Hyper-IgE syndrome: Difference between revisions

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__NOTOC__
{{Infobox_Disease |
{{Infobox_Disease |
   Name          = {{PAGENAME}} |
   Name          = {{PAGENAME}} |
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}}
}}
{{SI}}
{{SI}}
{{CMG}}; {{AE}} {{CZ}}
{{CMG}} {{shyam}}; {{AE}} {{JSS}}


{{SK}} Job-Buckley syndrome; Job syndrome; Buckley syndrome.
{{SK}} Job-Buckley syndrome; Job syndrome; Buckley syndrome


==Overview==
==Overview==
'''Hyper IgE syndrome''' (HIES) is a heterogeneous group of disorders characterized by recurrent [[Staphylococcus|staphylococcal]] [[infection]]s, unusual [[eczema]]-like skin rashes, severe [[lung]] infections that result in [[Pneumatocyst|pneumatoceles]] (balloon-like lesions that may be filled with air or pus or scar tissue) and very high concentrations of serum [[IgE]]. Some patients have an [[autosomal dominant]] form of the disease; these patients have problems with their bones including recurrent fractures and [[scoliosis]]. Many patients with [[autosomal dominant]] hyper IgE syndrome fail to lose their baby teeth and have two sets of teeth simultaneously.
'''Hyper IgE syndrome''' (HIES) is a group of disorders characterized by recurrent [[Staphylococcus|staphylococcal]] [[infection]]s, unusual [[eczema]]-like skin rashes, severe [[lung]] infections that result in [[Pneumatocyst|pneumatoceles]] (balloon-like lesions that may be filled with air or pus or scar tissue) and very high concentrations of serum [[IgE]]. Some patients have an [[autosomal dominant]] form of the disease. These patients have problems with their bones including recurrent fractures and [[scoliosis]]. Many patients with [[autosomal dominant]] hyper IgE syndrome fail to lose their [[baby teeth]] and have two sets of teeth simultaneously.


==Historical Perspective==
==Historical Perspective==
* HIES was first described by Davis et al in 1966 and it was named as Job's syndrome.
* HIES was first described by Davis et al in 1966 and was named as [[Job's syndrome]].


* The criterai included triad of eczema, recurrent skin and lung infections and high serum IgE .
* The criteria included triad of [[eczema]], recurrent skin and lung infections and high serum [[IgE]] .


==Classification==
==Classification==
Hyper IgE syndrome is classified into 2 types:
Hyper IgE syndrome is classified into 2 types:<ref name="pmid4161105">{{cite journal| author=Davis SD, Schaller J, Wedgwood RJ| title=Job's Syndrome. Recurrent, "cold", staphylococcal abscesses. | journal=Lancet | year= 1966 | volume= 1 | issue= 7445 | pages= 1013-5 | pmid=4161105 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4161105  }} </ref>
* Autosomal dominant.
* [[Autosomal dominant]]
* Autosomal recessive.
* [[Autosomal recessive]]


==Pathophysiology==
==Pathophysiology==
Abnormal neutrophil [[chemotaxis]] due to decreased production of [[interferon gamma]] is thought to cause the disease.<ref>{{cite journal |author=Borges W, Augustine N, Hill H |title=Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome |journal=J Pediatr |volume=136 |issue=2 |pages=176-80 |year=2000 |pmid=10657822}}</ref> But both [[autosomal dominant]] and [[autosomal recessive|recessive]] inheritance have been described. The disease was linked to mutations in the ''[[STAT3]]'' gene after cytokine profiles indicated alterations in the STAT3 pathway.<ref>Holland SM, DeLeo FR, Elloumi HZ ''et al''. (2007). [http://content.nejm.org/cgi/content/full/NEJMoa073687 STAT3 Mutations in the Hyper-IgE Syndrome]. ''N. Engl. J. Med.'' published online, [[2007-09-19]]. {{DOI|10.1056/NEJMoa073687}}.</ref>
* Hyper IgE syndrome may be caused due to mutations in ''STAT3'' and ''TYK2'' genes.<ref name="pmid5059313">{{cite journal| author=Buckley RH, Wray BB, Belmaker EZ| title=Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. | journal=Pediatrics | year= 1972 | volume= 49 | issue= 1 | pages= 59-70 | pmid=5059313 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5059313  }} </ref><ref name="pmid4129875">{{cite journal| author=Hill HR, Quie PG| title=Raised serum-IgE levels and defective neutrophil chemotaxis in three children with eczema and recurrent bacterial infections. | journal=Lancet | year= 1974 | volume= 1 | issue= 7850 | pages= 183-7 | pmid=4129875 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4129875  }} </ref>


==Causes==
* Signal transducer and activator of transcription 3 ([[STAT3]]) is a [[Cytoplasm|cytoplasmic]] protein and a component of the [[JAK-STAT signaling pathway|JAK-STAT]] pathway of signal [[transduction]].<ref name="pmid22751495">{{cite journal| author=Chandesris MO, Melki I, Natividad A, Puel A, Fieschi C, Yun L et al.| title=Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. | journal=Medicine (Baltimore) | year= 2012 | volume= 91 | issue= 4 | pages= e1-19 | pmid=22751495 | doi=10.1097/MD.0b013e31825f95b9 | pmc=3680355 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22751495  }} </ref>
* Hyper igE syndrome is caused due to mutations in the signal transducer and activator of transcription 3 (''STAT3'') and tyrosine kinase 2 (''TYK2'') gene.
* The binding of various [[Cytokine|cytokines]] to their receptors on the cell surface results in activation of [[Janus kinase|JAK]] proteins, which in turn [[Phosphorylation|phosphorylates]] [[STAT protein|STAT]] proteins.
* These STAT proteins then form [[Dimer|dimers]], translocate to the [[Cell nucleus|nucleus]], bind to specific sites on the [[DNA]], and activate target genes.
* [[Tyrosine kinase]] 2 (TYK2) is part of the [[Janus kinase|JAK]] family of [[kinases]] that are associated with [[cytokine]] receptors.
* A deletion in ''[[TYK2]]'' resulting in a truncated protein that is associated with abnormal signaling for type I [[interferon]], [[Interleukin 6|IL-6]], [[Interleukin 10|IL-10]], [[Interleukin 12|IL-12]], and IL-23.
* Both STAT3 and TYK2 defects lead to impaired [[T helper 17 cell|Th17]] function.
* A defect in Th17 function, results in decreased [[neutrophil]] proliferation and [[chemotaxis]], decreased [[inflammation]], and increased susceptibility to ''[[Candidiasis|Candida]]'' and [[Bacteria|bacterial]] infections.
 
=== Pathogenesis: ===
* [[Neutrophil]] chemotactic defect:<ref name="pmid4137601">{{cite journal| author=Hill HR, Ochs HD, Quie PG, Clark RA, Pabst HF, Klebanoff SJ et al.| title=Defect in neutrophil granulocyte chemotaxis in Job's syndrome of recurrent "cold" staphylococcal abscesses. | journal=Lancet | year= 1974 | volume= 2 | issue= 7881 | pages= 617-9 | pmid=4137601 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4137601  }} </ref><ref name="pmid17676033">{{cite journal| author=Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T et al.| title=Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. | journal=Nature | year= 2007 | volume= 448 | issue= 7157 | pages= 1058-62 | pmid=17676033 | doi=10.1038/nature06096 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17676033  }} </ref>
** [[T helper 17 cell|Th17]] cell production of IL-17 is involved in neutrophil [[chemotaxis]] and proliferation .
** Defective [[T helper 17 cell|Th17]] leads to defects in neutrophil chemotaxis and proliferation .
** [[Interferon-gamma|Interferon (IFN)-gamma]] production is also decreased which results in cutaneous and pulmonary infections.
** Defect in neutrophil chemotaxis results in [[Skin|cutaneous]] cold abscess formation, in which signs of acute [[inflammation]] are absent.
* '''T cell defects'''
** [[STAT3]] plays a crucial role in the differentiation of naive T cells into IL-17 producing [[T helper cell|CD4+ T cells]] (Th17 cells).<ref name="pmid20159255">{{cite journal| author=Woellner C, Gertz EM, Schäffer AA, Lagos M, Perro M, Glocker EO et al.| title=Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. | journal=J Allergy Clin Immunol | year= 2010 | volume= 125 | issue= 2 | pages= 424-432.e8 | pmid=20159255 | doi=10.1016/j.jaci.2009.10.059 | pmc=2878129 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20159255  }} </ref>
** [[T helper 17 cell|Th17]] cells are involved in the response to [[Fungus|fungal]] and extracellular bacterial infections.<ref name="pmid18337720">{{cite journal| author=Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM et al.| title=Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. | journal=Nature | year= 2008 | volume= 452 | issue= 7188 | pages= 773-6 | pmid=18337720 | doi=10.1038/nature06764 | pmc=2864108 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18337720  }} </ref>
** These cells are significantly reduced or absent in patients with HIES.
* '''B cell defects and abnormal IgE regulation'''
** [[B cell|B cells]] are responsible for the synthesis of [[Immunoglobulin E|IgE.]]
** A defect in the B cells leads to abnormal synthesis of IgE.
** [[Immunoglobulin E|IgE]] regulation involves T cell stimulation, appropriate [[cytokine]] production, and the ability of B cells to class switch toward the production of IgE.<ref name="pmid24058807">{{cite journal| author=Mogensen TH| title=STAT3 and the Hyper-IgE syndrome: Clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties. | journal=JAKSTAT | year= 2013 | volume= 2 | issue= 2 | pages= e23435 | pmid=24058807 | doi=10.4161/jkst.23435 | pmc=3710320 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24058807  }} </ref>
** Thus, defects in [[Interferon-gamma|IFN-gamma]] production or regulation contribute to the elevated levels of IgE.
 
== Causes ==
* Hyper IgE syndrome is caused due to mutations in the signal transducer and activator of transcription 3 (''[[STAT3]]'') and [[Tyrosine kinase 2|tyrosine kinase]] 2 (''TYK2'') gene.
* STAT 3 gene is essential for the differentiation of helper T cells, mutation causes autosomal dominant type.
* STAT 3 gene is essential for the differentiation of helper T cells, mutation causes autosomal dominant type.
* Tyrosine kinase 2 (''TYK2'') gene mutation causes autosomal recessive type.
* [[Tyrosine kinase 2]] (''TYK2'') gene mutation causes autosomal recessive type.


==Differentiating {{PAGENAME}} from Other Diseases==
==Differentiating {{PAGENAME}} from Other Diseases==
Hyper IgE syndrome can be differentiated from other diseases of the same kind by measuring the serum IgE levels.
Hyper IgE syndrome can be differentiated from other diseases of the same kind by measuring the serum IgE levels.<ref name="pmid28939137">{{cite journal| author=Gernez Y, Freeman AF, Holland SM, Garabedian E, Patel NC, Puck JM et al.| title=Autosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry. | journal=J Allergy Clin Immunol Pract | year= 2018 | volume= 6 | issue= 3 | pages= 996-1001 | pmid=28939137 | doi=10.1016/j.jaip.2017.06.041 | pmc=5858974 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28939137  }} </ref><ref name="pmid10053178">{{cite journal| author=Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL et al.| title=Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. | journal=N Engl J Med | year= 1999 | volume= 340 | issue= 9 | pages= 692-702 | pmid=10053178 | doi=10.1056/NEJM199903043400904 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10053178  }} </ref>
{| class="wikitable" style="text-align:center"
{| class="wikitable" style="text-align:center"
|+
|+
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==Epidemiology and Demographics==
==Epidemiology and Demographics==
 
* Incidence of hyper IgE syndrome is less than 1 in 100,000 individuals.
==Risk Factors==


==Screening==
==Screening==
Screening is not recommended for hyper IgE syndrome.


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
===Natural History===
===Natural History===
* Patients of hyper IgE syndrome are born with pustular or eczematoid rashes, or they may appear in first month of life.
* Patients of hyper IgE syndrome are born with [[Pustular rash|pustular]] or [[Eczema|eczematoid]] rashes, or they may appear in first month of life.<ref name="pmid20143652">{{cite journal| author=Cho C, Ferdman RM, Church JA, Ong PY| title=Skin-deep clues to a complex disease. | journal=Ann Allergy Asthma Immunol | year= 2010 | volume= 104 | issue= 1 | pages= 93-4 | pmid=20143652 | doi=10.1016/j.anai.2009.11.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20143652  }} </ref><ref name="pmid1891291">{{cite journal| author=Shyur SD, Hill HR| title=Immunodeficiency in the 1990s. | journal=Pediatr Infect Dis J | year= 1991 | volume= 10 | issue= 8 | pages= 595-611 | pmid=1891291 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1891291  }} </ref>
* Recurrent eczema and boils.
* Recurrent [[Eczema|eczema,]] [[Boil|boils]] and skin [[Abscess|abscesses]].
* Recurrent infections such as chronic otitis media, sinusitis, pneumonias, mucocutaneous infections, neurological and systemic.
* Recurrent infections such as chronic [[otitis media]], [[Rhinosinusitis|sinusitis]], [[Pneumonia|pneumonias]], [[Mucocutaneous zone|mucocutaneous]] infections, neurological and systemic.<ref name="pmid6348470">{{cite journal| author=Donabedian H, Gallin JI| title=The hyperimmunoglobulin E recurrent-infection (Job's) syndrome. A review of the NIH experience and the literature. | journal=Medicine (Baltimore) | year= 1983 | volume= 62 | issue= 4 | pages= 195-208 | pmid=6348470 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6348470  }} </ref>
* Hyperextensible joints/recurrent bone fractures, and distinctive coarse faces( prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance) in early childhood.
* Hyperextensible joints/recurrent bone [[Bone fracture|fractures]], and distinctive coarse faces( prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance) in early childhood.<ref name="pmid9709729">{{cite journal| author=Borges WG, Hensley T, Carey JC, Petrak BA, Hill HR| title=The face of Job. | journal=J Pediatr | year= 1998 | volume= 133 | issue= 2 | pages= 303-5 | pmid=9709729 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9709729  }} </ref>
* Eczema complicated by mucocutaneous candidiasis involving the mouth and diaper areas.
* Eczema complicated by mucocutaneous [[candidiasis]] involving the mouth and diaper areas.
* Skeletal abnormalities include scoliosis, osteopenia, minimal trauma fractures, hyperextensibility, and degenerative joint disease.
* Skeletal abnormalities include [[scoliosis]], [[Osteoporosis|osteopenia]], minimal trauma [[Bone fracture|fractures]], hyperextensibility, and [[Osteoarthritis|degenerative joint disease]].
* Retained primary teeth past the age of normal dental exfoliation.
* Retained primary teeth past the age of normal dental [[exfoliation]].
*  
*  


===Complications===
===Complications===
* Pustular and eczematoid rashes usually begin within the first month of life, usually affecting the face and scalp.
* [[Psoriasis|Pustular]] and [[Eczema|eczematoid]] [[Rash|rashes]] usually begin within the first month of life, usually affecting the face and scalp.<ref name="pmid17335882">{{cite journal| author=Freeman AF, Kleiner DE, Nadiminti H, Davis J, Quezado M, Anderson V et al.| title=Causes of death in hyper-IgE syndrome. | journal=J Allergy Clin Immunol | year= 2007 | volume= 119 | issue= 5 | pages= 1234-40 | pmid=17335882 | doi=10.1016/j.jaci.2006.12.666 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17335882  }} </ref>
* Recurrent pneumonias start in childhood.
* Recurrent [[pneumonia]]<nowiki/>s start in childhood.
* Recurrent lung infections cause bronchiectasis and formation of pneumatocoeles that lead to secondary infections such as fungal and gram negative bacterial infections resulting in pulmonary vessels rupture and haemoptysis.
* Recurrent lung infections cause [[bronchiectasis]] and formation of [[Pneumatocoele|pneumatocoeles]] that lead to secondary infections such as [[Fungus|fungal]] and gram negative bacterial infections resulting in pulmonary vessels rupture and [[Hemoptysis|haemoptysis]].<ref name="pmid17551753">{{cite journal| author=Antachopoulos C, Walsh TJ, Roilides E| title=Fungal infections in primary immunodeficiencies. | journal=Eur J Pediatr | year= 2007 | volume= 166 | issue= 11 | pages= 1099-117 | pmid=17551753 | doi=10.1007/s00431-007-0527-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17551753  }} </ref>
* Mucocutaneous candidiasis is common, manifesting typically as oral thrush, vaginal candidiasis or onychomycosis.
* Mucocutaneous [[candidiasis]] is common, manifesting typically as oral thrush, vaginal [[candidiasis]] or [[onychomycosis]].<ref name="pmid20392475">{{cite journal| author=Vinh DC, Sugui JA, Hsu AP, Freeman AF, Holland SM| title=Invasive fungal disease in autosomal-dominant hyper-IgE syndrome. | journal=J Allergy Clin Immunol | year= 2010 | volume= 125 | issue= 6 | pages= 1389-90 | pmid=20392475 | doi=10.1016/j.jaci.2010.01.047 | pmc=2879472 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20392475  }} </ref>
* Skeletal abnormalities include scoliosis, osteopenia, minimal trauma fractures, hyperextensibility, and degenerative joint disease.
* Skeletal abnormalities include [[scoliosis]], [[Osteoporosis|osteopenia]], minimal trauma fractures, hyperextensibility, and [[Osteoarthritis|degenerative joint disease]].
* Chiari 1 malformations are common.
* [[Chiari malformation|Chiari]] 1 malformations are common.
* Arterial aneurysms are fairly common. Aneurysms can be present in brain circulation or Aorta. It can lead to myocardial infarction or stroke.
* Arterial [[Aneurysm|aneurysms]] are fairly common. [[Aneurysm|Aneurysms]] can be present in brain circulation or [[Aorta]]. It can lead to [[ST elevation myocardial infarction|myocardial infarction]] or [[stroke]].
* Malignancies such as squamous cell carcinoma, cutaneous T-cell lymphoma/leukemia, Burkitt lymphoma, Hodgkin's and non-Hodgkin's lymphoma .
* Malignancies such as [[Squamous cell carcinoma laboratory tests|squamous cell carcinoma]], cutaneous [[T-cell lymphoma]]/[[leukemia]], [[Burkitt's lymphoma|Burkitt lymphoma]], [[Hodgkin's lymphoma|Hodgkin's]] and [[Non-Hodgkin lymphoma|non-Hodgkin's lymphoma]] .
* Systemic vasculitis.
* Systemic [[vasculitis]].


===Prognosis===
===Prognosis===
Infectious pulmonary complications are the leading cause of death in patients with HIES, followed by [[lymphoma]]:
* Prognosis depends on the complications arising from the disease.
* Pneumatoceles can become colonized with fungi and gram-negative bacteria, including ''A. fumigatus'' and ''[[Pseudomonas aeruginosa|P. aeruginosa]]''.
* Infected pneumatoceles can cause subsequent [[pneumonia]], systemic infection, or sudden pulmonary [[Bleeding|hemorrhage]].
* Vascular invasion by fungi may give rise to [[Mycosis|mycotic]] [[Aneurysm|aneurysms]] with subsequent [[hemorrhagic]] complications in the lungs and other organs.
* Patients developing [[lymphoma]] have a poor prognosis, with death resulting from superimposed infections.


==Diagnosis==
==Diagnosis==
===Diagnostic Criteria===
===Diagnostic Criteria===
Diagnosis requires clinical interepretation of symptoms along with laboratory findings.<ref name="pmid2531758">{{cite journal| author=Del Prete G, Tiri A, Maggi E, De Carli M, Macchia D, Parronchi P et al.| title=Defective in vitro production of gamma-interferon and tumor necrosis factor-alpha by circulating T cells from patients with the hyper-immunoglobulin E syndrome. | journal=J Clin Invest | year= 1989 | volume= 84 | issue= 6 | pages= 1830-5 | pmid=2531758 | doi=10.1172/JCI114368 | pmc=304061 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2531758  }} </ref><ref name="pmid22268731">{{cite journal| author=Sowerwine KJ, Holland SM, Freeman AF| title=Hyper-IgE syndrome update. | journal=Ann N Y Acad Sci | year= 2012 | volume= 1250 | issue=  | pages= 25-32 | pmid=22268731 | doi=10.1111/j.1749-6632.2011.06387.x | pmc=4103910 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22268731  }} </ref>
* Serum IgE levels above 2,000 IU/ml (100 times greater than normal).
* Increased levels of [[Eosinophil|eosinophils]] with normal levels of [[Neutrophil|neutrophils]] and [[Lymphocyte|lymphocytes]].
* A scoring system devised by NIH for the diagnosis of hyper IgE syndrome, score >30 suggests the presence of the disease.
{| class="wikitable"
| rowspan="2" |Clinical findings
| colspan="10" |Points*
|-
|0
|1
|2
|3
|4
|5
|6
|7
|8
|10
|-
|Highest serum-IgE level (international units/mL)¶
|<200
|200 to 500
|
|
|501 to 1000
|
|
|
|1001 to 2000
|>2000
|-
|Skin abscesses
|None
|
|1 to 2
|
|3 to 4
|
|
|
|>4
|
|-
|Pneumonia (episodes over lifetime)
|None
|
|1
|
|2
|
|3
|
|>3
|
|-
|Parenchymal lung anomalies
|Absent
|
|
|
|
|
|Bronchiectasis
|
|Pneumatocele
|
|-
|Retained primary teeth
|None
|1
|2
|
|3
|
|
|
|>3
|
|-
|Scoliosis, maximum curvature
|<10°
|
|10 to 14°
|
|15 to 20°
|
|
|
|>20°
|
|-
|Fractures with minor trauma
|None
|
|
|
|1 to 2
|
|
|
|>2
|
|-
|Highest eosinophil count (cells/microL)Δ
|<700
|
|
|700 to 800
|
|
|>800
|
|
|
|-
|Characteristic face
|Absent
|
|Mildly present
|
|
|Present
|
|
|
|
|-
|Midline anomaly◊
|Absent
|
|
|
|
|Present
|
|
|
|
|-
|Newborn rash
|Absent
|
|
|
|Present
|
|
|
|
|
|-
|Eczema (worst stage)
|Absent
|Mild
|Moderate
|
|Severe
|
|
|
|
|
|-
|Upper respiratory infections per year
|1 to 2
|3
|4 to 6
|
|>6
|
|
|
|
|
|-
|Candidiasis
|None
|Oral
|Fingernails
|
|Systemic
|
|
|
|
|
|-
|Other serious infections
|None
|
|
|
|Severe
|
|
|
|
|
|-
|Fatal infection
|Absent
|
|
|
|Present
|
|
|
|
|
|-
|Hyperextensibility
|Absent
|
|
|
|Present
|
|
|
|
|
|-
|Lymphoma
|Absent
|
|
|
|Present
|
|
|
|
|
|-
|Increased nasal width§
|<1 SD
|1 to 2 SD
|
|>2 SD
|
|
|
|
|
|
|-
|High palate
|Absent
|
|Present
|
|
|
|
|
|
|
|-
|Young-age correction
|>5 years
|
|
|2 to 5 years
|
|1 to 2 years
|
|≤1 year
|
|}


===History and Symptoms===
===History and Symptoms===
* Patients of hyper IgE syndrome are born with pustular or eczematoid rashes, or they may appear in first month of life.<ref name="pmid23606327">{{cite journal| author=Scheuerman O, Hoffer V, Cohen AH, Woellner C, Grimbacher B, Garty BZ| title=Reduced bone density in patients with autosomal dominant hyper-IgE syndrome. | journal=J Clin Immunol | year= 2013 | volume= 33 | issue= 5 | pages= 903-8 | pmid=23606327 | doi=10.1007/s10875-013-9895-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23606327  }} </ref>
* Recurrent [[eczema]], [[Boil|boils]] and skin [[Abscess|abscesses]].
* Recurrent infections such as chronic [[otitis media]], [[Rhinosinusitis|sinusitis]], [[Pneumonia|pneumonias]], [[Mucocutaneous zone|mucocutaneous infections]], neurological and systemic.
* Hyperextensible joints/recurrent bone [[Bone fracture|fractures]], and distinctive coarse faces( prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance) in early childhood.
* Eczema complicated by mucocutaneous [[candidiasis]] involving the mouth and diaper areas.
* Skeletal abnormalities include [[scoliosis]], [[Osteoporosis|osteopenia]], minimal trauma fractures, hyperextensibility, and [[Osteoarthritis|degenerative joint disease]].
* Retained primary teeth past the age of normal dental [[exfoliation]].


===Physical Examination===
===Physical Examination===
HIES often appears early in life with recurrent staphylococcal and candidal infections, pneumonias, and eczematoid skin. Characteristic facial, dental, and skeletal abnormalities have also been described. Patients with HIES 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 was rough with prominent pores. Finally, some patients have [[scoliosis]], as well as bones that fracture easily.<ref name="Grimbacher" />
* Coarse facial features( prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance).<ref name="pmid4011897">{{cite journal| author=Kirchner SG, Sivit CJ, Wright PF| title=Hyperimmunoglobulinemia E syndrome: association with osteoporosis and recurrent fractures. | journal=Radiology | year= 1985 | volume= 156 | issue= 2 | pages= 362 | pmid=4011897 | doi=10.1148/radiology.156.2.4011897 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4011897  }} </ref>
* Dental abnormalities- retained primary teeth.
* Facial pain ([[Rhinosinusitis|sinusitis]]), ear pain and discharge ([[otitis media]]).
* Purulent sputum producing cough or dry cough due to recurrent pneumonia.
* [[Dermatitis|Eczematous dermatitis]] and [[lichenification]] affect the face, trunk, and extremities.
* [[Boil|Boils]] and multiple skin [[Abscess|abscesses]].
* [[Purpura|Purpural]] [[rash]].
* Skeletal abnormalities include [[scoliosis]], [[Osteoporosis|osteopenia]] , minimal trauma fractures, hyper-extensible and degenerative joint disease.<ref name="pmid24402620">{{cite journal| author=Sowerwine KJ, Shaw PA, Gu W, Ling JC, Collins MT, Darnell DN et al.| title=Bone density and fractures in autosomal dominant hyper IgE syndrome. | journal=J Clin Immunol | year= 2014 | volume= 34 | issue= 2 | pages= 260-4 | pmid=24402620 | doi=10.1007/s10875-013-9982-2 | pmc=4484798 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24402620  }} </ref>


===Laboratory Findings===
===Laboratory Findings===
Elevated IgE is the hallmark of HIES, usually > 10 times normal. 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.<ref name="Grimbacher">{{cite journal |author=Grimbacher B, Holland S, Gallin J, Greenberg F, Hill S, Malech H, Miller J, O'Connell A, Puck J |title=Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder |journal=N Engl J Med |volume=340 |issue=9 |pages=692-702 |year=1999 |pmid=10053178}}</ref>
* Serum IgE levels above 2,000 IU/ml(100 times greater than normal).
* Increased levels of eosinophills ( >700) with normal levels of neutrophils and lymphocytes.


===Imaging Findings===
=== Electrocardiogram ===
There are no ECG findings associated with IgM defiicency.


===Other Diagnostic Studies===
=== X-ray ===
There are no specific findings for IgM deficiency on x ray but signs of lung disease may be present.
* Increased bronchovascular markings in [[bronchitis]].
* '''Lung''' hyperinflation with flattened hemidiaphragms in [[emphysema]].
* [[Consolidation (medicine)|Consolidation]] in [[pneumonia]].
* Tram track opacities in [[bronchiectasis]].
 
=== Echocardiography or Ultrasound ===
There are no echocardiography/ultrasound findings associated with hyper IgE syndrome.
 
=== CT scan ===
* There are no CT scan findings associated with hyper IgE syndrome.
 
* Changes of [[Copd|chronic lung disease]], if present will be visible on CT and can help differentiate the cause and extent of the disease.
* Chronic sinusitis- mucosal thickening, complete opacification, bone remodeling and thickening due to [[osteitis]], and [[Polyp|polyposis]].
 
=== MRI ===
There are no MRI findings associated with hyper IgE syndrome.
 
However, signs of chronic lung disease or chronic [[Sinus|sinsuitis]] may be present.
 
=== Other Imaging Findings ===
There are no other imaging findings associated with hyper IgE syndrome.
 
=== Other Diagnostic Studies ===
There are no other diagnostic studies associated with hyper IgE syndrome.


==Treatment==
==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]].<ref>{{cite journal |author=Kimata H |title=High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome |journal=J Allergy Clin Immunol |volume=95 |issue=3 |pages=771-4 |year=1995 |pmid=7897163}}</ref>
===Medical Therapy===
Treatment of hyper IgE syndrome includes prevention of infections, administering prohphylactic antibiotics, treating current infections and bone marrow transplant.<ref>{{cite journal |author=Kimata H |title=High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome |journal=J Allergy Clin Immunol |volume=95 |issue=3 |pages=771-4 |year=1995 |pmid=7897163}}</ref><ref name="pmid19912258">{{cite journal| author=Yavuz H, Chee R| title=A review on the vascular features of the hyperimmunoglobulin E syndrome. | journal=Clin Exp Immunol | year= 2010 | volume= 159 | issue= 3 | pages= 238-44 | pmid=19912258 | doi=10.1111/j.1365-2249.2009.04044.x | pmc=2819490 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19912258  }} </ref><ref name="pmid9723561">{{cite journal| author=Wakim M, Alazard M, Yajima A, Speights D, Saxon A, Stiehm ER| title=High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome. | journal=Ann Allergy Asthma Immunol | year= 1998 | volume= 81 | issue= 2 | pages= 153-8 | pmid=9723561 | doi=10.1016/S1081-1206(10)62802-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9723561  }} </ref>
* Skin care with antiseptic wash prevents infection with bacterias and fungi.
** Eczematous [[dermatitis]] is treated with a topical [[corticosteroid]], a moisturizing cream, and an [[antihistamine]] .
* Prophylactic administration of [[Sulfamethoxazole-Trimethoprim|trimethoprim-sulfamethoxazole]] is useful in the prevention of cutaneous [[Staphylococcaceae|staphylococca]]<nowiki/>l infections, including [[Abscess|abscesses]], as well as [[Rhinosinusitis|sinusitis]], [[otitis media]], and [[pneumonia]].
** 5 to 8 mg/kg/day of the [[trimethoprim]] component administered orally in two divided daily doses, or from 0 to 6 months, 120 mg/day; 6 months to 5 years, 240 mg/day; 6 to 12 years, 480 mg/day; and >12 years, 960 mg/day.
* Treatment of active infections:
** [[Pneumonia]] and deep-seeded [[Abscess|abscesses]] caused by ''[[Staphylococcus aureus|S aureus]]'' are treated intravenously with [[Nafcillin sodium|nafcillin]] and with [[vancomycin]] if it is [[methicillin]]-resistant.
** Lung [[Abscess|abscesses]] superinfected with ''[[Aspergillus]]'' species require intravenous [[amphotericin B]].
** ''P aeruginosa,'' requires an [[aminoglycoside]] and a third-generation [[cephalosporin]] or another synergistic antibiotic.
* Bone marrow transplantation (BMT) is also being studied to be used for treatment.


===Surgery===
===Surgery===
Surgery is not recommended for the treatment of hyper IgE syndrome.


===Primary Prevention===
===Primary Prevention===
There are no established measures for the primary prevention of hyper IgE syndrome.


===Secondary Prevention===
===Secondary Prevention===
Secondary prevention includes prevention of infections by:
* Avoidance- reduce exposure to others with potentially contagious illnesses, proper hand washing and [[Vaccination|immunization]] of family members and close contacts.
* [[Vaccination]] with conjugate vaccines - conjugated [[pneumococcal vaccine]], conjugated [[haemophillus influenza B]] and conjugated [[Meningococcal|meningococcal vaccine]] administered to prevent infections.   
* Use of prophylactic broad spectrum [[Antibiotic|antibiotics]].
* Skin care with [[antiseptic]] wash prevents infection with [[Bacteria|bacterias]] and [[Fungus|fungi]].


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
{{Immune disorders}}


[[Category:Hematology]]
[[Category:Hematology]]
[[Category:Pediatrics]]
[[Category:Pediatrics]]
[[Category:Immunology]
[[Category:Immunology]]
 
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Latest revision as of 06:42, 2 February 2019

Hyper-IgE syndrome
ICD-10 D82.4
ICD-9 288.1
OMIM 29572 147060
DiseasesDB 29572
eMedicine derm/845  ped/1074
MeSH D007589

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]; Associate Editor(s)-in-Chief: Jogeet Singh Sekhon, M.D. [3]

Synonyms and keywords: Job-Buckley syndrome; Job syndrome; Buckley syndrome

Overview

Hyper IgE syndrome (HIES) is a group of disorders characterized by recurrent staphylococcal infections, 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 serum IgE. Some patients have an autosomal dominant form of the disease. These patients have problems with their bones including recurrent fractures and scoliosis. Many patients with autosomal dominant hyper IgE syndrome fail to lose their baby teeth and have two sets of teeth simultaneously.

Historical Perspective

  • HIES was first described by Davis et al in 1966 and was named as Job's syndrome.
  • The criteria included triad of eczema, recurrent skin and lung infections and high serum IgE .

Classification

Hyper IgE syndrome is classified into 2 types:[1]

Pathophysiology

  • Hyper IgE syndrome may be caused due to mutations in STAT3 and TYK2 genes.[2][3]

Pathogenesis:

  • Neutrophil chemotactic defect:[5][6]
    • Th17 cell production of IL-17 is involved in neutrophil chemotaxis and proliferation .
    • Defective Th17 leads to defects in neutrophil chemotaxis and proliferation .
    • Interferon (IFN)-gamma production is also decreased which results in cutaneous and pulmonary infections.
    • Defect in neutrophil chemotaxis results in cutaneous cold abscess formation, in which signs of acute inflammation are absent.
  • T cell defects
    • STAT3 plays a crucial role in the differentiation of naive T cells into IL-17 producing CD4+ T cells (Th17 cells).[7]
    • Th17 cells are involved in the response to fungal and extracellular bacterial infections.[8]
    • These cells are significantly reduced or absent in patients with HIES.
  • B cell defects and abnormal IgE regulation
    • B cells are responsible for the synthesis of IgE.
    • A defect in the B cells leads to abnormal synthesis of IgE.
    • IgE regulation involves T cell stimulation, appropriate cytokine production, and the ability of B cells to class switch toward the production of IgE.[9]
    • Thus, defects in IFN-gamma production or regulation contribute to the elevated levels of IgE.

Causes

  • Hyper IgE syndrome is caused due to mutations in the signal transducer and activator of transcription 3 (STAT3) and tyrosine kinase 2 (TYK2) gene.
  • STAT 3 gene is essential for the differentiation of helper T cells, mutation causes autosomal dominant type.
  • Tyrosine kinase 2 (TYK2) gene mutation causes autosomal recessive type.

Differentiating Hyper-IgE syndrome from Other Diseases

Hyper IgE syndrome can be differentiated from other diseases of the same kind by measuring the serum IgE levels.[10][11]

Disease IgM levels IgG levels IgA levels IgE levels B cell defect T cell defect
IgM deficiency - - - - -
IgA deficiency - - - - -
IgG deficiency - - - - -
IgE deficiency - - - - -
Hypoproteinemia/Proteinuria - -
Comined Immunodeficiency + +
X linked agammaglobulinemia + -
Hyperimmunoglobulin M syndrome + -
Common variable immunodeficiency + -
Wiskott-Aldrich syndrome - +
Hyper IgE syndrome - - - - +

Epidemiology and Demographics

  • Incidence of hyper IgE syndrome is less than 1 in 100,000 individuals.

Screening

Screening is not recommended for hyper IgE syndrome.

Natural History, Complications, and Prognosis

Natural History

Complications

Prognosis

Infectious pulmonary complications are the leading cause of death in patients with HIES, followed by lymphoma:

  • Prognosis depends on the complications arising from the disease.
  • Pneumatoceles can become colonized with fungi and gram-negative bacteria, including A. fumigatus and P. aeruginosa.
  • Infected pneumatoceles can cause subsequent pneumonia, systemic infection, or sudden pulmonary hemorrhage.
  • Vascular invasion by fungi may give rise to mycotic aneurysms with subsequent hemorrhagic complications in the lungs and other organs.
  • Patients developing lymphoma have a poor prognosis, with death resulting from superimposed infections.

Diagnosis

Diagnostic Criteria

Diagnosis requires clinical interepretation of symptoms along with laboratory findings.[19][20]

  • Serum IgE levels above 2,000 IU/ml (100 times greater than normal).
  • Increased levels of eosinophils with normal levels of neutrophils and lymphocytes.
  • A scoring system devised by NIH for the diagnosis of hyper IgE syndrome, score >30 suggests the presence of the disease.
Clinical findings Points*
0 1 2 3 4 5 6 7 8 10
Highest serum-IgE level (international units/mL)¶ <200 200 to 500 501 to 1000 1001 to 2000 >2000
Skin abscesses None 1 to 2 3 to 4 >4
Pneumonia (episodes over lifetime) None 1 2 3 >3
Parenchymal lung anomalies Absent Bronchiectasis Pneumatocele
Retained primary teeth None 1 2 3 >3
Scoliosis, maximum curvature <10° 10 to 14° 15 to 20° >20°
Fractures with minor trauma None 1 to 2 >2
Highest eosinophil count (cells/microL)Δ <700 700 to 800 >800
Characteristic face Absent Mildly present Present
Midline anomaly◊ Absent Present
Newborn rash Absent Present
Eczema (worst stage) Absent Mild Moderate Severe
Upper respiratory infections per year 1 to 2 3 4 to 6 >6
Candidiasis None Oral Fingernails Systemic
Other serious infections None Severe
Fatal infection Absent Present
Hyperextensibility Absent Present
Lymphoma Absent Present
Increased nasal width§ <1 SD 1 to 2 SD >2 SD
High palate Absent Present
Young-age correction >5 years 2 to 5 years 1 to 2 years ≤1 year

History and Symptoms

Physical Examination

  • Coarse facial features( prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance).[22]
  • Dental abnormalities- retained primary teeth.
  • Facial pain (sinusitis), ear pain and discharge (otitis media).
  • Purulent sputum producing cough or dry cough due to recurrent pneumonia.
  • Eczematous dermatitis and lichenification affect the face, trunk, and extremities.
  • Boils and multiple skin abscesses.
  • Purpural rash.
  • Skeletal abnormalities include scoliosis, osteopenia , minimal trauma fractures, hyper-extensible and degenerative joint disease.[23]

Laboratory Findings

  • Serum IgE levels above 2,000 IU/ml(100 times greater than normal).
  • Increased levels of eosinophills ( >700) with normal levels of neutrophils and lymphocytes.

Electrocardiogram

There are no ECG findings associated with IgM defiicency.

X-ray

There are no specific findings for IgM deficiency on x ray but signs of lung disease may be present.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with hyper IgE syndrome.

CT scan

  • There are no CT scan findings associated with hyper IgE syndrome.
  • Changes of chronic lung disease, if present will be visible on CT and can help differentiate the cause and extent of the disease.
  • Chronic sinusitis- mucosal thickening, complete opacification, bone remodeling and thickening due to osteitis, and polyposis.

MRI

There are no MRI findings associated with hyper IgE syndrome.

However, signs of chronic lung disease or chronic sinsuitis may be present.

Other Imaging Findings

There are no other imaging findings associated with hyper IgE syndrome.

Other Diagnostic Studies

There are no other diagnostic studies associated with hyper IgE syndrome.

Treatment

Medical Therapy

Treatment of hyper IgE syndrome includes prevention of infections, administering prohphylactic antibiotics, treating current infections and bone marrow transplant.[24][25][26]

Surgery

Surgery is not recommended for the treatment of hyper IgE syndrome.

Primary Prevention

There are no established measures for the primary prevention of hyper IgE syndrome.

Secondary Prevention

Secondary prevention includes prevention of infections by:

References

  1. Davis SD, Schaller J, Wedgwood RJ (1966). "Job's Syndrome. Recurrent, "cold", staphylococcal abscesses". Lancet. 1 (7445): 1013–5. PMID 4161105.
  2. Buckley RH, Wray BB, Belmaker EZ (1972). "Extreme hyperimmunoglobulinemia E and undue susceptibility to infection". Pediatrics. 49 (1): 59–70. PMID 5059313.
  3. Hill HR, Quie PG (1974). "Raised serum-IgE levels and defective neutrophil chemotaxis in three children with eczema and recurrent bacterial infections". Lancet. 1 (7850): 183–7. PMID 4129875.
  4. Chandesris MO, Melki I, Natividad A, Puel A, Fieschi C, Yun L; et al. (2012). "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey". Medicine (Baltimore). 91 (4): e1–19. doi:10.1097/MD.0b013e31825f95b9. PMC 3680355. PMID 22751495.
  5. Hill HR, Ochs HD, Quie PG, Clark RA, Pabst HF, Klebanoff SJ; et al. (1974). "Defect in neutrophil granulocyte chemotaxis in Job's syndrome of recurrent "cold" staphylococcal abscesses". Lancet. 2 (7881): 617–9. PMID 4137601.
  6. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T; et al. (2007). "Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome". Nature. 448 (7157): 1058–62. doi:10.1038/nature06096. PMID 17676033.
  7. Woellner C, Gertz EM, Schäffer AA, Lagos M, Perro M, Glocker EO; et al. (2010). "Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome". J Allergy Clin Immunol. 125 (2): 424–432.e8. doi:10.1016/j.jaci.2009.10.059. PMC 2878129. PMID 20159255.
  8. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM; et al. (2008). "Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome". Nature. 452 (7188): 773–6. doi:10.1038/nature06764. PMC 2864108. PMID 18337720.
  9. Mogensen TH (2013). "STAT3 and the Hyper-IgE syndrome: Clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties". JAKSTAT. 2 (2): e23435. doi:10.4161/jkst.23435. PMC 3710320. PMID 24058807.
  10. Gernez Y, Freeman AF, Holland SM, Garabedian E, Patel NC, Puck JM; et al. (2018). "Autosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry". J Allergy Clin Immunol Pract. 6 (3): 996–1001. doi:10.1016/j.jaip.2017.06.041. PMC 5858974. PMID 28939137.
  11. Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL; et al. (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.
  12. Cho C, Ferdman RM, Church JA, Ong PY (2010). "Skin-deep clues to a complex disease". Ann Allergy Asthma Immunol. 104 (1): 93–4. doi:10.1016/j.anai.2009.11.015. PMID 20143652.
  13. Shyur SD, Hill HR (1991). "Immunodeficiency in the 1990s". Pediatr Infect Dis J. 10 (8): 595–611. PMID 1891291.
  14. Donabedian H, Gallin JI (1983). "The hyperimmunoglobulin E recurrent-infection (Job's) syndrome. A review of the NIH experience and the literature". Medicine (Baltimore). 62 (4): 195–208. PMID 6348470.
  15. Borges WG, Hensley T, Carey JC, Petrak BA, Hill HR (1998). "The face of Job". J Pediatr. 133 (2): 303–5. PMID 9709729.
  16. Freeman AF, Kleiner DE, Nadiminti H, Davis J, Quezado M, Anderson V; et al. (2007). "Causes of death in hyper-IgE syndrome". J Allergy Clin Immunol. 119 (5): 1234–40. doi:10.1016/j.jaci.2006.12.666. PMID 17335882.
  17. Antachopoulos C, Walsh TJ, Roilides E (2007). "Fungal infections in primary immunodeficiencies". Eur J Pediatr. 166 (11): 1099–117. doi:10.1007/s00431-007-0527-7. PMID 17551753.
  18. Vinh DC, Sugui JA, Hsu AP, Freeman AF, Holland SM (2010). "Invasive fungal disease in autosomal-dominant hyper-IgE syndrome". J Allergy Clin Immunol. 125 (6): 1389–90. doi:10.1016/j.jaci.2010.01.047. PMC 2879472. PMID 20392475.
  19. Del Prete G, Tiri A, Maggi E, De Carli M, Macchia D, Parronchi P; et al. (1989). "Defective in vitro production of gamma-interferon and tumor necrosis factor-alpha by circulating T cells from patients with the hyper-immunoglobulin E syndrome". J Clin Invest. 84 (6): 1830–5. doi:10.1172/JCI114368. PMC 304061. PMID 2531758.
  20. Sowerwine KJ, Holland SM, Freeman AF (2012). "Hyper-IgE syndrome update". Ann N Y Acad Sci. 1250: 25–32. doi:10.1111/j.1749-6632.2011.06387.x. PMC 4103910. PMID 22268731.
  21. Scheuerman O, Hoffer V, Cohen AH, Woellner C, Grimbacher B, Garty BZ (2013). "Reduced bone density in patients with autosomal dominant hyper-IgE syndrome". J Clin Immunol. 33 (5): 903–8. doi:10.1007/s10875-013-9895-0. PMID 23606327.
  22. Kirchner SG, Sivit CJ, Wright PF (1985). "Hyperimmunoglobulinemia E syndrome: association with osteoporosis and recurrent fractures". Radiology. 156 (2): 362. doi:10.1148/radiology.156.2.4011897. PMID 4011897.
  23. Sowerwine KJ, Shaw PA, Gu W, Ling JC, Collins MT, Darnell DN; et al. (2014). "Bone density and fractures in autosomal dominant hyper IgE syndrome". J Clin Immunol. 34 (2): 260–4. doi:10.1007/s10875-013-9982-2. PMC 4484798. PMID 24402620.
  24. Kimata H (1995). "High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome". J Allergy Clin Immunol. 95 (3): 771–4. PMID 7897163.
  25. Yavuz H, Chee R (2010). "A review on the vascular features of the hyperimmunoglobulin E syndrome". Clin Exp Immunol. 159 (3): 238–44. doi:10.1111/j.1365-2249.2009.04044.x. PMC 2819490. PMID 19912258.
  26. Wakim M, Alazard M, Yajima A, Speights D, Saxon A, Stiehm ER (1998). "High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome". Ann Allergy Asthma Immunol. 81 (2): 153–8. doi:10.1016/S1081-1206(10)62802-5. PMID 9723561.