Hyperimmunoglobulin E syndrome

Hyper-IgE syndrome
Classification and external resources
Specialty	hematology
ICD-10	D82.4
ICD-9-CM	288.1
OMIM	243700 147060
DiseasesDB	29572
MedlinePlus	001311
eMedicine	derm/845 ped/1074
MeSH	D007589

Hyperimmunoglobulinemia E syndrome^[1] (HIES), of which the autosomal dominant form is called Job's syndrome^[1] or Buckley syndrome,^[1] is a heterogeneous group of immune disorders.

Presentation

It is characterized by recurrent "cold" staphylococcal infections,^[2] 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 concentrations of the serum antibody IgE. Inheritance can be autosomal dominant or autosomal recessive.^[3] 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.

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.^[4] 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.^[5]

Pathophysiology

Abnormal neutrophil chemotaxis due to decreased production of interferon gamma by T lymphocytes is thought to cause the disease.^[6]

Both autosomal dominant and recessive inheritance have been described:^[7]^[8]

Autosomal dominant:

STAT3 may present as HIES with characteristic facial, dental, and skeletal abnormalities^[9] 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 [eczema]. The disease was linked to mutations in the STAT3 gene after cytokine profiles indicated alterations in the STAT3 pathway.^[10]

Autosomal recessive:

DOCK8 - DOCK8 Immunodeficiency Syndrome (DIDS) presents primarily with immune effects including HEIS.^[11] Eczema is prominent, food^[12] and environmental allergies are common,^[7] and asthma and anaphylaxis has been variably reported.^[7]
PGM3, a Congenital Disorder of Glycosylation, may present as HIES with neurocognitive impairment and hypomyelination. See PGM3 deficiency.^[13]
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,^[14] although more often only with immunodeficiency.^[15]

Laboratory studies

Elevated IgE is the hallmark of HIES. An IgE level greater than 2,000 IU/mL is often considered diagnostic.^[16] 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.^[17] 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.

Clinical characteristics

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's 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.^[17]

Treatment

Most patients with hyper IgE syndrome are treated with chronic antibiotics to help protect them from 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.^[18]

References

1 2 3 Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.
↑ "hyperimmunoglobulinemia E syndrome" at Dorland's Medical Dictionary
↑ Dermatologic Manifestations of Job Syndrome at eMedicine
↑ Davis S, Schaller J, Wedgwood R; Schaller; Wedgwood (1966). "Job's Syndrome. Recurrent, "cold", staphylococcal abscesses". Lancet 1 (7445): 1013–5. doi:10.1016/S0140-6736(66)90119-X. PMID 4161105.
↑ Buckley R, Wray B, Belmaker E; Wray; Belmaker (1972). "Extreme hyperimmunoglobulinemia E and undue susceptibility to infection". Pediatrics 49 (1): 59–70. PMID 5059313.
↑ Borges W, Augustine N, Hill H; Augustine; Hill (2000). "Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome". J Pediatr 136 (2): 176–80. doi:10.1016/S0022-3476(00)70098-9. PMID 10657822.
1 2 3 Rael, Efren L; Marshall, Robert T; McClain, Jonathan J (2012-07-15). "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. ISSN 1939-4551. PMC 3651150. PMID 23283142.
↑ Freeman, Alexandra F.; Holland, Steven M. (2009-05-01). "Clinical Manifestations, Etiology, and Pathogenesis of the Hyper IgE Syndromes". Pediatric research 65 (5 Pt 2): 32R–37R. doi:10.1203/PDR.0b013e31819dc8c5. ISSN 0031-3998. PMC 2919366. PMID 19190525.
↑ Rael, Efren L.; Marshall, Robert T.; McClain, Jonathan J. (2012-07-01). "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. ISSN 1939-4551. PMC 3651150. PMID 23283142.
↑ Holland, Steven M.; DeLeo, Frank R.; Elloumi, Houda Z.; Hsu, Amy P.; Uzel, Gulbu; Brodsky, Nina; Freeman, Alexandra F.; Demidowich, Andrew; Davis, Joie; Turner, Maria L.; Anderson, Victoria L.; Darnell, Dirk N.; Welch, Pamela A.; Kuhns, Douglas B.; Frucht, David M.; Malech, Harry L.; Gallin, John I.; Kobayashi, Scott D.; Whitney, Adeline R.; Voyich, Jovanka M.; Musser, James M.; Woellner, Cristina; Schäffer, Alejandro A.; Puck, Jennifer M.; Grimbacher, Bodo (2007). "STAT3 Mutations in the Hyper-IgE Syndrome". The New England Journal of Medicine 357 (16): 1608–19. doi:10.1056/NEJMoa073687. PMID 17881745.
↑ Zhang Q; Davis JC; Lamborn IT; et al. (November 2009). "Combined immunodeficiency associated with DOCK8 mutations". N. Engl. J. Med. 361 (21): 2046–55. doi:10.1056/NEJMoa0905506. PMC 2965730. PMID 19776401.
↑ Boos, A. C.; Hagl, B.; Schlesinger, A.; Halm, B. E.; Ballenberger, N.; Pinarci, M.; Heinz, V.; Kreilinger, D.; Spielberger, B. D. (2014-05-20). "Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE-based sensitization pattern". Allergy. doi:10.1111/all.12416. ISSN 1398-9995. PMID 24840882.
↑ Yang, Linlin; Fliegauf, Manfred; Grimbacher, Bodo (2014-12-01). "Hyper-IgE syndromes: reviewing PGM3 deficiency". Current Opinion in Pediatrics 26 (6): 697–703. doi:10.1097/MOP.0000000000000158. ISSN 1531-698X. PMID 25365149.
↑ Minegishi, Yoshiyuki; Saito, Masako; Morio, Tomohiro; Watanabe, Ken; Agematsu, Kazunaga; Tsuchiya, Shigeru; Takada, Hidetoshi; Hara, Toshiro; Kawamura, Nobuaki (2006-11-01). "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity". Immunity 25 (5): 745–755. doi:10.1016/j.immuni.2006.09.009. ISSN 1074-7613. PMID 17088085.
↑ Kreins, Alexandra Y.; Ciancanelli, Michael J.; Okada, Satoshi; Kong, Xiao-Fei; Ramírez-Alejo, Noé; Kilic, Sara Sebnem; El Baghdadi, Jamila; Nonoyama, Shigeaki; Mahdaviani, Seyed Alireza (2015-09-21). "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome". The Journal of Experimental Medicine 212 (10): 1641–1662. doi:10.1084/jem.20140280. ISSN 1540-9538. PMC 4577846. PMID 26304966.
↑ Ochs, HD; Notarangelo, LD (2010). Williams Hematology: Chapter 82. Immunodeficiency Diseases (8th ed.). New York: McGraw-Hill Medical. ISBN 9780071621519.
1 2 Grimbacher B, Holland S, Gallin J, Greenberg F, Hill S, Malech H, Miller J, O'Connell A, Puck J; Holland; Gallin; Greenberg; Hill; Malech; Miller; O'Connell; Puck (1999). "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder". N Engl J Med 340 (9): 692–702. doi:10.1056/NEJM199903043400904. PMID 10053178.
↑ Kimata H (1995). "High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome". J Allergy Clin Immunol 95 (3): 771–4. doi:10.1016/S0091-6749(95)70185-0. PMID 7897163.

External links

U.S. NIH Genetic Test Registry
GeneDx Hyper-IgE Syndrome Panel HIES information sheet
National Organization for Rare Disorders: Autosomal Dominant Hyper IgE Syndrome Autosomal Recessive Hyper IgE Syndrome
U.S. National Institutes of Health (NIH): Clinical Research Studies: National Institute of Allergy and Infectious Diseases (NIAID) (observational) study number 00-I-0159: Natural History, Management, and Genetics of the hyperimmunoglobulin E Recurrent Infection syndrome (HIES) - NCT00006150

Immune disorders: Lymphoid and complement immunodeficiency (D80–D85, 279.0–4)

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

AIDS

Leukopenia:
Lymphocytopenia

Idiopathic CD4+ lymphocytopenia

Complement deficiency

Genetic disorder, protein biosynthesis: Transcription factor/coregulator deficiencies

(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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