung, skin, lymph nodes, liver, bone)

Typical organisms: S. aurus, B cepacia, S marcescence, Norcardia Sp., Aspergillus Sp.

Wolach et al. Clin Immunol 2008

Chronic Granulomatous Disease

40%-50% of patients develop CD-like intestinal inflammation Survival depends on residual superoxide production Histology- granulomas and pigmented macrophages Prophylaxis: Trimethoprim/sulfamethoxazole, Itraconazole Survival into adulthood: 90% Serious infections rate: 1/3-4Y

CGD intestinal manifestations

Gastric outlet obstruction (15%) Intestinal inflammation (40%). Third fails medical therapies High rate of peri-anal disease Liver abscess (35%)

Holland SM. Hematol Oncol Clin North Am 2013

How would you not treat the colitis in this patient?

• a. Corticosteroids and then 5-ASA
• b. Corticosteroids and then thiopurines
• c. Anti TNFα agents
• d. Anti IL-1 agents
• e. Diversion ileostomy

f. Allogeneic HSCT

How would you not treat the colitis in this patient?

• a. Corticosteroids and then 5-ASA
• b. Corticosteroids and then thiopurines
• c. Anti TNFα agents
• d. Anti IL-1 agents
• e. Diversion ileostomy

f. Allogeneic HSCT

CGD treatment of intestinal disease

The cornerstone for remission induction: corticosteroids (CS) CS should be tapered down slowly 5-ASA maintenance is effective in a subset of patients Other therapeutic options:

 Thiopurines (few reports)1  Cyclosporine (one report)  IL-1 receptor blockade (Anakinra- one report)2  Diversion ileostomy (2/8 responded)3  Colectomy (5/5 responded)3

Definite treatment: Allogeneic HSCT

1Marks et al. Am J Gastroenterol 2009 2De-Luca et al. PNAS 2014 3Alvarez-Downing et al. Dis Colon Rectum 2013

When to suspect monogenic IBD

YOUNG AGE

Multiple family members and consanguinity YOUNG AGE onset Treatment failure Autoimmunity Thriving failure Endocrine concerns Recurrent infections Severe perianal disease Macrophage activation syndrome and HLH Obstruction and atresia

• f intestine

Skin lesions, dental\hair abnormalities Tumors

MOST MATTERS

Searching for monogenic IBD/IBD like disease

Back to the patient

Steroid dependent Need for recurrent transfusions Failed maintenance with 5-ASA and Azathioprine Awaiting Anakinra approval Considering diversion ileostomy