Hyper Ig E syndrome

Hyper IgE syndrome

Reviewed by Sirapassorn Sornphiphatphong, MD.

Overview

• Introduction

• Epidemiology

• Pathogenesis

• Clinical manifestations

• Diagnosis

• Management

• Prognosis

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

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

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

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

AD-HIES

• Mutations

• Missense mutations

• Small in-frame deletions

• Both the sporadic and familial forms

Holland SM, et al. NEJM 2007; 357: 16


AD-HIES

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

Pathogenesis

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


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


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

AR-HIES: DOCK8

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


Engelhardt KR, JACI 2015;136:402-12

DHR; Dock homology region

AR-HIES; TYK2

• Homologous deletion mutations

• FERM domain

• SH2 domain

• Kinase domain


AR-HIES TYK2

• 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


Clinical manifestations

Autosomal dominant HIES

• Diverse clinical manifestations and

heterogeneous genetic origins

• Clinical triad

1) Recurrent staphylococcal abscesses

2) Recurrent airway infections

3) Increased serum IgE


Autosomal dominant HIES

• Skin: neonatal rash, chronic dermatitis,

furunculosis and cellulitis, cold abscesses,

candida and other fungal skin infection




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

AD-HIES

Respiratory tract

• Pneumonias, lung abscesses,

bronchiectases,

pneumatocele,

bronchopleural fistulas

• Colonization: Pseudomonas

aeruginosa and Aspergillus

fumigatus

• Pulmonary sequelae: main

mortality

Middleton 8th ed



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



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



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


AD-HIES

• Autoimmune disease: SLE, dermatomyositis,

membranoproliferative glomerulonephritis

• Lymphoproliferative disorder : NHL, Hodgkin

disease

• Vascular manifestation : coronary, aortic

aneurysm

• Cerebellar artery thrombosis

Middleton 8th ed



AD-HIES

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

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


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


DOCK8 deficiency


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




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

Boos AC, et al. Allergy2014;10.1111

Laboratory findings

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

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


Freeman AF, Holland SM. Pediatr Res 65: 32R–37R, 2009



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





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





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



NIH HIES score

> 40 Probable

20-40 Possible

< 20 Unlikely

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

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

• 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


We propose the following diagnostic guidelines for

STAT3-deficient HIES

• 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


Treatment

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



Treatment

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

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



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


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



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

• 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


• 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


Treatment

• IVIg

– Controversy

– Helpful in AD-HIES, difficult to control

infection despite prophylactic ATB

Middleton 8th ed




• IFN-γ therapy

– No clinical benefit

• Anti-IgE antibody (omalizumab)

– lack of data associating therapeutic benefits

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

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

Prognosis

• Infectious pulmonary complications appear

to be the leading cause of death, followed

by lymphoma

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

Engelhardt KR, JACI 2015;136:402-12

Hyper Ig E syndrome

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