Hyper IgE syndrome Presented by Pornsiri Sae-lim, MD. July30, 2021

1. Hyper IgE syndrome
Pornsiri Sae-lim , MD
Pediatric Allergy and Immunology Department
King Chulalongkorn Memorial Hospital

2. Outline : HIES
• Introduction
• Epidemiology
• Classification (AD-HIES, AR-HIES)
• Pathogenesis
• Clinical manifestation
• Laboratory finding
• Diagnosis
• Management
• Prognosis

3. Introduction
A group of primary immunodeficiency disorders
Classical triad of HIES
• Significant high serum level of IgE
• Eczema
• Recurrent skin and pulmonary infections
Karin R. Engelhardt, Bodo Grimbacher,Chapter 19 - The Many Faces of the Hyper-IgE Syndrome

4. History aspect
In 1966 Davis et al. : Job’s syndrome
• 2 girls - early onset severe dermatitis
- recurrent staphylococcal infections with
cold abscess formation
- hyperextensible joints
In 1972 Buckley et al : Buckley syndrome
• 2 boys : - severe dermatitis
- recurrent cutaneous, pulmonary & joint abscesses
- coarse facies
- exaggerated with markedly elevated serum IgE levels & eosinophilia
Introduction
Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91
So went Satan forth from the presence of
the Lord, and smote Job with sore boils
from the sole of his foot unto his crown”
Job 2:7

5. History aspect
In 1974 Hill et al
• Defective granulocyte chemotaxis and elevated IgE level
• Hyper-IgE syndrome ( HIES )
In 1972 Grimbacher et al
• Autosomal dominant HIES
• Multisystem disease : immune & non-immune manifestations
(skeletal, dental and connective tissue abnormalities)
In 2004 Renner et al
• Autosomal recessive HIES
• Lack of skeletal and connective tissue abnormalities
• Heightened susceptibility to cutaneous viral infections
• Combined immunodeficiency
Introduction
Al‐Shaikhly T, Immunology and cell biology. 2019

6. Epidemiology
• Not known incidence
• Rare: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

7. Classification
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

8. Autosomal dominant HIES
Signal transducer and activator of transcription 3
(STAT3)

9. Characteristics
Immunologic characteristics
• Newborn rash
• Eczema
• Recurrent pneumonias
• Pneumatocoeles
• Mucocutaneous candidiasis
• Elevated IgE > 2000 IU/mL
• Eosinophilia and
• Increased incidence of lymphoma
Non-immunologic characteristics
• Characteristic face
• Retained primary teeth
• Minimal trauma fractures
• Scoliosis
• Hyperextensibility
• Focal brain hyperintensities
• Chiari 1 malformations
• Craniosynostosis
• Arterial aneurysms

10. Immunologic characteristics : skin rash
Newborn rash
• Papulopustular rash before
age 2 month
• Arising on face and scalp
Eczematous dermatitis
• Papular or papulopustular rash before age of 18 month
• Face, neck, shoulders, axillae, upper aspect of trunk, and
buttocks, posterior auricular areas
• usually driven by S. aureus
• improves with anti-staphylococcal antibiotics or
antiseptics Papular and prurigo-like lesions,
occurring onshoulders and back
Minegishi, Yoshiyuki, International immunology , 2009

11. Immunologic characteristics : infection
Infection
Bacterial:
Sinopulmonary and cutaneous
• staphylococcus aureus, streptococcal
pneumoniae, haemophilus, klebsiella.
Fungal:
• Chronic mucocutaneous candidiasis
• Pneumocystitis jiroveci
Viral:
• VZV reactivation, EBV viremia
Pneumatocoele formation and secondary
infection with Pseudomonas aeringosa,
Atypical mycobacteria or Aspergillus
fumigatus
Bronchiectasis
Cold abscess
chronic paronychia

12. Non-immunologic characteristics
Characteristic face
• Coarse face
• Asymmetric, with a
prominent forehead
• Mild prognathism
• Increased interalar
width of the nose
• Wide-set eyes
• Thickening of the soft
tissue of ears , nose &
cheeks
Not evident in young children Develop
progressively during teenage years

13. Non-immunologic characteristics
Skeletal Abnormality
• Retained primary
teeth
• High-arched palate
• Scoliosis
• Hyperextensible
joints
• Minimal trauma
fractures: Long
bones, ribs, and
pelvic bones
• Osteopenia

14. Others
• Vascular aneurysm
• Focal brain hyperintensity
• GERD,GI dysmotility, Eosinophilic esophagitis
Non-immunologic characteristics

15. Complication
• Malignancies especially non-Hodgkin's lymphoma. Other cancers
have also been reported such as Hodgkin's lymphoma, cancers of the
vulva, and the lung
• Autoimmune diseases : SLE, membranoproliferative
glomerulonephritis, vasculitis, and dermatomyositis
• Hypertension associated with vascular abnormalities
• Myocardial infarction due to the rupture of coronary aneurysms
• Lacunar infarcts due to the rupture of cerebral aneurysms

16. Incidence of Clinical & Laboratory Features

17. Schematic representation of STAT3 showing mutational hotspots in the DNA-binding (DNA-B) and
Src homology 2 (SH2) domain.
Further mutations are located in the amino-terminal (NT), the linker and the transcriptional
activation (TAD) domains.

18. Laboratory work up
• IgE
• Marked elevation in serum IgE (2000– 100,000 IU/mL )
• Start to rise only after birth
• May decrease or even normalize during adulthood
• Inversely correlated with patient age
• Eosinophilia
• more than 90% of patients
• usually ≥700 cells/lL
Neither IgE concentration nor eosinophilia correlate with disease activity

19. • Serum immunoglobulin concentrations are unexpectedly normal
• Exhibit diminished vaccine responses
• Abnormal B-cell maturation as exemplified by decreased CD27+
switched memory B cells
• T-cell number and function are usually normal
• Decreased central memory T cells
• Variable defects of mononuclear or polymorphonuclear chemotaxis
• Increase BAFF expression
Laboratory work up

20. 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

21. JAK- STAT signal pathway
Pathogenesis of hyper IgE syndrome." Clinical reviews in allergy & immunology 38.1 (2010): 32-38

22. Al‐Shaikhly T, Immunology and cell biology. 2019

23. IL 6
IL 11
IL 21
IL 10

24. Properties of the major subsets of CD4+ helper T cells

25. Functions of Th17 cells
• Cytokines produced by Th17 cells
stimulate local production of
chemokines that recruit neutrophils &
other leukocytes
• Increase production of antimicrobial
peptides (defensins)
• Promote epithelial barrier functions.

26. Gernez, Yael, et al. The Journal of Allergy and Clinical Immunology: In Practice 6.3 (2018): 996-1001.

27. Gernez, Yael, et al. The Journal of Allergy and Clinical Immunology: In Practice 6.3 (2018): 996-1001.

28. Autosomal-Recessive HIES
DOCK8 deficiency
TYK2 deficiency
PHOSPHOGLUCOMUTASE-3 deficiency
Zinc Finger 341 (ZNF341)

29. DOCK8 deficiency
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

30. Engelhardt, Karin R., et al. Journal of Allergy and Clinical Immunology 124.6 (2009): 1289-1302.
Hypothetical function of DOCK8

31. DOCK8 is important for numerous cellular processes.
The identified roles of DOCK8 include cell polarization and migration through 3-dimensional space, adhesion
molecule accumulation & immune synapse formation, regulation of STAT3 phosphorylation and nuclear
translocation, Treg suppressive function, actin cytoskeleton organization, as well as cytolytic granule release

32. Karin R. Engelhardt, Bodo Grimbacher,Chapter 19 - The Many Faces of the Hyper-IgE Syndrome

33. Kearney, Cellular & molecular immunology , 2017

34. Al‐Shaikhly T, Immunology and cell biology. 2019

35. Laboratory work up
•M/C : Eosinophilia, Hyper IgE
•Progressive lymphopenia : most often affects first
CD4 T cells, then CD8 T cells and NK cells
•Lymphopenia less frequently affects total B cells
•although memory B cell numbers are decreased
•T cell proliferation is decreased
•most often low IgM, occurs
•Specific antibodies are variably impaired.

36. In 2006 Minegishi et al.
• Reported the first TYK2-deficient patient. The patient was Japanese
with the triad of HIES signs
Recently recognized
• No high serum IgE concentration, atopy, nor staphylococcal disease
• Intracellular bacteria and/or viral infections, and the most typical
feature is BCG disease
• IUIS 2020 : classified into Mendelian Susceptibility to Mycobacterial
Disease
TYK2 deficiency
Wu, Peilin, et al. "A TYK2 gene mutation c. 2395G> A leads to TYK2 deficiency: a case report and literature review." Frontiers in pediatrics 8 (2020): 253.

37. the HIES features were not displayed by the other TYK2-deficient patients
Wu, Peilin, et al. "A TYK2 gene mutation c. 2395G> A leads to TYK2 deficiency: a case report and literature review." Frontiers in pediatrics 8 (2020): 253.

38. Journal of Clinical Immunology (2020) 40:66–81

39. TYK2 deficiency
• Tyk2 : a nonreceptor tyrosine kinase of the Janus kinase family
• Impairing signal transduction from IFN-αβ, IL-6, IL-10 , IL-12
Al‐Shaikhly T, Immunology and cell biology. 2019
• Impaired IL-12 signaling >>
diminishing the production of IFN-γ
• explains the susceptibility to
intracellular organisms

40. PHOSPHOGLUCOMUTASE-3 deficiency
In 2014 Sassi et al. and Zhang et al
• 17 patients with homozygous hypomorphic mutations in the
phosphoglucomutase-3 (PGM3) gene
 AR HIES phenotype
 preponderance of neurologic manifestations
 Developmental delay, intellectual impairment and motor symptoms
(ataxia, hypotonia)
-- Hyperimmunoglobulin E-like syndrome with glycosylation defects --

41. • PGM3 : synthesis of uridine diphosphate N-acetylglucosamine (UDP-
GlcNAc)
• UDP-GlcNAc >> essential precursor for protein glycosylation
>> substrate for O-GlcNAc
transferase can modulates cellular signaling
including TCR signaling via NF-kB and NFAT,
contributing to Th2 expansion
• PGM3 deficiency : glycosylation defect , cellular signaling including
TCR defect >> results in HIES
PHOSPHOGLUCOMUTASE-3 deficiency
Al‐Shaikhly T, Immunology and cell biology. 2019
PHOSPHOGLUCOMUTASE-3 deficiency
PHOSPHOGLUCOMUTASE-3 deficiency

42. PHOSPHOGLUCOMUTASE-3 deficiency
• More polymorphic
• marked IgE elevation
• substantial atopic disease
• including severe refractory atopic dermatitis, food allergy, eosinophilic gastrointestinal
disease, asthma, anaphylaxis
• Infections
• Infections including bacterial respiratory, skin and soft tissue infection, viral skin infection
and EBV viremia
• SCID and bony abnormalities (T-B-NK+ )
-- Share features of both STAT3 and DOCK8 deficiency --

43. Laboratory findings:
• Eosinophilia and elevated serum IgE
• T and B cell lymphopenia
• Decreased memory B-cell percentage
• Hypergammaglobulinemia
• Antibody titers to protein and carbohydrate antigens are
mostly protective
PHOSPHOGLUCOMUTASE-3 deficiency

44. Zinc Finger 341 (ZNF341)
• Marked serum IgE elevation
• bacterial skin and respiratory tract infections, fungal infections,
atypical inflammatory responses : cold abscesses
• and connective tissue abnormalities
-- All similar seen in STAT3DN--
• A series of disorders in the STAT3 pathway
• Phenotypic overlap with STAT3DN
• Inability of patient cells to properly express adequate STAT3 in
response to IL-6 and other STAT3 inducing cytokines
Milner, Joshua D. "Primary immune deficiencies associated with a Th2 diathesis." Stiehm's Immune Deficiencies. Academic Press, 2020

46. IL6ST
• homozygous IL6ST mutations
• eczema, elevated IgE, and eosinophilia
• craniosynostosis and scoliosis
• recurrent infections, bronchiectasis, decreased memory B cells, and
an impaired acute-phase response were also described
• Gp130 : co-receptor critical for signaling for a variety of cytokines
including IL-6, IL-11, IL-27, OSMR, LIF and others
• Gp130 signals can be propagated via STAT3

47. Diagnosis
• Based on
• Clinical
• Laboratory findings
• Gene mutation analysis

48. Int Rev Immunol. 2016;35(1):39-56

49. Int Rev Immunol. 2016;35(1):39-56

50. Int Rev Immunol. 2016;35(1):39-56

51. Immunological and somatic phenotypes and associated immunological abnormalities in
AD-HIES (STAT3 deficiency) and AR-HIES (DOCK8- and TYK2 deficiency)
Int Rev Immunol. 2016;35(1):39-56

52. • 40 points: Likely
• 20-40 points:
Uncertain
• < 20 points: Unlikely

53. Treatment
Skin care
• maintaining skin hydration
• controlling the associated pruritus
Antimicrobial prophylaxis
Treatment of infections
Control of pulmonary complications
J Clin Immunol (2016) 36:107–109

54. Practice parameter for the diagnosis and management of primary immunodeficiency." Journal of Allergy and Clinical Immunology ,2015

55. Immunomodulating agents
• Recombinant human IFN-γ
• High-dose IVIg
• Omalizumab
• Dupliumab
Treatment of skeletal abnormalities
Transplantation
J Clin Immunol (2016) 36:107–109

56. Al‐Shaikhly T, Immunology and cell biology. 2019

57. Prognosis
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 complication
• Pneumatoceles can become colonized with fungi and gram negative bacteria
• Lymphoma
J Clin Immunol (2016) 36:107–109