Hematology

Hyper-IgE syndromes

What every physician needs to know:

There are two major diseases included under the heading of hyper-IgE syndromes (HIES): STAT3 deficiency (autosomal dominant HIES or Job's syndrome) and DOCK8 deficiency (autosomal recessive HIES).

Job's syndrome is due to heterozygous dominant-negative mutations in STAT3, a major transcription factor, that lead to impaired inflammation with consequent infections and impaired tissue remodeling as well as elevated IgE (immunoglobulin E). These patients have a characteristic appearance (facies), eczema, scoliosis, recurrent fractures as well as elevated IgE, recurrent pneumonias with cyst formation and skin infections, typically with Staphylococcus aureus.

Lymphoma occurs at a much higher rate in STAT3 deficient patients than in the general population.

There are also complications in other organ systems: coronary artery aneurysms which occasionally cause myocardial infarctions, demyelinated plaques in the brain, craniosynostosis and failure of primary teeth to deciduate. Despite the elevated IgE these patients have very little in the way of abnormal allergic phenomena. Cutaneous viral infections are not part of STAT3 deficiency.

DOCK8 deficiency is caused by complete deficiency of the protein DOCK8, encoded by the gene of the same name. These patients also have elevated IgE and recurrent infections, but the somatic aspects (lung cysts, scoliosis, fractures) are typically less severe or absent. DOCK8 deficient patients typically have early onset of severe eczema with superinfection with S. aureus, as well as severe recurrent cutaneous infections with herpes simplex viruses, human papilloma viruses, and molluscum contagiosum. The risk of malignancy is higher in DOCK8 deficiency than STAT3 deficiency. Allergies tend to be to a broad array of items, including foods.

Are you sure your patient has hyper-IgE syndrome? What should you expect to find?

Patients with proven STAT3 mutated Job's syndrome almost always have both immune and somatic signs. Eczema, recurrent boils, IgE elevation, and pneumonia are classic findings. Onychomycosis and mucocutaneous candidiasis are also common. T cells producing IL-17 (Th17 cells) are characteristically very low in the circulation in Job's syndrome. Scoliosis, pathologic fractures, and lung cysts are seen in more than half of cases at some point in their lives.

Some of the features of the full-blown Job’s syndrome are developmental, such as the characteristic facies, the failure of primary teeth to deciduate and craniosynostosis; therefore, it can be hard to make a firm clinical diagnosis in a young child. By late adolescence, there is usually no question about the diagnosis, as patients have had events in each of the above categories. DNA sequencing of STAT3 is the diagnostic test to confirm Job's syndrome.

Patients with DOCK8 deficiency have eczema, allergies, IgE elevation and recurrent infections. The somatic features are unreliable and less pronounced, if present at all. Cutaneous viral infections increase in frequency and severity with age. Th17 cells are reduced, but not to the extent that is seen in STAT3 deficiency. DNA sequencing of DOCK8 is the diagnostic test to confirm DOCK8 deficiency.

Beware of other conditions that can mimic hyper-IgE syndrome:

Patients with severe eczema and allergies often have associated elevated IgE, so hyper IgE syndromes are often considered in the differential diagnosis. These considerations are especially difficult in early childhood, when the full disease expression is not yet apparent. The most important considerations in the diagnosis of STAT3 or DOCK8 deficiencies are infections and somatic features. Those with isolated severe eczema or allergies do not typically have skin abscesses, pneumonias, or lung cysts.

Which individuals are most at risk for developing hyper-IgE syndrome:

No environmental, racial or gender effects are recognized.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Job's syndrome is associated with IgE elevation in all patients at some point in their lives, typically over 2000 IU/ml, and often many times higher. However, in about 20% of patients, IgE falls into the normal range over time, so that in adults, there are some individuals with the disease who have normal IgE levels. Eosinophils are typically elevated, but usually less that 10% and not correlated with the IgE levels. Memory T and B cells are low. Th17 cells are characteristically low in Job's syndrome (about 1 to 2% of CD4 T cells in normals and one tenth of that in Job's syndrome).

STAT3 DNA sequence is the critical diagnostic test, and should show a heterozygous change in the coding sequence. However, somatic mosaics and intronic mutations can be missed by straightforward exonic sequencing.

DOCK8 patients have IgE levels that are usually quite high, up to 100,000 IU/ml, as well as moderate eosinophilia. In contrast to Job's syndrome, the patients have a moderate lymphopenia and very poor in vitro T cell function. IgM is usually low or undetectable. The constellation of elevated IgE and low IgM with severe allergies or eczema should raise the possibility of DOCK8 deficiency. DOCK8 DNA sequence is the critical diagnostic test, and should show a homozygous or compound heterozygous change in the coding sequence. The DOCK8 gene is very susceptible to internal recombination and deletion, making the recognition of compound heterozygotes difficult.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of hyper-IgE syndrome?

Job's syndrome patients almost all eventually develop pneumonias, which are associated with bronchiectasis and pulmonary cysts. A normal chest CT scan is unusual in Job's syndrome. Scoliosis is usually present and easily seen on spine radiographs by adolescence. Craniosynostosis can be appreciated by CT, MRI, or plain films.

There are no characteristic radiographic signs in DOCK8 deficiency. While pneumonias do occur, they do not usually cavitate.

If you decide the patient has hyper-IgE syndrome, what therapies should you initiate immediately?

No emergency management is usually indicated but in general, patients with Job's syndrome are often sicker than they appear and sicker than they think they are. If they have pneumonia in an undamaged lung, it is usually due to S. aureus, Hemophilus influenzae, or Streptococcus pneumoniae. Pneumonias in lungs with pre-existing cavities may represent infection with Pseudomonas aeruginosa or Aspergillus fumigatus or other filamentous molds. Therapy for these should be dictated by culture data, and patients should be evaluated by early bronchoscopy if unable to produce sputum.

The spectrum of pneumonias in DOCK8 deficiency is less well defined but likely has some overlap with Job's syndrome as well as including histoplasmosis.

More definitive therapies?

In both diseases, prophylactic antibiotics are advisable, and trimethoprim/sulfamethoxazole 2.5mg/kg of trimethoprim twice daily is prudent.

For patients with Job's syndrome, pulmonary hygiene is important, especially after development of bronchiectasis. The role of intravenous immunoglobulin (IVIG) varies from patient to patient and is indicated in the setting of impaired antibody response. Even though many Job's syndrome patients have normal antibody responses those with severe recurrent infections may nevertheless benefit from IVIG. Onychomycosis is almost always due to Candida albicans and responds well to oral fluconazole or other azole anti-fungals.

Bone marrow transplantation is highly effective in DOCK8 deficiency and should be considered early in life. The role of bone marrow transplantation in Job's syndrome is undefined, but may be effective.

What other therapies are helpful for reducing complications?

Bleach baths are quite effective in the control of recurrent skin infections with S. aureus. 125ml household bleach in a tub of water in which the patient soaks for 15 minutes three times weekly is very effective in reducing staphylococcal carriage, preventing skin abscesses and improving eczema. An emollient is applied after emerging from the bath to keep the skin from overdrying.

What should you tell the patient and the family about prognosis?

STAT3 mutations occur spontaneously at certain spots in the gene. However, once they have occurred, they are transmitted in an autosomal dominant fashion. Survival is not well defined, but patients typically survive well into adulthood. The major determinant of mortality is the severity of lung disease. Fatal hemoptysis can complicate cavitary lung disease due to either fungi or gram negative bacteria.

DOCK8 deficiency is autosomal recessive, but the DOCK8 gene is also a site of genomic instability. Mortality is relatively high due to recurrent infections or cancers caused by viral infections (human papillomavirus and squamous cell carcinoma) or lymphomas. In the initial series, reported mortality was 50%. For these reasons, bone marrow transplantation should be considered as early as possible.

What if scenarios.

In Job's syndrome, patients are usually poorly cognizant of their degree of illness, including pneumonias, abscesses, and bone fractures. A high index of suspicion buttressed by effective imaging is important. While there is a high rate of Chiari I malformation in Job's syndrome, there has been relatively little in the way of direct consequences from it. On the other hand, scoliosis is a problem in most patients and can involve the cervical spine with cervical nerve root compromise. Surgery for these complications has been successful and well tolerated.

Lung surgery in Job's syndrome is a special problem. The tendency to form cysts after treatable pneumonias suggests impaired wound healing and tissue remodeling. This is very apparent in lung surgery to remove infected cavities in adolescents and adults, in whom the residual lung often fails to heal and expand properly, resulting in prolonged chest tubes and occasional thoracoplasty. Abdominal wounds also have complicated healing, with prolonged drainage.

While viral infections are not especially increased in Job's syndrome, recurrent varicella-zoster virus infections are common, occurring at a rate about 10-fold higher than in the general population. These reflect impaired T cell memory.

For unknown reasons, Pneumovax vaccination is associated with severe local reactions in many Job's syndrome patients while other vaccines are not.

Pathophysiology

STAT3 is a major signal transduction molecule that mediates signals from a variety of immune and somatic pathways, including IL-6, IL-10, IL-11, IL-23, leukemia inhibitory factor and oncostatin M. The mutations found in STAT3 cause dominant inhibitory molecules that reduce STAT3 signal to approximately 20-40% of wild type.

The reduction in IL-17 producing cells and in IL-17 responsiveness probably accounts for their recurrent epithelial infections. IL-11 signal impairment accounts for the craniosynostosis and primary tooth deciduation defect. IL-6 signal impairment accounts for the failure to adequately upregulate inflammation in the face of infection, while IL-10 signal impairment accounts for failure to down-regulate inflammation once it is begun.

DOCK8 is a member of the DOCK family of proteins and is a guanine nucleotide exchange factor. Exactly where it has its major effect is unknown, but it seems likely to influence cell shape and migration as well as immune cell responsiveness. DOCK8 deficiency results in a major combined immunodeficiency in T and B cell function leading to recurrent infection, dysregulated immunity with allergy, and cancers that are consistent with failures of immune surveillance.

What other clinical manifestations may help me to diagnose hyper-IgE syndrome?

The critical historical points surround invasive infections, viral infections, somatic features, and allergies. If invasive bacterial infections (pneumonias, boils) are coupled to the other features, one of these diseases is more likely. Simple questions about parental consanguinity, dental history, and mortality in related children can be helpful.

Skin exam, scoliosis examination, search for onychomycosis, examination for retained teeth can all be helpful.

What other additional laboratory studies may be ordered?

Aside from IgE and other immunoglobulins, most of the diagnostic information is syndromic. Decreased T and B cell memory cells are found in Job's syndrome, and lymphopenia is common in DOCK8, but these are non-specific. The Th17 determination is suggestive of STAT3 deficiency, but not specific.

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