Combined Immunodeficiency Due to RAG1/2 Deficiency

Combined immunodeficiency due to RAG1/2 deficiency is a serious inherited disease where the immune system cannot build normal T cells and B cells, which are the main “soldiers” that fight germs. This happens because the RAG1 and RAG2 genes, which are needed to cut and join pieces of DNA to make T-cell and B-cell receptors, do not work properly. As a result, the child has very few or no working T cells and B cells, and cannot fight infections, so even common germs can cause very severe, long-lasting, or unusual infections early in life. [1]

Combined immunodeficiency due to RAG1/2 deficiency is a rare, serious genetic disease where a baby is born with a very weak immune system because the RAG1 and RAG2 genes do not work properly. These genes normally help white blood cells (T cells and B cells) build their “antennas” (receptors) so they can recognize germs. When RAG1/2 are faulty, the body cannot make normal T and B cells, so the child gets many, often severe, infections and may develop problems like granulomas, autoimmunity, or failure to grow. [1]

In complete (severe) RAG1/2 deficiency, there is almost no V(D)J recombination, so T and B cells are very low or absent, causing a form of severe combined immunodeficiency (SCID). In milder (hypomorphic) forms, some T and B cells exist, but they are abnormal and can cause both infections and immune system “misfires” such as granulomas in the skin or organs, chronic diarrhea, and inflammation. [2]

In many patients, natural killer (NK) cells are still present, so this form of severe combined immunodeficiency (SCID) is often called “T-B- NK+ SCID.” This pattern means that both T and B lymphocyte numbers are very low or absent, but NK cells are normal. Children with this condition are at very high risk of life-threatening infections unless they receive early and proper treatment, usually hematopoietic stem cell transplantation. [2]

Other names

Doctors and researchers use several other names for combined immunodeficiency due to RAG1/2 deficiency. These names may sound different but point to the same basic problem in the RAG genes. [3]

• RAG1 deficiency SCID

• RAG2 deficiency SCID

• T-B- NK+ SCID due to RAG1/2 defect

• RAG1/2-related severe combined immunodeficiency

• RAG deficiency with granulomas and autoimmunity (sometimes written CID-G/AI)

• Leaky RAG deficiency / partial RAG1/2 deficiency

• RAG-associated Omenn syndrome

These different names usually reflect how strong the mutation is and how the disease looks in the patient, but the root cause is still a fault in RAG1 or RAG2 genes. [4]

Basic role of RAG1 and RAG2

RAG1 and RAG2 are special proteins that help the immune system build a huge variety of T-cell receptors and B-cell receptors. They do this by cutting DNA at certain places called recombination signal sequences and helping to join variable (V), diversity (D), and joining (J) gene segments. This process is called V(D)J recombination and is needed to make T and B cells that can recognize many different germs. [5]

When both copies of RAG1 or RAG2 are completely broken (null mutations), the V(D)J recombination process stops, so T and B cells cannot mature. This causes the most severe form of SCID. When the mutations are weaker (hypomorphic), some receptors can still be formed, so a small number of T and B cells develop. These patients may have “leaky” SCID or other types of combined immunodeficiency, often with autoimmunity and granulomas. [6]

Types (clinical forms)

Doctors now know that RAG1/2 deficiency does not look the same in every patient. The disease can appear as a spectrum of related conditions. [7]

• Classic T-B- NK+ SCID due to RAG1/2 deficiency – Very early-onset, severe infections, almost no T or B cells.

• Omenn syndrome due to RAG1/2 mutations – SCID with red scaly skin rash, enlarged liver and spleen, swollen lymph nodes, and high numbers of abnormal activated T cells.

• Leaky or partial RAG deficiency (combined immunodeficiency) – Some T and B cells are present but function is poor, so patients have recurrent infections, autoimmunity, or granulomas, often later in childhood.

• Combined immunodeficiency with granulomas and/or autoimmunity (CID-G/AI) – Patients have chronic skin or organ granulomas and autoimmune problems with evidence of RAG mutations.

• Delayed-onset RAG-related combined immunodeficiency – Symptoms begin later in childhood or even adulthood, often with recurrent infections and autoimmunity rather than classic SCID signs.

These types show that the amount of remaining RAG1/2 activity strongly influences how early and how severely the disease appears. [8]

Causes

1. Biallelic loss-of-function RAG1 mutations
   The main cause is when both copies of the RAG1 gene (one from each parent) carry strong mutations that destroy the protein function. This stops V(D)J recombination completely, so T and B cells cannot mature, leading to classic T-B- NK+ SCID. [9]

2. Biallelic loss-of-function RAG2 mutations
   In some patients, both copies of the RAG2 gene are severely mutated. This gives a similar picture to RAG1-related SCID, because RAG2 is also essential for the recombination process, so T and B cells fail to develop. [10]

3. Hypomorphic (partially working) RAG1 mutations
   Some RAG1 changes do not fully destroy the protein but reduce its activity. This partial function allows some T and B cells to form, but their number and variety are limited. Patients may show “leaky” SCID, Omenn syndrome, or combined immunodeficiency with autoimmunity rather than classic SCID. [11]

4. Hypomorphic RAG2 mutations
   Similar partially working mutations in RAG2 also cause a range of disease severities, from Omenn syndrome to delayed-onset combined immunodeficiency. The remaining RAG2 activity partly supports receptor formation but not enough for full immune defense. [12]

5. Compound heterozygous RAG1 variants
   Some children inherit two different faulty RAG1 variants, one from each parent. Together, these “compound heterozygous” changes reduce or block RAG1 function and cause immunodeficiency, even though each parent is healthy with only one variant. [13]

6. Compound heterozygous RAG2 variants
   The same pattern can happen with RAG2. Two different RAG2 mutations in the same child can combine to reduce enzyme activity below a safe level, leading to SCID or combined immunodeficiency with autoimmunity. [14]

7. Nonsense mutations in RAG1 or RAG2
   Nonsense mutations create early “stop” signals in the gene, so the protein is cut short and usually destroyed. When both alleles have such changes, RAG1/2 activity is almost zero and the child develops severe T-B- NK+ SCID. [15]

8. Frameshift mutations in RAG1 or RAG2
   Insertions or deletions that shift the reading frame change many amino acids and often add a premature stop codon. These frameshift mutations usually cause very severe loss of function, again resulting in absent T and B cells. [16]

9. Splice-site mutations affecting RAG1/2 RNA processing
   Some variants affect how the cell cuts and joins the RNA message from RAG genes. Abnormal splicing can remove important exons or insert extra sequences, making the protein faulty and causing different levels of immunodeficiency. [17]

10. Large deletions involving RAG1 or RAG2
    In a few patients, big pieces of DNA that contain part or all of the RAG1 or RAG2 gene are missing. This structural defect prevents the cell from making the protein at all and leads to a very severe SCID phenotype. [18]

11. Founder mutations in specific populations
    Some ethnic groups or geographic regions show repeated cases of the same RAG mutation, called a founder mutation, often because of shared ancestry. Children who inherit this founder mutation from both parents can develop RAG-related SCID or Omenn syndrome. [19]

12. Consanguinity (parents related by blood)
    When parents are related (for example, cousins), they are more likely to carry the same rare RAG mutation. This greatly increases the chance that their child will inherit two faulty copies and develop combined immunodeficiency due to RAG deficiency. [20]

13. De novo (new) RAG1 mutations in the child
    In some cases, a RAG1 mutation arises for the first time in the egg or sperm or very early after conception. Even if neither parent carries the variant, the child can have biallelic defects if a second mutation is also present or if there is uniparental inheritance. [21]

14. De novo RAG2 mutations
    New mutations can also affect RAG2. Although less common, these events still produce the same basic biological effect: impaired DNA recombination and poor T- and B-cell development. [22]

15. Mutations that reduce RAG1/2 stability or folding
    Some missense variants change the protein shape so it cannot fold correctly or it is quickly broken down inside the cell. Even if the catalytic site is intact, the lowered protein level leads to reduced recombinase activity and immunodeficiency. [23]

16. Mutations that alter DNA-binding or catalytic sites
    Other missense changes lie in key regions that contact DNA or cut the DNA strands. These mutations directly weaken the ability of RAG1/2 to start V(D)J recombination, giving a more severe phenotype even if the protein level looks normal. [24]

17. Mutations that disturb RAG1–RAG2 complex formation
    RAG1 and RAG2 work together as a complex. Some variants interfere with this partnership, so the proteins cannot assemble and bind recombination signal sequences properly, decreasing receptor diversity. [25]

18. Genetic background modifying disease severity
    Other genes that help repair DNA breaks or regulate lymphocyte survival can change how a given RAG mutation behaves. This means two patients with the same RAG mutation may have different levels of immunodeficiency because of differences in their genetic background. [26]

19. Environmental exposures revealing an underlying defect
    Live vaccines or early severe infections do not cause RAG deficiency, but they can expose a hidden immune problem. A child with unrecognized RAG mutations may become very ill after live viral vaccines or common respiratory viruses, bringing the genetic defect to medical attention. [27]

20. Delayed diagnosis in settings without newborn screening
    Lack of newborn screening for SCID does not cause the genetic defect but allows unrecognized RAG deficiency to lead to repeated infections and complications. Early detection programs using TREC assays help find these babies before infections become life-threatening. [28]

Symptoms

1. Recurrent severe infections
   Babies with RAG1/2 deficiency often have repeated and severe infections of the lungs, gut, blood, skin, or mouth. These infections may be caused by common bacteria, viruses, or fungi, but they are unusually severe, long-lasting, or hard to treat because the immune system cannot respond well. [29]

2. Opportunistic infections
   Children may develop infections with germs that rarely cause disease in healthy people, such as Pneumocystis jirovecii, cytomegalovirus, or severe chronic thrush. These “opportunistic” infections are a key warning sign of severe T-cell deficiency. [30]

3. Chronic diarrhea
   Many infants have long-lasting diarrhea due to infections or inflammation in the gut. This leads to poor absorption of nutrients, dehydration, and weight loss, and often does not improve with usual treatments. [31]

4. Failure to thrive and poor weight gain
   Because of repeated infections, diarrhea, and poor nutrient absorption, affected babies often do not gain weight or grow as expected. They may look small, thin, or weak compared with other children of the same age. [32]

5. Persistent oral thrush and skin fungal infections
   White patches in the mouth (oral candidiasis) and recurrent fungal rashes on the skin are common. These infections tend to come back quickly after treatment, which suggests an underlying T-cell defect. [33]

6. Severe or atypical pneumonia
   Lung infections may be very serious and may not respond well to standard antibiotics. Chest X-ray or CT may show widespread changes, sometimes due to Pneumocystis, viral infections, or multiple simultaneous pathogens. [34]

7. Generalized skin rash (erythroderma) in Omenn syndrome
   In patients with Omenn syndrome due to hypomorphic RAG mutations, the skin can become very red, thick, and scaly over large areas of the body. This rash reflects infiltration by abnormal activated T cells and ongoing inflammation. [35]

8. Enlarged liver, spleen, and lymph nodes
   Some children, especially with Omenn or CID-G/AI forms, have hepatosplenomegaly and lymphadenopathy. These enlarged organs contain activated or abnormal immune cells and may be tender on examination. [36]

9. Autoimmune cytopenias and other autoimmune problems
   In partial RAG deficiency, the immune system may attack the body’s own cells, leading to low blood counts (autoimmune hemolytic anemia, thrombocytopenia, or neutropenia) or other autoimmune diseases such as thyroiditis or vasculitis. [37]

10. Chronic granulomatous skin or organ lesions
    Some patients develop firm, persistent nodules or plaques in the skin or internal organs called granulomas. These represent chronic immune reactions and are typical of combined immunodeficiency with granulomas and autoimmunity due to RAG mutations. [38]

11. Recurrent ear and sinus infections
    Frequent otitis media and sinusitis are common early signs. While these infections are also common in healthy children, in RAG deficiency they tend to occur more often, last longer, and respond poorly to usual antibiotics. [39]

12. Prolonged fever of unknown origin
    Because the immune system is not working, even minor infections can cause long-lasting fever. Sometimes doctors cannot find a clear source of infection, but blood tests show inflammation and low lymphocyte counts. [40]

13. Reactions to live vaccines
    In countries where live vaccines (such as BCG or oral polio) are given at birth, infants with RAG1/2 deficiency may develop severe local or disseminated infection with the vaccine strain, which is a strong clue that there is a profound T-cell defect. [41]

14. Neurological problems from severe infections
    Some patients develop meningitis, encephalitis, or seizures due to uncontrolled infections of the central nervous system. These problems may cause developmental delay, weakness, or learning difficulties. [42]

15. Increased risk of early death without treatment
    If the condition is not recognized and treated with stem cell transplantation or other intensive care, children with classic RAG-related SCID are at high risk of dying in early infancy from overwhelming infections. [43]

Diagnostic tests

Physical exam tests

1. Comprehensive newborn or child physical examination
   The doctor carefully checks the baby’s general appearance, muscle tone, breathing, and vital signs. In RAG1/2 deficiency, the child may look ill, underweight, or struggle with breathing because of repeated infections, which alerts the doctor to a possible immune problem. [44]

2. Growth and nutritional status assessment
   The child’s weight, height, and head size are compared with standard growth charts. Poor growth or weight loss despite adequate feeding suggests chronic illness, which in this context may be due to repeated infections from severe immunodeficiency. [45]

3. Skin and mucous membrane examination
   The clinician looks for rashes, erythroderma, mouth ulcers, thrush, and signs of granulomas. In Omenn syndrome and CID-G/AI, the skin findings are often striking, and persistent thrush is a classic sign of T-cell failure. [46]

4. Examination of lymph nodes, liver, and spleen
   By gently feeling the neck, armpits, abdomen, and groin, the doctor can detect enlarged lymph nodes, liver, or spleen. This may indicate chronic immune activation or infiltration by abnormal lymphocytes, often seen in partial RAG deficiency and Omenn syndrome. [47]

Manual tests (clinical and bedside assessments)

5. Detailed infection and symptom history
   The doctor takes a careful history of all infections, hospital stays, antibiotic courses, and vaccine reactions. A pattern of frequent severe or unusual infections from early life strongly suggests a primary immunodeficiency such as RAG-related SCID. [48]

6. Family pedigree and consanguinity assessment
   A manual drawing of the family tree helps identify other affected relatives, early childhood deaths, or cases of unexplained severe infection. Consanguinity raises the suspicion of autosomal recessive conditions like RAG1/2 deficiency. [49]

7. Review of vaccination record and responses
   The clinician reviews which vaccines the child received and whether they had severe side effects or failed to develop protection. Severe reactions to live vaccines or poor response to inactivated vaccines are important clues to severe T- and B-cell problems. [50]

8. Developmental and neurological assessment
   Simple bedside checks of motor skills, speech, and behavior are done. Delay or regression in milestones may be due to chronic illness or brain infections related to the immunodeficiency, guiding further testing. [51]

Lab and pathological tests

9. Complete blood count (CBC) with differential
   This basic blood test measures the numbers of red cells, white cells, and platelets. In RAG-related SCID, total lymphocyte count is often very low, and there may be abnormal patterns, which point to a serious problem in lymphocyte development. [52]

10. Lymphocyte subset analysis by flow cytometry
    Flow cytometry uses fluorescent antibodies to count T cells (CD3+), B cells (CD19+ or CD20+), and NK cells (CD16+/CD56+). In classic RAG1/2-related SCID, T and B cells are absent or very low, while NK cells are normal, giving the characteristic T-B- NK+ pattern. [53]

11. Serum immunoglobulin levels (IgG, IgA, IgM, IgE)
    Blood levels of antibodies are usually very low because B cells cannot mature and switch classes. Measuring immunoglobulins helps confirm that the humoral (antibody) arm of the immune system is severely impaired. [54]

12. T-cell proliferation assays
    In these tests, T cells from the patient’s blood are exposed to mitogens or anti-CD3 antibodies to see if they multiply. In RAG1/2 deficiency, T cells are very few or function poorly, so proliferation is absent or greatly reduced, supporting the diagnosis of SCID. [55]

13. Specific antibody response to vaccines
    Doctors can measure antibodies against previous vaccines, such as tetanus or pneumococcus. Failure to produce or maintain these antibodies, despite vaccination, is evidence of faulty B-cell function, which is typical in RAG-related combined immunodeficiency. [56]

14. Newborn screening using T-cell receptor excision circles (TRECs)
    Many regions now test dried blood spots from newborns for TRECs, small DNA circles made during normal T-cell receptor rearrangement. Very low TRECs suggest severe T-cell lymphopenia, including RAG-related SCID, and allow diagnosis before infections occur. [57]

15. Genetic testing for RAG1 and RAG2 mutations
    Sequencing of the RAG1 and RAG2 genes is the definitive test. It can identify the exact mutations, help classify the disease type (null vs hypomorphic), guide family counseling, and sometimes predict the clinical course. [58]

16. Functional assays of RAG recombination activity
    In research or specialized centers, patient mutations may be tested in cell lines to measure how much they reduce recombination activity. These functional studies help understand why some mutations cause classic SCID while others cause milder combined immunodeficiency. [59]

17. Biopsy of granulomatous lesions or lymphoid tissue
    When granulomas or enlarged lymph nodes are present, a small tissue sample may be examined under a microscope. Pathology can show chronic granulomatous inflammation and abnormal or oligoclonal T cells, supporting the diagnosis of partial RAG deficiency with immune dysregulation. [60]

Electrodiagnostic tests

18. Electrocardiogram (ECG)
    An ECG measures the heart’s electrical activity. In children with severe infections or sepsis related to SCID, the heart may be under stress. While the ECG does not diagnose RAG deficiency directly, it helps monitor complications of severe illness and guide safe treatment. [61]

19. Electroencephalogram (EEG)
    An EEG records electrical activity in the brain. If a child with RAG1/2 deficiency develops seizures or suspected encephalitis due to infection, EEG helps evaluate brain involvement and supports decisions about further imaging and antiviral or antimicrobial therapy. [62]

Imaging tests

20. Chest X-ray and high-resolution CT scan
    Chest imaging is very important in children with suspected SCID. Chest X-ray can show pneumonia or an absent thymic shadow, which is common in T-cell deficiency, while CT scans reveal detailed patterns of lung damage or lymph node enlargement. These findings, together with lab tests, support the diagnosis of RAG-related combined immunodeficiency. [63]

Non-pharmacological treatments

1. Protective isolation and infection control at home
Children with RAG1/2 deficiency need strong infection control. Families are taught to use good hand washing, masks during outbreaks, and to limit close contact with sick people and crowded places. The aim is to reduce exposure to viruses, bacteria, and fungi that the weak immune system cannot fight well. This lowers the risk of pneumonia, sepsis, and hospital stays, and buys time until stem cell transplant is done. [1]

2. Protective isolation in hospital
When the child is admitted, care teams may use special protective rooms with filtered air and strict visitor rules. Staff wear gowns, gloves, and sometimes masks. The purpose is to keep hospital germs away, because these infections can be life-threatening in SCID-like conditions. Careful cleaning of surfaces and equipment is part of this process. [2]

3. Avoiding live vaccines
Live vaccines (for example oral polio, live measles, mumps, rubella, or live varicella) can cause serious infection in children with severe immune defects. Doctors therefore avoid live vaccines in the child and sometimes in close household contacts if they could shed vaccine virus. The goal is to prevent vaccine-derived disease while still using safe inactivated vaccines in family members to create a “protective circle.” [3]

4. Household vaccination (“cocooning”)
Parents, siblings, and caregivers receive recommended inactivated vaccines such as influenza and COVID-19 vaccines when appropriate. This “cocooning” reduces the chance that they bring serious infections home. It is an important non-drug way to protect a very vulnerable child, especially before HSCT or gene therapy. [1]

5. Strict food and water hygiene
Because gut infections can become severe, families are advised to use safe drinking water, avoid food from street vendors, and ensure all food is cooked well. Unpasteurized milk, raw eggs, and raw or undercooked meat and fish are avoided to reduce bacterial and parasitic infections like Salmonella or Giardia. [2]

6. Environmental control (mold, dust, pets)
Home checks for dampness, visible mold, and heavy dust are important. Removing mold, improving ventilation, and regular cleaning can reduce fungal spores and allergens that may trigger infections or lung problems. Close contact with some pets (especially young cats, reptiles, or birds) may be limited to decrease exposure to specific germs. [3]

7. Early infection recognition training for parents
Parents are taught very simple rules: “fever, fast breathing, poor feeding, unusual sleepiness, or new rash = call or visit the doctor urgently.” This education helps families bring the child to medical care quickly, before infections become life-threatening. [1]

8. Growth and nutrition monitoring
Regular weight and height checks help the team see if the child is growing well. Poor growth may be due to chronic infections or poor food intake. Dietitians can then adjust feeding plans or recommend high-energy formulas. This prevents malnutrition, which would further weaken the immune system. [2]

9. Physiotherapy and chest physiotherapy
Simple breathing exercises, gentle percussion, and postural drainage guided by physiotherapists can help clear mucus from the lungs. This reduces the risk of pneumonia and chronic lung damage. These techniques are especially helpful after chest infections. [3]

10. Oral and dental care
Good mouth care (soft brushing, mild antiseptic mouth rinses if advised) lowers the germ load in the mouth and helps prevent gum disease, oral thrush, and bacterial spread to the bloodstream. This is important when immune defenses are very low. [1]

11. Skin care and wound care
Because skin is the first barrier against germs, keeping it clean and moisturized, treating eczema, and caring for cuts quickly is essential. For children with granulomas, gentle skin care and protection reduce bleeding, infection, and scarring around the lesions. [2]

12. Psychosocial support for family
Living with a child who has SCID-like disease is stressful. Counseling, parent support groups, and social worker help can reduce anxiety and depression in caregivers. Emotional support improves adherence to complex treatment plans and hospital visits. [3]

13. Education planning and infection-safe schooling
Some children need home-based or online learning to avoid infection during high-risk periods (for example before HSCT). Later, individualized plans for safe return to school (extra hygiene, smaller groups) can be made. This allows normal development while still protecting health. [1]

14. Sunlight and gentle physical activity
Supervised outdoor time with sun protection and gentle play supports vitamin D production, bone health, and mood. Simple indoor exercises or play also help maintain muscle strength and lung capacity. This is adjusted based on the child’s clinical status. [2]

15. Reproductive and genetic counseling for parents
Because RAG1/2 deficiency is usually autosomal recessive, parents may wish to understand recurrence risk in future pregnancies. Genetic counseling explains carrier status, options for prenatal or preimplantation testing, and can help families plan future pregnancies safely. [3]

16. Newborn screening and early diagnosis in siblings
In regions with SCID newborn screening, future babies in the family can be tested early. If they have low T-cell numbers, they can be evaluated for RAG1/2 deficiency and started on protective measures quickly. Early diagnosis improves survival because HSCT can be done before severe infections occur. [1]

17. Infection-safe travel planning
Families are advised to avoid travel to areas with high infection risk or poor medical access. If travel is necessary, doctors plan in advance, give emergency letters, and sometimes provide “standby” antibiotics. This planning lowers the chance of being caught far from expert care when serious infection happens. [2]

18. Home emergency action plan
Families may be given written instructions on what to do if fever or breathing problem appears at night or on weekends. This includes phone numbers, nearest emergency hospital, and when to call an ambulance. Clear plans reduce delays in life-saving care. [3]

19. Coordination of multidisciplinary care
Care is often shared between immunologists, transplant specialists, infectious disease doctors, dietitians, and psychologists. Regular multidisciplinary meetings or joint clinics keep everyone aligned on timing of HSCT, drug changes, and monitoring. This improves safety and outcomes. [1]

20. Long-term follow-up after HSCT or gene therapy
Even after cure of the immune defect, late effects such as growth problems, hormone issues, or chronic lung disease can appear. Long-term follow-up visits help detect and manage these issues early, giving the child the best possible quality of life. [2]

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Drug treatments

⚠️ Very important: All medicines and doses must be chosen and adjusted only by specialist doctors. The information below is general and must never be used for self-treatment. [1]

1. Intravenous immunoglobulin (IVIG) – pooled antibodies
IVIG (for example preparations like PRIVIGEN, GAMMAGARD, or GAMUNEX-C) is a solution of antibodies from healthy donors given through a vein every 3–4 weeks. It replaces missing antibodies, helping to prevent serious bacterial and viral infections. Typical doses are about 400–800 mg/kg every 3–4 weeks, adjusted by the doctor. Common side effects include headache, fever, and infusion reactions; rare risks include blood clots and kidney problems. [2]

2. Sulfamethoxazole-trimethoprim (SMX-TMP) – antibacterial prophylaxis
This combination antibiotic (often known by brand names like Bactrim) is widely used to prevent Pneumocystis jirovecii pneumonia and some bacterial infections in immunodeficient patients. Typical prophylactic dosing in children is based on trimethoprim 5 mg/kg/day (divided doses) on several days per week, but exact regimens vary. It works by blocking folate pathways in bacteria. Side effects can include allergy, rash, low blood counts, and high potassium. [3]

3. Broad-spectrum IV antibiotics (e.g., cefepime, piperacillin-tazobactam)
When a child with RAG deficiency develops fever or sepsis, doctors often start broad-spectrum IV antibiotics right away to cover many possible bacteria, including Pseudomonas. Doses depend on weight and kidney function. These drugs work by damaging bacterial cell walls. Side effects can include allergy, diarrhea, and changes in gut flora. [1]

4. Antifungal prophylaxis (e.g., fluconazole)
Because fungal infections can be deadly in SCID-like conditions, oral or IV fluconazole may be used to prevent Candida infections, especially during neutropenia around HSCT. It blocks fungal cell membrane synthesis. Doctors adjust dose by weight and liver function. Side effects include liver enzyme changes and drug interactions. [2]

5. Mold-active antifungals (e.g., posaconazole, voriconazole)
In high-risk patients, stronger antifungals that cover molds such as Aspergillus may be used. They are often reserved for HSCT periods or proven invasive fungal disease. Close monitoring of levels and liver function is needed. Side effects include vision changes (for voriconazole), liver problems, and many drug interactions. [3]

6. Antiviral prophylaxis (e.g., acyclovir)
Acyclovir helps prevent or treat herpesviruses such as HSV or VZV in immunocompromised patients. It stops viral DNA replication. Doses and schedules depend on age and kidney function. Side effects are usually mild (nausea, headache) but kidney function must be monitored, especially with IV use. [1]

7. Ganciclovir / valganciclovir for CMV
For cytomegalovirus (CMV) infection, ganciclovir or its oral pro-drug valganciclovir may be used. They interfere with viral DNA polymerase. These drugs can cause low blood counts (neutropenia, anemia) and require careful monitoring. They are especially important after HSCT, when CMV reactivation is common. [2]

8. Palivizumab (RSV monoclonal antibody)
Palivizumab is a monoclonal antibody given monthly during RSV season to high-risk infants to prevent severe respiratory syncytial virus disease. It is injected into muscle. It does not replace other measures but lowers hospitalization risk. Side effects are usually mild, such as injection-site pain or fever. [3]

9. Systemic corticosteroids (e.g., prednisone) for autoimmunity / inflammation
Some patients with hypomorphic RAG variants develop autoimmunity or granulomatous inflammation. Short-term systemic steroids can reduce inflammation by broadly suppressing immune responses. Doses vary by condition and are slowly tapered. Long-term side effects include weight gain, high blood pressure, diabetes, bone loss, and infection risk, so steroids are used carefully. [1]

10. Rituximab (anti-CD20 monoclonal antibody)
Rituximab depletes B cells and may be used when RAG-related immune dysregulation leads to severe autoimmune cytopenias (like autoimmune hemolytic anemia) that do not respond to steroids. It is given IV in cycles. Main side effects include infusion reactions, low immunoglobulin levels, and increased infection risk. In RAG deficiency, it must be used only by very experienced teams. [2]

11. G-CSF (filgrastim) for neutropenia episodes
Granulocyte colony-stimulating factor (G-CSF) encourages the bone marrow to make more neutrophils. It may be used short-term during severe infections with low neutrophil counts. Filgrastim is given as a subcutaneous injection. Side effects can include bone pain and, rarely, spleen issues. It does not fix the RAG defect but helps fight acute infection. [3]

12. Antidiarrheal and gut-support drugs (e.g., oral rehydration solutions)
In chronic diarrhea due to infections or gut inflammation, oral rehydration solutions, proton-pump inhibitors, and sometimes gut-active antibiotics or anti-inflammatory medicines may be used. The main goals are to prevent dehydration, maintain nutrition, and support healing of the gut. Side effects and doses vary with specific medicines chosen. [1]

13. Antimycobacterial drugs when needed
If a child with RAG1/2 deficiency develops tuberculosis or related infections, multidrug regimens (such as isoniazid, rifampin, pyrazinamide, and ethambutol) are used under specialist guidance. Doses are weight-based. Side effects include liver toxicity, nerve problems, and drug interactions, so close monitoring is essential. [2]

14. Broad antiviral therapy in HSCT (e.g., foscarnet, cidofovir)
For resistant or severe viral infections after HSCT, strong antivirals like foscarnet or cidofovir may be used. They target viral DNA polymerase but can be hard on kidneys and other organs. These drugs are reserved for life-threatening infections and given with intensive monitoring. [3]

15. Immunoglobulin subcutaneous formulations (SCIG)
Some patients may receive immunoglobulin through the skin (SCIG) instead of IV. Smaller doses are given weekly or more often via a small pump at home. This can provide more stable IgG levels and fewer systemic side effects, though local swelling or redness can occur. [1]

16. Antithymocyte globulin (ATG) in conditioning regimens
ATG is used as part of HSCT conditioning to deplete T cells and lower graft rejection risk. It works by targeting human T cells. It is given IV before transplant. Side effects include infusion reactions, fever, serum sickness, and infection risk. Doses and timing are carefully calculated by transplant teams. [2]

17. Calcineurin inhibitors (e.g., cyclosporine, tacrolimus)
After HSCT, calcineurin inhibitors help prevent graft-versus-host disease (GVHD) by suppressing T-cell activation. They are taken orally or IV, and blood levels are monitored. Side effects can include kidney damage, high blood pressure, and tremor. They are usually tapered as the new immune system matures. [3]

18. Methotrexate (low-dose) for GVHD prophylaxis
Low-dose methotrexate may be added to calcineurin inhibitors to prevent GVHD. It interferes with DNA synthesis in rapidly dividing cells. Dosing follows strict transplant protocols. Side effects include low blood counts, mouth sores, and liver toxicity, so monitoring is required. [1]

19. Broad-spectrum antifungal prophylaxis post-HSCT (e.g., echinocandins)
Drugs like caspofungin may be used in very high-risk periods after transplant to prevent invasive Candida or Aspergillus infections. They work on fungal cell walls and are given IV. Side effects include liver enzyme changes and infusion reactions. [2]

20. Supportive medicines (antiemetics, pain control, growth factors)
During chemotherapy conditioning and HSCT, children may receive anti-nausea drugs (like ondansetron), pain medicines, and other supportive agents. These do not treat RAG deficiency directly but make intense treatments safer and more tolerable. [3]

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Dietary molecular supplements

1. Vitamin D
Vitamin D supports bone health and modulates immune responses. In children with chronic illness, low vitamin D is common. Doctors may prescribe drops or tablets, with doses based on blood levels (for example 400–1000 IU/day, sometimes more). Too much can cause high calcium, so testing and medical supervision are essential. [1]

2. Omega-3 fatty acids (fish oil)
Omega-3s may reduce inflammation and support heart and brain health. They are sometimes used as supportive nutrition in chronic inflammatory states. Doses vary by age and product. Side effects can include fishy aftertaste and, rarely, bleeding risk at high doses. They do not replace medical treatment for RAG deficiency. [2]

3. Zinc
Zinc is important for immune cell function and wound healing. Supplementation may be considered if deficiency is shown. Typical pediatric doses are low and adjusted to diet and lab results. Too much zinc can cause nausea and interfere with copper absorption, so it should not be taken without supervision. [3]

4. Vitamin A
Vitamin A supports skin, gut lining, and immune defenses. In deficiency states, careful supplementation can help, but excess vitamin A can be toxic (causing liver problems and raised pressure in the skull). Therefore, any vitamin A supplement must be prescribed and monitored by a doctor. [1]

5. Vitamin C
Vitamin C is an antioxidant that supports collagen and immune functions. Moderate supplementation may be used to support general health, but large doses can cause stomach upset and kidney stones in some people. It cannot fix the genetic immune defect. [2]

6. Selenium
Selenium is part of antioxidant enzymes and may help limit oxidative damage. It is usually provided in small doses through multivitamins or diet. High doses can be toxic, causing hair loss and nerve problems, so targeted, low-dose use is important. [3]

7. B-complex vitamins (including folate and B12)
B vitamins are important for blood cell production and nerve function. If tests show anemia or deficiencies, supplementation can correct them and support overall health before and after HSCT. Doses depend on lab results and are set by the care team. [1]

8. Iron (when deficient)
Iron helps the body make hemoglobin for red blood cells. If iron deficiency anemia is present, oral or IV iron may be given. However, iron can also feed some germs, so doctors use it carefully, based on tests. Too much iron can damage organs. [2]

9. Probiotics (with caution)
Probiotics may help gut balance in some immune-normal people, but in severe immunodeficiency they can, rarely, cause bloodstream infections. Because of this, their use in RAG1/2 deficiency is controversial and must only be decided by specialists. [3]

10. Glutamine and protein supplements
Additional protein or amino acids like glutamine can help maintain muscle and gut integrity during long illness or HSCT. They are usually given as special formulas under dietitian guidance. They support recovery but are not a cure. [1]

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Immunity-booster / regenerative / stem-cell–related drugs

1. Filgrastim (G-CSF)
Filgrastim stimulates the bone marrow to produce neutrophils, improving defense against bacteria during severe infections or chemotherapy. It is given as injections under the skin. It does not fix the genetic defect but helps in acute situations. Bone pain is a common side effect. [1]

2. Sargramostim (GM-CSF)
Sargramostim increases several white cell types (neutrophils, monocytes) and is sometimes used after chemotherapy or HSCT to speed immune recovery. It is given by injection. Side effects include fever, bone pain, and fluid retention, so monitoring is needed. [2]

3. Eltrombopag (thrombopoietin receptor agonist)
Eltrombopag helps stimulate platelet production and may be used in severe immune-mediated thrombocytopenia or post-HSCT platelet problems. It is taken orally. Side effects include liver test changes and blood clots, so doctors monitor labs carefully. [3]

4. Romiplostim
Romiplostim is an injectable thrombopoietin receptor agonist that also boosts platelet counts in certain immune thrombocytopenias. It may be considered when other options fail. Doses are titrated to response. It is not specific for RAG deficiency but can help manage complications. [1]

5. Mesenchymal stromal cell (MSC) infusions
In some transplant centers, MSCs may be used as a cell-based therapy to treat severe GVHD that does not respond to steroids. They can modulate immune responses and promote tissue repair. This is a specialized, hospital-based therapy with close safety monitoring. [2]

6. Experimental gene therapy products
Clinical trials are testing lentiviral or other vectors that deliver a correct RAG1 gene into the patient’s own stem cells. These modified cells are then returned to the patient to rebuild a working immune system. This is highly specialized and currently only available in research settings. [3]

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Surgeries and procedures

1. Allogeneic hematopoietic stem cell transplantation (HSCT)
HSCT is the main curative procedure. Stem cells from a matched donor (sibling, family member, or unrelated donor) or cord blood are infused after conditioning chemotherapy. These cells rebuild the immune system with working RAG1/2. The purpose is to correct the root defect. Risks include infections, graft failure, GVHD, and organ toxicity, so it is done in expert centers only. [1]

2. Central venous catheter insertion
Children who need long-term IV therapies or HSCT often require a central line (port or Hickman catheter). This procedure provides secure access for IVIG, chemotherapy, blood draws, and transfusions. The benefit is fewer needle sticks; the risks include infection and clotting. Strict line care is essential. [2]

3. Gastrostomy tube placement
If oral intake is poor because of chronic illness or vomiting, a feeding tube directly into the stomach may be placed surgically or endoscopically. This allows reliable nutrition and medicine delivery, supporting growth before and after transplant. Infection and leakage are possible complications. [3]

4. Bronchoscopy with lavage
In cases of unexplained or severe lung disease, doctors may perform bronchoscopy to look into the airways and wash out samples for testing. This can help identify specific germs or inflammatory patterns and guide therapy. It is done under anesthesia and carries risks like bleeding or low oxygen, so it is used only when necessary. [1]

5. Splenectomy (rare, selected cases)
In rare cases of severe, treatment-resistant autoimmune destruction of blood cells, removal of the spleen may be considered. The goal is to reduce destruction of red cells or platelets. However, splenectomy increases infection risk, so it is avoided whenever safer options exist and always combined with strong infection prevention measures. [2]

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Prevention strategies

1. Early diagnosis through newborn screening or family history
Early detection of RAG1/2 deficiency allows protective steps and timely HSCT, which greatly improves survival. [1]

2. Avoiding live vaccines in the affected child
This prevents vaccine-strain infections in a severely immunodeficient baby. [2]

3. Full vaccination of family and close contacts (with safe vaccines)
This reduces the chance of bringing home dangerous infections like influenza or pertussis. [3]

4. Strict hygiene and infection-control habits
Regular handwashing, respiratory etiquette, and cleaning of surfaces lower everyday infection risk. [1]

5. Safe food and water practices
Using safe water, avoiding raw animal products, and careful food handling reduce gut infections. [2]

6. Environmental control of mold and dampness
Fixing leaks, removing mold, and avoiding smoky environments protect the lungs. [3]

7. Careful travel planning and avoidance of high-risk regions
Limiting travel to areas with poor medical care or high infection risk helps prevent uncontrolled infections. [1]

8. Rapid treatment of any suspected infection
Parents are taught to seek immediate care for fever, cough, or unusual behavior, so infections are treated early. [2]

9. Regular follow-up with immunology and transplant specialists
Ongoing visits allow early detection of complications such as chronic lung disease, autoimmunity, or late effects of HSCT. [3]

10. Genetic counseling for future pregnancies
Understanding recurrence risk helps families plan and consider options like prenatal diagnosis or preimplantation genetic testing. [1]

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When to see a doctor or go to emergency

Families should contact the child’s doctor immediately or go to an emergency department if the child has any of the following: fever (especially ≥38.0°C), fast or difficult breathing, bluish lips, poor feeding, vomiting with dehydration (dry mouth, no tears, no wet diaper), extreme sleepiness, confusion, or seizures. These can be signs of severe infection or sepsis that needs urgent IV antibiotics and monitoring. [1]

Even outside emergencies, regular visits with an immunologist and transplant team are essential. Parents should also call the clinic if they notice new rashes, big lymph nodes, abdominal swelling, jaundice, behavior changes, or any side effects from medicines. [2]

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Diet – what to eat and what to avoid

1. Eat: well-cooked meats, fish, and eggs – to provide protein and iron while avoiding undercooked animal products that may carry germs. [1]

2. Eat: pasteurized dairy products – such as pasteurized milk, yogurt, and cheese, which provide calcium and protein with lower infection risk. [2]

3. Eat: washed, peeled fruits and cooked vegetables – fresh produce is important but should be washed well; some centers recommend peeling or cooking during high-risk times. [3]

4. Eat: energy-dense foods and supplements if needed – high-calorie formulas or shakes may be used to support growth, based on dietitian advice. [1]

5. Drink: safe, treated water – boiled or bottled water may be advised in some areas to reduce gut infections. [2]

6. Avoid: raw or undercooked meat, fish, and eggs – including sushi, runny eggs, and undercooked burgers, which can carry dangerous bacteria or parasites. [3]

7. Avoid: unpasteurized milk, cheese, and juices – to reduce exposure to pathogens like Listeria and other bacteria. [1]

8. Avoid: food from buffets or street vendors in high-risk settings – because temperature control and hygiene may be poor. [2]

9. Avoid: alcohol, energy drinks, and herbal products without medical approval – these may interact with medications or strain organs. [3]

10. Individualize diet with a dietitian – special conditions (e.g., gut disease, kidney or liver problems) may need specific plans; therefore, diet must always be tailored, not general. [1]

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Frequently asked questions

1. Is RAG1/2 deficiency the same as “SCID”?
RAG1/2 deficiency is one cause of severe combined immunodeficiency (SCID). When the defect is complete, the child has a classic SCID picture with very low T and B cells. Milder RAG changes can cause “combined immunodeficiency with granulomas and autoimmunity,” which is related but not identical to typical SCID. [1]

2. Can my child’s immune system ever be normal?
Without curative therapy, the immune system stays weak and infections remain a high risk. With successful HSCT (or, in the future, gene therapy), many children can build a functioning immune system and live much more normal lives, though long-term follow-up is always needed. [2]

3. Is HSCT always needed?
For severe RAG1/2 deficiency with SCID, HSCT is strongly recommended because it is the only established cure. In some hypomorphic cases with milder disease, timing and need for HSCT are decided individually by experts, balancing infection risk, autoimmunity, and transplant risks. [3]

4. What is the success rate of HSCT?
Survival depends on donor type, infection status at transplant, and center experience. Recent studies show improving survival, especially when transplant is performed early and with good donor matches. However, there are still risks of death, GVHD, and long-term complications, so it must be done in specialized centers. [1]

5. Will my child always need IVIG?
Many children need IVIG before HSCT and sometimes for months or years afterwards until their own B cells make enough antibodies. Some may need lifelong IVIG if antibody production remains poor. Doctors monitor IgG levels and infection history to decide. [2]

6. Can my child go to school?
Yes, but timing and setting must be carefully planned. Before HSCT or in high-risk periods, home schooling or online learning may be safest. After immune recovery, many children attend school with some extra precautions (hand hygiene, staying home when classmates are sick). Plans are personalized. [3]

7. Can we have more children, and what is the risk?
Because RAG1/2 deficiency is usually autosomal recessive, each pregnancy between two carriers has a 25% chance of an affected child, 50% chance of a carrier, and 25% chance of an unaffected non-carrier. Genetic counseling can explain options for prenatal or preimplantation testing. [1]

8. Is gene therapy available now?
Gene therapy for RAG1 deficiency is in early-phase clinical trials in a few specialized centers. It is not yet standard care and is usually offered only in research protocols. Families interested should talk with their immunologist about current studies and eligibility. [2]

9. Are complementary or herbal medicines safe?
Many herbal products have not been tested in severe immunodeficiency and may interact with drugs or carry contamination. They should not be used without full discussion with the medical team. Standard treatments like HSCT, IVIG, and proven antimicrobials are always the priority. [3]

10. Can diet alone fix my child’s immune system?
No. Good food supports growth and general health, but it cannot repair a broken RAG1/2 gene. Curative options are HSCT (and possibly gene therapy in the future). Diet is supportive, not curative. [1]

11. Will my child look different or have physical abnormalities?
Many children with RAG1/2 deficiency look physically normal, especially early in life. Over time, chronic illness, poor growth, or skin granulomas can change appearance. Regular medical and nutritional care helps reduce these effects. [2]

12. Is this condition contagious?
No. RAG1/2 deficiency is genetic and cannot be “caught” from someone else. However, because the immune system is weak, the child can catch infections from others very easily, which is why infection control is so important. [3]

13. What about sports and physical activity?
Activity is important for strength and mood, but intensity must match health status. Gentle play is often encouraged. After HSCT and good immune recovery, some children can join regular sports with medical advice. Contact sports may be limited if bone or organ issues exist. [1]

14. How long will my child live?
Without curative treatment, severe forms have a high risk of death in early childhood due to infections. With early diagnosis, modern HSCT care, and strong infection prevention, survival and quality of life have improved greatly. Each case is unique, so prognosis should be discussed with the child’s doctors. [2]

15. Where can families find support?
Families can seek help from national primary immunodeficiency organizations, patient groups, hospital social workers, and online communities moderated by experts. These resources offer practical tips, emotional support, and up-to-date information on research and treatment. [3]

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 18, 2025.