What Is The Hyper IgE Syndrome?
Hyperimmunoglobulin E syndrome (HIES) is a hereditary immunodeficiency syndrome characterized by elevated IgE, also known as hyperimmunoglobulin E syndrome.
It was caused by defects in signal transduction and transcriptional activator protein -3 in the Janus kinase-stat signaling pathway. There are three main clinical signs:
- Repeated (cold) skin abscesses.
- Repeated pneumonia and other infections.
- High IgE (often ≥ 10 times the upper limit of normal).
The treatment of this disease is difficult, and the main treatments are skin abscess and infection control or prevention. The prognosis is poor, and most patients die from severe infectious complications of the lung.
High IgE syndrome is a rare condition, and the exact prevalence is unclear. It is estimated to be 0.2–1/100,000. There was no difference in incidence between men and women, with cases reported for people of African, Asian, and Caucasian ethnicity.
What Is The Cause Of The Hyper IgE Syndrome?
What is the pathogenesis of Hyper IgE Syndrome?
Defects in the JAK-STAT pathway result in impaired differentiation and function of T helper cell -17. However, it is not clear exactly how this causes the simultaneous occurrence of predisposition to infection, skin diseases, bone diseases and immune diseases.
Elevated serum IgE levels are likely to be a concomitant abnormality of the disease rather than the core of the pathogenesis. It is currently believed that a deficiency in interferon-γ production or regulation in patients with this disease contributes to elevated IgE levels.
What are the genetic characteristics of Hyper IgE Syndrome?
Most patients with high IgE syndrome have autosomal dominant inheritance, but some may also be caused by gene mutations, with relatively vague genetic characteristics.
What Is The Symptoms Of The Hyper IgE Syndrome?
What are the symptoms and signs of patients with Hyper IgE syndrome?
Hyp IgE syndrome can cause multiple system diseases:
- It begins in the first few weeks of life as a papular, pustular, and often crust-forming rash that originates on the face and scalp and spreads to the upper trunk/shoulders and buttocks. The rash progresses to a eczema-like, pustulating, and severely pruritic rash that resembles atopic dermatitis. The rash is diffuse in distribution and may produce lichenoid changes.
- Infectious foci such as pustules are "cold" like. General infection can cause local skin temperature increases, have warm feeling. However, the local temperature of the skin-infected lesion in this group of patients was not elevated.
Respiratory tract infection:
- Severe infections are common, but they do not give off heat and feel good.
- Chronic upper airway infection with persistent and/or recurrent sinusitis, suppurative otitis media, and mastoiditis.
- Pulmonary infections occur repeatedly and can be life-threatening; They are often complicated with pulmonary structural lesions such as bronchiectasis, pulmonary cavity/bulla, pulmonary nodules, and bronchopleural fistula. This structural lesion of the lung is also susceptible to opportunistic infections such as fungi and non-tuberculous mycobacteria.
- Most commonly Staphylococcus aureus, Candida albicans, Haemophilus influenzae, Group A and B streptococcus, Gram-negative pathogens (such as Pseudomonas), other fungi.
- Staphylococcus aureus was mainly distributed in the skin, Staphylococcus aureus and Haemophilus influenzae were mainly distributed in the lung, and Candida albicans was mainly distributed in the mouth, vagina and nails.
- It is a strange phenomenon that the similarity of faces between patients in this disease exceeds the similarity between patients and their families.
- The most characteristic manifestations are widened nasal ala (wide nasal base) and widened nasal bridge. Other features include a prominent forehead (eminence of the forehead), an increased distance from the lateral canthus of the eye, and a deep fovea. In infancy, a prominent forehead, lower lip and broad nose are observed.
- The soft tissues of his face and ear, nose and mouth were markedly thickened, giving the skin a dough-like appearance, often referred to as a "rough face". This feature is evident in 80% to 100% of patients and becomes more prominent with age. It is often absent at birth and begins to thicken at the age of 2 to 5 years, especially after adolescence.
- Retention of primary teeth is common, resulting in the formation of double rows of teeth.
- Osteoporosis, prone to minor fractures.
- Scoliosis, joint hyperextension seen.
- The risk of lymphoma increases.
- Neurological abnormalities, resulting in relatively poor cognitive skills, visual-sensory skills, working memory, etc.
- There are congenital vascular abnormalities and acquired vascular abnormalities, such as aneurysms, pseudoaneurysms, and vasculitis. Abnormalities of the coronary arteries include tortuosity, dilation, and local aneurysms, which can lead to serious complications and even death.
How To Check The Hyper IgE Syndrome?
Are there any special laboratory abnormalities in patients with Hyper IgE syndrome?
Elevated serum IgE levels and increased peripheral blood eosinophils are the most common.
- IgE: It is often between 1 000 and 50 000 U/mL, but some are lower or higher. The level of serum IgE has nothing to do with the severity of the disease. In infancy, the patient's IgE level may be extremely high. The level of IgE may remain stable or decrease over time, and the IgE level of some adult HIES patients may become normal.
- Eosinophil count: often increases when an acute infection is about to occur.
- Others: increased levels of total IgG, IgM and IgA, normal complement, increased part of IgD, etc.
How to diagnose hyper IgE syndrome?
There are a number of causes for elevated blood IgE. Therefore, symptoms, signs, and laboratory tests were required to definitively identify the cause of the STAT3 mutation. The more consistent a patient's clinical features are, the more likely it is that STAT3 mutations are associated with:
- Typical face.
- Internal organ tissue abscess.
- Severe infection.
- Pulmonary bullae.
- Candidiasis of nail and skin mucosa.
- Doctors should actively differentiate from other diseases causing increased IgE when making a diagnosis. Only in this way can the misdiagnosis and missed diagnosis be reduced.
Which diseases need to be differentiated from hyper IgE syndrome?
- Atopic dermatitis (eczema): everyone has severe itching and an increase in IgE. But atopic dermatitis is more likely to have food allergies. In contrast, high IgE syndrome usually involves opportunistic infection, severe infection and organ abscess. And has a special face, scoliosis, fracture.
- Cytokinesis factor -8(DOCK8) deficiency: Some physicians classify it as another type of high IgE syndrome. Because of similar clinical features with STAT3 mutations. Clinical features may differ as follows:
- People with DOCK8 defects have liver injury. And more common malignancy, frequent upper respiratory tract infections, viral infection of that skin, more prominent eosinophilia. It is similar to atopic dermatitis and predisposes to severe food allergies.
- STAT3 mutations, on the other hand, are more common in structural lung lesions, residual deciduous teeth, and minimally invasive fractures, and are less likely to result in severe atopic dermatitis or severe food allergies. And has its unique: neonatal purulent skin, special face.
- Deficiency of tyrosine kinase -2(Tyrosine kinase 2 gene, TyK2): TyK2 is a member of the JAK kinase family. Defects in both STAT3 and TyK2 lead to impaired Th17 function. Thus, the TyK2 deficiency has also been classified as high IgE syndrome. However, it appears to be less common and differs from STAT3 mutations in clinical features. TyK2 deficiency is also predisposed to atopic dermatitis, more commonly viral infection of the skin.
- Glucose-phosphate mutase -3(Phosphoglucomutase 3, PGM3) deficiency: elevated IgE, eczema, recurrent respiratory infections, pneumonia, candidiasis, and abscesses. It also causes bone marrow failure and decreases neutrophil counts. But it has no special face.
- Zinc fingerprint -341 gene (ZNF341) abnormality: The ZNF341 gene encodes a transcription regulator to regulate STAT3 expression. This is a newly discovered genetic abnormality causing high IgE. Its characteristics are still unknown.
- Eczema thrombocytopenia with immunodeficiency syndrome (WAS): Patients with WAS have thrombocytopenia, thrombocytopenia, and may present with ecchymosis. In addition, abscesses are uncommon and do not present with distinctive features in patients with WAS.
- Severe combined immunodeficiency: this is a combination of a large class of diseases. They are susceptible to infection and may have elevated IgE levels, as shown generally by a marked decrease in the number of T cells by flow cytometry.
How To Prevent The Hyper IgE Syndrome?
Can hyper IgE syndrome be prevented?
High IgE syndrome is a hereditary disease caused by gene mutation and cannot be prevented yet. It is recommended that patients undergo genetic counseling before conception to avoid the birth of a diseased next generation.
How To Treat The Hyper IgE Syndrome?
Which department should patients with hyper IgE syndrome go to?
This disease starts in infancy and generally requires a pediatric visit. Some patients may also visit the Rheumatology and Immunology Department.
How to treat hyper IgE syndrome?
There are currently no high-quality prospective randomized controlled trials to support our approach. More based on observational data and clinical experience.
The main therapeutic objectives at present are the control of pruritus and eczema-like dermatitis, the prevention of infection and the prevention of serious systemic infections.
- Dermatosis: The treatment of eczema-like dermatitis is similar to that of atopic dermatitis. But unfavorable systemic hormone, cyclosporine; Topical calcineurin inhibitor for skin and light therapy.
- Prophylactic use of antibiotics: prophylactic use of compound sulfamethoxazole. It is effective in preventing skin staphylococcal infections (including abscesses), sinusitis, otitis media, and possibly pneumonia. This is similar to patients with chronic granulomatous disease. While preventive antifungal regimen can be found in patients with HIV.
- Anti-infective therapy: Deep bacterial infections should be actively treated with systemic antibiotics and may also require surgical drainage, and clinicians should be alert to the occurrence of osteomyelitis. Oral and topical antifungal agents are effective for chronic cutaneous mucosal candida infection.
- Control of pulmonary complications: Large, persistent bullae may require treatment with segmental or even lobectomy. But this is rare. It may be related to preventive antibacterial therapy to reduce lung complications.
- Immunomodulatory therapy: recombinant human interferon-γ therapy may be beneficial. However, there is a lack of high-quality prospective randomized controlled trials. The benefit of intravenous heavy immunoglobulin therapy is also uncertain unless there is a decrease in immunoglobulin or IgG subtype levels and a decrease in antibody response to protein and/or polysaccharide antigens.
- Bone-specific management: bisphosphonates improve bone density, but are not known to reduce fracture risk. Calcium, vitamin d is similar.
- Bone marrow transplantation: may improve long-term prognosis of patients. But high quality clinical trials are need to assist in judgement.
What is the prognosis of patients with hyper IgE syndrome?
The prognosis of patients with high IgE syndrome is often poor, and some of them will die due to complicated lung infections. In addition, lymphoma can also be complicated. Once lymphoma appears, the prognosis is often poor.
What Should Patients With Hyper IgE Syndrome Pay Attention To In Life?
Reducing the risk of infection is key. Therefore, we should reduce the need to go to areas with high risk of infectious diseases and wash hands frequently to ensure clean food and water.
As for whether patients can benefit from vaccination? It's not clear. However, it is generally recommended to avoid inoculation with live attenuated vaccines.