Autosomal Recessive Hyper-IgE Recurrent Infection Syndrome 2

Autosomal recessive hyper-IgE recurrent infection syndrome 2 is a rare genetic immune system disease where the body cannot fight germs properly and blood levels of the antibody IgE are very high. It is usually caused by harmful changes (mutations) in a gene called DOCK8, and children often have many skin and lung infections from an early age. [1] In this condition, both copies of the DOCK8 gene (one from each parent) do not work well, so immune cells like T cells, B cells and natural killer (NK) cells cannot move, survive or talk to each other in a normal way. This makes the child very prone to infections, allergies and sometimes cancers. [2]

Autosomal recessive hyper-IgE recurrent infection syndrome 2 is a very rare primary immune deficiency where a gene called DOCK8 does not work properly. Because of this gene problem, the immune system cannot build strong, well-coordinated T-cells, B-cells and natural killer cells. As a result, the person has very high IgE levels, severe eczema, allergies, and many repeated infections of the skin, lungs and other organs, especially from viruses, bacteria and fungi. [1] [2]

In this condition, both copies of the DOCK8 gene (one from each parent) are faulty, so the disease appears when a child inherits the altered gene from both parents. This is called autosomal recessive inheritance. Parents are usually healthy carriers. The disease is sometimes described as “combined immunodeficiency due to DOCK8 deficiency” because both antibody and cellular immune responses are affected, not only IgE. [3]

Doctors see very high IgE levels in the blood, frequent skin infections, repeated chest infections such as pneumonia, and sometimes viral infections that affect the skin for a long time. This disease is different from the autosomal dominant type of hyper-IgE syndrome because it usually does not cause bone or teeth problems, but it has more severe infections and allergy problems. [3]

Other names

This disease has several other names that doctors may use in reports and articles. It is also called “DOCK8 immunodeficiency syndrome,” “combined immunodeficiency due to DOCK8 deficiency,” “autosomal recessive hyper-IgE syndrome 2 with recurrent infections,” and “hyper-IgE recurrent infection syndrome 2.” All these names describe the same basic problem of DOCK8 gene defects with high IgE and many infections. [4]

Doctors group hyper-IgE conditions into different “types” based on which gene is affected and how the disease is inherited. One well-known type is autosomal dominant hyper-IgE syndrome related to STAT3 gene changes. Another group includes autosomal recessive forms caused by defects in genes such as DOCK8, PGM3, SPINK5 and TYK2. Our topic, autosomal recessive hyper-IgE recurrent infection syndrome 2, is the DOCK8-related autosomal recessive type. [5]

Causes

Although there is one main genetic cause, it helps to break it into several related “cause” factors and mechanisms to understand the disease more clearly.

1. Biallelic DOCK8 gene mutations
The main and direct cause is harmful changes (mutations) in both copies of the DOCK8 gene. The child inherits one faulty copy from each parent, so the body cannot make enough working DOCK8 protein. Without this protein, the immune system cannot protect the body from infections in the normal way. [6]

2. Loss or severe reduction of DOCK8 protein
Many mutations in DOCK8 cause a shortened or unstable protein that breaks down quickly, so levels of DOCK8 in immune cells are very low or absent. This loss of protein leads to failure of key immune cell functions such as movement, survival and proper shape change when cells respond to germs. [7]

3. Defective T-cell function
DOCK8 is important for T cells, which guide the immune response against viruses, bacteria and fungi. When DOCK8 is missing, T cells cannot move well into tissues, do not survive well, and do not signal correctly, so viral and other infections become more frequent and harder to clear. [8]

4. Defective B-cell and antibody responses
B cells make antibodies to fight germs and to remember past infections. DOCK8 defects disturb B-cell survival and the formation of high-quality antibodies. As a result, the person may not make strong or long-lasting antibodies after infections or vaccines, which adds to the risk of repeated infections. [9]

5. Impaired NK-cell function
Natural killer (NK) cells help control virus-infected cells and some early cancers. In DOCK8 deficiency, NK cells show poor killing function and abnormal movement. This problem contributes to long-lasting viral skin infections and an increased risk of certain cancers such as lymphomas and squamous cell carcinoma. [10]

6. Abnormal actin cytoskeleton in immune cells
DOCK8 helps control the actin cytoskeleton, the internal “skeleton” that allows immune cells to change shape and move through tissues. When DOCK8 is missing, cells can stretch too much or break when they pass through tight spaces, which leads to cell death and reduced numbers of working immune cells. [11]

7. Problems in Toll-like receptor (TLR) and STAT3 signaling
DOCK8 also supports signals from pathways such as MyD88-dependent Toll-like receptors and the STAT3 transcription factor. These pathways help immune cells respond to germs and to growth factors. When DOCK8 is faulty, these signals are weaker, so the immune response is less effective even when germs are present. [12]

8. Imbalance of T-helper cell types (Th2 and Th17)
People with DOCK8 deficiency often show an immune imbalance, with stronger Th2 (allergy-type) responses and weaker Th17 responses. Th17 cells are important for fighting certain bacteria and fungi, especially in the skin and lungs. This imbalance contributes to eczema, allergies and recurrent infections. [13]

9. Very high IgE levels (hyper-IgE)
Because of the immune imbalance and abnormal signaling, IgE antibody levels in the blood become very high, often more than ten times the upper limit of normal. High IgE by itself does not cause the disease, but it reflects the underlying immune problem and is linked to eczema, allergies and tissue inflammation. [14]

10. Eosinophilia and allergy-related inflammation
Many patients have high numbers of eosinophils, a type of white blood cell linked to allergy and parasitic infection. Eosinophils release toxic proteins that can damage tissues while trying to fight germs. This eosinophilia adds to skin and lung inflammation, making symptoms like rashes and breathing problems worse. [15]

11. Consanguinity (parents related by blood)
Because the disease is autosomal recessive, it is more common in families where the parents are related (for example, cousins). In these families, the chance that both parents carry the same rare DOCK8 mutation is higher, so the risk that a child will inherit two faulty copies and develop the disease increases. [16]

12. Family history of early infections or known DOCK8 deficiency
A history of several close relatives with severe early-onset infections, unexplained high IgE or diagnosed DOCK8 deficiency increases the chance that a new child may carry the same mutations. This “family cluster” is not a separate cause but is an important inherited risk marker. [17]

13. Large deletions of the DOCK8 gene
Some patients have big missing segments (deletions) of the DOCK8 gene instead of small point mutations. These large deletions usually remove many important parts of the gene, leading to complete loss of DOCK8 protein and a more severe disease picture. [18]

14. Splice-site and truncating mutations
Other patients have splice-site or nonsense mutations that cause errors when the cell cuts and joins the gene message or that add a “stop” signal too early. The result is a shortened protein that cannot work correctly, again leading to loss of DOCK8 function. [19]

15. Genetic modifiers that change severity
Not all patients with similar DOCK8 mutations have the exact same disease severity. Other genes and environmental factors may act as “modifiers” that make infections and allergies milder or more severe. These modifiers do not cause the disease alone but can shape its course. [20]

16. Environmental exposure to germs in an immunodeficient host
Once the immune defect exists, common viruses, bacteria and fungi can cause serious disease because the body cannot handle them well. Repeated exposure to germs at home, school or community settings therefore contributes to frequent infections, though it does not create the underlying genetic defect. [21]

17. Delay in diagnosis and treatment
If the condition is not recognized early, infections may go untreated or be treated only partially, causing chronic damage to skin, lungs and other organs. This “cause” of worse outcomes is secondary, but it shows why early suspicion and testing for DOCK8 deficiency is very important. [22]

18. Chronic skin barrier damage
Eczema, scratching and recurrent skin infections break the skin barrier. Broken skin allows more germs and allergens to enter the body, which then trigger even more infections and immune reactions, creating a vicious circle that worsens disease. [23]

19. Chronic lung damage such as bronchiectasis
Repeated chest infections can damage the airways and lead to bronchiectasis, where airways become widened and scarred. Damaged airways trap mucus and germs, which again increase the risk of new infections and make breathing problems worse over time. [24]

20. Increased risk of malignancy in a weak immune system
Because DOCK8 plays a role in controlling cell survival and immune surveillance, patients have a higher risk of some cancers, especially lymphomas and squamous cell carcinoma. A weak immune system may fail to remove abnormal cells early, allowing cancers to develop and progress. [25]

Symptoms

1. Recurrent skin infections and abscesses
Many patients develop repeated skin infections with bacteria such as Staphylococcus aureus, which can form painful pus-filled lumps called abscesses. These infections may heal slowly, come back often, and sometimes leave scars. [26]

2. Chronic eczema-like rash (atopic dermatitis)
An itchy, red, scaly rash that looks like severe eczema is very common. It often starts in early childhood, may cover large body areas, and can be very difficult to control, leading to sleep problems and skin damage from scratching. [27]

3. Viral skin infections (warts, molluscum, herpes, varicella-zoster)
Because virus control is poor, patients often get widespread or stubborn viral skin infections such as warts, molluscum contagiosum, herpes simplex and varicella-zoster. These infections may last a long time and may not respond well to usual treatments. [28]

4. Recurrent ear, nose and throat infections
Ear infections (otitis media), sinus infections and throat infections occur frequently. Children may have ear pain, discharge, hearing problems or chronic blocked nose, and these infections can lead to long-term ear or sinus damage if not treated well. [29]

5. Recurrent pneumonia and other lung infections
Repeated chest infections, especially pneumonia, are a hallmark feature. Symptoms include fever, cough, chest pain and breathing trouble, and repeated episodes can damage lung tissue and cause bronchiectasis and chronic breathing problems. [30]

6. Asthma and wheezing
Many patients have asthma or asthma-like symptoms such as wheezing, chest tightness and shortness of breath. These problems relate both to allergic inflammation and to damage from infections in the airways. [31]

7. Severe food and environmental allergies
Food allergies (such as to milk, eggs, nuts) and environmental allergies (such as to dust or pollen) are common. Reactions can range from skin flares and stomach upset to more serious symptoms like breathing difficulty, and they often combine with eczema and asthma. [32]

8. Oral and mucosal infections
Fungal infections like thrush in the mouth, and sores or ulcers on mucosal surfaces, may occur again and again. These infections signal that local immune defenses are weak, especially in the mouth and throat. [33]

9. Gastrointestinal infections and diarrhea
Some patients have recurrent stomach and intestinal infections, causing diarrhea, abdominal pain and poor nutrient absorption. Over time, this can lead to weight loss and poor growth in children. [34]

10. Failure to thrive and poor growth in children
Because of repeated illness, poor appetite and malabsorption, children may not gain weight or height as expected. They may look smaller or thinner than peers, which is called failure to thrive, especially if infections start early in life. [35]

11. Enlarged lymph nodes, liver or spleen
The immune system organs such as lymph nodes, liver and spleen may become enlarged because they are constantly stimulated by infections. Parents or doctors may feel swollen nodes in the neck, armpits or groin, or notice a large abdomen due to liver or spleen enlargement. [36]

12. Frequent fevers and feeling generally unwell
Because infections are so common, patients often have fevers, tiredness, body aches and a general feeling of being unwell. These symptoms may come and go with different infections and can affect school, work and daily life. [37]

13. Skin scarring and pigment changes
Long-standing eczema, scratching and repeated infections can leave scars, darker or lighter skin patches, or thickened skin in some areas. These changes can be cosmetic concerns and may also signal chronic inflammation. [38]

14. Increased risk of certain cancers
Although cancers are not usually the first sign, patients have higher risk of lymphomas and squamous cell carcinoma of the skin or mucosa. These may present as persistent lumps, weight loss, unexplained fevers or non-healing skin lesions and require urgent medical attention. [39]

15. Serious or unusual infections that are hard to treat
Doctors may see infections that are unusually severe, affect unusual sites, or do not respond well to standard treatment. Examples include invasive fungal infections, deep abscesses or chronic viral infections that last for months or years. This pattern often raises suspicion for DOCK8 deficiency or other primary immunodeficiencies. [40]

Diagnostic tests

Physical examination

1. Detailed medical history and full physical exam
The doctor first takes a careful history, asking about frequency of infections, age at first infection, hospital stays, antibiotic courses, allergies and family history. A full physical exam checks the skin, lungs, mouth, abdomen and general growth to look for signs suggesting an underlying immune problem such as DOCK8 deficiency. [41]

2. Skin examination for eczema, infections and scars
The doctor carefully looks at the skin for eczema-like rashes, bacterial abscesses, viral warts, molluscum, herpes sores and scars from past infections. The pattern, severity and persistence of these findings can strongly point to autosomal recessive hyper-IgE syndrome. [42]

3. Respiratory system examination
Listening to the chest with a stethoscope helps detect wheezing, crackles, reduced breath sounds or signs of chronic lung disease. Doctors also inspect the chest shape and breathing pattern, which may show damage from repeated pneumonia or asthma-like airway problems. [43]

4. Growth and nutrition assessment
Height, weight and head size are measured and compared with age-matched charts. Poor growth, weight loss or failure to thrive alongside frequent infections and high IgE levels supports the suspicion of a serious primary immunodeficiency like DOCK8 deficiency. [44]

5. Examination of lymph nodes, liver and spleen
The doctor feels for enlarged lymph nodes in the neck, armpits and groin, and checks the size of the liver and spleen in the abdomen. Chronic infections and immune activation in DOCK8 deficiency often cause these organs to enlarge, which helps guide further testing. [45]

Manual and bedside tests

6. Peak expiratory flow measurement
A simple handheld device can measure how fast a patient can blow air out of the lungs. Low or variable peak flow readings may suggest asthma or chronic airway obstruction related to repeated infections and allergic inflammation. [46]

7. Spirometry (basic lung function testing)
Spirometry measures how much air the patient can breathe in and out and how fast. Patterns of obstruction or restriction help identify chronic lung disease from repeated pneumonias or asthma in autosomal recessive hyper-IgE syndrome. [47]

8. Ear, nose and throat (ENT) examination
An ENT specialist may use lights and simple tools to look into the ears, nose and throat. They check for chronic ear fluid, perforated eardrums, sinus swelling or nasal polyps, all of which are common in people with long-standing recurrent upper airway infections. [48]

9. Dental and oral cavity examination
The mouth, gums, teeth and tongue are examined to look for thrush, ulcers, gum disease or tooth problems. In DOCK8-related disease, oral infections can be frequent, and the exam also helps distinguish this autosomal recessive form from autosomal dominant hyper-IgE syndrome, which often has specific tooth and skeletal features. [49]

Laboratory and pathological tests

10. Complete blood count with differential and eosinophil count
A complete blood count (CBC) measures numbers of red cells, white cells and platelets. In DOCK8 deficiency, white cell counts may show high eosinophils and sometimes other abnormalities. The pattern supports but does not prove the diagnosis and must be interpreted with other findings. [50]

11. Serum IgE and other immunoglobulin levels
Blood tests measure IgE, IgG, IgA and IgM levels. Very high IgE is a key clue to hyper-IgE syndromes, while levels of other immunoglobulins may be normal or abnormal. This profile helps distinguish DOCK8-related disease from other immune deficiencies. [51]

12. Lymphocyte subset analysis by flow cytometry
This test uses fluorescent markers to count different lymphocyte types, such as CD4 and CD8 T cells, B cells and NK cells. In DOCK8 deficiency, there may be changes in the numbers of these cells, especially reduced memory T cells and NK cells, which support the diagnosis. [52]

13. Lymphocyte function and proliferation tests
Laboratories can test how well lymphocytes divide and respond when exposed to certain stimulants in a test tube. Poor proliferation shows that T-cell function is weak, which is typical of combined immunodeficiencies including DOCK8 deficiency. [53]

14. Measurement of specific antibody responses to vaccines
Doctors may check antibody levels after standard vaccines such as tetanus or pneumococcal vaccines. Weak or absent antibody responses suggest that B-cell function is impaired and that the immune system cannot form strong protective memory. [54]

15. Microbiology cultures and PCR tests
Samples from blood, sputum, skin lesions or other sites can be cultured or tested by PCR to identify bacteria, viruses or fungi causing infections. In DOCK8 deficiency, these tests often show repeated infections with organisms like Staphylococcus aureus, herpes viruses or other pathogens. [55]

16. Genetic testing for DOCK8 mutations
Genetic testing is the key confirmatory test. Techniques such as sequencing and deletion/duplication analysis look for disease-causing variants in the DOCK8 gene. Finding harmful changes in both copies of DOCK8 in a patient with the right clinical picture confirms the diagnosis of autosomal recessive hyper-IgE recurrent infection syndrome 2. [56]

Electrodiagnostic test

17. Nerve conduction studies and electromyography (EMG) when indicated
If a patient develops symptoms like weakness, numbness or muscle problems, doctors may use nerve conduction studies and EMG to see how well nerves and muscles are working. These tests are not specific for DOCK8 deficiency but can help detect nerve damage from infections, treatments or rare complications in people with this immune disorder. [57]

Imaging tests

18. Chest X-ray
A chest X-ray is a simple imaging test that shows the lungs and heart. It can reveal pneumonia, lung scarring, over-inflation or other changes caused by repeated infections in patients with DOCK8-related hyper-IgE syndrome. [58]

19. High-resolution computed tomography (CT) of the chest
High-resolution CT scans give more detailed images of the lungs and airways than standard X-rays. They are very useful for detecting bronchiectasis, small airway disease and subtle scarring, which are common after long-standing recurrent chest infections in this condition. [59]

20. Sinus CT or MRI and abdominal imaging
CT or MRI scans of the sinuses help detect chronic sinusitis, polyps or other problems caused by repeated ENT infections. Ultrasound or CT of the abdomen may be used to look at the liver, spleen and lymph nodes, which can be enlarged in DOCK8 deficiency. These imaging tests help map the full extent of organ involvement and guide management. [60]

Non-pharmacological treatments (Therapies and other measures)

Below are supportive, non-drug strategies used together with medicines. They do not replace medical treatment but help reduce infections and improve day-to-day life.

1. Intensive infection-prevention education
   Teaching the family simple rules like frequent hand-washing, mask use during outbreaks, and avoiding crowded places when sick people are around helps reduce exposure to germs. Understanding early warning signs of infection means the patient can reach a doctor before complications develop, which is very important because infections in DOCK8 deficiency can become severe quickly. [1] [2]

2. Daily eczema skin-care routine
   Gentle bathing with lukewarm water, fragrance-free cleansers, and immediate use of thick, bland moisturizers helps repair the skin barrier and reduce itching. Better skin integrity lowers the chance of bacteria and viruses entering through cracks in the skin, which is crucial because these patients get frequent skin abscesses and viral lesions. [2] [4]

3. Dilute bleach baths (when prescribed)
   Short baths in very dilute household bleach, as guided by a dermatologist, reduce the number of bacteria (especially Staphylococcus aureus) on the skin. This can decrease recurrent skin infections and help eczema control. The solution is always very weak and carefully measured, so it disinfects without burning or damaging the skin. [2] [5]

4. Nasal and sinus hygiene
   Regular saline nasal rinses or sprays, humidification of indoor air, and avoidance of cigarette smoke help clear mucus and reduce sinus infections. In a person whose immune system is already weak, keeping the sinuses clean lowers the risk of chronic sinusitis and spread of infection to the lungs or brain. [2] [4]

5. Chest physiotherapy and airway clearance
   Simple breathing exercises, chest percussion, postural drainage and use of airway-clearing devices can help move mucus out of the lungs. This reduces the risk of pneumonia and long-term bronchiectasis, which are common in DOCK8 deficiency because recurrent lung infections damage the airways. [2] [4]

6. Structured nutrition support
   Dietitians can design high-protein, high-calorie meals with enough vitamins, minerals and healthy fats to support growth, wound healing and immune function. Good nutrition helps the body recover from infections and limits weight loss during long illness. [1] [4]

7. Allergen and irritant avoidance
   Many patients have severe atopy and food or environmental allergies. Identifying triggers such as certain foods, dust mites, animal dander or pollen and reducing exposure can decrease eczema flares, asthma attacks, and anaphylaxis risk. Less inflammation also lowers the likelihood of secondary infections. [4] [6]

8. Environmental mould and damp control
   Keeping the home dry, fixing leaks, improving ventilation and using dehumidifiers where needed helps prevent mould growth. This is important because fungal infections can be serious in immunocompromised people and mould allergens can worsen respiratory symptoms. [2] [4]

9. Careful wound and skin-lesion care
   Any cuts, blisters, warts, or molluscum lesions should be gently cleaned, monitored and dressed according to medical advice. Early attention helps prevent abscess formation and spreading skin infections, which are a major feature of this syndrome. [2] [5]

10. Regular dental and oral care
    Daily brushing, flossing, dental check-ups and treatment of oral thrush or ulcers reduce the load of bacteria and fungi in the mouth. This lowers the risk of bloodstream infections and makes eating less painful, helping maintain nutrition. [1] [2]

11. Respiratory infection avoidance at school or work
    Planning vaccination of classmates, staying home during outbreaks of flu or other contagious illnesses, and good ventilation can reduce exposure to respiratory viruses. This is key because viral infections in DOCK8 deficiency are often unusually severe and prolonged. [2] [4]

12. Psychological and social support
    Long-term illness, visible skin disease and repeated hospital visits can cause anxiety, depression and social isolation. Counselling, support groups and school/work accommodations help patients cope emotionally and stay engaged in education or employment. Better mental health also improves treatment adherence. [1] [2]

13. Emergency infection action plan
    Families should have a written plan describing what to do for fever, breathing difficulty, sudden rash or suspected sepsis. This plan includes which hospital to go to and which doctors to contact. Quick action is vital in immunodeficiency, where infections can become life-threatening in hours. [1] [2]

14. Household vaccination and infection control
    Close contacts should be fully vaccinated with recommended non-live vaccines and should stay away or wear masks when ill. This “cocooning” strategy reduces the number of germs brought home to the immunocompromised person. [2] [4]

15. Avoidance of tobacco smoke and pollutants
    Not smoking and staying away from second-hand smoke or polluted environments protects already vulnerable lungs from further irritation and damage. Cleaner air makes it easier to control chronic cough and bronchitis. [2] [4]

16. Sun protection and gentle clothing
    Using sunscreen, protective clothing and soft, non-irritating fabrics helps protect eczema-damaged skin and prevent further inflammation. Less scratching means fewer breaks in the skin barrier and lower infection risk. [2] [5]

17. Physiotherapy and safe physical activity
    Regular, moderate exercise, guided by a physiotherapist when needed, helps maintain lung capacity, muscle strength and mood. Activity plans are adjusted around infections and hospital stays to avoid over-exertion. [2] [4]

18. Genetic counselling for the family
    Because this is an autosomal recessive disorder, genetic counselling can explain carrier status, recurrence risk in future pregnancies, and options such as prenatal or pre-implantation genetic diagnosis. This helps families make informed reproductive choices. [3] [7]

19. Regular specialist follow-up clinics
    Scheduled visits with immunology, dermatology, pulmonology and allergy specialists allow early detection of complications like chronic lung disease or malignancy. Ongoing monitoring also helps decide the best timing for stem-cell transplantation in many patients. [4] [5]

20. Education about clinical trials and registries
    Families can be informed about national or international registries and clinical trials focusing on DOCK8 deficiency and hyper-IgE syndromes. Participation can give access to new treatments and also improves scientific understanding of the disease. [3] [4]

Drug treatments

Important: All medicines for this syndrome must be chosen and monitored by specialist doctors. Many are used off-label to manage complications, and doses are adjusted for age, weight, organ function and infection severity.

1. Trimethoprim–sulfamethoxazole (TMP-SMX)
   This antibiotic combination is widely used as long-term prophylaxis to prevent bacterial skin infections and Pneumocystis jirovecii pneumonia in immunodeficient patients. It works by blocking folate metabolism in bacteria. Typical dosing is once or twice daily, based on weight and kidney function. Common side effects include rash, bone-marrow suppression and kidney problems, so blood tests are needed. [4] [8]

2. Azithromycin
   Azithromycin is a macrolide antibiotic sometimes used as regular low-dose prophylaxis for chronic lung disease and bronchiectasis. It helps reduce bacterial load and also has mild anti-inflammatory effects in the airways. Dose and frequency depend on age and liver function. Side effects may include stomach upset, liver enzyme changes and rare heart rhythm problems, so doctors monitor carefully. [4] [5]

3. Amoxicillin–clavulanate
   This broad-spectrum antibiotic treats acute bacterial sinusitis, otitis media and lower-respiratory infections, which are frequent in this syndrome. It combines a penicillin antibiotic with a beta-lactamase inhibitor to overcome resistant bacteria. Courses are usually short but may be repeated. Diarrhoea, rash and, rarely, liver injury can occur, so medical review is required if side effects appear. [2] [4]

4. Cephalosporin antibiotics (e.g. ceftriaxone, cefotaxime)
   Third-generation cephalosporins are often used in hospital for serious systemic infections, including sepsis or severe pneumonia. They work by disrupting bacterial cell wall synthesis. Doses are given intravenously and adjusted for age and kidney function. Possible side effects include allergy, diarrhoea and changes in blood counts. [2] [4]

5. Itraconazole
   Itraconazole is an oral antifungal drug that can be given prophylactically or therapeutically for mould and yeast infections, which are a concern in immunodeficiency. It blocks ergosterol synthesis in fungal cell membranes. Dosing is weight-based, and blood levels may be monitored. Side effects include liver toxicity, gastrointestinal upset and drug interactions, so liver tests and drug reviews are important. [4] [5]

6. Fluconazole
   Fluconazole is another antifungal, especially useful for candidiasis of the mouth, oesophagus and genital area. It works by inhibiting fungal cytochrome P450 enzymes. It can be used as short courses or longer prophylaxis in recurrent disease. Main side effects are liver enzyme elevation, nausea and rare severe skin reactions, and doctors check other medicines for interactions. [2] [4]

7. Voriconazole or posaconazole
   These newer triazole antifungals are reserved for serious invasive mould infections such as aspergillosis. They inhibit fungal ergosterol synthesis and are often given intravenously at first. Dosing is carefully individualised and levels are monitored. Possible adverse effects include visual changes, skin photosensitivity and liver toxicity. Because of complexity, they are used in specialist centres only. [4] [5]

8. Acyclovir / valacyclovir
   These antivirals are used to treat and prevent recurrent herpes simplex or varicella-zoster infections, which are unusually severe in DOCK8 deficiency. They inhibit viral DNA polymerase. Doses depend on renal function and severity of infection, and can be oral or intravenous. Side effects include kidney toxicity and neurotoxicity at high levels, so hydration and monitoring are important. [4] [9]

9. Ganciclovir / valganciclovir
   In very immunocompromised patients with cytomegalovirus (CMV) disease, these antivirals may be used. They are potent inhibitors of viral DNA synthesis. Doses are calculated carefully, and duration depends on response and viral load. Bone-marrow suppression, kidney toxicity and gastrointestinal symptoms are important side effects, so frequent blood counts are required. [4] [5]

10. Intravenous immunoglobulin (IVIG)
    IVIG is pooled human antibody given through a vein every few weeks in some patients with poor antibody responses. It supplies broad protective antibodies and can reduce the number and severity of infections. Dose is calculated per kg body weight. Common side effects include headache, flushing and infusion reactions; rare effects include kidney problems or thrombosis, so infusions are closely supervised. [1] [4]

11. Subcutaneous immunoglobulin (SCIG)
    SCIG delivers similar antibody replacement under the skin in smaller, more frequent doses that can sometimes be given at home. This provides steadier IgG levels and may improve quality of life compared with hospital IV infusions. Local site reactions like redness and swelling are common but usually mild. Systemic reactions are less frequent than with IVIG. [1] [4]

12. Omalizumab
    Omalizumab is a monoclonal antibody that binds IgE, reducing allergic inflammation. It is licensed for severe allergic asthma and chronic urticaria, and has been used off-label in DOCK8-related hyper-IgE syndrome to improve eczema and allergy burden. [6] [7] It is injected under the skin every 2–4 weeks, with dose based on body weight and IgE level. Side effects include injection-site reactions and rare anaphylaxis, so patients are observed after injections.

13. Dupilumab
    Dupilumab targets the IL-4 receptor alpha subunit, blocking IL-4 and IL-13 signalling, which are key in type-2 allergic inflammation. It is licensed for atopic dermatitis and asthma and has been reported to help skin disease in DOCK8 deficiency. [7] It is given as subcutaneous injections at intervals decided by the specialist. Possible adverse effects include eye irritation, conjunctivitis and local injection reactions.

14. Topical corticosteroids
    Mild to potent topical steroid creams and ointments (for example hydrocortisone, mometasone or betamethasone) are used in short courses to control eczema flares. They reduce local inflammation and itching, making the skin less likely to crack and become infected. Overuse can cause skin thinning and stretch marks, so doctors guide strength and duration carefully. [2] [4]

15. Topical calcineurin inhibitors (tacrolimus, pimecrolimus)
    These creams modulate local immune responses in the skin without causing steroid-type thinning. They are useful for delicate areas such as the face and folds in chronic eczema. Burning or stinging at application sites is common early on. Long-term safety is monitored, but they can be very helpful in reducing steroid use. [2] [4]

16. Systemic corticosteroids (short courses)
    Oral or intravenous steroids like prednisolone or methylprednisolone may be used briefly for severe inflammation, such as asthma attacks or severe skin disease. They broadly suppress immune activity and inflammation. Because long-term use can cause serious side effects (weight gain, diabetes, bone loss, infection risk), doctors keep the dose and duration as low as possible. [2] [4]

17. Cyclosporine or other systemic immunosuppressants
    In exceptional cases of extremely severe eczema or autoimmune complications, medicines like cyclosporine may be tried to control T-cell–mediated inflammation. They inhibit calcineurin and reduce cytokine production. Because they can damage kidneys, raise blood pressure and increase infection risk, they are used only in specialist centres with intense monitoring. [4] [6]

18. Inhaled corticosteroids and bronchodilators
    For patients with asthma-like symptoms, maintenance inhaled steroids and short-acting bronchodilators help control wheeze and cough. They reduce airway inflammation and relax airway muscles, improving breathing. Side effects include oral thrush and hoarseness for inhaled steroids, so rinsing the mouth after use is advised. [2] [4]

19. Antihistamines (e.g. cetirizine, loratadine)
    Non-sedating oral antihistamines reduce itching, sneezing and runny nose in allergic rhinitis and urticaria. They block histamine receptors but do not treat the underlying immunodeficiency. Doses are age-adjusted. Side effects are usually mild and include drowsiness in some people. [2] [4]

20. Interferon-gamma (in selected cases)
    Interferon-gamma is an immune-modulating cytokine sometimes used in other primary immunodeficiencies to boost macrophage activity. Its use in DOCK8 deficiency is limited and experimental, but it may be considered in research settings. It is given as subcutaneous injections under strict specialist control because it can cause flu-like symptoms, systemic inflammation and laboratory abnormalities. [4] [5]

Dietary molecular supplements

Supplements must never replace medical treatment. Doses and combinations should always be checked by a doctor, especially in children.

1. Vitamin D
   Vitamin D supports bone health and modulates both innate and adaptive immunity. Many people with chronic illness and limited sun exposure have low levels. Supplementation at doses chosen by the clinician can help correct deficiency and may reduce respiratory infections modestly. Too much vitamin D can cause high calcium, kidney stones and nausea, so blood levels should be monitored. [4] [5]

2. Omega-3 fatty acids (fish oil)
   Omega-3 fats from fish oil have anti-inflammatory effects and may help calm eczema, support cardiovascular health and modulate immune responses. They influence cell-membrane composition and eicosanoid production. Usual doses are based on age and weight. Side effects can include fishy aftertaste, diarrhoea and, at high doses, increased bleeding tendency, so they are used with caution. [4]

3. Zinc
   Zinc is essential for skin repair, taste, appetite and immune cell function. Chronic diarrhoea, infections and poor diet can lead to low zinc in primary immunodeficiencies. Supplementation at recommended doses can support wound healing and resistance to infection, but excessive zinc can cause nausea and interfere with copper balance, so medical supervision is needed. [4] [5]

4. Selenium
   Selenium helps antioxidant enzymes and influences antiviral immunity. Low selenium status has been associated with more severe viral infections in other settings. Controlled supplementation may help balance oxidative stress in chronically inflamed tissues, but high doses are toxic and can cause hair loss and nerve problems, so dosing must stay within safe limits. [4]

5. Vitamin C
   Vitamin C is a water-soluble antioxidant that supports collagen formation, wound healing and white-blood-cell function. Supplemental vitamin C within recommended daily ranges can help maintain overall health, though it does not cure immunodeficiency. Very high doses may cause stomach upset and kidney stones, so mega-dosing is not recommended. [4]

6. Vitamin A
   Vitamin A is important for epithelial surfaces and immune regulation in the gut and respiratory tract. Mild deficiency can worsen susceptibility to infections. Carefully dosed supplements can support mucosal immunity, but too much vitamin A is toxic to the liver and nervous system, so clinicians individualise dosing, especially in children. [4]

7. Probiotics (selected strains)
   Certain probiotic strains may help balance gut microbiota, support barrier integrity and modulate immune responses. In mild immune deficiencies they may reduce some infections, but in severe immunocompromise there is a rare risk of probiotic bacteria entering the bloodstream. Therefore, probiotic choice and dosing should only be made with specialist advice. [4] [5]

8. Glutamine
   Glutamine is a key fuel for rapidly dividing cells in the gut and immune system. Supplementation in some critical-illness studies has supported gut barrier function. In DOCK8 deficiency, it may help overall nutritional status, but evidence is limited; dosing must consider kidney function and overall protein intake. [4]

9. N-acetylcysteine (NAC)
   NAC is a precursor of glutathione, an important antioxidant, and also acts as a mucolytic agent, thinning mucus in the lungs. It may be used to support antioxidant defences and help mucus clearance in chronic lung disease. Potential side effects include nausea and rare allergic reactions, so it should be used under supervision. [4] [5]

10. Multivitamin–mineral complexes
    A balanced multivitamin–mineral supplement may help cover small dietary gaps in people with poor appetite or restricted diets due to allergies. It provides many micronutrients at modest doses, supporting general health. However, it must not delay proper medical treatment or be seen as a cure for the underlying genetic disorder. [4]

Immunity-booster, regenerative and stem-cell–related drugs

These approaches are highly specialised and used only under expert supervision, often in transplant or research centres.

1. Intravenous immunoglobulin (IVIG) as immune replacement
   Beyond infection control, IVIG also has immunomodulatory properties, helping rebalance abnormal immune responses. In DOCK8 deficiency, it can reduce infection frequency and sometimes dampen autoimmune or inflammatory complications. It is considered a “biologic” blood-derived product and is usually continued until a successful stem-cell transplant or as long-term therapy in non-transplanted patients. [1] [4]

2. Hematopoietic stem cell transplantation (HSCT) grafts
   Allogeneic HSCT, using donor bone-marrow or peripheral-blood stem cells, is currently the only established cure, because it replaces the defective immune system with healthy donor cells. Studies show major improvements in survival and infection control after HSCT in DOCK8 deficiency when performed under optimised regimens. [4] [5]

3. G-CSF (filgrastim) in selected cytopenias
   Granulocyte colony-stimulating factor stimulates bone-marrow production of neutrophils. In some primary immunodeficiencies with neutropenia, it is used to temporarily boost neutrophil counts and infection defence. In DOCK8 deficiency, its role is limited and individualised. Injections can cause bone pain and very high white-cell counts, so usage is cautious. [4]

4. Experimental gene-therapy vectors
   Researchers are exploring gene-therapy approaches for combined immunodeficiencies, including strategies to correct DOCK8 in hematopoietic stem cells. These involve viral or genome-editing vectors that insert a functional gene copy. At present, such therapies are experimental and only available in clinical trials with strict safety monitoring. [4] [5]

5. Biologic agents targeting allergic pathways (omalizumab, dupilumab)
   As discussed earlier, anti-IgE and anti-IL-4Rα biologics can partly “reset” allergic inflammation, improving skin and respiratory symptoms. While they do not repair the underlying genetic defect, by controlling severe atopy they may lower secondary infection risk and improve quality of life, particularly before or after HSCT. [6] [7]

6. Supportive growth factors in transplant protocols
   During HSCT, short-term use of growth factors and supportive biologic agents helps donor cells engraft and recover. These drugs support regeneration of neutrophils, platelets and lymphocytes after conditioning chemotherapy. Their dosing and timing are strictly protocol-driven within transplant centres to balance engraftment success and side-effect risks. [4] [5]

Surgeries and procedures

1. Allogeneic hematopoietic stem cell transplantation (HSCT)
   HSCT is the key procedure for long-term cure. Doctors first give conditioning chemotherapy to make space in the bone marrow, then infuse donor stem cells through a vein. These cells travel to the marrow and build a new immune system that does not have the DOCK8 defect. The goal is to stop recurrent infections, reduce allergies and prevent malignancy. [4] [5]

2. Surgical drainage of skin and soft-tissue abscesses
   Because large abscesses are common, surgeons may need to open and drain them. This removes pus and necrotic tissue, lowers the amount of bacteria, and allows antibiotics to work better. Proper drainage also reduces pain and the risk of infection spreading to deeper tissues or the bloodstream. [2] [4]

3. Functional endoscopic sinus surgery (FESS)
   In patients with chronic, severe sinusitis that does not respond to medicines, ENT surgeons may perform FESS to open blocked sinus passages and remove diseased tissue. Better drainage reduces chronic infection and improves breathing. This is particularly helpful when recurrent sinus disease contributes to repeated chest infections. [2] [4]

4. Bronchoscopy and lung surgery
   Bronchoscopy allows doctors to inspect airways, sample secretions and clear mucus plugs in people with repeated pneumonia. In rare cases of localised, destroyed lung segments or abscesses, surgeons may remove a part of the lung. The aim is to control infection sources and prevent life-threatening bleeding or chronic sepsis. [4] [5]

5. Insertion of central venous catheters or ports
   Some patients need long-term intravenous antibiotics, antivirals, or immunoglobulin. A central line or implanted port gives reliable venous access and avoids repeated needle sticks. The procedure is done in theatre using sterile technique. The team also teaches line-care routines to reduce the risk of line infections, which are particularly dangerous in immunodeficiency. [4] [5]

Prevention and lifestyle

1. Keep all vaccinations (recommended by the immunologist) up to date, especially inactivated flu and pneumococcal vaccines. Live vaccines are decided case-by-case. [2] [4]

2. Ensure close contacts are fully vaccinated and practise good hygiene to build a protective “cocoon” around the patient. [2] [4]

3. Avoid smoking and second-hand smoke to protect fragile lungs and reduce respiratory infections. [2] [4]

4. Maintain daily skin-care and trigger avoidance to keep eczema under control and prevent skin infections. [2] [4]

5. Follow infection-control advice when travelling, including safe food and water, vaccines approved by the immunologist, and carrying summary medical documents. [1] [2]

6. Seek prompt medical care for fever, new rashes, breathing problems or rapidly worsening skin lesions. Delay increases risk. [1] [2]

7. Keep regular follow-up with immunology, dermatology, pulmonology and other specialists, even when the patient feels well. [4] [5]

8. Plan ahead for HSCT evaluation in centres with experience in DOCK8 deficiency, as outcomes are better when done before severe organ damage occurs. [4] [5]

9. Use written care plans for school or workplace so teachers or employers know what to do in emergencies and how to reduce infection exposure. [2] [4]

10. Consider psychological support to cope with chronic disease stress, body-image issues from eczema and scars, and fear of infections or hospital stays. [1] [2]

When to see a doctor

A person with autosomal recessive hyper-IgE recurrent infection syndrome 2 should see a doctor urgently or go to emergency care if there is fever, chills, difficulty breathing, chest pain, confusion, severe headache, rapidly spreading skin redness, very painful abscess, or signs of sepsis such as fast heart rate and low blood pressure. These can indicate a serious infection that needs intravenous antibiotics or hospital admission. [1] [2]

They should also contact their immunology team promptly if there are more frequent infections than usual, new or worsening warts, molluscum or fungal lesions, weight loss, persistent diarrhoea, night sweats, or new lumps or swellings. These could be early signs of complications like chronic lung disease or malignancy, which benefit from early diagnosis and treatment. [4] [5]

What to eat and what to avoid

1. Eat a balanced, high-protein diet with eggs, dairy (if tolerated), lean meats, fish, legumes and nuts to support tissue repair and immune function. [4]

2. Include plenty of fruits and vegetables of different colours to supply vitamins, minerals and antioxidants that help fight oxidative stress. [4]

3. Choose whole grains (brown rice, oats, whole-wheat bread) instead of refined grains to maintain energy and gut health. [4]

4. Use healthy fats such as olive oil, nuts, seeds and oily fish rather than trans-fats or deep-fried foods to support heart and immune health. [4]

5. Drink enough water throughout the day to stay well hydrated, especially during fever or diarrhoea. [4]

6. Avoid foods that are known allergy triggers for the individual (for example certain nuts, eggs or milk) after formal assessment, because allergic reactions can be severe in hyper-IgE syndromes. [4] [6]

7. Limit high-sugar foods and drinks, which can worsen weight gain without giving useful nutrients and may impair metabolic health. [4]

8. Avoid raw or undercooked animal products (raw eggs, raw fish, rare meat) and unpasteurised milk to reduce the risk of food-borne infections in a weakened immune system. [4]

9. Be cautious with street food or food kept warm for long periods, as it may carry higher bacterial loads. Choose freshly prepared, hot foods instead. [4]

10. Do not start herbal supplements or extreme diets without discussing with the medical team, because some herbs interact with medicines and restrictive diets can worsen malnutrition. [4]

Frequently asked questions

1. Is autosomal recessive hyper-IgE recurrent infection syndrome 2 the same as “classic” hyper-IgE syndrome?
   No. Classic hyper-IgE syndrome is usually autosomal dominant due to STAT3 gene variants and often has bone and dental abnormalities. DOCK8-related, autosomal recessive hyper-IgE syndrome has more severe viral infections, allergy and malignancy risk but lacks the typical skeletal problems. [1] [3]

2. What causes this condition?
   It is caused by biallelic (two-copy) mutations in the DOCK8 gene, which disrupts cytoskeletal organisation and signalling in immune cells. This leads to defective T-cell survival, impaired antibody responses and abnormal allergen-driven inflammation. [3] [4]

3. Can it be cured?
   Currently, the only established curative approach is allogeneic hematopoietic stem cell transplantation, which can rebuild a functional immune system in many patients. Without HSCT, treatment focuses on preventing and treating infections and controlling eczema and allergies. [4] [5]

4. What is the outlook with modern treatment?
   Prognosis has improved with earlier diagnosis, better infection prophylaxis and HSCT. Studies show that many transplanted patients achieve good immune reconstitution and fewer infections, especially when transplanted before severe organ damage. Outcomes are poorer if diagnosis and treatment are delayed. [4] [5]

5. Does everyone with this condition need a stem-cell transplant?
   Most experts recommend HSCT for eligible patients because of the high lifetime risk of severe infections and malignancy. However, timing depends on age, overall health, donor availability and organ function. Some patients may be managed conservatively if transplant risk is very high. [4] [5]

6. Are live vaccines safe?
   Live vaccines are often not recommended or require very careful case-by-case assessment in combined immunodeficiency because the weakened immune system may not control the vaccine strain. The immunology team decides which vaccines are safe, usually favouring inactivated vaccines. [2] [4]

7. Why are viral infections so severe in DOCK8 deficiency?
   DOCK8 is important for cytoskeletal dynamics and immune-synapse formation in T-cells and NK cells. When it is defective, these cells have trouble killing virus-infected cells and forming long-lived memory responses, so viral skin and respiratory infections are unusually persistent and extensive. [3] [4]

8. Is this condition inherited?
   Yes. It is autosomal recessive, meaning each parent usually carries one faulty gene copy without being ill. When both parents are carriers, each pregnancy has a 25% chance of an affected child, 50% chance of a carrier child and 25% chance of a non-carrier. [3] [7]

9. Can prenatal or pre-implantation diagnosis be done?
   If the exact DOCK8 mutation in the family is known, genetic specialists can offer prenatal testing during pregnancy or pre-implantation genetic diagnosis with IVF to select embryos without the mutation. These are complex decisions that require counselling and ethical discussion. [3] [7]

10. What is the difference between DOCK8 deficiency and PGM3-related disease?
    Both can present with high IgE and recurrent infections, but PGM3 deficiency is a congenital glycosylation disorder with broader developmental problems, while DOCK8 deficiency is a combined immunodeficiency driven by cytoskeletal signalling defects. They are genetically and mechanistically distinct conditions. [3] [8]

11. Can biologic drugs like omalizumab or dupilumab replace transplant?
    No. These biologics can greatly improve eczema and allergies and reduce some infections but do not correct the deeply impaired immune system. They are usually used as supportive therapy before or after HSCT, or when transplant is not immediately possible. [6] [7]

12. Is everyday exercise safe?
    Most patients are encouraged to do light to moderate exercise when they feel well, as it supports lung function, strength and mood. Activity should be reduced during acute infections and tailored to each person’s condition, especially if there is lung or heart involvement. The medical team can advise on safe levels. [4]

13. Can people with this condition live normal lives?
    Many can attend school, work and have families, especially if they receive early diagnosis, aggressive infection prevention and, when indicated, HSCT. However, frequent medical visits and treatment side effects can affect daily life, making family and social support important. [1] [2]

14. Is there a special “hyper-IgE diet”?
    There is no single diet that cures the condition. The focus is on balanced nutrition, avoiding specific allergies, and ensuring enough calories and nutrients. Any diet changes should be guided by healthcare professionals to prevent malnutrition. [4] [6]

15. Where can families find support and more information?
    Patient organisations for primary immunodeficiencies and hyper-IgE syndromes, as well as rare-disease registries, provide educational materials, peer support and updates on research. National immunology societies and rare-disease centres can direct families to trustworthy resources and specialist clinics. [1] [2]

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: February 13, 2025.