Hyper-IgE syndrome

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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.

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