Summary

Hyperimmunoglobulin E syndromes (HIES) are very rare, inherited conditions that affect both males and females, with symptoms usually beginning in childhood. Common features are severe eczema, increased susceptibility to infections and markedly raised levels of immunoglobulin E (IgE).

Currently, two distinct HIES have been defined. These are autosomal dominant HIES, also known as Job’s syndrome and autosomal recessive HIES. The autosomal dominant HIES is caused by genetic changes (mutations) in the STAT3 gene and is associated with a cluster of facial, dental, skeletal, and connective tissue abnormalities that are not seen in the recessive type. Three different subgroups have been identified within the autosomal recessive form, distinguishable by different clinical symptoms. These are caused by mutations in the genes DOCK8 and TYK2, and as yet undefined genetic causes.

Treatment is centred on preventing and treating infections using antibiotic, antifungal and antiviral medicines. Good skincare and hygiene to prevent infection are essential. Moisturising creams and steroid creams are used to treat the severe eczema associated with these conditions.

Recent reports document success in treating both the autosomal dominant and the autosomal recessive DOCK8 form of HIES using bone marrow transplantation. With early diagnosis and treatment of infections, most patients with HIES go on to lead full lives.

The diagnosis of Hyper IgE syndromes is based on a combination of distinctive clinical symptoms and laboratory findings and not just on having raised levels of IgE and raised numbers of eosinophils, specialised white blood cells that help to combat parasites and infections. This is because other patients with severe allergies may also have these symptoms without having Hyper IgE syndrome.

An IgE of over 2,000 IU/ml (normal adult value is less than 100 IU/ml) has been used as a cutoff level for Hyper IgE Syndrome when other features including boils and pneumonia are present. It is noteworthy that in some adults with Hyper IgE Syndrome, IgE may decrease and even become normal. For young children in whom normal IgE levels are very low, an IgE of 10 times the age-appropriate level is a reasonable guide for Hyper IgE Syndrome. This is why the presence of other clinical features described below helps to guide the diagnosis.

Autosomal dominant Hyper IgE Syndrome (Job Syndrome) presenting features include:

  • Distinctive facial features – broad nose, deep set eyes, prominent forehead, facial asymmetry
  • Eczema can be severe, very itchy and can become infected
  • Repeated bouts of ear and sinus infections – otitis and sinusitis
  • Skin abscesses (boils) that are characteristically not red or inflamed. These are sometimes referred to as ‘cold’ abscesses
  • Repeated bouts of pneumonia-causing air-filled cysts in the lungs – pulmonary pneumatoceles 
  • Delay in losing baby teeth – known as retained primary teeth. Sometimes in adults, secondary teeth may be present at the same time as baby teeth
  • Skin and nail infections. These are often caused by candida fungal infections (the fungus that causes thrush) of mucus membranes, such as the mouth and throat, and the nail beds
  • Curving of the spine – scoliosis
  • Bones that break (fracture) easily due to osteoporosis
  • Over flexible joints – hyper extensibility
  • An abnormally shaped skull caused by fuse skull bones – Craniosynostosis
  • Dry eyes.

Infections may be caused by:

Bacteria

Staphylococcus aureus – affecting the lungs and skin is the major source of infection

Streptococcus pneumoniae – affecting the lungs

Haemophilus influenzae – affecting the lungs

Pseudomonas aeruginosa – affecting the lungs

Cryptococcus – affecting the brain and gastrointestinal tract

Nontuberculous mycobacterium – affecting the lungs

Fungi

Candida albicans – infections of the skin and nails and causing thrush

Aspergillus species – affecting the lungs

Scedosporium species – affecting the lungs

Pneumocystis jiroveci  – affecting the lungs

Histoplasma – affecting the gastrointestinal tract

Autosomal recessive Hyper IgE Syndromes

This type of Hyper IgE Syndrome lacks the connective tissue and skeletal abnormalities of STAT3 deficiency. This means those affected lose their baby teeth normally, do not have the facial characteristics and their bones do not fracture easily.

Presenting features include:

  • Repeated bouts of pneumonia but usually without the formation of air-filled cysts in the lungs called pulmonary pneumatoceles
  • Susceptibility to infections caused by bacteria particularly Mycobacteria and Salmonella; fungi and viruses particularly Molluscum contagiosum, a viral infection of the skin; Herpes simplex, the cold sore virus and repeated infections with Varicella zoster, the virus that causes chicken pox and shingles.
  • Infection of the blood – sepsis
  • Symptoms affecting the central nervous system (CNS) such as facial paralysis, paralysis of the arm, leg, and trunk on the same side of the body (hemiplegia) and bleeding in the brain.

TYK2 deficiency

People with Tyk2 deficiency tend to show more severe clinical features. Those affected have extreme vulnerability to intracellular bacteria, that is bacteria that can grow within cells, as well as bacteria that grow on the outside of cells. These include mycobacteria and Salmonella.

DOCK8 deficiency

This is also characterised by CNS symptoms caused by inflammation of blood vessel (vasculitis) within the CNS and susceptibility to fungal and viral infections. Viral infections caused by the JC (John Cunningham) virus may lead to a serious condition involving inflammation of the white matter of the brain, known as progressive multifocal leukoencephalopathy.

Those affected are also known to be at high risk of malignancies including squamous cell carcinoma, a cancer of the skin; lymphoma, leukemia, and Burkitt lymphoma in late childhood and early adulthood.

Associated health complications with Hyper IgE syndrome

Systemic lupus erythematosus (SLE) and other autoimmune diseases have been associated with Hyper IgE syndrome.

The clinical differentiation of autosomal recessive from dominant forms of hyper IgE syndrome in early childhood may be difficult since the distinctive facial features of autosomal dominant hyper IgE syndrome may not be evident until many years later.

Diagnosis

Doctors will want to carry out a number of tests and scans. These may include:

  • Counting the number of eosinophils and types of other immune cells in your blood
  • Examining the level of IgE in your blood
  • Testing the responses of your T cells
  • Identifying the organisms causing infections by taking samples of the infected site
  • X-rays of the chest, bones and sinuses

Currently, two distinct genetic types of Hyper IgE syndromes have been defined.

Autosomal dominant Hyper IgE Syndrome (Job syndrome)

This is caused by a genetic mutation in the STAT3 gene, present on chromosome 4, that makes the STAT3 protein. This protein is involved in cell signalling in pathways in the immune system; wound healing, cancer and blood vessel growth (angiogenesis). STAT3 mutations particularly affect the maturation of T cells.

As the name suggests this disorder is inherited in an autosomal dominant manner meaning you need to inherit only one copy of the mutated gene to be affected. It affects both males and females equally and all ethnic groups.

Some cases arise due to new mutations occurring at conception. These are sporadic and are referred to as de novo mutations.

Autosomal recessive Hyper IgE Syndrome

This type of Hyper IgE syndrome shows different clinical features and is currently classified into three different subgroups.

These subgroups are inherited in an autosomal recessive manner meaning you need to inherit two copies of the mutated gene, one from each parent to be affected.

  • TYK2 deficiency is caused by mutations in the TYK2 gene that codes for the enzyme non-receptor tyrosine-protein kinase, TYK2. TYK2 is important in relaying cell signals in response to chemical factors known as cytokines.  Cytokines play an important role in the immune system and in inflammation.
  • DOCK8 deficiency is caused by mutations in the gene encoding the DOCK8 member of the family of what is known as the guanine nucleotide exchange factors. These factors interact with other enzymes that work as signalling networks within cells. This condition is extremely rare with less than 12 cases reported.

A third clinical subgroup is characterised by problems with the central nervous system and haemorrhaging in addition to susceptibility to fungal and viral infections. The genetic causes of this disorder are not yet known.

In the UK gene testing is available at Cardiff SAS Porphyria Service, Department of Medical Biochemistry and Immunology, University Hospital of Wales, Heath Park, Cardiff.

Family planning

Pre-implantation genetic diagnosis (PGD) is available for hyper IgE syndrome.

Treatment of Hyper IgE syndromes depends on preventing and management of infections to reduce the threat of overwhelming infection and limit damage to the lungs. It is really important to find out what particular bug is causing the infection so that can specific treatment can be given.

  • Long-term treatment with antibiotics and antifungal therapy to prevent and treat infections. These are especially important to treat infections caused by Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae and Candida albicans. The development of resistance in the course of long-term therapy outweighs the risk of severe infections and lung damage when it is discontinued.
  • Skin abscesses may need to be cut and drained, but these can largely be prevented with continuous oral antibiotics.
  • Lung abscesses may require drainage or resection, but surgery is difficult in Hyper IgE patients because the remaining lung tissue often fails to expand to fill the chest cavity. Prolonged chest tube drainage and intensive intravenous antibiotic treatment is sometimes needed. Pulmonary surgery (surgery on the lungs) therefore requires specialist advice and should not be undertaken lightly, and ideally should be done at centres with experience with the disease.
  • Super infections caused by Pseudomonas aeruginosa, Aspergillus and other fungal species following the resolution of acute pneumonias. Treatment strategies include continuous treatment with antifungal drugs and/or, aerosolised antibiotics.
  • Immunoglobulin therapy may also help in the case of severe infections. Infections caused by viruses are treated using anti-viral medicines, for example acyclovir to treat chicken pox.
  • Good skin care and prompt treatment of skin infections is really important. Topical (meaning applied on the skin) antibacterial and oral antibiotics are often effective at preventing infection. Attention to skin care is essential when plaster casts are used to treat fractures or scoliosis.
  • Using moisturising creams helps treat eczema and your doctor may give you on occasion steroid creams to use. Antiseptic treatments of the skin can help to reduce the bacterial burden in your skin without leading to the emergence of antibiotic-resistant bacteria. Your doctor may also recommend something to help relieve itching so that areas of eczema don’t become infected.

Role of bone marrow transplantation

There has been some success over the last few years in treating both the autosomal dominant and the autosomal recessive DOCK8 form of Hyper IgE using bone marrow transplantation (BMT).

Although the number of people treated by BMT remains small and the long-term outcomes are as yet unclear clinical outcomes were the disappearance of skin problems and severe infections, improvement of lung function and a drop in IgE levels. The recommendation is that BMT should be considered early before life-threatening complications develop.

Immunisation

There are no contra-indications to the use of killed or inactivated vaccines. The use of live vaccines is however best avoided because of the risk of vaccine-induced disease as seen in some patients with TYK2 deficiency.

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