Hyperimmunoglobulin E syndrome

(Redirected from Hyper-IgE syndrome) Medical condition

Hyper-IgE syndrome
Other names	HIES

The structure of the Immunoglobulin E (IgE) antibody.
Specialty	Immunology

Hyperimmunoglobulinemia E syndrome (HIES), of which the autosomal dominant form is called Job's syndrome or Buckley syndrome, is a heterogeneous group of immune disorders. Job's is also very rare at about 300 cases currently in the literature.

Presentation

It is characterized by recurrent "cold" staphylococcal infections (due to impaired recruitment of neutrophils), unusual eczema-like skin rashes, severe lung infections that result in pneumatoceles (balloon-like lesions that may be filled with air or pus or scar tissue) and very high (> 2000 IU/mL or 4800 mcg/L) concentrations of the serum antibody IgE. Inheritance can be autosomal dominant or autosomal recessive. Many patients with autosomal dominant STAT3 hyper-IgE syndrome have characteristic facial and dental abnormalities, fail to lose their primary teeth, and have two sets of teeth simultaneously.

Pathophysiology

Abnormal neutrophil chemotaxis due to decreased production of interferon gamma by T lymphocytes is thought to cause the disease.

Both autosomal dominant and recessive inheritance have been described:

Autosomal dominant:

STAT3 may present as HIES with characteristic facial, dental, and skeletal abnormalities that has been called Job's Syndrome. A common mnemonic used to remember the symptoms is FATED: coarse or leonine facies, cold staph abscesses, retained primary teeth, increased IgE, and dermatologic problems . The disease was linked to mutations in the STAT3 gene after cytokine profiles indicated alterations in the STAT3 pathway. This altered pathway directly reduces the modulation capacity of interleukins 6 and 10 which, respectively, inhibit the genesis of Th17 cells that, in tandem with CD4 cells, protect against bacterial and fungal infections, and foster the inappropriate immune responses exhibited by those with Job Syndrome.

Autosomal recessive:

DOCK8 - DOCK8 Immunodeficiency Syndrome (DIDS) presents primarily with immune effects including HEIS. Eczema is prominent, food and environmental allergies are common, and asthma and anaphylaxis has been variably reported.
PGM3, a Congenital Disorder of Glycosylation, may present as HIES with neurocognitive impairment and hypomyelination. See PGM3 deficiency.
SPINK5 may present as HIES with skin and hair effects such as trichorrhexis invaginata (bamboo hair). See Netherton Syndrome (NTS).
TYK2 may present as HIES, although more often only with immunodeficiency.

Diagnosis

Elevated IgE is the hallmark of HIES. An IgE level greater than 2,000 IU/mL is often considered diagnostic. However, patients younger than 6 months of age may have very low to non-detectable IgE levels. Eosinophilia is also a common finding with greater than 90% of patients having eosinophil elevations greater than two standard deviations above the normal mean. Genetic testing is available for STAT3 (Job's Syndrome), DOCK8 (DOCK8 Immunodeficiency or DIDS), PGM3 (PGM3 deficiency), SPINK5 (Netherton Syndrome - NTS), and TYK2 genetic defects.

Types

HIES often appears early in life with recurrent staphylococcal and candidal infections, pneumonias, and eczematoid skin.

Autosomal dominant Hyper-IgE Syndrome caused by STAT3 defects, called Job Syndrome, have characteristic facial, dental, and skeletal abnormalities. Patients with STAT3 HIES may have either delay of or failure in shedding of primary teeth. The characteristic facial features are usually set by age 16. These include facial asymmetry, a prominent forehead, deep-set eyes, a broad nasal bridge, a wide, fleshy nasal tip, and mild prognathism. Additionally, facial skin is rough with prominent pores. Finally, some patients with STAT3 HIES have scoliosis, as well as bones that fracture easily.
Autosomal recessive

Treatment

Most patients with hyper IgE syndrome are treated with long-term antibiotic therapy to prevent staphylococcal infections. Good skin care is also important in patients with hyper IgE syndrome. High-dose intravenous gamma-globulin has also been suggested for the treatment of severe eczema in patients with HIES and atopic dermatitis.

History

HIES was first described by Davis et al. in 1966 in two girls with red hair, chronic dermatitis, and recurrent staphylococcal abscesses and pneumonias. They named the disease after the biblical figure Job, whose body was covered with boils by Satan. In 1972, Buckley et al. described two boys with similar symptoms as well as coarse facies, eosinophilia, and elevated serum IgE levels. These two syndromes are thought to be the same and are under the broad category of HIES.

References

^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
"hyperimmunoglobulinemia E syndrome" at Dorland's Medical Dictionary
"Hyper-IgE Syndrome". Merck Manual. Merck Sharp & Dohme Corp. Retrieved 3 August 2021.
Dermatologic Manifestations of Job Syndrome at eMedicine
^ Freeman, Alexandra F.; Holland, Steven M. (2008). "The Hyper-IgE Syndromes". Immunology and Allergy Clinics of North America. 28 (2). Elsevier BV: 277–291. doi:10.1016/j.iac.2008.01.005. ISSN 0889-8561. PMC 2683262. PMID 18424333.
Borges WG, Augustine NH, Hill HR (February 2000). "Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome". The Journal of Pediatrics. 136 (2): 176–80. doi:10.1016/S0022-3476(00)70098-9. PMID 10657822.
^ Rael EL, Marshall RT, McClain JJ (July 2012). "The Hyper-IgE Syndromes: Lessons in Nature, From Bench to Bedside". The World Allergy Organization Journal. 5 (7): 79–87. doi:10.1097/WOX.0b013e31825a73b2. PMC 3651150. PMID 23283142.
Freeman AF, Holland SM (May 2009). "Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes". Pediatric Research. 65 (5 Pt 2): 32R – 37R. doi:10.1203/PDR.0b013e31819dc8c5. PMC 2919366. PMID 19190525.
Rael EL, Marshall RT, McClain JJ (July 2012). "The Hyper-IgE Syndromes: Lessons in Nature, From Bench to Bedside". The World Allergy Organization Journal. 5 (7): 79–87. doi:10.1097/WOX.0b013e31825a73b2. PMC 3651150. PMID 23283142.
Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. (October 2007). "STAT3 mutations in the hyper-IgE syndrome". The New England Journal of Medicine. 357 (16): 1608–19. doi:10.1056/NEJMoa073687. PMID 17881745.
Hafsi, Wissem; Yarrarapu, Siva Naga S. (2021), "Job Syndrome", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30247822, retrieved 2021-11-28
Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. (November 2009). "Combined immunodeficiency associated with DOCK8 mutations". The New England Journal of Medicine. 361 (21): 2046–55. doi:10.1056/NEJMoa0905506. PMC 2965730. PMID 19776401.
Boos AC, Hagl B, Schlesinger A, Halm BE, Ballenberger N, Pinarci M, et al. (2014-05-20). "Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE-based sensitization pattern". Allergy. 69 (7): 943–953. doi:10.1111/all.12416. PMID 24840882.
Yang L, Fliegauf M, Grimbacher B (December 2014). "Hyper-IgE syndromes: reviewing PGM3 deficiency". Current Opinion in Pediatrics. 26 (6): 697–703. doi:10.1097/MOP.0000000000000158. PMID 25365149. S2CID 24566050.
Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. (November 2006). "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity". Immunity. 25 (5): 745–55. doi:10.1016/j.immuni.2006.09.009. PMID 17088085.
Kreins AY, Ciancanelli MJ, Okada S, Kong XF, Ramírez-Alejo N, Kilic SS, et al. (September 2015). "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome". The Journal of Experimental Medicine. 212 (10): 1641–62. doi:10.1084/jem.20140280. PMC 4577846. PMID 26304966.
Ochs, HD; Notarangelo, LD (2010). Williams Hematology: Chapter 82. Immunodeficiency Diseases (8th ed.). New York: McGraw-Hill Medical. ISBN 9780071621519.
^ Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, et al. (March 1999). "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder". The New England Journal of Medicine. 340 (9): 692–702. doi:10.1056/NEJM199903043400904. PMID 10053178.
Yaakoubi, Roukaya; Mekki, Najla; Ben-Mustapha, Imen; Ben-Khemis, Leila; Bouaziz, Asma; Ben Fraj, Ilhem; Ammar, Jamel; Hamzaoui, Agnès; Turki, Hamida; Boussofara, Lobna; Denguezli, Mohamed; Haddad, Samir; Ouederni, Monia; Bejaoui, Mohamed; Chan, Koon Wing; Lau, Yu Lung; Mellouli, Fethi; Barbouche, Mohamed-Ridha; Ben-Ali, Meriem (January 10, 2023). "Diagnostic challenge in a series of eleven patients with hyper IgE syndromes". Frontiers in Immunology. 13. Frontiers Media SA. doi:10.3389/fimmu.2022.1057679. ISSN 1664-3224. PMC 9871884. PMID 36703986.
"Hyper IgE syndrome". Immune Deficiency Foundation. August 9, 2023. Retrieved October 14, 2023.
Kimata H (March 1995). "High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome". The Journal of Allergy and Clinical Immunology. 95 (3): 771–4. doi:10.1016/S0091-6749(95)70185-0. PMID 7897163.
Davis SD, Schaller J, Wedgwood RJ (May 1966). "Job's Syndrome. Recurrent, "cold", staphylococcal abscesses". Lancet. 1 (7445): 1013–5. doi:10.1016/S0140-6736(66)90119-X. PMID 4161105.
Buckley RH, Wray BB, Belmaker EZ (January 1972). "Extreme hyperimmunoglobulinemia E and undue susceptibility to infection". Pediatrics. 49 (1): 59–70. doi:10.1542/peds.49.1.59. PMID 5059313. S2CID 245107427.

External links

Classification	D ICD-10: D82.4 ICD-9-CM: 288.1 OMIM: 243700 147060 MeSH: D007589 DiseasesDB: 29572
External resources	MedlinePlus: 001311 eMedicine: derm/845 ped/1074

Lymphoid and complement disorders causing immunodeficiency

Primary

Antibody/humoral
(B)

Hypogammaglobulinemia	X-linked agammaglobulinemia Transient hypogammaglobulinemia of infancy
Dysgammaglobulinemia	IgA deficiency IgG deficiency IgM deficiency Hyper IgM syndrome (1 2 3 4 5) Wiskott–Aldrich syndrome Hyper-IgE syndrome
Other	Common variable immunodeficiency ICF syndrome

T cell deficiency
(T)

thymic hypoplasia: hypoparathyroid (Di George's syndrome)
euparathyroid (Nezelof syndrome
Ataxia–telangiectasia)

peripheral: Purine nucleoside phosphorylase deficiency

Hyper IgM syndrome (1)

Severe combined
(B+T)

x-linked: X-SCID
autosomal: Adenosine deaminase deficiency
Omenn syndrome
ZAP70 deficiency
Bare lymphocyte syndrome

Acquired

HIV/AIDS

Leukopenia:
Lymphocytopenia

Idiopathic CD4+ lymphocytopenia

Complement
deficiency

Genetic disorders relating to deficiencies of transcription factor or coregulators

(1) Basic domains

1.2	Feingold syndrome Saethre–Chotzen syndrome
1.3	Tietz syndrome

(2) Zinc finger
DNA-binding domains

2.1	(Intracellular receptor): Thyroid hormone resistance Androgen insensitivity syndrome PAIS MAIS CAIS Kennedy's disease PHA1AD pseudohypoaldosteronism Estrogen insensitivity syndrome X-linked adrenal hypoplasia congenita MODY 1 Familial partial lipodystrophy 3 SF1 XY gonadal dysgenesis
2.2	Barakat syndrome Tricho–rhino–phalangeal syndrome
2.3	Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome Denys–Drash syndrome Duane-radial ray syndrome MODY 7 MRX 89 Townes–Brocks syndrome Acrocallosal syndrome Myotonic dystrophy 2
2.5	Autoimmune polyendocrine syndrome type 1

(3) Helix-turn-helix domains

3.1	ARX Ohtahara syndrome Lissencephaly X2 MNX1 Currarino syndrome HOXD13 SPD1 synpolydactyly PDX1 MODY 4 LMX1B Nail–patella syndrome MSX1 Tooth and nail syndrome OFC5 PITX2 Axenfeld syndrome 1 POU4F3 DFNA15 POU3F4 DFNX2 ZEB1 Posterior polymorphous corneal dystrophy Fuchs' dystrophy 3 ZEB2 Mowat–Wilson syndrome
3.2	PAX2 Papillorenal syndrome PAX3 Waardenburg syndrome 1&3 PAX4 MODY 9 PAX6 Gillespie syndrome Coloboma of optic nerve PAX8 Congenital hypothyroidism 2 PAX9 STHAG3
3.3	FOXC1 Axenfeld syndrome 3 Iridogoniodysgenesis, dominant type FOXC2 Lymphedema–distichiasis syndrome FOXE1 Bamforth–Lazarus syndrome FOXE3 Anterior segment mesenchymal dysgenesis FOXF1 ACD/MPV FOXI1 Enlarged vestibular aqueduct FOXL2 Premature ovarian failure 3 FOXP3 IPEX
3.5	IRF6 Van der Woude syndrome Popliteal pterygium syndrome

(4) β-Scaffold factors
with minor groove contacts

4.2	Hyperimmunoglobulin E syndrome
4.3	Holt–Oram syndrome Li–Fraumeni syndrome Ulnar–mammary syndrome
4.7	Campomelic dysplasia MODY 3 MODY 5 SF1 SRY XY gonadal dysgenesis Premature ovarian failure 7 SOX10 Waardenburg syndrome 4c Yemenite deaf-blind hypopigmentation syndrome
4.11	Cleidocranial dysostosis

(0) Other transcription factors

0.6	Kabuki syndrome

Ungrouped

Transcription coregulators

Coactivator:	CREBBP Rubinstein–Taybi syndrome
Corepressor:	HR (Atrichia with papular lesions)

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