Hyper Ig E syndrome 2018 Presented by Pannipa Kittipongpattana, MD. September21, 2018

1. Pannipa Kittipongpattana, M.D.
21 September 2018
Division of Allergy & Immunology, Department of Pediatrics
Faculty of Medicine, Chulalongkorn University
King Chulalongkorn Memorial Hospital,Thai Red Cross Society
Hyper IgE Syndrome

2. ▪Introduction: History of Hyper IgE Syndrome (HIES)
▪Classification
▪Clinical and pathogenesis of Autosomal Dominant-HIES
▪Clinical and pathogenesis of Autosomal Recessive-HIES
▪Diagnosis
▪Management
▪Prognosis

3. ▪Group of primary immunodeficiencies
▪Recurrent skin infection
▪Eczema
▪Pulmonary infection
▪Significant elevation of IgE level
Cur Opin Hematol 2015, 22:12-22

4. ▪Rare, incidence ≈ 1:100,000 to 1:500,000
▪Males = females
▪Found in all ethnics
Mogensen TH. JAK-STAT 2013;2(2):e23435
J Res Med Sci. 2017; 22: 53.

5. Heterogeneous genetic origin: 2 forms
▪Autosomal dominant HIES:
▪ Signal transducer and activator of transcription 3 (STAT3): chromosome 17q21
▪Autosomal recessive HIES:
▪ Dedicator of cytokinesis 8 (DOCK8): chromosome 9p24
▪ Tyrosine kinase 2 (TYK2): chromosome 19p13.2
▪ Phosphoglucomutase 3 (PGM3): chromosome 6q14.1
▪ Zinc Finger Protein (ZNF341): chromosome 20q11.22

6. Davis, et al. 1966
Lancet. 1966 May 7;1(7445):1013-5.

7. Davis, et al. 1966
Lancet. 1966 May 7;1(7445):1013-5.
Pediatrics. 1972 Jan;49(1):59-70.
Buckley, et al. 1972
“Hyper IgE Syndrome”

8. Davis, et al. 1966
Lancet. 1966 May 7;1(7445):1013-5.
Pediatrics. 1972 Jan;49(1):59-70.
Lancet. 1974 Sep 14;2(7881):617-9.
Hill, et al. 1974Buckley, et al. 1972
IgE
“Hyper IgE Syndrome”

9. Davis, et al. 1966
Hill, et al.
1974
Buckley, et al. 1972
IgE
Van Scoy, et al. 1975
Lancet. 1966 May 7;1(7445):1013-5. // Pediatrics. 1972 Jan;49(1):59-70.. Lancet. 1974 Sep 14;2(7881):617-9. Ann Intern Med. 1975 Jun;82(6):766-71. Radiology. 1985 Aug;156(2):362.
Eur J Pediatr. 1985 Nov;144(4):414-7. // N Engl J Med. 1999 Mar 4;340(9):692-702. // N Engl J Med 2007; 357:1608-1619 // Nature. 2008 Apr 10;452(7188):773-6

10. Davis, et al. 1966
Hill, et al.
1974
Buckley, et al. 1972
IgE
Van Scoy, et al. 1975
• Familial, AD
• Variable in expression
Kirchner, et al. 1985, Hoger, et al. 1985
Lancet. 1966 May 7;1(7445):1013-5. // Pediatrics. 1972 Jan;49(1):59-70.. Lancet. 1974 Sep 14;2(7881):617-9. Ann Intern Med. 1975 Jun;82(6):766-71. Radiology. 1985 Aug;156(2):362.
Eur J Pediatr. 1985 Nov;144(4):414-7. // N Engl J Med. 1999 Mar 4;340(9):692-702. // N Engl J Med 2007; 357:1608-1619 // Nature. 2008 Apr 10;452(7188):773-6

11. Davis, et al. 1966
Hill, et al.
1974
Buckley, et al. 1972
IgE
Van Scoy, et al. 1975
• Familial, AD
• Variable in expression
Kirchner, et al. 1985
Hoger, et al. 1985
Grimbacher, et al. 1999
Lancet. 1966 May 7;1(7445):1013-5. // Pediatrics. 1972 Jan;49(1):59-70.. Lancet. 1974 Sep 14;2(7881):617-9. Ann Intern Med. 1975 Jun;82(6):766-71. Radiology. 1985 Aug;156(2):362.
Eur J Pediatr. 1985 Nov;144(4):414-7. // N Engl J Med. 1999 Mar 4;340(9):692-702. // N Engl J Med 2007; 357:1608-1619 // Nature. 2008 Apr 10;452(7188):773-6

12. Davis, et al. 1966
Hill, et al.
1974
Buckley, et al. 1972
IgE
Van Scoy, et al. 1975
• Familial, AD
• Variable in expression
Kirchner, et al. 1985
Hoger, et al. 1985
Grimbacher, et al. 1999
Holland, et al. 2007, Milner, et al. 2008
Identified STAT3 mutation in AD-HIES
Renner, et al. 2004
AR-HIES Minegushi, et al. 2006
TYK2 identified
Zhang, et al. 2009
DOCK8 identified
Lancet. 1966 May 7;1(7445):1013-5. // Pediatrics. 1972 Jan;49(1):59-70.. Lancet. 1974 Sep 14;2(7881):617-9. Ann Intern Med. 1975 Jun;82(6):766-71. Radiology. 1985 Aug;156(2):362.
Eur J Pediatr. 1985 Nov;144(4):414-7. // N Engl J Med. 1999 Mar 4;340(9):692-702. // N Engl J Med 2007; 357:1608-1619 // Nature. 2008 Apr 10;452(7188):773-6

13. AD-HIES
Autosomal Dominant Hyper IgE Syndrome
• Signal transducer and activator of transcription 3 (STAT3)

14. Craniofacial anomalies
• Coarse face
• Prominent forehead
• Deep seated eyes
• Broad nose
• Facial asymmetry
Skin
• Newborn eczema
• Cold abscess
• S.aureus
• C.albicans
Sinopulmonary infection
• Sinusitis
• Otitis media
• Mastoiditis
• Pneumonia
• Lung abscess
• Pneumatocele
• Bronchiectasis
• Retained primary teeth
• High arch palate
• Craniosynostosis
Musculoskeletal
• Minimal trauma
fracture
• Osteopenia
• Joint hyperextensibility
• Scoliosis
Others
• Vascular aneurysm
• Focal brain hyperintensity
• Lymphoproliferative disorders
• GERD,GI dysmotility, Eosinophilic
esophagitis
Clinical manifestations
J Clin Immunol. 2017 Oct;37(7):695-700.
Allergy. 2018 Jul 25.

15. Laboratory findings
• Hallmark: Increased serum IgE
• Cut-point: 2,000 Unit/ml, may not elevated in infants
• Other immunoglobulin levels usually normal
• Specific IgE against staphylococci and candida may
present
N Engl J Med. 1999 Mar 4;340(9):692-702
IgE may falls below cut-point as aged in 20% of patients
* Level of IgE does not correlates with disease severity *
• Eosinophilia
• present in >90% of patients
• not correlate with the elevation in IgE
• WBC usually normal
• Decrease levels of
• CD45RO+ central memory T cells and
• CD27+ memory B cells
• TH17
• Variable defects of mononuclear or
polymorphonuclear chemotaxis

16. JAK-STAT Pathway

17. JAK-STAT Pathway

18. ▪ Despite STAT3 loss-of-function mutation identified in majority of AD-
HIES cases, definite pathogenesis leading to clinical & laboratory
manifestations are not yet clearly explained
▪ Partly due to
▪ Complex, overlapping function of cytokines-JAK-STAT pathways
▪ Limitation to translate findings from in-vitro and animal study

19. IL-6, Jak-STAT3, & Th17
Front. Genet., 14 July 2015

20. Th17 & Immune manifestations
Mammalian Genome (2018) 29:603–617
Am J Pathol. 2012 Jul;181(1):8-18
Th17
IL-17
IL-22
IL-21
𝛽-defensins, hyperplasia
chemoattraction
B
Class switching to
IgG1, IgG3
IL-6
STAT3
STAT3
TGF𝛽
ERBIN
Treg
Skin - Respiratory
tract infection
Chemotaxis defect
Elevated IgE level

21. Connective tissue manifestations
Mammalian Genome (2018) 29:603–617
Am J Pathol. 2012 Jul;181(1):8-18
Th17
IL-6
STAT3
STAT3
IL-17
Fibroblast
OsteoclastsIL-11
Craniofacial disorder
Skeletal disorder
Osteoporosis

22. AR-HIES
Autosomal Recessive Hyper IgE Syndrome
• Dedicator of cytokinesis 8 (DOCK8)
• Tyrosine kinase 2 (TYK2)
• Phosphoglucomutase 3 gene (PGM3)
• Serine Peptidase Inhibitor Kazal type 5 (SPINK5)
• Zinc Finger 341 (ZNF341)

23. Davis, et al. 1966
Lancet. 1966 May 7;1(7445):1013-5. // Pediatrics. 1972 Jan;49(1):59-70.. Lancet. 1974 Sep 14;2(7881):617-9. Ann Intern Med. 1975 Jun;82(6):766-71. Radiology. 1985
Aug;156(2):362. Eur J Pediatr. 1985 Nov;144(4):414-7. // N Engl J Med. 1999 Mar 4;340(9):692-702. // N Engl J Med 2007; 357:1608-1619 // Nature. 2008 Apr 10;452(7188):773-6
Hill, et al.
1974
Buckley, et al. 1972
IgE
Van Scoy, et al. 1975
• Familial, AD
• Variable in expression
Kirchner, et al. 1985
Hoger, et al. 1985
Grimbacher, et al. 1999
Holland, et al. 2007, Milner, et al. 2008
Identified STAT3 mutation in AD-HIES
Renner, et al. 2004
AR-HIES Minegushi, et al. 2006
TYK2 identified
Zhang, et al. 2009
DOCK8 identified

24. Autosomal Recessive
Hyper IgE Syndrome
J Pediatr. 2004 Jan;144(1):93-9.

25. AR-HIES
● This subset of HIES shares the same triads as AD-HIES
○ Eczema
○ Sinopulmonary infection
○ Skin abscess
● No craniofacial or skeletal disorders
● Prominent CMI defects  recurrent mucocutaneous viral
infection: HPV (Warts), HHV, Poxvirus (Molluscum contagiosum)
● Severe atopy, anaphylaxis
● High prevalence of skin cancer and lymphoma
● Laboratory findings
○ High Ig E level, Hypereosinophilia
○ Lymphopenia
○ High Ig G titer toward virus
J Pediatr. 2004 Jan;144(1):93-9.
N Engl J Med 2009; 361:2046-2055

26. comparative genomic hybridization arraysZhang, et al. 2009: DOCK8

27. DOCK8
Clin Immunol. 2017 Aug;181:75-82.

28. DOCK8 defect: CID & Severe Atopy
J Clin Immunol. 2016 Jul;36(5):441-9.
Cell Mol Immunol. 2017 May;14(5):406-411.

29. Minegushi, et al. 2006
● A 22-year-old Japanese man with HIES
○ Severe atopic dermatitis
○ Elevated serum IgE
○ Recurrent infection from: virus, bacteria, fungi, and MYCOBACTERIA
○ Normal number of T, B, NK cells
○ Normal in vitro neutrophil function
Immunity. 2006; 25: 745-755.

30. Minegushi, et al. 2006
● Work up for mycobacterial susceptible primary immunodeficiency
(IL-12 p40, IL-12 R𝛽1, IFNGR1, IFNGR2, STAT1)  negative
● IL-12 production (stimulated with mitogens)  normal
● IFN𝛾 production from T-cell (stimulated with IL-2)  FAILED
● Intact IFN𝛾 response to other mediator  IL-12 signaling defect
● Only known cause (at that time) is IL-12R𝛽1 deficiency
● But stimulation with IFN𝜶/𝜷 also failed
Immunity. 2006; 25: 745-755.

31. Cytokines and receptors that utilize Tyk2
Immunity. 2006 Nov;25(5):745-55.
Int Immunol. 2009 Feb;21(2):105-12

32. PGM3
Curr Opin Pediatr. 2014 Dec;26(6):697-703

33. PGM3
J. Allergy Clin. Immun. 133: 1400-1409, 2014.
Allergic-Skin
- Atopy
- AD
- Vasculitis
Infection
- Sinopulmonary infection
- Otitis media
- SSI
- EBV viremia
Connective tissue
- Scoliosis
- Esophageal stricture
- Bronchiectasis
Neurologic ***
- Low IQ
- Myoclonus
- Demyelination

34. ZNF341
Sci Immunol. 2018 Jun 15;3(24).
- DOCK8 & PGM3 mutations account for > 80% of AR-HIES
- Both mutations have different phenotype from AD-HIES from STAT3
mutation
- Cases of AR-HIES with clinical manifestation resembles AD-HIES has just
been reported

35. ZNF341
Sci Immunol. 2018 Jun 15;3(24).

36. Int Rev Immunol. 2016;35(1):39-56.
IL-12, IFN𝜶/𝜷, CD8+
NK, cytothripsis
IL-12, IFN𝜸
Th2 expansion, IL-4, IL-13

37. Int Rev Immunol. 2016;35(1):39-56.
IL-11

38. ▪Based on
▪Clinical
▪Laboratory findings
▪Gene mutation analysis

39. NIH clinical feature scoring system
>40 suggestive
20-40 intermediate
<20 Unlikely
Scoring System with Clinical and Laboratory Tests for Individuals in Kindreds with HIES
J Allergy Clin Immunol. 2010 Feb; 125(2):424-432.e8.

40. ▪Treatment is based upon:
▪Observational data and clinical experience
▪No randomized trials.
▪The general management goals:
▪Control the pruritus and eczematoid dermatitis
▪Prevent the occurrence of severe systemic infections
▪early diagnosis
J Clin Immunol (2016) 36:107–109

41. ▪ Skin care
▪ maintaining skin hydration
▪ controlling the associated pruritus
▪ Antimicrobial prophylaxis
▪ Treatment of infections
▪ Control of pulmonary
complications
▪ Immunomodulating agents
▪ Recombinant human IFN-γ
▪ high-dose IVIg
▪ Omalizumab
▪ Treatment of skeletal abnormalities
▪ Transplantation
J Clin Immunol (2016) 36:107–109

42. ▪DOCK8 deficiency has a worse prognosis than AD-HIES
▪most patients dying in the 2nd and 3rd decade of life.
▪The leading cause of death in patients with HIES:
▪Infectious pulmonary complications
▪Pneumatoceles can become colonized with fungi and
gram-negative bacteria
▪Lymphoma
J Clin Immunol (2016) 36:107–109