✦

A Review on Hyper-IgE
Syndromes, Clinical
Manifestations, Diagnosis &
Therapeutic Approaches
Penyaji
dr. Maichel Yorgen
✦
Pembimbing
Dr. dr. Eko E. Surachmanto, Sp.PD-KAI
1. INTRODUCTION
 History of IgE Isolation
Hyper-IgE Syndromes
“Isolation of IgE & description of hyper IgE syndrome occurred in
Group of congenital
the same year”
primary immunodeficiency
diseases with variable
infectious & non-infectious [Davis et al., 1966]
manifestations • First report of two female patients with fair skin & red hair
• Experienced antibiotic required respiratory infections, eczema,
staphylococcal “cold abscesses”, hyperextensible joints
• Named as “Job’s syndrome”

Several distinct syndromes with

autosomal recessive or
dominant inheritance

Rreported as hyper-IgE
syndromes
 Familial & sporadic cases
Mutations in signal transducer &
activator of transcription 3
(STAT3)
Principal reason for
hyper-IgE syndrome
AD-HIES
Autosomal Dominant Hyper-IgE
Syndrome
[Minegishi et al., 2007]
• Pathogenesis of AD-HIES
• STAT3 dominant-negative
mutations
Mutation in ERBB2- Mutation in
interacting protein (ERBIN) CARD11
Two distinct autosomal dominant
disorders
Severe Atopy
AR-HIES PGM3
Autosomal Recessive Hyper-IgE Mutations in
Syndrome phosphoglucomutase 3
Mutations of DOCK8 dedicator: • Atopy
• Cutaneous viral infection • High serum IgE level
• Molluscum contagiosum • Autoimmunity &
• Mucocutaneous candidiasis neurological
• Severe atopy impairment
• Malignancy & recurrent classified as AR-
respiratory infection HIES
2.
AUTOSOMAL DOMINANT
HYPER-IgE SYNDROME
 STAT3 Loss of Function (STAT3 LOF)

History of
AD-HIES caused by STAT3 LOF
1966
• Davis et al. in
• Called as “Job’s syndrome”
1972
• Buckley et al.
• Increased serum IgE level
• Characteristic facies
• Called as “Buckley syndrome”, has been
explained by
Grimbacher et al.
• Clinical features of hyper-IgE syndrome in 72
patients
• Primary teeth shedding delay
• Permanent teeth eruption failure
• Unique facial characters
• Skeletal & connective tissue abnormalities
 Loss or substitution of amino-acid
Missense or in-frame deletions in the
DNA-binding or SH-2 domain of STAT3
gene
Normal but dysfunctional STAT3 protein
Absolute & specific level of serum IgE is
significantly high
No manifestations of anaphylaxis & food
allergy
Defect of STAT3 mediates the effects of
mast cell products on vascular
permeability
Extensive Expression of STAT3 Role
• Wound repair
• Remodeling of vessels (matrix metalloproteinases)
• Cancer prevention
• Leukemia inhibitory factor
• Oncostatin M
• Cardiovascular system
• Cardiotrophin -1
• Cardiotrophin-like cytokine
• Signal transduction of cytokines
• IL-6, 10, 11, 17, 21, 22, 23 ⇢ presented as
staphylococcus & candida infections
 Clinical Manifestations

• Cutaneous eczema • Scoliosis

• Recurrent pulmonary • Extent of osteopenia

• Skin infections • Typical coarse facies

• Staphylococcal cold abscesses • Central nervous system defects

• Cutaneous and pulmonary infections • Arterial malformations (aneurysm)

• Primary teeth retention • Abnormalities in peripheral circulation

• Permanent teeth eruption failure • Abnormalities in coronary circulation

• Fracture not appropriate to severity of trauma • Abnormalities in brain circulation

 Susceptibility of STAT3 LOF Patients Cutaneous Eczema of AD-HIES (STAT3 LOF)

• Starts at: first days of neonatal period

• Enduring: throughout adolescent
• Staphylococcal aureus • Induced or exacerbated by: staphylococcal infection
• Streptococcus pneumoniae • Treatment: anti-staphylococcal antibiotics
• Haemophilus influenzae
• Cold abscesses
• Pneumatocoeles HERPES ZOSTER
• Cutaneous boils containing pus INFECTION
• Without apparent inflammatory & ITS
manifestations RECURRENCY
• Soreness
• Warmness
• Painfulness In relatively
• Chronic mucocutaneous candidiasis younger people
• Mucosa
• Skin
• Nail involvement Defect of central
• Pneumonia memory T cells
 • Pseudomonas
Fungal infection
aeruginosa
& pneumonia
• Pneumocystis jiroveci

Invasive fungal
infection & • Aspergillus fumigatus
Tissue damage &
aspergilloma
bronchiectasis caused
by prolonged &
recurrent pulmonary Gastrointestinal &
• Cryptococcus
infections meningeal
• Histoplasma
infections

Meninges • Coccidioidomycosis

Skin or in lung • Staphylococcus

cold abscesses aureus
 Non-infectious manifestations of STAT3 LOF
• Typical coarse facies appearance
• Chin prominence
• Forehead prominence
• Nose prominence
• Vascular
• Coronary artery aneurysms
• Brain & peripheral vessels
• involvement
• Musculoskeletal
• Craniosynostosis
• Scoliosis
• Osteopenia
• Fracture vulnerability
• Gastrointestinal
• Gastroesophageal
reflux disease
• Eosinophilic esophagitis
• Dysphagia
• Dysmotility Neurologic
abnormalities
• Joint hyper-ex- tensibility
• Malignancies
• Hodgkin & non-Hodgkin
B cell
• T cell lymphoma not
related to EBV infection
Immunologic features of STAT3
LOF
• Non-protective antibody
response to encapsulated
bacteria in contrast with
normal serum IgG & IgM
level
• Extremely high serum IgE
level (>2000 IU/ml)
• Found at birth
• Serum eosinophilia ↑
• Proportional neutropenia ↑
• γ-interferon ↑
• TNF-α ↑
• Lack of Th1
• Th2 dominance
• Th1 defect
• Memory T & B cells ↓
• Significant drop of T cells
• Sources of IL-17
 “Management of AD-HIES caused by STAT3 LOF”

• Infections prevention • Improves patients’ prognosis

• Infections controlling • Enhances patients’ quality of
life
• Recurrent & carefully organized history taking
• Recurrent & carefully organized physical examination • Clean the airway ⇢ prevent
• Applicable paraclinical study secondary infections
• Parenchymal defects of
Drug Treatments • Antifungals
the lung
• Local antiseptic ⇢ • Pneumatoceles: anti- • Bronchiectasis changes
decolonize the skin aspergillus
• Chlorhexidine • Living in endemic area for • Physiotherapy maneuvers
• Diluted bleach mycoses: coccidioides &
• Antibiotics with Histoplasma • i.v or sub-cutaneous
staphylococcus aureus • Topical or systemic steroids + H2 immunoglobulin
coverage blockers or proton pump inhibitors replacement therapy
• Preventive doses • Hematopoietic stem cell
• Therapeutic doses transplantation (HSCT) • Regular vaccination
 Autosomal Recessive Hyper-IgE Syndrome

Group of combined primary

AR-HIES immunodeficiency disorders similar to
AD-HIES

Different Features

Secondary to several autosomal recessive mutations

• Mutations in dedicator of cytokinesis 8 (DOCK8)

• Mutations in phosphoglucomutase 3 (PGM3)

• Mutations in thyrosin kinase2 (TYK2)

 Dedicator of Cytokinesis 8 (DOCK8) Deficiency

DOCK8 Deficiency Features History of AR-HIES

Combined immunodeficiency:
• Elevated serum level of IgE • 2004 by Renner et al.
• Severe respiratory • 13 patients from 6 consanguineous families
• Dermatologic viral infections
• Atopic disorders Features:
• Malignancies • Recurrent pneumonia
• Pulmonary abscesses
History of Mutations in The • Atopic dermatitis
DOCK8 Gene • Elevated serum IgE levels
• Peripheral blood eosinophilia
• Identified in 2009 • Not having the connective tissue & skeletal
• Considered for the majority of abnormalities (minimal trauma fractures,
AR-HIES patients retained primary teeth & characteristic
• Pathogenesis facies)
• Homozygous & compound • Increased rate of viral skin infections
heterozygous mutations • Neurological symptoms
• Large deletions • Autoimmunity
 Large Deletions
Absent or reduced levels of
DOCK8 protein
Defective migration of
dendritic cells to lymph nodes
& defective priming of CD4+
T-cells
DOCK8 is a member of family
of DOCK180 proteins
• Cell migration
• Cell adhesion
• Cell growth
As they are a part of
cytoskeletal structure
Dysfunction of cytotoxic & helper T cells in
addition to B cells
Susceptibility to an extensive variety of
bacterial and viral infections
Dysfunction of long-
lived memory B cells
& virus-specific CD8+
T cells DOCK8 deficiency laboratory findings:
• High serum IgE levels
• Peripheral blood eosinophilia
DOCK8 in B cells is an • Severe early-onset eczema
adaptor protein • Recurrent sinopulmonary infections
downstream of TLR9 & • Dermal & less frequently pulmonary
upstream of STAT3 staphylococcal abscesses
• Mucocutaneous candidiasis
• B cell proliferation • High malignancies rates
• Immunoglobulin • Several allergic disorders
production • Food allergy
• Respiratory allergies
 Complications in DOCK8
deficiency
• Disseminated viral infections
of skin with molluscum
contagious
• Human Papillomavirus (HPV)
• Herpes zoster
• Herpes simplex
• Systemic viral infections
• Cytomegalovirus disease
• Progressive multifocal
leukoencephalopathy
• Sclerosing cholangitis ⇢
cryptosporidial colitis
• Granulomatous soft tissue
lesions
• Primary central nervous
system lymphomas
• Fatal leiomyosarcomas
Clinical Manifestations in
DOCK8 deficiency
• Allergic
• Atopic dermatitis
• Food allergies
• Asthma
• Eosinophilic esophagitis
• Recurrent sinopulmonary infections
• Pneumocystis jiroveci pneumonia
• Complications like bronchiectasis
• Malignancy
• Microcystic adnexal carcinoma
• Rapidly progressive T-cell lymphoma
• Leukemia
• Vascular abnormalities
• Cerebral arterial aneurysms
• Stenosis
• Vasculitis of aorta & other arteries
• Autoimmune hemolytic anemia
• Eosinophilic pneumonia
 Cause of Malignancies
Poor control of viral infections:
• HPV-associated squamous cell carcinomas
• Ebstein barr virus (EBV) related lymphomas
• Soft tissue tumors like leiomyosarcomas
Prognosis in DOCK8 deficiency
• Rate of mortality is high at young ages
• Die before the age of 20 years old

Rare Presentations

EOSINOPHILIC PNEUMONIA

Associated with other

symptoms of AR-HIES

• Non-tuberculosis disseminated mycobacterial

infection
• Eosinophilic esophagitis
• Anaphylaxis
• Autoimmune hemolytic anemia
 Tyrosin Kinase 2 (TYK2) Deficiency

1. History
• In patient who was under treatment because
of Bacille Calmette-Guérin infection
• Had recurrent salmonella infections
• Has some features of HIES
• Found in interferon-gamma/ IL-12
pathway defects
2. History
• In patient with atypical mycobacterial
infections & viral disorders without infections
caused by pyogenic bacteria
• Presence of the HIES phenotype in
Tyk2 deficient patients ⇢ depends on
other genetic loci

TYK2 DEFICIENCY

Impairing signal transduction from IL- 12,

IFNα/β

Predisposition to intracellular bacteria

(mainly mycobacteria & occasionally viruses)
 Phosphoglucomutase 3 (PGM3) Deficiency

History Clinical findings in Human

Hypomorphic mutations in PGM3
• In 2014
• 9 patients from four consanguineous
families who all indicated autosomal
recessive pattern
Human PGM3
Belongs to the
phosphohexose mutases
Converting glucose-1-
phos-phate to glucose-6-
phosphate
• Severe Combined Immunodeficiency
(SCID)
• HIES
Clinical findings in Mice
• Bone marrow failure
• Tindolent course
• Frequent respiratory tract infections
• Bronchiectasis
• ↑ serum IgE levels
• Atopy
• Neurologic disorders
• Autoimmunity
• Connective tissue & skeletal
abnormalities (joint hyperextensibility,
scoliosis & short limbs)
Unique feature of PGM3 patients with Homozygous IL6ST
hyper-IgE phenotype Mutations
• Eczema
• Increased Th17 cells • High serum IgE levels
• Autoimmunity • Peripheral blood eosinophilia
• Craniosynostosis
• Scoliosis
• Severe infections
IL6ST
• Bronchiectasis
• Low switched memory-B
Required for transformation of the cells
message through: • Abrogated acute-phase
inflammation
• IL-6
• IL-11
• IL-27
• Leukemia inhibitory factor
DIAGNOSED
WITH
Phosphorylation of STAT3 & STAT1 HIES
 Rare Genetic Syndromes with Features of HIES

• Postnatal growth retardation

Coexistence of
HIES & Dubowitz • Microcephaly
syndrome
RARE GENETIC • Characteristic facies
SYNDROMES WITH
FEATURES OF
HIES HIES & pentasomy • Acroceph-alosyndactyly
X and HIES &
• Hypertelorism
Saether-Chotzen
syndrome • Ptosis ⇢ mutations in TWIST gene

“The mutual mechanisms among these syndromes

& STAT3 & DOCK8 deficiency still remain
undefined”
 Laboratory Findings & Diagnosis in AR-HIES

DOCK8 DEFICIENCY Naiive T Cells High IgE Level

• Low • Presented

Involvement of Thymic Emigrant T Cells Blood Eosinophilia

• Low • Presented
T & B cells
Th2 Skewing Specific Antibody Responses
• Observed • Variable
• Progressive lymphopenia
• Absence of memory B cells Memory T Cells Serum IgA level
• Switched memory B cells • The number is variable • Normal

Serum IgM level

• Low, and
• Gradually decreases

Serum IgG level

• Normal, or
• Elevated
 Differentiate between DOCK8
deficiency & AD-HIES to some extent

LABORATORY FEATURES

• Peripheral blood eosinophil count: low • B-cells: variable

• Absolute lymphocyte count: reduced • Natural killer (NK) cells: variable
• T-lymphocytes: reduced • Serum IgM low
• CD4+ T-cells: reduced • Serum IgE: low
• CD8+ T-cells: reduced
• Lymphopenia: profound
• Normal CD4/CD8 ratio: maintained
• Lymphocyte proliferative: abnormal
• Neutrophils: normal
• Main defect: CD8+ T cell compartment
• Monocyte: normal among DOCK8 deficiency
 “IMPAIRED DIFFERENTIATION
OF TH17 CELLS IS MORE
PREVALENT IN AR-HIES COMPARED
WITH AD- HIES”
Reduced Th17 Counts
• Dominant forms of HIES
• Recessive forms of HIES
Normal Counts of Th17 Cells
• Documented in patients with atopic
dermatitis
Enumeration of Th17 Cells
• Be a clue
• Clinical finding
• Differentiation between isolated atopic
dermatitis & HIES
TYK2 Deficient Patients
• Level of serum IgE: less increase
• Other immunoglobulin’s serum levels: normal
• Nitroblue tetrazolium (NBT) tests: normal
• T-cells: normal
• B-cells: normal
• NK cells: normal
• Neutrophils function: normal
• HLA class I: increased along with decreased
response to type I interferons
• Gamma interferon production by stimulation
through IL-12: absence
 Treatment of AR-HIES

Management of ANY 1. Prevent from bacterial infections

AR-HIES INFECTION & • Anti-bacterial drugs
PNEUMONIA • Tri-methoprim-sulfamethoxazole
2. Prevent from fungal infections (aspergillus)
Based on • Itraconazole
prevention from 3. Prevent from virus infections
abscess formation • Antivirals
& other infections
SEVERE 1. Standard therapies
VIRAL • Salicylic acid
INFECTIONS • Cryotherapy
• Imiquimod
2. Systemic INF-α
• Activate effector lymphocytes
• Decrease viral replication
3. Intravenous immunoglobulin replacement
therapy
 CUTANEOUS 1. Chlorhexidine (topical) INTERVENTION
INFECTIONS 2. Bleach baths
(STAPHYLOCOCCAL)
When infection occurs Surgical
3. Prompt seeking for • Rarely essential
organism • Controlling complications of
• Culture from skin disease
• Sputum • Pneumatocele
• Blood • Abscesses

Hematopoietic Stem Cell

Transplantation (HSCT)
• Previous: inappropriate selection
• Now: the only curative option for
DOCK8 deficiency
• Early stages of the disease
• Respect to the high morbidity
& mortality rate in this
genetic defect
• ~50% of patients die < 20
years
“Severe complications related to infection/malignancy Education for Patients
must be precisely control at the time that • Avoid potentially water contaminated with
transplantation process is ongoing” Cryptosporidium
• Prevent from stroke
• Vascular imaging of cerebral vessels for
stenosis detection
Often Occur after HSCT • Itching
• Histamine receptor blockers
• Resolution of infections • Pathologic fractures
(cutaneous Molluscum • Calcium
spp. infections) • Vitamin D
• Eczema • Allergic & atopic disorders
• Corticosteroids (inhaled-forms)
• Antihistamine
Rare Continuitation • Regularly visit dentists
• Extract primary teeth
• Food allergy • Prenatal diagnosis
• Normalization of IgE • Amniocentesis or chorionic villus
levels sampling
• Vasculitis • DNA analysis
3. CONCLUSION
Hyper IgE syndromes are a series of primapresented with some
features of allergic diseases, unusual infections & some
syndromic non-immunologic features

The distinction among different types needs the knowledge

about special characteristics of each syndrome

However the definitive diagnosis is made by mutation analysis

THANK
YOU