Pediatrics

Hyper IgE Syndromes

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Hyper-IgE syndrome? What are the typical findings for this disease?

Patients with Hyper-IgE syndrome usually present with some combination of severe eczema, recurrent skin infections (pyoderma and abscesses), and recurrent lung, sinus, and middle ear infections. Frequent staphylococcal infections may result in deep seated soft tissue abcesses, lymphadenitis or osteomyelitis. Lung involvement can lead to formation of pneumatocoeles.

Patients may also have recurrent infection with other pyogenic bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and other enteric gram negative bacteria, fungal infections such as mucocutaneous candidiasis, pulmonary aspergillosis, cryptococcosis, histoplasmosis, Scedosporidiosis, or other opportunistic infections such as Pneumocystis jiroveci pneumonia. Strikingly, local signs of inflammation may be very mild or even absent.

The onset of the eczematous rash often occurs in the neonatal period. By the time patients reach adolescence, they have often exhibit a characteristic facial appearance characterized by a broad nose, fleshy nasal tip, prominent forehead, facial asymmetry, prominent skin pores, and deep set eyes.

Other clinical findings that appear as patients age may include joint hyperextensibility, craniosynostosis, midline anomalies (high arched palate; double row teeth or delayed shedding of primary teeth), osteoporosis with atraumatic bone fractures, scoliosis, degenerative joint disease, coronary vasculature anomalies, intracranial aneurysms, Arnold chiari type I malformation, and esophageal dysfunction. Patients have an increased risk of developing lymphoma.

Many of the non-infectious clinical features of this disease, such as the facial appearance, as well as connective tissue, skeletal, and vascular abnormalities become evident only with increasing age.

What other disease/condition shares some of these symptoms?

Atopic Dermatitis

IPEX syndrome

Wiskott-Aldrich Syndrome

Cornel-Netherton syndrome

Di George syndrome

Chronic Granulomatous Disease

Common Variable Immunodeficiency

Chronic mucocutaneous candidiasis

Parasitic disease

HIV-AIDS

Hematological malignancies - Sézary's syndrome

Aspergillosis

ABPA

Churg-Stauss syndrome

Omenn Syndrome

What caused this disease to develop at this time?

The genetic defect in the Hyper-IgE syndromes result in poor host defenses against Staphylococcus Aureus and fungi, leading to early onset of skin infections, pneumonias and soft tissue abscesses. As noted below, several genetic mutations have been identified that all lead to the clinical manifestations of the Hyper-IgE syndrome.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

IgE levels. In Hyper-IgE syndromes the IgE level is usually > 1000 IU/mL. The IgE level can vary substantially over the years. Its level has no correlation with the severity of disease and its infectious complications.

CBC often demonstrates eosinophilia, or other abnormalities in white blood cells such as lymphopenia.

IgM, IgG and IgA levels may be normal or decreased.

Specific antibody production in response to immunization is defective in many patients.

Systemic inflammatory markers (WBC, ESR, CRP) often fail to rise normally during an infectious episode.

A defect in the differentiation and regulation of a newly characterized subset of T helper lymphocytes called the Th17 cells lead to a significant decrease of IL-17 producing CD4+ T cells. A lack of Th17 cells is a useful tool for the diagnosis of Hyper IgE syndrome, although this is currently only performed in specialized laboratories.

A mutation in the STAT3 gene can be found in 95% of patients presenting with the typical clinical features, confirming the diagnosis of the autosomal dominant form of the disease. Autosomal recessive forms of the Hyper-IgE syndrome have been described associated with the genes DOCK8 (over 100 cases) and rarely TYK2 (2 cases).

Would imaging studies be helpful? If so, which ones?

Chest X-rays are useful to diagnose the extent and severity of pneumonia. Computed tomography (CT) scan of the chest may be helpful to examine the lungs for presence of pneumatocoeles and/or bronchiectasis, and to detect mediastinal lymphadenopathy.

Abdominal ultrasound is used to detect hepatic abcesses if clinically suspected and to rule out retroperitoneal lymphadenopathy.

Skeletal survey and bone densitometry can help assess the patients for the presence of scoliosis, fractures and osteopenia. Panorex dental films can be used to examine for dental abnomalities.

A bone and gallium scan may be indicated to rule out infectious arthritis and osteomyelitis.

Magnetic resonance imaging (MRI) of the brain for intracranial aneurysms and T2 weighted hyperdensities.

Cardiac echography is used to rule out coronary aneurysms.

Confirming the diagnosis

See Table Ion Scoring Systems. Diagnostic guidelines for the autosomal dominant form of the hyper IgE syndrome associated with STAT3-mutations were proposed by Woellner et al.

Table I.

A clinical diagnosis of hyper IgE can be considered as likely if:

IgE >1000 IU/mL

A weighted score of clinical features >30 (based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate)

The diagnosis is judged probable if:

The above criteria are present

Lack of Th17 cells or a family history

For a definitive diagnosis:

The above criteria are present

There is a mutation in STAT3 (or in DOCK8. although not all criteria are found in the autosomal recesive disorder).

If you are able to confirm that the patient has Hyper IgE syndrome, what treatment should be initiated?

Currently there is no definitive cure for this syndrome.

Aggressive antimicrobial therapy should be instituted when an infection is suspected following a thorough investigation for the etiology. The index of suspicion for infection as a cause of the patient's symptoms should always remain high in these patients, as they often lack signs of systemic and local inflammation as a result of their impaired inflammatory response.

Long term prophylaxis with agents such as Trimethoprim/sulfamethoxazole (2.5mg/kg of TMP component twice daily) should be considered, aiming at decreasing the risk of staphylococcal infections.

Although considered in those with recurrent fungal infections the efficacy of prophylactic anti-fungal therapy remains unproven. Azoles (fluconazole, itraconazole) may be used (ex. Itraconazole 5mg/kg once daily).

If pneumatocoeles and bronchiectasis are detected, antimicrobial prophylaxis often needs to be broadened to cover Gram-negative bacteria and fungi. In managing pneumatocoeles and bronchiectasis consideration should be given to possible complications such as poor lung re-expansion and persisting broncho-pleural fistulas following surgical interventions.

Immunoglobulin replacement therapy (400-600 mg/kg per month) may be of clinical benefit in those who have a poor humoral response following immunization.

In addition to emollients and topical anti-inflammatory medications, systemic antibiotics can be of significant benefit for the treatment of these patients` eczema, as they often are colonized with Staphylococcus aureus. Bleach baths (120 ml of bleach in a tub of water) for 15 minutes 3 times weekly can be helpful to decrease such cutaneous colonization.

Dental extraction of the primary teeth might be required.

Orthopedic care should be provided for the fractures and scoliosis when present.

IFN-gamma and alpha have been used with inconsistent benefit in some patients.

Bone marrow transplantation, which may provide reconstitution of the immunologic and hematopeotic systems, does not address the skeletal, vascular and connective tissue problems, and is not performed in the vast majority of patients with autosomal dominant HIE. However, bone marrow transplantation is recommended for the autosomal recessive form associated with DOCK8. For this reason, early genetic evaluation is recommended if the disease is suspected.

What are the adverse effects associated with each treatment option?

Trimethoprim/sulfamethoxazole: rash, hepatitis, cytopenia, nausea, vomiting, diarrhea, allergic reactions, bacterial resistance, fevers.

Azoles: nausea, headache, skin rash, vomiting, abdominal pain, diarrhea, hepatitis, allergic reactions.

IVIg: Acute symptoms: Headache, myalgia, arthralgia, allergic reaction, nephropathy, cytopenia. Consideration is given that IVIg is a human blood product, with potential risk of infectious agents transmission.

Interferon alpha and gamma: Flu-like symptoms, insomnia, mood changes, nausea and vomiting, weight loss.

What are the possible outcomes of Hyper IgE syndrome?

There are few long term follow up studies available on patients suffering from autosomal dominant hyper-IgE syndrome. Many patients who are followed and managed adequately will survive well into adulthood, sometimes reaching the end of 5th decade of life. However the majority of patients suffer from infectious and non-infectious complications of the disease.

Some of the patients` eczema remains difficult to manage despite optimal therapy.

Death is often due to infectious complications such as sepsis. Opportunistic and other bacterial and fungal infections of the lung and the brain also contribute to mortality in these patients.

Finally, the incidence of lymphoma appears to be higher than the general population. Autosomal recessive HIE carries with it a very high risk of malignancy, frequently due to Human Papiloma Virus infections. This underscores the need for early detection of this form of HIE, with planning for bone marrow transplantation.

What causes this disease and how frequent is it?

The exact prevalence of autosomal dominant hyper IgE syndrome remains unknown, although the condition is thought to be rare. A heterozygote mutation in the gene encoding for the Signal Transducer and Activator of Transcription 3 (STAT3) were shown to be one of the most frequent causes of the autosomal dominant and sporadic cases of hyper IgE syndrome. Indeed, 95% of patients presenting with clinical features suggestive of the autosomal dominant hyper IgE syndrome (NIH clinical scores >40) have a mutation in the gene encoding for STAT3, altering the expression of the resultant protein.

More recently, a second genetic defect which presents with eczema, recurrent infections and extremely high levels of IgE has been reported, with mutations in the Dedicator of Cytogenesis 8 protein (Dock8) as the cause. One other mutation that has been found in 2 cases is that of Tyk2, a signal transduction protein associated with cytokine receptors including IL-4 and IL-13 receptors.

How do these pathogens/genes/exposures cause the disease?

STAT3, an important transcription factor is intimately involved in the signaling pathways of several cytokines, including IL-6, IL-22 and IL-23. These signals induce production of molecules that are crucial in host defense, especially IL-17. The majority of cases in autosomal dominant HIE have mutations that code for a so-called dominant negative mutation in this gene. This implies that the protein is produced, but is defective. It binds as a transcription factor, but no signaling is produced.

The increased susceptibility to streptococcal and candidal infections in these patients is probably at least in part explained by the near absence of Th17 cells as a result of STAT3 mutation. These CD4 helper lymphocytes produce several pro-inflammatory cytokines such as IL-17, hence their name. These cells play an essential role in the recruitment of neutrophils to the site of infection. In addition they seem to enhance the production of several anti-microbial peptides.

The reason behind extremely high levels of IgE is still not very clear and remains subject to much speculation. It has been hypothesized that there is a defect in the STAT3 dependent IL-10 signaling. This defect would potentially be responsible for a lack of inhibition of IL-4 action which in term would drive IgE production. As stated before the level of IgE has no impact on the clinical course of this disease and is merely a consequence of the STAT3 mutation. IgE is in no way an etiological factor of the clinical features.

The IL-6 impairment may be responsible for the diminished monocyte chemoattractant protein-1 (MCP-1) levels in these patients. MCP-1 is an important chemokine involved in chemotaxis.

In humans osteoclasts generated from peripheral monocytes of patients with STAT3 mutations have a higher level of bone resorption than normal controls. This might explain the observed osteopenia and easy fractures.

DOCK8 defects are less well understood. This protein plays a role in signal transduction in lymphocyte development. Paitents with this defect lose their lymphocytes progressively and become more susceptible to viral infection and malignancies. They also do not have the facial features or bony abnormalities.

What complications might you expect from the disease or treatment of the disease?

There is long list of complications in this disease, most related to infection. Chronic lung disease and pulmonary insufficiency often arise from recurrent acute infections.

There is a 5% risk of lymphoma. Both Hodgkin`s and non-Hodgkin`s lymphomas have been described in these patients.

Patients with DOC8 defects are at risk for malignancies associated with viral infections such as those induced by Human Papilloma Virus.

Are additional laboratory studies available; even some that are not widely available?

At present quantification of Th17 lymphocytes, which is a useful screening tool for the diagnosis of Hyper IgE syndrome, and STAT3 genetic sequencing which can help to confirm the diagnosis, are only performed in specialized centers.

How can Hyper IgE syndrome be prevented?

Most cases are sporadic with no affected parents. If a sibling is affected the risk is not increased unless one of the parents is also affected. In this case there will be a 50% risk for other siblings to be affected. The risk for the patient’s offspring is 50%.

In the autosomal dominant form, the risk for siblings of a confirmed patient appears to be low unless the parents exhibit signs of the same disease, as the mutations are usually sporadic. However, it is possible that the parents have undiagnosed disease or there is a germline mosaicism in one of the parents.

Genetic counseling should be offered to patients who reach the reproductive age.

Currently, there is no generally-available neonatal screening. Such screening may potentially be available through centers who offer specific genetic and immunologic testing.

What is the evidence?

Woellner, C, Grimbacher, B. "Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome". J Allergy Clin Immunol. vol. 125. 2010 Feb. pp. 424-432.

(Description of the HIES-associated mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells and proposed diagnostic guidelines for STAT3-deficient HIES.)

Grimbacher, B, Schaffer, A.A, Holland, S.M, Davis, J, Gallin, J.I, Malech, H.L. "Genetic linkage of hyper-IgE syndrome to chromosome 4". American Journal of Human Genetics. vol. 65. pp. 735-744.

(An early description of the genetics of HIES.)

Ongoing controversies regarding etiology, diagnosis, treatment

Much still needs to be learned about the etiology of this disease and the reason for the appearance of its different clinical features. We need to find easier and more accessible screening tools for its diagnosis. In addition, there is no definitive therapy with only supportive treatment available for STAT3 defects.

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