Atlas of Genetic Diagnosis and Counseling || Hyper-IgE Syndrome

Hyper-IgE Syndrome

Hyper-IgE syndrome (HIES) is a rare, hereditary

multisystem disorder characterized clinically by

hyperimmunoglobulinemia E, recurrent infections,

and eczematoid dermatitis. In 1966, Job reported

two patients with eczematous dermatitis, recurrent

staphylococcal boils, hyperextensible joints, and

distinctive coarse facies. In 1972, Buckley et al.

expanded the clinical picture by adding elevated

immunoglobulin E (IgE).

Synonyms and Related Disorders

Job syndrome

Genetics/Basic Defects

1. Inheritance (Erlewyn-Lajeunnesse 2000)

a. Autosomal dominant with variable penetrance

and expressivity

b. Linkage to a region on chromosome 4q21dem-

onstrated in several affected families

c. An upregulating mutation in the interleukin-4

receptor gene on chromosome 16, demonstrated

in some patients with hyper-IgE syndrome

d. Autosomal recessive hyper-IgE syndrome: a

similar but distinct syndrome reported by Renner

et al. (2004)

2. Autosomal dominant hyper-IgE syndrome

(AD-HIES): caused by dominant-negative mutations

in signal transducer and activator of transcription 3

(STAT3) in most cases of autosomal dominant HIES

(Holland et al. 2007; Minegishi et al. 2007; Jiao et al.

2008; Renner et al. 2008)

a. Most cases are sporadic.

b. When familial, all individuals carrying the muta-

tion have the HIES phenotype.

3. Autosomal recessive hyper-IgE syndrome (AR-HIES)

(Freeman and Holland 2009; Engelhardt et al. 2009)

a. Homozygous mutation of Tyk2with a four nucle-

otide deletion resulting in a premature stop

codon reported in one patient (Minegishi et al.

2006). This patient had the following common

features of AR-HIES:

i. Eczema

ii. Viral infections

iii. Recurrent sinopulmonary infections

iv. Bacille Calmette–Guerin and Salmonellainfections, classic for IL-12/IFN-gamma

defects

b. Mutations of Tyk2 have been absent in the other

reported cases of AR-HIES (Woellner et al. 2007).

c. Homozygous mutations (large deletions and

point mutations) in the dedicator of cytokinesis

8 (DOCK8) identified recently in most patients

with AR-HIES (Engelhardt et al. 2009)

Clinical Features

1. Classic triad (77%) (Grimbacher et al. 1999a;

Erlewyn-Lajeunnesse 2000)

a. Abscesses

b. Pneumonia

c. An elevated IgE

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_124,# Springer Science+Business Media, LLC 2012

1097

2. Skin manifestations

a. Onset with distinctive neonatal rash

i. Typically pruritic, secondary to intradermal

mast cell histamine release triggered by the

elevation of available IgE

ii. Often lichenified

iii. A distribution atypical for true atopic

dermatitis

b. Chronic eczema and dermatitis

c. Skin infections

i. Frequent presentation in infancy

a) Furuncles

b) Occasional “cold” abscesses

c) Cellulitis

ii. Multiple staphylococcal abscesses on the

skin (furunculosis)

a) Most common around the face

b) Tender and warm to touch

iii. Cold abscesses

a) A large fluctuant mass that feels like

a tumor or cyst

b) Neither hot or tender

c) Not associated with systemic symptoms,

fever, or other signs of local or general-

ized inflammation

d) Filled with pus that always grows Staph-

ylococcus aureuse) Pathognomic to hyper-IgE syndrome

f) Not essential to the diagnosis

d. Skin abscesses

e. Candidiasis

3. Infections

a. Pulmonary infections

i. Recurrent and severe

ii. Most common infecting organism: Staphylo-

coccus aureusiii. Chronic infections

a) Sinusitis

b) Discharging otitis media

c) Otitis externa

d) Mastoiditis

iv. Long-term complications

a) Bronchiectasis

b) Bronchopleural fistulae

c) Pneumatocele secondary to staphylococ-

cal pneumonia

b. Mucocutaneous candidiasis and fungal infection

i. Chronic candidiasis (83%)

a) Mucosa sites (oral moniliasis)

b) Nail fungal infection and dystrophy sec-

ondary to Candida albicans

ii. Aspergillus infectioniii. Cryptococcal infection

c. Other serious infections

i. Skin, sinopulmonary, and bone infections:

most common

ii. Staphylococcus: the most frequently

infecting organisms

iii. Encapsulated organisms

a) Haemophilus

b) Streptococcus pneumoniaeiv. Opportunistic infections: Pneumocystis

carinii

4. Facial and dental abnormalities

a. Characteristic coarse facies

i. Frontal bossing

ii. Wide alar base of the nose

iii. Wide outer canthal distance

iv. Rare craniosynostosis

v. Midline facial defects

vi. High-arched palate

b. Red hair: uncommon finding

c. Retained primary teeth (72%): failure or delay of

shedding of the primary teeth secondary to lack

of root resorption

5. Skeletal abnormalities

a. Scoliosis (76%)

b. Pathological fractures

i. Secondary to minor trauma

ii. Associated with osteopenia

iii. Frequent recurrent fractures (57%)

iv. Systemic infections at fracture sites

a) Recurrent bacterial arthritis

b) Staphylococcal osteomyelitis

c. Generalized joint hyperextensibility (68%)

i. Fingers

ii. Wrists

iii. Shoulders

iv. Hips

v. Knees

vi. Genu valgum

6. Vascular features (Yavuz and Chee 2009): consti-

tute one of the major clinical characteristics in HIES

a. Types of vascular abnormalities

i. Aneurysms (coronary, aortic, carotid, and

cerebral)

ii. Pseudoaneurysms

iii. Congenital patent ductus venosus

1098 Hyper-IgE Syndrome

iv. Superior vena cava syndrome

v. Vasculitides

vi. Vascular ectasia

vii. Thrombosis

viii. Others

b. May be congenital or acquired, in the veins and

arteries, affecting both sexes

c. Can be seen in all subtypes of HIES

d. Can be fatal in children and adults

e. Limited pathological investigations revealed

the presence of vasculitis.

f. Presence of hypereosinophilia, vasculitis, and

defective angiogenesis in HIES may contribute to

the formation of vascular abnormalities in HIES.

7. Association with isolated reports of autoimmune

disease

a. Systemic lupus erythematosus

b. Dermatomyositis

c. Membranoproliferative glomerulonephritis

8. Malignant changes

a. Hodgkin disease

b. Lymphoma

c. Leukemias

d. Cancers of the vulva, liver, and lung

9. Autosomal recessive hyper-IgE syndrome (AR-HIES)

(Renner et al. 2004)

a. Similar features

i. Extremely elevated serum IgE

ii. Severe eczema

iii. Recurrent skin bacterial and viral infections

as well as sinopulmonary infection

b. Distinctive features

i. Lack the somatic features, such as the char-

acteristic facies, scoliosis, and the failure of

baby teeth to exfoliate

ii. Although pneumonias occur in AR-HIES,

pneumatoceles do not form.

iii. Has a much higher rate of cutaneous viral

infections such as Molluscum contagiosum,Herpes simplex, and varicella infections

iv. Has frequent neurologic disease, ranging

from facial paralysis to hemiplegia, in

some cases due to CNS vasculitis

v. Mortality: high at a young age in AR-HIES

with sepsis more frequent than in AD-HIES

vi. Eosinophilia and elevated serum IgE:

the most consistent laboratory findings

andmay bemore dramatic than in AD-HIES

vii. Autoimmune cytopenias may occur.

Diagnostic Investigations

1. Routine laboratory workup

a. Grossly elevated serum polyclonal IgE: at least

ten times normal (peak serum IgE>2,000 IU/mL)

b. Accompanying eosinophilia

2. Radiographs, CT scan, and MRI imaging

a. Pulmonary abnormalities

i. Recurrent alveolar lung infections

ii. Pneumatoceles

iii. Occasional pneumothorax

b. Skeletal abnormalities

i. Full evaluations and monitor vigilantly for

fractures after even minor trauma

ii. Scoliosis

c. CNS abnormalities on brain MRI (Freeman et al.

2007)

i. Remarkably common and previously

unrecognized aspect of HIES

ii. Several patients with lacunar infarcts in addi-

tion to focal hyperintensities suggest possible

small vessel disease.

3. Skin biopsy (Chamlin et al. 2002)

a. An eosinophilic infiltrate similar to that seen in

eosinophilic pustular folliculitis

b. Spongiosis

c. Perivascular dermatitis

4. Molecular genetic diagnosis

a. AD-HIES: investigate STAT3 mutations

b. AR-HIES: investigate DOCK8 mutations in

patients with a phenotype of elevated IgE, eosin-

ophilia, and recurrent skin boils, pneumonia,

and viral infections (especially molluscum

contagiosum and herpes) (Engelhardt et al. 2009)

Genetic Counseling

1. Recurrence risk

a. Autosomal recessive inheritance

i. Patient’s sib: 25%

ii. Patient’s offspring: not increased unless the

spouse is a carrier

b. Autosomal dominant inheritance

i. Patient’s sib: not increased unless one of the

parents is affected, in which case, there will

be 50% risk of sibling affected

ii. Patient’s offspring: 50%

Hyper-IgE Syndrome 1099

2. Prenatal diagnosis for AD-HIES (Freeman et al. 2010)

a. Possible for pregnancies at increased risk by

analysis of DNA extracted from fetal cells

obtained by amniocentesis or chorionic villus

sampling (CVS):The disease-causing allele of

an affected family member must be identified

before prenatal testing can be performed.

b. Preimplantation genetic diagnosis (PGD) may

be available for families in which the disease-

causing mutation has been identified previously.

3. Management (Erlewyn-Lajeunnesse 2000; Freeman

and Holland 2009)

a. Largely supportive

b. Prompt treatment of infection with prolonged

intravenous antibiotics

c. Treatment of eczema and prevention of

S. aureus abscesses are most successfully

accomplished with antiseptics such as bathing

in bleach (120 mL of bleach in tub of water for

15 min three times weekly) or swimming in

chlorinated pools.

d. Active suspicion of pneumonia is necessary

because systemic symptoms of illness are

often lacking.

e. Antimicrobial prophylaxis

i. Prevents recurrent sinopulmonary infec-

tions with trimethoprim–sulfamethoxazole,

a frequent choice

ii. Pneumonias should be treated aggressively

to try to prevent parenchymal damage.

iii. If pneumatocoeles and bronchiectasis are

present, antimicrobial prophylaxis often

needs to be broadened to cover Gram-

negative bacteria and fungi.

iv. Management of pneumatocoeles is com-

plex, as these cysts when secondarily

infected carry significant risk for morbidity

and mortality; however, surgery is not with-

out risk, as HIES patients may have trouble

re-expanding their lungs and soilage of the

pleural space can occur.

f. Cimetidine, the histamine receptor-2 (H2)

antagonist

i. Shown to reverse the hyper-IgE syndrome

neutrophil chemotactic defect in vitro

ii. A single patient showed a clinical improve-

ment on treatment with improved neutrophil

chemotaxis in spite of a clinical relapse.

iii. Another seven patients treated with H2

antagonist with benefit.

g. Cyclosporine may be helpful.

h. Bronchoscopy may help isolate causative path-

ogens and clear pus.

i. Dental extraction of primary teeth

j. Surgical intervention by incision and drainage

of abscesses

k. Chest tube drainage and lobectomy for compli-

cations of pneumonias

l. Orthopedic cares for fractures and scoliosis

m. Dermatitis

i. Topical steroid

ii. Topical antifungals

iii. Emollient creams

n. Isotretinoin used to improve dermatitis

o. High-dose intravenous g-globulin for patients

with aberrant humoral immunity: Intravenous

immunoglobulin (IVIG) may decrease the

number of infections for some individuals

and is the most frequent immunomodulator

used.

p. Invasive approach with plasmapheresis with

temporary improvement of skin condition and

free of infections

q. Bone marrow transplantation: only hope of cure

at present, likely not fully corrective

r. A single report of a peripheral stem cell

transplantation

i. Serum IgE returned to normal

ii. Disappearance of symptoms

iii. Unfortunately, patient died of interstitial

pneumonia

s. Hematopoietic cell transplantation (Gatz et al.

2010)

i. Curative in patients with AR-HIES

ii. Should be considered early before life-

threatening complications develop, which

include malignancies

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a c

b

d

Fig. 1 (a–d) A 3-year-9-month-old patient with hyperimmuno-

globulin E syndrome showing skin scars on his arm and bowing

of the legs. Facial features included frontal bossing, wide alar

basis of the nose, and wide outer canthal distance. He had history

of recurrent pneumonias, otitis media, asthma, and fractures of

the leg bones. At 2 years and 10 months of age, IgE was 15,610

(�93 KU/L). He is currently on intravenous immunoglobulin

therapy with antibiotic prophylaxis


Fig. 2 A 13-year-old boy had a history of recurrent pneumonias,

a right hip infection, and significant atopic dermatitis. Facial

features included frontal bossing, wide alar basis of the nose,

and wide outer canthal distance. Laboratory tests showed

hyperimmunoglobulin E


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Atlas of Genetic Diagnosis and Counseling || Hyper-IgE Syndrome