Combined Immunodeficiency Due to Partial RAG1 Deficiency

Combined immunodeficiency due to partial RAG1 deficiency is a rare genetic disease where a child is born with an immune system that works, but works only a little, not normally. The problem comes from a change in a gene called RAG1, which is needed to build normal T cells and B cells, the white blood cells that fight germs. Because the RAG1 protein is only partly working (“partial” or “hypomorphic”), some T and B cells are made, but they are too few and often do not work well. This leads to repeated infections, problems with viruses like cytomegalovirus (CMV), and sometimes autoimmune problems, where the immune system attacks the body’s own cells.

Combined immunodeficiency due to partial RAG1 deficiency is a rare genetic immune system disease. In this condition, the RAG1 gene does not work fully, so the body cannot build normal T cells and B cells, which are the white blood cells that recognize germs and make antibodies. Because of this, the child’s immune system is weak and confused at the same time. Children often have long-lasting viral infections (especially CMV), repeated chest and gut infections, and problems where the immune system attacks their own blood cells (autoimmune cytopenia). Without proper care, infections and autoimmune problems can become life-threatening. [1][2][3][4][5]

In complete RAG1 deficiency, almost no T or B cells develop, and babies have classic severe combined immunodeficiency (SCID). In partial RAG1 deficiency, there is still some gene activity, so some lymphocytes are present, but they are abnormal. Doctors call this a form of combined T- and B-cell immunodeficiency, often with autoimmunity, granulomas (small inflammatory lumps), and severe or unusual infections.

Other names

Doctors and scientific papers may use several other names for this condition, such as:

• Hypomorphic RAG1 deficiency with combined immunodeficiency – “hypomorphic” means the gene works partly but not fully.

• Leaky RAG1 SCID – “leaky” means some immune cells are present, unlike classic SCID where they are almost absent.

• Combined immunodeficiency with granulomas and/or autoimmunity due to RAG1 mutation – used when granulomas and autoimmune disease are strong features.

• RAG1-related combined immunodeficiency (RAG1-CID) – a general term linking the disease to RAG1 gene changes.

Types

Doctors now understand that changes in the RAG1 gene can cause a spectrum of problems, from very severe to milder, later-onset disease. Partial RAG1 deficiency usually falls in the “combined immunodeficiency” part of this spectrum.

1. Childhood-onset combined immunodeficiency due to partial RAG1 deficiency
   In this form, symptoms start in early infancy or childhood. Children have repeated infections, poor growth, and low but not absent T and B cells. Immunoglobulin (antibody) levels may be low or sometimes near normal, but the body cannot make good specific responses to vaccines or infections.

2. Atypical SCID / Omenn-like disease with partial RAG1 activity
   Some children with partial RAG1 mutations develop features similar to Omenn syndrome, such as red, scaly skin rash, hair loss, enlarged lymph nodes, and very active but abnormal T cells, while still having some immune cells and some antibody production. This is sometimes called “leaky” or “atypical” SCID.

3. Combined immunodeficiency with granulomas and autoimmunity
   Another group of patients with partial RAG1 deficiency present later with chronic infections plus granuloma formation in skin or internal organs and autoimmune diseases such as autoimmune cytopenias (low blood counts caused by immune attack).

4. Late-onset or adult combined immunodeficiency due to hypomorphic RAG1
   Rarely, adults are diagnosed after years of recurrent infections, sinusitis, pneumonia, or autoimmunity. They may have some antibody responses but still have underlying RAG1 mutations and combined immunodeficiency (“leaky” RAG deficiency).

Causes

The main cause of this disease is always a pathogenic change (mutation) in both copies of the RAG1 gene. Below are different ways this can happen and factors that influence how the disease looks in each person.

1. Autosomal recessive RAG1 mutation
   Most patients inherit one faulty RAG1 gene from each parent. Each parent is usually healthy but carries a single mutation (a “carrier”). When a child gets two mutated copies, the RAG1 protein does not work properly, and combined immunodeficiency develops.

2. Missense (small change) mutations that weaken RAG1
   Missense mutations change one amino acid in the protein. In partial RAG1 deficiency, these changes often reduce, but do not totally stop, the ability of RAG1 to cut DNA during V(D)J recombination. This leaves some T and B cells but with poor diversity and function.

3. Compound heterozygous RAG1 mutations
   Some patients have two different RAG1 mutations, one on each copy of the gene. Together, these two mutations lower the activity of the protein enough to cause disease but still allow some residual function, leading to a partial immunodeficiency picture.

4. Nonsense mutations that leave tiny residual activity
   Nonsense mutations usually create a stop signal and cause severe SCID. But in some rare cases, the cell may still make a little functional RAG1 protein, or there may be second-site changes that partially “rescue” function, giving a partial deficiency instead of complete SCID.

5. Frameshift mutations with partial function
   Small insertions or deletions can shift the reading frame of the gene. If some alternative splicing or other mechanisms allow a shortened but partly active protein, the result can be partial, not complete, RAG1 deficiency.

6. Splice-site mutations in RAG1
   Some mutations affect how the gene’s RNA is spliced. Abnormal splicing may reduce, but not totally remove, RAG1 protein. This can lead to a “leaky” combined immunodeficiency with variable severity.

7. Mutations in the core catalytic domain of RAG1
   When changes happen in the central part of the protein that binds and cuts DNA, recombination is inefficient. The body produces few T- and B-cell receptors, so immune cells are present but cannot recognize many germs.

8. Mutations in regulatory or N-terminal regions
   Changes in regions outside the core catalytic site can still alter the stability, location, or regulation of RAG1. This can lower functional activity and contribute to partial deficiency and immune dysregulation.

9. RAG1 gene deletions or copy-number changes
   Larger deletions or duplications affecting RAG1 or its regulatory elements can reduce how much protein is made. If some protein remains, the result is partial deficiency rather than complete SCID.

10. De novo RAG1 mutation in the egg or sperm
    Sometimes the RAG1 mutation is not inherited from parents but appears for the first time in the child. This “de novo” mutation can still cause partial combined immunodeficiency if it is hypomorphic.

11. Genetic background in other immune genes
    Variants in other immune-related genes (such as cytokine or signaling genes) may modify how a partial RAG1 mutation shows itself, influencing infection risk, autoimmunity, and severity.

12. Founder mutations in certain populations
    In some regions or ethnic groups, a specific RAG1 mutation may be more common because of a “founder” effect. Children born in such populations have a higher chance of inheriting the same harmful variant from both parents.

13. Parental consanguinity (parents related by blood)
    When parents are closely related, they are more likely to carry the same rare RAG1 mutation. This increases the chance that their child will inherit two copies and develop partial RAG1 deficiency.

14. Family history of SCID or unexplained infant deaths
    A family history of severe infections in infancy, unexplained early deaths, or known SCID can signal inherited RAG1 mutations, even if earlier cases were not genetically tested.

15. Chronic viral infection as a disease trigger (for example CMV)
    In some patients, CMV infection seems to uncover or worsen the disease. The immune system, already weak from partial RAG1 deficiency, fails to clear the virus, leading to persistent infection and more immune dysregulation.

16. Vaccine-strain infections in undiagnosed infants (BCG, live poliovirus)
    Live vaccines are safe for healthy infants but can cause severe or widespread infection in infants with underlying combined immunodeficiency. These infections do not cause the gene change but can reveal the underlying partial RAG1 defect.

17. High exposure to common respiratory and gut viruses
    Children with partial RAG1 deficiency may appear well until they face repeated viral or bacterial exposures in crowded homes or daycare. Frequent infections stress their limited immune system and make the disease more obvious.

18. Disordered immune tolerance leading to autoimmunity
    Hypomorphic RAG1 activity can disturb T-cell and B-cell selection in the thymus and bone marrow, letting self-reactive cells survive. Over time this mechanism contributes to autoimmune cytopenias and organ-specific autoimmunity.

19. Intestinal microbiota and environmental modifiers
    Studies in animals and humans suggest that gut bacteria and other environmental factors can further shape autoimmunity and inflammation in RAG deficiency, influencing disease severity and features.

20. Delayed diagnosis and lack of curative treatment
    While not the original cause, late diagnosis and delayed hematopoietic stem cell transplantation (HSCT) allow ongoing infections and autoimmune damage. This makes the outcome of partial RAG1 deficiency worse and adds complications.

Symptoms

Children and sometimes adults with combined immunodeficiency due to partial RAG1 deficiency can show many different symptoms. Some have mostly infections; others have autoimmunity or granulomas.

1. Repeated ear, nose, and throat infections
   Many patients get frequent middle ear infections, sinus infections, or sore throats because their immune system cannot clear everyday bacteria and viruses well.

2. Recurrent chest infections and pneumonia
   Persistent or repeated cough, wheeze, and pneumonia are common, often caused by usual respiratory viruses or bacteria that become unusually severe or long-lasting.

3. Chronic diarrhea and gut infections
   Ongoing or repeated diarrhea can occur due to viral, bacterial, or parasitic infections that the body cannot control, sometimes leading to poor nutrient absorption.

4. Failure to thrive or poor weight gain
   Babies and children may not gain weight or grow as expected because of constant infections, poor appetite, and increased energy use by the body.

5. Persistent or severe viral infections (for example CMV)
   Viral infections such as CMV, EBV, or vaccine-related viruses can be persistent or severe, sometimes affecting many organs at once.

6. Oral thrush and chronic Candida infections
   Yeast infections in the mouth (white patches), skin, or diaper area may keep coming back because T-cell function is weak.

7. Skin rashes and eczema-like changes
   Some patients develop red, scaly, itchy rashes. Others may show Omenn-like erythroderma (widespread red, thickened skin) due to abnormal, overactive T cells.

8. Enlarged lymph nodes, liver, or spleen
   Swollen glands in the neck or elsewhere, and enlargement of the liver or spleen, can result from chronic infection, immune activation, or immune cell buildup.

9. Autoimmune cytopenias (low blood counts)
   The immune system may attack its own red cells, platelets, or white cells, causing anemia, easy bruising, or infections from low neutrophils.

10. Granulomas in skin or internal organs
    Some patients form firm nodules called granulomas in the skin, lungs, or other organs. These are collections of immune cells that reflect chronic immune activation, sometimes linked to vaccine viruses like rubella.

11. Prolonged or recurrent fever
    Ongoing or repeated fevers without quick recovery can signal hidden infections or autoimmune inflammation in this disease.

12. Sepsis or severe bloodstream infections
    Because the immune system is weak, infections can spread into the bloodstream and become life-threatening sepsis, especially in young children.

13. Reactions to live vaccines
    Infants may develop severe disease after live vaccines (for example BCG) because their immune system cannot control even weakened germs.

14. Fatigue and general weakness
    Chronic infection, anemia, and inflammation can make children and adults feel tired, weak, and less able to play or work.

15. Neurological problems from CNS infections
    In some severe cases, infections such as viral encephalitis or progressive multifocal leukoencephalopathy (PML) can affect the brain, causing seizures, weakness, or behavior change.

Diagnostic tests

Doctors use a mix of clinical examination and laboratory and imaging tests to diagnose combined immunodeficiency due to partial RAG1 deficiency and to rule out other problems. Below are 20 key tests, grouped by type but numbered together.

1. Full physical examination and growth check (Physical exam)
   The doctor carefully examines the child, looking for signs of infection (fever, cough, ear pain), poor growth, rashes, enlarged lymph nodes, or organ enlargement. Height, weight, and head size are plotted on growth charts to see if the child is falling behind.

2. Detailed skin and mucous membrane exam (Physical exam)
   The doctor looks at the skin for eczema, red scaly rashes, granulomas, or signs of Omenn-like erythroderma, and checks the mouth, eyes, and genital area for ulcers or fungal infections.

3. Lymph node, liver, and spleen palpation (Physical exam)
   By gently feeling the neck, underarms, abdomen, and groin, the doctor checks for swollen glands or enlarged liver and spleen, which can suggest chronic infection, immune activation, or blood problems.

4. Respiratory and chest examination (Physical exam)
   Listening to the lungs with a stethoscope and observing breathing pattern helps detect pneumonia, chronic lung disease, or wheeze, which are common in combined immunodeficiency.

5. Serial temperature measurement (Manual test)
   Regularly checking body temperature with a thermometer helps document persistent or recurring fever, which guides infection work-up and treatment decisions.

6. Manual measurement of weight, height, and head circumference over time (Manual test)
   Repeated measurements plotted on growth charts show whether the child is thriving or failing to gain weight and height, a key sign of chronic immune-related illness.

7. Clinical assessment of hydration and nutrition (Manual test)
   Simple bedside checks such as skin turgor, moistness of the mouth, and eye appearance, combined with dietary history, help judge dehydration and malnutrition due to repeated diarrhea or infections.

8. Manual respiratory rate and oxygen saturation monitoring (Manual test)
   Counting breaths per minute and using a pulse oximeter helps detect respiratory distress and low oxygen levels during chest infections or sepsis, guiding urgent care.

9. Complete blood count (CBC) with differential (Lab / pathological)
   A CBC shows hemoglobin, white cell counts, and platelets. Many patients have low lymphocytes or specific cytopenias caused by autoimmunity or marrow stress. The differential white count helps reveal lymphopenia and eosinophilia patterns.

10. Lymphocyte subset analysis by flow cytometry (Lab / pathological)
    This test counts T cells, B cells, and NK cells and looks at their subtypes. Partial RAG1 deficiency often shows low or abnormal T and B cells, with NK cells often preserved, fitting a combined immunodeficiency pattern.

11. Serum immunoglobulin (IgG, IgA, IgM, IgE) levels (Lab / pathological)
    Measuring antibody levels shows whether the body can make enough immunoglobulins. Levels may be low, absent, or occasionally near normal but with poor function, especially in partial forms.

12. Specific antibody responses to vaccines or infections (Lab / pathological)
    Doctors check antibody titers after routine vaccines or past infections. Poor or absent specific responses, even when total IgG seems normal, support a diagnosis of combined immunodeficiency.

13. T-cell function tests (lymphocyte proliferation assays) (Lab / pathological)
    In the lab, patient T cells are exposed to mitogens or antigens to see if they divide normally. In partial RAG1 deficiency, responses are often reduced, showing functional T-cell impairment.

14. Genetic testing of the RAG1 gene (Lab / pathological)
    DNA sequencing of the RAG1 gene is the key test that confirms the diagnosis. It identifies the exact mutations and helps predict whether they are hypomorphic (partial) or null. This also guides family counseling and treatment planning.

15. Newborn screening for SCID using T-cell receptor excision circles (TREC) (Lab / pathological)
    In places where newborn screening is available, a dried blood spot test measures TRECs. Low TRECs can suggest T-cell development problems, including RAG1 defects, and trigger early detailed immune and genetic evaluation.

16. Viral PCR tests and cultures (Lab / pathological)
    Tests for CMV, EBV, adenovirus, or other viruses using PCR or culture help explain persistent or severe infections and guide therapy in children with suspected partial RAG1 deficiency.

17. Electroencephalogram (EEG) for seizures or encephalopathy (Electrodiagnostic)
    If there are seizures or altered consciousness due to brain infections or inflammation, EEG helps show abnormal brain electrical activity and supports diagnosis and follow-up.

18. Nerve conduction studies (Electrodiagnostic)
    In rare patients with neuropathy after infections or immune complications, nerve conduction tests check how quickly nerves send signals, helping to detect damage linked to chronic infection or autoimmunity.

19. Chest X-ray (Imaging)
    A chest X-ray can show lung infections, chronic lung changes, or sometimes an absent or small thymic shadow, which suggests T-cell development problems as seen in combined immunodeficiency.

20. CT or MRI scans of chest, abdomen, or brain (Imaging)
    CT or MRI imaging is used when more detail is needed. It can show granulomas, lymph node enlargement, organ involvement, or brain lesions from infections such as PML or severe viral encephalitis in RAG1-deficient patients.

Non-pharmacological treatments

1. Infection-control lifestyle education
   The most basic treatment is teaching the family how to lower infection risk in daily life. This includes hand-washing with soap many times a day, using alcohol hand rub when outside, wearing masks in crowded places, and avoiding close contact with anyone who has cough, cold, diarrhea, or fever. For a child with partial RAG1 deficiency, simple infections can become very serious, so these small daily steps make a big difference in keeping them out of the hospital. [1][3]

2. Avoidance of live vaccines
   Live vaccines (like some measles, mumps, rubella, varicella, or oral polio vaccines) contain weakened but living germs. In children with serious immune problems, these weakened germs may still cause disease. Doctors usually plan a special vaccination schedule that avoids live vaccines for the patient and may adapt vaccines for family members as well. This reduces the chance that a vaccine strain germ can spread and cause serious illness. [1][3]

3. Household vaccination strategy
   Even if the child cannot safely receive some vaccines, parents, siblings, and other close contacts should be fully vaccinated with non-live vaccines. This “cocooning” strategy means people around the child are less likely to catch and bring infections like flu, pertussis, or COVID-19 into the home. In this way, the family’s vaccines act as a shield for the child with immunodeficiency. [1][3]

4. Protective isolation during outbreaks
   During bad flu seasons, RSV season, or local outbreaks of serious infections, doctors may advise staying at home more, avoiding school or daycare for a time, and limiting visitors. For hospital stays, special rooms with filtered air and strict infection-control rules may be used. This temporary isolation reduces exposure to dangerous viruses that the child’s weak immune system cannot control well. [1][3][5]

5. Safe food and water hygiene
   Children with combined immunodeficiency are at higher risk from food-borne and water-borne germs. Families are often taught to use safe drinking water, avoid raw or under-cooked meat, eggs, and seafood, and to wash fruits and vegetables very well. Leftover food should be cooled quickly and reheated properly. These simple measures lower the chance of diarrhea, sepsis, and other serious infections from contaminated food. [1][2]

6. Good skin and wound care
   Skin breaks are easy entry points for bacteria and fungi. Caregivers are advised to keep the skin moisturized, treat eczema gently, and clean any cuts or insect bites with mild antiseptic. Nails should be kept short, and scratching should be discouraged to prevent deeper infection. Early care of small problems helps stop them from turning into big abscesses or bloodstream infections. [1][3]

7. Oral and dental hygiene
   The mouth is full of germs. Regular tooth-brushing with fluoride toothpaste, flossing where possible, and dental check-ups reduce gum infection and tooth decay. Mouth infections can quickly spread to the blood in people with low immune defenses. Dentists may work closely with immunology doctors to time any dental procedures when infection risk is lowest and to plan antibiotic cover if needed. [1][3]

8. Nutritional support and growth monitoring
   Good nutrition supports all parts of the immune system. Children with partial RAG1 deficiency may not gain weight well because of repeated infections, diarrhea, or poor appetite. A dietitian can design high-calorie, high-protein meal plans, sometimes including oral supplements or special formulas. Regular checks of weight, height, and blood nutrients help find problems early so that extra feeding support can be given. [1][2]

9. Physiotherapy and breathing exercises
   Chest physiotherapy, deep breathing, and coughing exercises help clear mucus from the lungs. This is important after pneumonia or when the child has chronic cough or bronchiectasis. Keeping the lungs as clear as possible lowers the risk of repeated chest infections and helps preserve lung function in the long term. [1][3]

10. Early-warning infection action plan
    Families are usually given a clear written plan about what to do if the child has fever, fast breathing, poor feeding, or unusual tiredness. The plan may include checking temperature, giving extra fluids, and going quickly to the emergency department or immunology clinic. Having this plan reduces delays in starting antibiotics and other urgent care when serious infections appear. [1][3]

11. Regular immunology follow-up
    Children with partial RAG1 deficiency need regular visits with an immunologist. At these visits, doctors review infection history, growth, blood counts, kidney and liver function, and drug side effects. They may adjust prophylactic medicines and plan for bigger treatments such as stem cell transplant. Continuous follow-up helps catch problems early and improve long-term outcome. [1][4][5]

12. Monitoring for autoimmune disease and malignancy
    This condition can cause autoimmune cytopenias (low red cells, platelets, or neutrophils due to self-attack) and increases the risk of some cancers. Doctors therefore order regular blood tests, physical exams, and sometimes imaging. If warning signs appear, early treatment with immunosuppressive drugs or other therapies can be started before complications become severe. [2][4][9]

13. Psychological counseling and family support
    Living with a chronic, serious disease is stressful for the child and caregivers. Counseling can help family members cope with fear, guilt, and fatigue. Support groups and rare-disease networks provide emotional support and practical tips. Good mental health care improves treatment adherence, quality of life, and long-term adjustment. [1][3]

14. Educational and school adaptation
    Many children can still attend school but may need adjustments. Examples are smaller class size, flexible attendance during infections, and help with online learning during high-risk periods. Teachers and school nurses are educated about the child’s condition and when to send the child home or call parents. This allows the child to keep learning while staying as safe as possible. [1][3]

15. Genetic counseling for the family
    Because this is a genetic disorder of the RAG1 gene, other family members may be carriers or at risk of having affected children. Genetic counseling explains inheritance patterns, carrier testing, and options such as prenatal diagnosis or pre-implantation genetic testing. This helps families make informed choices about future pregnancies. [2][16][20]

16. Physical activity within limits
    Gentle regular exercise, chosen with the doctor and physiotherapist, helps maintain muscle strength, bone health, and mood. Activities should avoid crowded indoor gyms or high-impact contact sports that increase injury or infection risk. A balanced activity plan supports general health without putting the child at extra risk. [1][3]

17. Sunlight and vitamin D safety advice
    Children with chronic illness may have low vitamin D, but some medicines and autoimmune problems can also make the skin sensitive to sunlight. Doctors and dietitians give tailored advice about safe sun exposure, sunscreen use, and vitamin D intake to support bone and immune health without causing skin damage. [1][3]

18. Home environment optimization
    Smoke-free homes, good ventilation, and control of indoor mold and dust help reduce lung irritation and infection. Pets may be allowed or discouraged based on the animal type and the child’s infection history. Simple changes like using HEPA filters or avoiding wood-burning stoves can make breathing easier for a vulnerable child. [1][3]

19. Palliative and supportive care when needed
    In very severe cases, especially if curative options such as stem cell transplant are not available or have failed, palliative care teams can help. Their focus is relief of symptoms, comfort, and support for the family’s emotional and spiritual needs. This care can be given alongside active medical treatment, not only at the end of life. [1][5][29]

20. Planning for stem cell transplant or gene therapy
    For many children with RAG-related combined immunodeficiency, allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative treatment. Research is also exploring gene therapy to correct the RAG1 defect. Families and doctors may start planning early, even while the child is receiving supportive treatments, so that the timing and donor choice are as safe as possible. [1][5][21][29][32]

---

Drug treatments

Important: The medicines below are examples that specialists may use. They must never be started, stopped, or changed without a pediatric immunologist or other qualified doctor. Doses are individualized; only your doctor can choose the right dose and schedule.

1. Intravenous immune globulin (IVIG) products
   IVIG is made from pooled antibodies from many healthy donors. For children with partial RAG1 deficiency and low antibody levels, IVIG replaces missing antibodies and helps prevent bacterial and some viral infections. It is given by slow drip into a vein every few weeks in hospital or a clinic, under close monitoring for side effects like headache, fever, or allergic reactions. [1][3][10]

2. Subcutaneous immune globulin (SCIG) products
   SCIG preparations allow smaller amounts of immunoglobulin to be given under the skin at home using a pump and small needles. Families are trained to give these infusions weekly or bi-weekly. SCIG keeps antibody levels stable, avoids big peaks and troughs, and may cause fewer systemic side effects, though local redness and swelling at the infusion site are common. [1][3][10][16][22]

3. Trimethoprim-sulfamethoxazole (TMP-SMX)
   This antibiotic combination is commonly used to prevent Pneumocystis jirovecii pneumonia, a serious lung infection in immunocompromised patients. It may also protect against some urinary and gut infections. Doctors choose dose and schedule carefully based on age, kidney function, and other medicines, and they monitor blood counts and allergy signs, because TMP-SMX can cause rash, low blood cells, and kidney problems in some people. [7][19][31]

4. Broad-spectrum intravenous antibiotics
   When a child with combined immunodeficiency develops fever or suspected sepsis, doctors often start strong IV antibiotics (for example, third- or fourth-generation cephalosporins or carbapenems) right away. These drugs cover many possible bacteria until cultures identify a specific germ. Early and aggressive treatment of infection is crucial in preventing shock and organ failure in immunodeficient patients. [1][3]

5. Oral prophylactic antibiotics (e.g., amoxicillin or azithromycin)
   Some children receive daily or several-times-per-week oral antibiotics to reduce recurrent ear, sinus, or chest infections. Choice of drug and duration depends on local resistance, previous infections, and tolerance. Long-term antibiotics can cause diarrhea, antibiotic resistance, or allergic reactions, so doctors balance benefits and risks and review the plan often. [1][3]

6. Antiviral drugs for CMV (e.g., ganciclovir, valganciclovir)
   Persistent cytomegalovirus infection is a hallmark of many partial RAG1 deficiency cases. Antivirals such as ganciclovir and its oral prodrug valganciclovir can reduce viral load and improve symptoms. These medicines are powerful and can lower blood counts or affect kidney function, so they are used only under specialist care with frequent blood tests and dose adjustments. [1][2][13]

7. Other antiviral agents (e.g., acyclovir for herpes viruses)
   Acyclovir and related drugs can be used for prophylaxis or treatment of herpes simplex and varicella-zoster infections in immunocompromised patients. They are usually given orally or by IV, depending on severity. Doctors check kidney function and hydration because these medicines are cleared by the kidneys and can cause kidney problems if dosing is not carefully managed. [1][3]

8. Antifungal prophylaxis (e.g., fluconazole)
   Children with severe combined immunodeficiency are at risk of serious fungal infections of the mouth, gut, blood, or lungs. Fluconazole or other antifungals may be used to prevent or treat such infections, especially during times of intense immunosuppression or after stem cell transplant. Liver function tests and drug interactions are monitored closely, since many antifungals affect liver enzymes. [1][3][29]

9. Corticosteroids (e.g., prednisone)
   Low or moderate doses of corticosteroids may be used to treat autoimmune cytopenias or inflammatory complications. These drugs work by calming down an overactive immune response. However, long-term steroid use can further weaken infection defenses, raise blood sugar and blood pressure, and affect growth and bones, so doctors aim for the lowest effective dose and taper as soon as possible. [2][9]

10. Other immunosuppressive agents (e.g., mycophenolate, cyclosporine)
    When autoimmune problems are severe or do not respond to steroids alone, additional immunosuppressive drugs may be added. These medicines dampen specific parts of the immune system and can help control hemolytic anemia, thrombocytopenia, or organ-targeted autoimmunity. Because they also increase infection risk and can affect kidneys, liver, or blood pressure, they are used only by experienced specialists with regular monitoring. [2][9][21]

11. Rituximab and other monoclonal antibodies
    Rituximab targets CD20-positive B cells and can help in autoimmune cytopenias or lymphoproliferative complications. It is given by IV infusion and may cause infusion reactions, low immunoglobulin levels, or reactivation of some viruses. Before giving rituximab, doctors review vaccination history and screen for hepatitis and other infections where possible. [2][9]

12. RSV-preventive monoclonal antibodies (e.g., palivizumab, nirsevimab)
    Respiratory syncytial virus can be very severe in infants with immunodeficiency. Long-acting antibodies like palivizumab or newer agents such as nirsevimab are used during RSV season to lower the risk of hospitalization. They are given as injections in the muscle, with dose and timing based on body weight and season. Side effects are usually mild but injection-site pain and rare allergic reactions can occur. [5][14][17][29]

13. Growth factor for white cells (e.g., G-CSF / filgrastim)
    In some patients with very low neutrophil counts, granulocyte colony-stimulating factor (G-CSF) can be used to boost neutrophils and lower the risk of bacterial infection. It is given as a subcutaneous injection at doses chosen by weight and blood count response. Bone pain and temporary enlargement of the spleen are known side effects, so monitoring is important. [1][2][29]

14. Immunoglobulin for specific exposures (e.g., VZIG, hepatitis B immunoglobulin)
    When a child with partial RAG1 deficiency is exposed to certain infections like varicella (chickenpox) or hepatitis B, special immune globulin preparations can be given soon after exposure. These products contain high levels of specific antibodies that may prevent or soften the infection. They are given by injection under the skin or into a muscle, and side effects are similar to other immunoglobulins. [18][26]

15. Prophylactic anticoagulation when indicated
    Some patients with severe infections, central lines, or autoimmune problems may be at higher risk of blood clots. In such cases, doctors may prescribe low-dose anticoagulants (blood thinners). These drugs are chosen very carefully because they increase bleeding risk and require regular monitoring, especially in children. [1][3]

16. Supportive medicines for gut health (e.g., proton pump inhibitors, anti-emetics)
    Recurrent infections, antibiotics, and strong drugs can irritate the stomach and intestines. To help the child tolerate treatments and keep taking needed medicines, doctors sometimes prescribe drugs to protect the stomach or control nausea and vomiting. These supportive medicines do not treat immunodeficiency itself but help keep overall care possible and safer. [1][3]

17. Analgesics and antipyretics (e.g., paracetamol under supervision)
    Pain and fever control are essential for comfort and to allow proper rest. Simple medicines like paracetamol may be used, with doses strictly based on weight and liver function. They do not treat the infection itself but help the child feel better while antibiotics and other treatments work. Parents are taught never to exceed the recommended dose and to use them only under medical advice. [1][3]

18. Electrolyte and fluid replacement solutions
    Severe diarrhea, vomiting, or sepsis may cause dehydration and dangerous changes in salts in the blood. Oral rehydration solutions and IV fluids are used to correct these imbalances. Precise fluid volumes and speeds are calculated by doctors based on age, weight, kidney function, and vital signs to avoid fluid overload or organ damage. [1][3]

19. Blood products (red cell, platelet, or plasma transfusions)
    Autoimmune cytopenias or marrow suppression from infection or drugs can lead to very low red cells or platelets. Transfusions of carefully screened blood products can correct anemia, prevent bleeding, and stabilize the patient before procedures or transplant. Doctors match blood type and follow strict safety rules to prevent reactions and infections. [2][9]

20. Conditioning and supportive drugs for stem cell transplant
    When HSCT is planned, a special combination of chemotherapy and other medicines is used to prepare the bone marrow and prevent transplant rejection. During and after transplant, additional drugs prevent graft-versus-host disease and control infections. These regimens are complex and are managed only in transplant centers with intensive monitoring. [1][5][21][29]

---

Dietary molecular supplements

Note: Supplements should only be started after discussion with the child’s specialists, because some can interfere with medicines or lab tests.

1. Vitamin D – supports bone strength and immune regulation; given in drops or tablets.

2. Vitamin A – important for healthy skin and gut lining, which act as barriers against infection.

3. Vitamin C – helps white cells work properly and supports collagen in skin and blood vessels.

4. Zinc – needed for many immune enzymes and for wound healing.

5. Selenium – supports antioxidant defenses in immune cells.

6. Omega-3 fatty acids – may help control inflammation and support heart and brain health.

7. Probiotics (selected strains) – can support gut barrier function, but must be used cautiously in severe immunodeficiency.

8. Iron (if deficient) – corrects iron-deficiency anemia and improves oxygen delivery to tissues.

9. Folate and vitamin B12 – needed for normal red blood cell production and DNA synthesis.

10. Glutamine or protein-rich supplements – support gut cells and overall protein stores during illness.

Doctors choose doses based on blood tests, age, diet, and kidney and liver function to avoid toxicity. [1][3]

---

Immune-booster, regenerative, and stem-cell-related drugs

1. Granulocyte colony-stimulating factor (G-CSF) – boosts neutrophil production, as described above, and can lower bacterial infection risk when neutrophils are very low. [1][2][29]

2. Other hematopoietic growth factors (e.g., GM-CSF) – can stimulate wider groups of white cells and may be used in selected cases, especially around transplant or severe infections, always under specialist care. [1][29]

3. Erythropoiesis-stimulating agents – may be used in some chronic anemia cases to help the bone marrow make more red blood cells, reducing the need for transfusions when appropriate. [1][29]

4. Conditioning-related agents for HSCT – some newer regimens use reduced-toxicity drugs that allow donor stem cells to engraft with less damage to organs, supporting better long-term immune recovery. [1][5][21][29]

5. Investigational RAG1 gene therapy products – clinical trials are testing viral vectors carrying a healthy RAG1 gene to correct the defect in a patient’s own stem cells. Early animal and human studies show promise, but these therapies remain experimental and are only available in research centers. [1][21][32]

6. Biologic agents to rebalance immune regulation – in selected patients with severe immune dysregulation, biologics targeting specific cytokines or cell pathways may be used to reduce inflammation while trying to preserve infection defense; these decisions are highly individualized and made by expert teams. [9][29]

---

Surgeries and procedures

1. Central venous catheter insertion
   Many children need a long-term central line for IVIG, antibiotics, or transplant conditioning. This small surgery places a catheter into a large vein under anesthesia. It allows easy access for treatment but also increases infection risk, so strict line-care protocols are followed. [1][3]

2. Hematopoietic stem cell transplantation (HSCT)
   HSCT replaces the child’s defective immune system with healthy donor stem cells. It is the main curative option for severe RAG-related combined immunodeficiency. The procedure includes conditioning chemotherapy, infusion of donor cells, and long-term monitoring for graft-versus-host disease, infections, and organ toxicity. Outcomes have improved over time but the procedure still carries serious risks. [1][5][21][29]

3. Gastrostomy tube placement
   If oral feeding is not enough because of fatigue, swallowing problems, or chronic illness, doctors may place a feeding tube directly into the stomach. This allows safe delivery of calories, fluids, and medicines. Better nutrition supports growth, healing, and preparation for HSCT. [1][3]

4. Splenectomy (in selected severe autoimmune cytopenias)
   In rare cases where the spleen is destroying blood cells despite medical therapy, surgical removal of the spleen may be considered. This can improve blood counts but further increases infection risk, so vaccines and lifelong antibiotic prophylaxis are usually needed afterward. [2][9]

5. Biopsy or diagnostic procedures
   Sometimes lymph node, bone marrow, or organ biopsies are needed to diagnose infections, cancers, or unusual immune reactions. These procedures guide treatment choices. Because patients are fragile, they are done with careful planning, antibiotic cover when needed, and close post-procedure observation. [1][3]

---

Prevention tips

1. Strict hand-washing and mask use during high-risk seasons.

2. Keeping sick visitors away and avoiding crowded indoor places.

3. Following the special vaccination plan advised by the immunologist.

4. Making sure all household members are fully vaccinated with recommended non-live vaccines.

5. Using safe water and avoiding raw or under-cooked foods.

6. Keeping the home smoke-free and well-ventilated.

7. Going to the doctor early for any fever, breathing trouble, or unusual tiredness.

8. Attending all scheduled follow-up visits and blood tests.

9. Keeping a list of all medicines and doses, and bringing it to every clinic or hospital visit.

10. Having an emergency plan and knowing which hospital to go to at any time of day or night. [1][3][17]

---

When to see a doctor urgently

Parents or caregivers should seek urgent medical care if the child has:

• Fever (especially above 38°C), chills, or looks very unwell.

• Fast or difficult breathing, chest pain, or persistent cough.

• Very poor feeding, vomiting, or diarrhea that does not stop.

• Sleepiness, confusion, or sudden behavior changes.

• New bruises, bleeding, or very pale skin.

• Any rash with fever or that spreads quickly.

• Pain and swelling around a central line or surgical wound.

Because infections can become severe very quickly in partial RAG1 deficiency, it is safer to go early to hospital rather than wait at home. [1][3][17]

---

Diet: what to eat and what to avoid

1. Eat well-cooked meat, fish, and eggs; avoid raw or under-cooked versions such as runny eggs, sushi, or raw minced meat.

2. Eat pasteurized milk and dairy; avoid unpasteurized milk, soft cheeses made from raw milk, and street ice creams.

3. Eat well-washed fruits and vegetables; avoid unwashed raw produce and salads from unsafe sources.

4. Drink safe, boiled, or filtered water; avoid untreated water from wells, rivers, or unknown taps.

5. Choose home-cooked meals when possible; avoid food that has been left at room temperature for many hours.

6. Include enough protein (meat, eggs, beans, lentils) to support growth; avoid very low-protein fad diets.

7. Use healthy fats such as vegetable oils and limited amounts of nuts or seeds if safe; avoid very fatty fried fast foods.

8. Include colorful fruits and vegetables rich in vitamins; avoid very sugary snacks and drinks that replace real food.

9. Follow the dietitian’s advice about extra calorie or protein supplements; avoid starting herbal products or “immune boosters” without telling the doctor.

10. Watch for lactose intolerance or food triggers that worsen symptoms; avoid forcing foods that clearly cause repeated problems, and discuss with the care team. [1][3]

---

Frequently asked questions

1. Is partial RAG1 deficiency the same as classic SCID?
   It is related but not exactly the same. Classic SCID often has almost no T or B cells, while partial RAG1 deficiency usually has some T and B cells that do not work properly, leading to combined immunodeficiency with infections and autoimmunity. [1][2][12][20]

2. Can my child ever have a normal immune system?
   Some children may achieve near-normal immune function after a successful stem cell transplant or (in the future) gene therapy. Others may always need long-term immunoglobulin replacement and infection prevention, but with good care they can still live longer and better lives. [1][5][21][29][32]

3. Will every child with partial RAG1 deficiency have the same severity?
   No. The exact mutation in the RAG1 gene and other genetic and environmental factors cause a wide range of severity. Some children are very sick in early infancy, while others are diagnosed later with autoimmune problems and repeated infections. [2][8][12][28]

4. Is this condition inherited?
   Yes, it is usually inherited in an autosomal recessive way. This means both parents carry one faulty copy of the gene but are usually healthy themselves. Each pregnancy has a 25% chance of producing an affected child. Genetic counseling can explain this in more detail. [2][16][20]

5. Can vaccines protect my child?
   Some non-live vaccines may be given safely and can still provide partial protection, but live vaccines are usually avoided. Vaccinating family members and close contacts is also very important. The exact plan is always made by the specialist team. [1][3]

6. Why do doctors give so many antibiotics and antivirals?
   Because the immune system cannot fight germs well, medicines must help do that job. Drugs are used both to treat active infections and to prevent new ones. The team tries to use the smallest effective number of drugs and to stop them when they are no longer needed. [1][3][7][19][31]

7. Is long-term IVIG or SCIG safe?
   Immunoglobulin replacement has been used for many years in primary immunodeficiencies and is generally safe and effective. Side effects like headache, fever, or infusion reactions can occur but are usually manageable. The benefits in preventing serious infections are often much greater than the risks. [1][3][10][16][22]

8. Can my child go to school?
   Many children can attend school with special precautions, especially when their condition is stable. This may include avoiding school during severe outbreaks, ensuring classmates are vaccinated, and arranging flexible learning plans. Decisions are individualized. [1][3]

9. Will my child need a stem cell transplant?
   For many patients, especially those with severe infections or immune dysregulation, HSCT is strongly considered because it offers the best chance of long-term cure. The timing and whether it is recommended depend on disease severity, donor availability, and local transplant expertise. [1][5][21][29]

10. What are the main risks of HSCT?
    HSCT can cause serious short-term complications like infections, organ damage, or graft-versus-host disease, and long-term effects like growth and fertility problems. However, for severe combined immunodeficiency, the risk of doing nothing is often higher than the risk of transplant. [1][5][21][29]

11. Is gene therapy available now?
    RAG1 gene therapy is currently being studied in clinical trials and is not yet standard treatment. Early results are encouraging, but more data are needed to confirm safety and long-term benefit. Families interested in trials should discuss options with their immunology center. [1][21][32]

12. Will my child always need to avoid crowds and travel?
    During early years and when the disease is unstable, strong restrictions may be needed. If the immune system improves after HSCT or other treatments, some restrictions may be relaxed. The care team will give specific advice for travel, school, and social activities at each stage. [1][3][17]

13. Can diet alone fix the immune problem?
    No. Good nutrition is very important for overall health and can support the immune system, but it cannot correct the genetic defect in RAG1. Medical treatments like immunoglobulin replacement, antibiotics, and possibly HSCT are still necessary. [1][2][3]

14. Is there a cure?
    The only proven curative approach is allogeneic stem cell transplant. Gene therapy may provide another curative option in the future. Supportive care alone cannot cure the disease but can greatly reduce complications and improve quality of life. [1][5][21][29][32]

15. What should I do next as a parent or caregiver?
    The most important steps are to stay closely connected with your child’s immunology team, follow their prevention and treatment plans, and seek help early when problems arise. Asking questions, keeping good records, and caring for your own health and stress levels will help you support your child over the long term. [1][3][17]

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 14, 2025.