Hyper IgE syndrome Presented by Sirapassorn Sornphiphatphong, MD. August28, 2015

1. Hyper IgE syndrome
Reviewed by Sirapassorn Sornphiphatphong, MD.

2. Overview
• Introduction
• Epidemiology
• Pathogenesis
• Clinical manifestations
• Diagnosis
• Management
• Prognosis

3. Introduction
• Recurrent staphylococcal abscesses,
sinopulmonary infections, and severe eczema
• Described in 1966; Job’s syndrome
– Severe dermatitis with cold abscesses
• In 1972, Buckley’s syndrome
– Severe dermatitis, coarse faces, ↑serum IgE
• In the 1970s, hyper-IgE recurrent infection
syndrome (HIERIS)
Buckley RH, et al. Pediatrics 1972; 49:59
Hill HR, et al. Lancet 1974; 1:183
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

4. Epidemiology
• Rare
• Not known incidence,
ranging 1:100,000-500,000
• Males and females equally
• Caucasians as well as in individuals of
Asian and African origin
Woellner C, et al. J Allergy Clin Immunol 2010; 125:424
Mogensen TH. JAKSTAT 2013; 2:e23435

5. Pathogenesis
• Heterogeneous genetic origin; 2 forms
• AD-HIES:
– Signal transducer and activator of
transcription 3 (STAT3), chromosome 17q21
• AR-HIES:
– Dedicator of cytokinesis 8 (DOCK8)
• chromosome 9p24
– Tyrosine kinase 2 (TYK2)
• chromosome 19p13.2
Middleton 8th ed
Rael E, et al. WAO Journal 2012; 5:79–87

6. AD-HIES
• Dominant negative heterozygous mutations in
the gene encoding the STAT3 protein
• Src homology 2 (SH2)
• DNA-binding domain (DBD) region
• Transactivation domain
Holland SM, et al. NEJM 2007; 357: 16
Freeman AF, Holland SM. Disease Markers 29 (2010) 123-130

7. AD-HIES
• Mutations
• Missense mutations
• Small in-frame deletions
• Both the sporadic and familial forms
Holland SM, et al. NEJM 2007; 357: 16
Freeman AF, Holland SM. Disease Markers 29 (2010) 123-130

8. AD-HIES
Woellner C, et al. JACI 2010;125:424-32

9. Pathogenesis

10. STAT3
• Signal transducers in many diverse pathways
• Many cytokines transmit signals through Jak-
STAT pathways
– Bind to Jak proteins, STAT recruitment,
phosphorylation, dimerizes, translocates to
the nucleus, activation
• IL-6, IL-10, IL-21, IL-22, and IL-23
• Immunity, wound healing, angiogenesis,
cancer
Freeman AF, Holland SM. Disease Markers 29 (2010) 123-130

11. Mogensen TH. JAK-STAT 2013;2(2):e23435

13. Rael E, et al. WAO Journal 2012; 5:79–87
AR-HIES: DOCK8
• Guanine exchange factors that activate Rho-
GTPases CDC42 and RAC1
• Which expressed in lymphocytes, affects cell
signalling and reorganisation of the cytoskeleton
• Exact molecular mechanism to immunological
findings has not yet been well defined
• Effects occur at multiple stages in T- and B-cell
development
AR-HIES: DOCK8

14. AR-HIES: DOCK8
Bittner TC, et al. Klin Padiatr 2010, 222:351-355

15. Rael E, et al. WAO Journal 2012; 5:79–87
Engelhardt KR, JACI 2015;136:402-12
DHR; Dock homology region

16. AR-HIES; TYK2
• Homologous deletion mutations
• FERM domain
• SH2 domain
• Kinase domain
Rael E, et al. WAO Journal 2012; 5:79–87
AR-HIES TYK2

17. • Transduces signals
• Type I IFN receptors (IFN-α, β), IL-13
• Cytokine receptors sharing IL-12Rb1 subunit
(IL-12, IL-23)
• Cytokine receptors sharing a gp130 subunit
(IL-6, IL-10, CNTF, LIF, IL-11)
Watford WT, John J. O’Shea JJ. Immunity 25, 2006
Rael E, et al. WAO Journal 2012; 5:79–87

18. Clinical manifestations

19. Autosomal dominant HIES
• Diverse clinical manifestations and
heterogeneous genetic origins
• Clinical triad
1) Recurrent staphylococcal abscesses
2) Recurrent airway infections
3) Increased serum IgE
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

20. Autosomal dominant HIES
• Skin: neonatal rash, chronic dermatitis,
furunculosis and cellulitis, cold abscesses,
candida and other fungal skin infection
Rael E, et al. WAO Journal 2012; 5:79–87
Freeman AF, Holland SM. Disease Markers 29 (2010) 123-130
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

21. neonatal rash
5 days old
2 weeks old
Eberting CLD, et al. Arch Dermatol. 2004;140:1119-1125
• Infected ezcematoid
skin lesions
• Generalized dermatitis,
similar to AD, but
atypical
• Papulopustular eruption
predominantly at face,
scalp within 1st yr of life

22. AD-HIES
Respiratory tract
• Pneumonias, lung abscesses,
bronchiectases,
pneumatocele,
bronchopleural fistulas
• Colonization: Pseudomonas
aeruginosa and Aspergillus
fumigatus
• Pulmonary sequelae: main
mortality
Middleton 8th ed
Rael E, et al. WAO Journal 2012; 5:79–87
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

23. AD-HIES
Recurrent respiratory
infections
• Paranasal sinusitis,
otitis media,
mastoiditis
• Staphylococcus aureus
• Haemophilus influenzae
• Streptococcus
pneumoniae
Reported organisms
• PCP
• Cryptococcosis
• Histoplasmosis
• Disseminated pulmonary
candidiasis
• Mycobacterium
• Nocardia infection
• post-BCG vaccination
complications
Rael E, et al. WAO Journal 2012; 5:79–87
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

24. AD-HIES
• Characteristic features: coarse face, rough skin,
deep-set eyes, a prominent forehead,
prognathism, mid-face anomalies, high arched
palate
• Oral and dental: delayed loss of primary teeth,
severe dental caries, periapical abscesses,
periodontitis
Middleton 8th ed
Rael E, et al. WAO Journal 2012; 5:79–87
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

25. AD-HIES
Bone and joints
• Scoliosis
• Pathological bone fractures: long bones, ribs
• Excessive bone resorption
• Hyperextensibility
Minegishi Y, et al. Nature 2007, 448:1058-1062
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

26. AD-HIES
• Autoimmune disease: SLE, dermatomyositis,
membranoproliferative glomerulonephritis
• Lymphoproliferative disorder : NHL, Hodgkin
disease
• Vascular manifestation : coronary, aortic
aneurysm
• Cerebellar artery thrombosis
Middleton 8th ed
Rael E, et al. WAO Journal 2012; 5:79–87
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

27. AD-HIES
Mogensen TH. JAK-STAT 2013;2(2):e23435

28. DOCK8 deficiency
• AD, eczema, recurrent upper and lower
respiratory tract infections
• Parenchymal lung abnormalities, pneumatocele
formation have not been observed
• Severe fungal and viral cutaneous infections:
HSV, herpes zoster, molluscum contagiosum,
HPV
• Food and environmental allergies
Rael E, et al. WAO Journal 2012; 5:79–87
Freeman AF, Holland SM. Disease Markers 2010, 123-130
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

29. DOCK8 deficiency
Freeman AF, Holland SM. Disease Markers 2010, 123-130

30. DOCK8 deficiency
• Malignancies: lymphoma, squamous cell CA
• Higher mortality from sepsis and malignancy
• CNS vasculitis, facial paralysis, hemiplegia,
ischemia, cerebral aneurysms, subarachnoid
hemorrhages
• Neither skeletal abnormalities, pathological bone
fractures, dental disorders, nor characteristic
facial
Rael E, et al. WAO Journal 2012; 5:79–87
Freeman AF, Holland SM. Disease Markers 2010, 123-130
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

31. AR-HIES : Tyk2
• Eczema, recurrent sinopulmonary infections,
candidiasis
• Molluscum contagiosum, herpes infections
• Defective responses to IL12, IFN-ɣ STAT1
pathway
– Atypical Mycobacterium infection, BCG
– Non typhi salmonella gastroenteritis
Rael E, et al. WAO Journal 2012; 5:79–87
Freeman AF, Holland SM. Disease Markers 2010, 123-130

32. Rael E, et al. WAO Journal 2012; 5:79–87

33. Boos AC, et al. Allergy2014;10.1111

34. Boos AC, et al. Allergy2014;10.1111

35. Laboratory findings

36. Laboratory findings
Increased serum IgE
• Hallmark
• Frequently >5000 U/ml,
even >100,000 U/ml
• 2000 U/ml: cut-off point
• Not in all patients,
expected in adulthood
• 20% normal range
• Not correlate with
infectious complications
Eosinophilia
• >2SD, typically >700/μl
• not correlating with either
the IgE or the infectious
complications
Rael E, et al. WAO Journal 2012; 5:79–87
Freeman AF, Holland SM. Disease Markers 2010, 123-130

37. AD-HIES
• ↑serum IgD
• normal IgG, IgA, IgM
• Low anamnestic
antibody responses to
booster
immunizations
• Poor Ab-mediated,
cell-mediated
responses to
neoantigens
AR-HIES
• ↓serum IgM
• variable IgG antibody
responses
• Impaired generation
of secondary Ab
response to specific
antigens
Middleton 8th ed
Rael E, et al. WAO Journal 2012; 5:79–87
Freeman AF, Holland SM. Pediatr Res 65: 32R–37R, 2009
Freeman AF, Holland SM. Disease Markers 2010, 123-130
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

38. AD-HIES
• Normal lymphocyte
counts
• ↓ Memory T cells
(CD45RO)
• ↓ TH17 cells
• Defective Th1-dependent
cytokine response
• ↓ DTH responses
• Impaired response of
lymphocyte to antigenic
and alloantigenic
stimulation
AR-HIES
• Lymphopenia
• ↓ T, B, NK cells
• ↓ T cell function
• Normal CD4/CD8 ratio
Middleton 8th ed
Rael E, et al. WAO Journal 2012; 5:79–87
Freeman AF, Holland SM. Pediatr Res 65: 32R–37R, 2009
Freeman AF, Holland SM. Disease Markers 2010, 123-130
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

39. AD-HIES
• Defective neutrophil
chemotaxis
• Normal phagocytic cell
ingestion, metabolism,
killing, and total hemolytic
complement activity
AR-HIES: Tyk2
• ↓ Th1, ↑Th2
differentiation
• Defective responses to
IL12, IFN-ɣ STAT1
pathway
Middleton 8th ed
Rael E, et al. WAO Journal 2012; 5:79–87
Freeman AF, Holland SM. Pediatr Res 65: 32R–37R, 2009
Freeman AF, Holland SM. Disease Markers 2010, 123-130
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

40. Diagnosis
• Based on clinical and laboratory findings
• Gene mutation analysis
• NIH HIES scoring criteria: 21 features
WAO Journal 2012; 5:79–87
Orphanet Journal of Rare Diseases 2011, 6:76

41. Rael E, et al. WAO Journal 2012; 5:79–87
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76
NIH HIES score
> 40 Probable
20-40 Possible
< 20 Unlikely

42. Schimke LF, et al. JACI 2010;126:611–17
We propose key findings combined with TH17 cell
numbers, predict AD-HIES with STAT3 mutations,
supporting early diagnosis of AD-HIES

43. Schimke LF, et al. JACI 2010;126:611–17

44. • Possible: IgE ≥1000 IU/mL plus a weighted score of clinical
• features >30 based on recurrent pneumonia, newborn
• rash, pathologic bone fractures, characteristic face, and
• high palate (Table E4).
• d Probable: These characteristics plus lack of TH17 cells or a
• family history for definitive HIES.
• d Definitive: These characteristics plus a dominant-negative
• heterozygous mutation in STAT3
Woellner C, et al. JACI 2010;125:424-32
We propose the following diagnostic guidelines for
STAT3-deficient HIES

45. • Possible:
– IgE >1000 IU/mL
– plus weighted score >30
• Recurrent pneumonia
• Newborn rash
• Pathologic bone fractures
• Characteristic face
• High palate
• Probable :
– Characteristics
(possible)
– plus lack of TH17 cells
– or a family history for
definitive HIES
• Definitive:
– Characteristics plus a dominant-negative heterozygous
mutation in STAT3
Woellner C, et al. JACI 2010;125:424-32

46. Treatment

47. Treatment
• Prevention and management of infections
• Regular long-term intake of systemic antibiotics
and antifungal drugs
– Prevent serious infections, lung parenchymal damage
• Thoracic surgery: Superinfected pneumatoceles
(Pseudomonas spp., Aspergillus, nontuberculus mycobacteria or
persisting beyond 6 mo.
Middleton 8th ed
Rael E, et al. WAO Journal 2012; 5:79–87
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

48. Treatment
Kuruvilla M, et al. JACI Pract 2013;1:573-82

49. Treatment
• Skin:
– Antibacterial and antifungal drugs
– Other : topical antibacterial treatment,
emollients, corticosteroids, dilute bleach, or
chlorinated water
– Isothretinoine effective in the treatment of
cutaneous complications
Middleton 8th ed
Rael E, et al. WAO Journal 2012; 5:79–87
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

50. Hematopoietic stem cell
transplantation (HSCT)
• No any clinical benefit bone marrow
transplantation
• Successful immunologic reconstitution in
patients with both AD and AR-HIES esp.DOCK8
deficiency
• Should be early before development of life-
threatening complications, malignancies
Goussetis E, et al. JACI 2010, 126:392-394
McDonald DR, et al. JACI 2010, 126:1304-1305
Bittner TC, et al. Klin Padiatr 2010, 222:351-355
Gatz SA, et al. Bone Marrow Transplant 2011, 46:552-556
Rael E, et al. WAO Journal 2012; 5:79–87
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76

51. Goussetis E, et al. JACI 2010, 126:392-394

52. • First report indicating HCT to be curative in
patients with AR-HIES
• Stable, full donor cell chimerism
• Exception of persistent low- IgA serum levels
and the exception of normal immune functions
Gatz SA, et al. Bone Marrow Transplant 2011, 46:552-556

53. Gatz SA, et al. Bone Marrow Transplant 2011, 46:552-556

54. • 2-year-old girl from consanguineous parents of Turkish
• HLA-matched related donor at 7 years of age
• 6 years after HSCT, alive and well and attending
regular school service
• No longer severe infections
• Still suffers from multiple food allergies (chocolate,
eggs, nuts) without respiratory or gastrointestinal
symptoms
Bittner TC, et al. Klin Padiatr 2010, 222:351-355

55. Bittner TC, et al. Klin Padiatr 2010, 222:351-355

56. Bittner TC, et al. Klin Padiatr 2010, 222:351-355

57. Treatment
• IVIg
– Controversy
– Helpful in AD-HIES, difficult to control
infection despite prophylactic ATB
Middleton 8th ed
Rael E, et al. WAO Journal 2012; 5:79–87
Freeman AF, Holland SM. Disease Markers 29 (2010) 123-130
Szczawinska-Poplonyk A., et al. Orphanet Journal of Rare Diseases 2011, 6:76
• IFN-γ therapy
– No clinical benefit
• Anti-IgE antibody (omalizumab)
– lack of data associating therapeutic benefits

58. IFN-γ therapy
• In vitro studies revealed an improvement in the
neutrophil chemotactic function with IFN-γ
• No clinical observations on IgE concentration
and on episodes of infection in patients with
HIES
Jeppson JD, et al. J Pediatr 1991, 118:383-387
King CL, et al. Proc Natl Acad Sci USA 1989, 86:10085-10089

59. Treatment
• H2-receptor antagonists: improve neutrophil
chemotactic function assessed in vitro
• Sodium cromoglycate: improve neutrophil
phagocytosis and in respiratory burst
Mawhinney H, et al. Clin Immunol Immunopathol 1980, 17:483-491
Kojima K, et al. Inoue. Allergy 1998, 53:1101-1103
Yokota S, et al. Lancet 1990, 335:857-858

60. Prognosis
• Infectious pulmonary complications appear
to be the leading cause of death, followed
by lymphoma

61. Alexandra F. Freeman AF, et al. JACI 2007;119:1234-40

62. Alexandra F. Freeman AF, et al. JACI 2007;119:1234-40

63. Engelhardt KR, JACI 2015;136:402-12