Hyper-IgE Syndrome is a primary immunodeficiency disorder (PIDD). This means it is a genetic condition that impairs the normal function of the immune system, making an individual more susceptible to certain types of infections. The name “Hyper IgE” comes from one of its hallmark laboratory findings: a markedly elevated level of an antibody called Immunoglobulin E (IgE) in the blood. While IgE is normally associated with allergic reactions, in HIES its high level is a sign of a deeper problem in immune system regulation.

The core problem in the most common form of HIES is a breakdown in a critical cellular communication pathway known as the JAK-STAT pathway.

• A helpful analogy is to think of your immune system as a sophisticated national defense network. It has many different branches: soldiers to fight bacteria, an air force to fight viruses, and emergency response teams.
• All these branches are coordinated by a central communication system that relies on specific signals, called cytokines, to deploy the right troops to the right place at the right time.
• The protein affected in HIES, called STAT3, is like a master communication officer responsible for relaying a wide variety of these crucial signals.
• In HIES, this communication officer is faulty. When a threat appears, like a Staphylococcus infection on the skin, the officer fails to send the correct signal to deploy the “special forces” (a type of white blood cell called a neutrophil) needed to effectively fight that specific bacteria. This leads to deep-seated skin abscesses.
• At the same time, the faulty officer sends out a constant, unnecessary “allergy alert” signal, causing the parts of the immune system that produce IgE and eosinophils to be chronically overactive.

This paradox of a poor response to real bacterial and fungal threats, combined with an over-the-top allergic-type response, is the key feature of Hyper-IgE Syndrome.

In my experience, children with recurring skin abscesses and unusual infections often turn out to have rare immunodeficiencies, Hyper IgE Syndrome is one that’s frequently overlooked.

The cause of HIES is a genetic mutation in a gene that is critical for the normal function and signaling of immune system cells, and cells involved in skeletal and dental development.

There are several different genes that can cause HIES, leading to different forms of the disease.

• Mutations in the STAT3 gene: This is the cause of the most common form of HIES, known as autosomal dominant HIES or classic Job’s Syndrome. The STAT3 protein is a crucial signaling molecule used by many different parts of the body to regulate inflammation, immunity, and tissue remodeling. A defect in this protein leads to the wide-ranging symptoms of the disease.
• Mutations in other genes: Rarer, autosomal recessive forms of HIES are caused by mutations in other genes, such as DOCK8 or PGM3. These forms often have more severe skin-related viral infections and neurological problems.

In my experience, it’s important to differentiate the genetic forms, as DOCK8 deficiency tends to have more severe viral infections and higher mortality.

Hyper-IgE Syndrome is an inherited genetic disorder. It is not contagious and cannot be acquired. How it is passed down through families depends on the specific gene involved.

Autosomal Dominant HIES (AD-HIES)

This is the most common form, caused by mutations in the STAT3 gene.

• Inheritance: It is inherited in an autosomal dominant pattern. This means an individual only needs to inherit one copy of the mutated gene from one parent to have the condition. An affected parent has a 50% chance of passing the gene on to each of their children.
• De Novo Mutation: Importantly, in more than half of all cases of AD-HIES, the mutation is de novo, or “new.” This means the genetic error occurred spontaneously in the child and was not inherited from either parent. In these cases, there is no prior family history of the disorder.

Autosomal Recessive HIES (AR-HIES)

This rarer group of HIES is inherited in an autosomal recessive pattern.

• Inheritance: A child must inherit a mutated gene (e.g., DOCK8) from both of their parents to be affected. The parents are typically unaffected carriers.
• Because both parents must carry the same rare faulty gene, the chances of having a child with an autosomal recessive condition are higher in populations where marriage between close relatives is a common cultural practice.

In my experience, most patients are born with the condition, it’s inherited, though some cases arise from new (de novo) mutations, especially in families with no known history.

The signs and symptoms of HIES are diverse, affecting the immune system, skin, skeleton and teeth. The classic presentation involves a triad of clinical findings.

The Classic Clinical Triad:

1. Recurrent “Cold” Skin Abscesses: This is a hallmark feature. Individuals develop recurrent boils and deep-seated abscesses, typically caused by Staphylococcus aureus. They are often described as “cold” because they lack the intense heat, redness, and inflammation of a normal abscess.
2. Recurrent Pneumonia: Individuals suffer from repeated, severe lung infections, also often caused by Staph aureus. These infections can be destructive, leading to the formation of permanent, air-filled cystic spaces in the lungs called pneumatoceles.
3. Severe Eczema (Atopic Dermatitis): A chronic, intensely itchy skin rash is usually present from infancy.

The Hallmark Laboratory Finding:

• Markedly Elevated Serum IgE Level: A blood test will reveal an extremely high level of IgE, often greater than 2,000 IU/mL (normal is typically less than 100 IU/mL).

Other Characteristic Features

Individuals with the classic AD-HIES due to STAT3 mutations often have a number of other distinctive features.

• Connective Tissue and Skeletal Issues:
  • A distinctive facial appearance can develop over time, including a broad nasal bridge, a prominent forehead, and increased facial skin thickness.
  • Hyperextensible joints (joints that can move beyond the normal range).
  • Scoliosis (curvature of the spine).
  • Increased risk of bone fractures with minimal trauma, due to osteoporosis.
• Dental Abnormalities: This is a very characteristic feature. There is often a retention of the primary (baby) teeth. The baby teeth fail to fall out on schedule, which prevents the permanent teeth from erupting properly, leading to a double row of teeth or impacted permanent teeth.
• Fungal Infections: Chronic mucocutaneous candidiasis (persistent thrush or fungal infections of the skin and nails) is common.

Clinically, I watch for classic signs like coarse facial features, delayed shedding of baby teeth, and high serum IgE levels. These can help differentiate it from severe atopic dermatitis.

The diagnosis of HIES can be challenging due to its rarity and its wide range of symptoms that can mimic other, more common conditions like severe allergies or simple recurrent infections. Diagnosis is usually made by a clinical immunologist.

• Clinical Suspicion: A doctor will suspect HIES in a child with the characteristic history of the clinical triad: recurrent cold skin abscesses, recurrent pneumonia, and severe eczema.
• Laboratory Tests:
  • The first step is a blood test to measure the serum IgE level. A very high level (often in the thousands) is a key supportive finding.
  • A complete blood count may also indicate a high level of another immune cell, the eosinophil.
• Clinical Scoring System: Doctors can use a scoring system developed at the National Institutes of Health (NIH) that assigns points for the various clinical and laboratory features to help determine the likelihood of a diagnosis of HIES.
• Definitive Diagnosis with Genetic Testing: The diagnosis is definitively confirmed by molecular genetic testing. A blood sample is sent to a specialized laboratory to sequence the genes known to cause HIES, primarily STAT3 and DOCK8. Identifying a disease-causing mutation confirms the diagnosis.

In my experience, I’ve found that early referral to immunology is critical, some children go undiagnosed for years because the symptoms mimic common conditions like eczema or asthma.

There is no cure for the underlying genetic defect in Hyper-IgE Syndrome. Therefore, management is a lifelong, proactive, multidisciplinary approach. The primary goal is to prevent and aggressively treat infections to minimize organ damage and preserve health.

The cornerstone of management involves several key strategies:

1. Prophylaxis Against Infections

This is the most critical part of managing the disease and improving quality of life.

• Prophylactic Antibiotics: Patients are typically placed on a long-term, daily dose of an antibiotic to prevent bacterial infections. The most commonly used antibiotic is trimethoprim-sulfamethoxazole. This is very effective in preventing dangerous Staphylococcus aureus skin and lung infections.
• Prophylactic Antifungals: A daily antifungal medication, such as itraconazole, is often prescribed to prevent chronic fungal infections of the skin and nails.

2. Diligent Skin Care

Meticulous skin care is essential. This involves the daily management of eczema with gentle cleansers, thick moisturizers to maintain the skin barrier, and the use of topical steroids as needed to control inflammation. A healthy skin barrier is crucial for preventing bacteria from gaining entry.

3. Management of Acute Infections

Any “breakthrough” infections that occur despite prophylaxis must be treated promptly and aggressively. This often requires hospitalization for intravenous (IV) antibiotics and may involve the surgical drainage of large abscesses.

4. Dental and Orthodontic Care

Regular monitoring by a dentist who is knowledgeable about HIES is crucial. The problem of retained baby teeth often requires a coordinated plan with an oral surgeon to extract the primary teeth to allow the permanent teeth to erupt.

5. Hematopoietic Stem Cell Transplant (HSCT)

A bone marrow transplant has been used successfully to cure some of the rarer, more severe autosomal recessive forms of HIES, particularly DOCK8 deficiency. For the more common autosomal dominant form (STAT3-HIES), HSCT is still considered experimental and is reserved for very severe cases, as the risks are significant and the benefits are less certain.

I’ve seen patients benefit from long-term prophylactic antibiotics, antifungals, and aggressive treatment of skin and lung infections plus careful skin care for eczema.

Hyper-IgE Syndrome, or Job’s Syndrome, is a rare and complex primary immunodeficiency that presents a lifetime of medical challenges. Its characteristic combination of recurrent “cold” skin abscesses, severe pneumonia, and chronic eczema is driven by a genetic defect in the immune system’s communication network. While the diagnosis can be daunting, it provides families with the crucial understanding needed to begin a proactive management plan. There is no cure for HIES, but a dedicated, lifelong commitment to preventative care, centered on daily prophylactic antibiotics and diligent skin care can dramatically reduce the frequency and severity of dangerous infections. Clinically, I’ve found that long-term management by a multidisciplinary team including dermatology, immunology, and pulmonology, is key to improving outcomes and quality of life.

The Immune Deficiency Foundation (IDF). (n.d.). Hyper IgE Syndromes. Retrieved from https://primaryimmune.org/disease/hyper-ige-syndromes

National Organization for Rare Disorders (NORD). (2023). Hyperimmunoglobulin E Syndrome. Retrieved from https://rarediseases.org/rare-diseases/hyperimmunoglobulin-e-syndrome/

National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2023). Autosomal dominant hyper-IgE syndrome. Retrieved from https://rarediseases.info.nih.gov/diseases/28/autosomal-dominant-hyper-ige-syndrome