513 Hyper-IgE syndrome is a rare, hereditary multisystem disor- der characterized clinically by hyperimmuno-globulinemia 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).
GENETICS/BASIC DEFECTS
1. Inheritance:
a. Autosomal dominant with variable penetrance and expressivity
b. Linkage to a region on chromosome 4q demonstrated in several affected families
c. An up-regulating mutation in the interleukin-4 recep- tor gene on chromosome 16, demonstrated in some patients with hyper IgE syndrome
2. Etiology
a. The underlying cause of hyper IgE syndrome still unknown
b. Reduced neutrophil chemotaxis
c. Variable T cell defects demonstrated in some patients d. Cytokine and chemokine dysregulation
CLINICAL FEATURES
1. Classic triad (77%) a. Abscesses b. Pneumonia c. An elevated IgE 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 generalized inflammation
d) Filled with pus that always grows Staphylo- coccus aureus
e) 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 aureus
iii. 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 staphylococcal pneumonia
b. Mucocutaneous candidiasis and fungal infection i. Chronic candidiasis (83%)
a) Mucosa sites (oral moniliasis)
b) Nail fungal infection and dystrophy secondary to Candida albicans
ii. Aspergillus infection iii. 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 pneumoniae
iv. 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
Hyper-IgE Syndrome
514 HYPER-IgE SYNDROME
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. Association with isolated reports of autoimmune disease a. Systemic lupus erythematosus
b. Dermatomyositis
c. Membranoproliferative glomerulonephritis 7. Malignant changes
a. Hodgkin disease b. Lymphoma
DIAGNOSTIC INVESTIGATIONS
1. Routine laboratory workup
a. Grossly elevated serum polyclonal IgE: at least 10 times normal (>2000 IU/mL)
b. Accompanying eosinophilia 2. Radiographs and CT scan
a. Pulmonary abnormalities
i. Recurrent alveolar lung infections ii. Pneumatoceles
iii. Occasional pneumothorax b. Skeletal abnormalities
i. Full evaluations and monitor vigilantly for frac- tures after even minor trauma
ii. Scoliosis 3. Skin biopsy
a. An eosinophilic infiltrate similar to that seen in eosinophilic pustular folliculitis
b. Spongiosis
c. Perivascular dermatitis
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: not increased unless one of the parents is affected, in which case there will be 50% risk of sibling affected
b. Patient’s offspring: 50%
2. Prenatal diagnosis currently not available 3. Management
a. Antibiotics prophylaxis b. Dermatitis
i. Topical steroid ii. Topical antifungals iii. Emollient creams
c. Prompt treatment of infection with prolonged intra- venous antibiotics
d. Dental extraction of primary teeth
e. Surgical intervention by incision and drainage of abscesses
f. Chest tube drainage and lobectomy for complications of pneumonias
g. Orthopedic cares for fractures and scoliosis
h. Cimetidine, the histamine receptor-2 (H2) antagonist i. Shown to reverse the hyper-IgE syndrome neu-
trophil chemotactic defect in vitro
ii. A single patient showed a clinical improvement on treatment with improved neutrophil chemo- taxis in spite of a clinical relapse
iii. Another seven patients treated with H2 antago- nist with benefit
i. Cromoglycate tried in a single patient with good clinical effect
j. Isotretinoin used to improve dermatitis
k. High dose intravenous γ-globulin for patients with aberrant humoral immunity
l. Invasive approach with plasmapheresis with temporary improvement of skin condition and free of infections m. Bone marrow transplantation: only hope of cure at
present
n. 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 pneu- monia
REFERENCES
Buckley RH: The hyper-IgE syndrome. Clin Rev Allergy Immunol 20:139–154, 2001.
Buckley RH, Wray BB, Belmaker EZ: Extreme hyperimmunoglobulin E and undue susceptibility to infection. Pediatrics 49:59–70, 1972.
Chamlin SL, McCalmont TH, Cunningham BB, et al.: Cutaneous manifesta- tions of hyper-IgE syndrome in infants and children. J Pediatr 141:572–575, 2002.
Chehimi J, Elder M, Greene J, et al.: Cytokine and chemokine dysregulation in hyper-IgE syndrome. Clin Immunol 100:49–56, 2001.
Dahl MV: Hyper-IgE syndrome revisited. Int J Dermatol 41:618–619, 2002.
Dau PC: Remission of hyper-IgE treated with plasmapheresis and cytotoxic immunosuppression. J Clin Apheresis 4:8–12, 1988.
Davis SD, Schaller J, Wedgwood RJ: Job’s syndrome: recurrent, “cold,”
staphylococcal abscesses. Lancet 1:1013–1015, 1966.
Donabedian H, Gallin JI: The hyperimmunoglobulin E recurrent – infection (Job’s) syndrome: a review of the NIH experience and the literature.
Medicine 62:195–208, 1983.
Erlewyn-Lajeunesse MDS: Hyperimmunoglobulin-E syndrome with recurrent infection: A review of current opinion and treatment. Pediatr Allergy Immunol 11:133–141, 2000.
Gennery AR, Flood TJ, Abinun M, et al.: Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant 25:1303–1305, 2000.
Grimbacher B, Holland SM, Gallin JI, et al.: Hyper-IgE syndrome with recur- rent infections—an autosomal dominant multisystem disorder. N Engl J Med 340:692–702, 1999.
Grimbacher B, Schaffer AA, Holland SM, et al.: Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet 65:735–744, 1999.
Jhaveri KS, Sahani DV, Shetty PG, et al.: Hyperimmunoglobulinaemia E syndrome: Pulmonary imaging features. Austral Radiol 44:328–330, 2000.
Khurana-Hershey GK, Friedrich MF, Esswein LA, et al.: The association of atopy with a gain of function mutation in the alpha subunit of the inter- leukin-4 receptor. N Engl J Med 337:1720–1725, 1997.
Kikkawa Y, Kamimura K, Hamajima T, et al.: Thymic alymphoplasia with hyper-IgE-globulinemia. Pediatrics 51:690–696, 1973.
HYPER-IgE SYNDROME 515
Kimata H: High-dose intravenous gamma-globulin treatment for hyperim- munoglobulin E syndrome. J Allergy Clin Immunol 95:771–774, 1995.
Mawhinney H, Killen M, Fleming WA, et al.: The hyperimmunoglobulin E syndrome-a neutrophil chemotactic defect reversible by histamine H2 receptor blockade? Clin Immunol Immunopathol 17:483–491, 1980.
Nester TA, Wagnon AH, Reilly WF, et al.: Effects of allogeneic peripheral stem cell transplantation in a patient with Job syndrome of hyperim- munoglobulinemia E and recurrent infections. Am J Med 105:162–164, 1998.
Ochs HD, Kraemer MJ, Lindgren CG, et al.: Immune regulation in the hyper- IgE/Job syndrome. Birth Defects Orig Artic Ser 19:57–61, 1983.
Ohga S, Nomura A, Ihara K, et al.: Cytokine imbalance in hyper-IgE syn- drome: reduced expression of transforming growth factor beta and inter- feron gamma genes in circulating activated T cells. Br J Haematol 121:324–331, 2003.
Paganelli R, Quinti I, Carbonari M, et al.: IgG anti-IgE in circulating immune complexes in the hyper-IgE syndrome. Clin Allergy 16:513–521, 1986.
Ring J, Landthaler M: Hyper-IgE syndromes. Curr Probl Dermatol 18:79–88, 1989.
Shemer A, Weiss G, Confino Y, et al.: The hyper-IgE syndrome. Two cases and review of the literature. Int J Dermatol 40:622–628, 2001.
Thompson RA, Kumararatne DS: Hyper-IgE syndrome and H2-recptor block- ade. Lancet 2:630, 1989.
Vercelli D, Jabara HH, Cunningham-Rundles C, et al.: Regulation of immunoglobulin (Ig)E synthesis in the hyper-IgE syndrome. J Clin Invest 85:1666–1671, 1990.
Wakim M, Alazard M, Yajima A, et al.: High dose intravenous immunoglobu- lin in atopic dermatitis and hyper-IgE syndrome. Ann Allergy Asthma Immunol 81:153–158, 1998.
Yokota S, Mitsuda T, Shimizu H, et al.: Cromoglycate treatment of a patient with Hyperimmunoglobulin E syndrome. Lancet 335:857–858, 1990.
516 HYPER-IgE SYNDROME
Fig. 1. A 3 year 9 month old patient with hyperimmunoglobulin E syn- drome showing bowing of the legs. He had history of recurrent pneu- monias, otitis media, asthma, and fractures of the leg bones. At 2 year 10 month of age, IgE was 15,610 (≤93 KU/L). He is currently on intra- venous immunoglobulin therapy with antibiotic prophylaxis.
