Combined Immunodeficiency Due to Calcium Release-Activated Calcium (CRAC) Channel Dysfunction

Combined immunodeficiency due to calcium release-activated calcium (CRAC) channel dysfunction is a very rare, inherited immune system disease. In this condition, important white blood cells (especially T-cells) cannot bring calcium into the cell properly when they are “switched on.” Because calcium signals are weak, the cells cannot fully wake up, multiply, and fight germs. Children with this disease have very frequent, severe infections, poor growth, and often problems with muscles, teeth, skin, and sweating. Doctors sometimes call this a “SCID-like” (severe combined immunodeficiency–like) disease, because the infections are serious and start early in life. [1]

Combined immunodeficiency due to calcium release–activated calcium (CRAC) channel dysfunction is a very rare, inherited immune disease in which the “on-switch” for calcium entry into immune cells is broken. In healthy T cells, B cells and some other white cells, a small protein channel in the cell membrane (made mainly by the ORAI1 or STIM1 genes) opens when calcium stores inside the cell run low, allowing calcium to flow in and fully activate the immune response. In this condition, loss-of-function mutations in these genes stop store-operated calcium entry, so T cells are present in normal or near-normal numbers but cannot switch on properly. This leads to a severe combined immunodeficiency (CID) picture with frequent, serious infections and immune dysregulation. 1

Children usually present in early infancy with recurrent bacterial, viral, fungal and sometimes mycobacterial infections such as pneumonia, meningitis, chronic diarrhoea and sepsis. Because the immune system cannot clear germs well, infections tend to be unusually severe, long-lasting or caused by “opportunistic” organisms that rarely make healthy people sick. Many patients also develop autoimmune problems such as haemolytic anaemia or low platelets, as well as muscle weakness (congenital myopathy) and ectodermal changes like poor tooth enamel and reduced sweating. Without aggressive treatment and often hematopoietic stem cell transplantation (HSCT), life expectancy can be markedly reduced. 2

At the cellular level, CRAC channelopathy is unusual compared with classic severe combined immunodeficiency (SCID). In many SCID types, lymphocytes fail to develop, so counts are very low. Here, lymphocyte numbers may be near normal, but store-operated calcium entry (SOCE) is almost absent. This means T-cell receptor signals cannot trigger normal gene activation, cytokine release and cell division, so the immune system is “present but paralysed.” This same calcium pathway is used in muscle and ectodermal tissues, which explains the combination of immune, muscular and dental/skin features seen in affected patients. 3

This problem usually happens because of harmful changes (mutations) in two genes called ORAI1 or STIM1. These genes work together to form and control the CRAC channel, which is a special doorway that lets calcium flow into immune cells when they are activated. When the channel or its control system is broken, calcium cannot enter correctly, and the immune response becomes weak, even though the number of lymphocytes can be normal. [2]

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Other names

Doctors and medical databases use several other names for this disease. All of them point to the same or closely related conditions: [1][2]

1. Combined immunodeficiency due to CRAC channel dysfunction – focuses on the broken CRAC channel. [1]

2. Combined immunodeficiency due to calcium release-activated calcium channel dysfunction – a longer form that fully spells out the CRAC name. [1]

3. Immune dysfunction due to T-cell inactivation due to calcium entry defect – stresses that T-cells cannot be activated because calcium cannot enter. [2]

4. Immune dysfunction with T-cell inactivation due to calcium entry defect – very similar wording; again highlighting poor T-cell activation. [2]

5. CRAC channelopathy (ORAI1/STIM1 deficiency) – “channelopathy” means a disease caused by a faulty ion channel; here the CRAC channel. [3]

These different phrases all describe the same basic idea: a combined immunodeficiency caused by failure of the calcium channel needed for immune cell activation. [3]

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Types

There are a few main ways experts group this disease. The most important classification uses the gene that is affected. [1]

1. Combined immunodeficiency due to ORAI1 deficiency – Here, harmful changes in the ORAI1 gene make the CRAC channel pore itself non-functional or poorly functional. Children usually have early, severe infections, muscle weakness, and tooth enamel problems. [1][2]

2. Combined immunodeficiency due to STIM1 deficiency – In this type, the STIM1 gene, which senses calcium in the endoplasmic reticulum and talks to ORAI1, is damaged. Patients often have infections plus autoimmunity, enlarged lymph organs, and ectodermal problems such as abnormal teeth and sweating. [2][3]

3. Classic early-onset SCID-like form – Some children become sick in the first months of life, with many serious infections, failure to thrive, and life-threatening problems unless they receive stem cell transplantation. [3]

4. Hypomorphic or later-onset form – Certain “milder” mutations (hypomorphic variants) leave a little CRAC function intact. Symptoms may start later in childhood, sometimes with more autoimmunity and muscle or skin signs in addition to infections. [4]

5. Syndromic CRAC channelopathy with multi-system involvement – In many patients, immune problems come together with muscle weakness, abnormal teeth, poor sweating, and eye or skin features. Doctors may group these as a broader CRAC channelopathy syndrome rather than a “pure” immune defect. [5]

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Causes

In simple words, the “cause” of this disease is genetic damage to the CRAC channel system, especially the ORAI1 and STIM1 genes. Below are 20 related causes and mechanisms, written in easy language.

1. Biallelic loss-of-function mutations in ORAI1
   Most patients have harmful changes in both copies of the ORAI1 gene (one from each parent). These changes stop ORAI1 from forming a proper calcium channel in the cell membrane. Without a working ORAI1 channel, calcium cannot flow in when the cell is activated, so T-cells cannot do their job. [1]

2. Biallelic loss-of-function mutations in STIM1
   Some patients have harmful changes in both copies of STIM1. STIM1 normally senses when calcium inside the cell store is low and then opens ORAI1 channels. When STIM1 is missing or broken, the signal to open ORAI1 never arrives, so the calcium entry step fails. [2]

3. Missense mutations that distort ORAI1 structure
   A single letter change in the DNA of ORAI1 can swap one amino acid for another, bending or blocking the ion pore. This kind of “missense” change may allow some protein to be made, but it works very poorly, so store-operated calcium entry is almost absent. [3]

4. Nonsense or frameshift mutations in ORAI1
   Some mutations insert a stop signal too early or shift the reading frame, so the ORAI1 protein is cut short and quickly destroyed. This is like trying to build a channel with only half the parts; it never reaches the cell surface or cannot open. [4]

5. Mutations that block ORAI1 trafficking to the membrane
   A few variants let ORAI1 be made but stop it from moving from inside the cell to the cell membrane. The protein gets trapped inside, so even though it exists, it cannot form the outer channel that lets calcium in. [5]

6. STIM1 mutations that impair calcium sensing
   STIM1 has a special domain that binds calcium in the internal store. Some mutations change this sensor so it cannot correctly feel when calcium is low. Because STIM1 does not sense the drop, it fails to cluster and open ORAI1, so the calcium signal is never started. [6]

7. STIM1 mutations that prevent contact with ORAI1
   Other STIM1 changes affect the parts of the protein that must touch ORAI1. STIM1 may sense low calcium but cannot physically bind and open the channel, so the final step in the pathway is blocked. [7]

8. Complete absence of store-operated calcium entry (SOCE)
   When ORAI1 or STIM1 mutations are very severe, laboratory tests show almost no store-operated calcium entry in T-cells. This “zero SOCE” state is a direct cause of the immune defect, because many activation signals depend on this calcium influx. [8]

9. Defective activation of NFAT and other calcium-dependent pathways
   Calcium flows into T-cells to turn on transcription factors such as NFAT. When calcium entry is blocked, these factors stay silent. The genes needed for T-cell growth, cytokine release, and killing of infected cells are not expressed, causing combined immunodeficiency. [9]

10. Autosomal recessive inheritance from carrier parents
    The disease is usually autosomal recessive. Each parent carries one faulty copy but is healthy. When a child receives both faulty copies (one from each parent), the CRAC channel pathway is badly damaged, and the disease appears. [10]

11. Consanguinity (parents related by blood)
    In some reported families, parents are related (for example, cousins). This increases the chance that both carry the same rare mutation, and so it increases the risk that a child will inherit two faulty copies and develop the disease. [11]

12. Founder mutations in certain populations
    Sometimes a specific mutation starts in one ancestor and spreads through a population (founder effect). In such groups, the same ORAI1 or STIM1 variant may cause CRAC channelopathy in several unrelated families. [12]

13. Mutations with mixed loss- and gain-of-function effects
    Rarely, a single ORAI1 mutation may partly block normal calcium entry and also cause abnormal constant opening in some settings. This mixed effect still leads to severe combined immunodeficiency and serious infections. [13]

14. Genetic changes affecting related signaling partners
    Research suggests that other proteins that interact with ORAI1 and STIM1 may modulate disease severity. Changes in these partners do not directly cause the basic syndrome but can worsen or slightly soften the clinical picture. [14]

15. Splice-site mutations disrupting normal RNA processing
    Mutations at splice sites can cause exons to be skipped or introns to be kept in the RNA. The final ORAI1 or STIM1 protein becomes abnormal, again leading to defective calcium entry and immunodeficiency. [15]

16. Copy-number variants (deletions/duplications) of ORAI1 or STIM1
    Large stretches of DNA containing parts of these genes can be lost (deletions) or repeated (duplications). Either change may alter gene dosage and disturb CRAC channel function, contributing to disease in some patients. [16]

17. Mutations leading to ectodermal dysplasia features
    Because ORAI1 and STIM1 are used in many tissues, some variants strongly affect teeth, skin, and sweat glands. The same mutation that causes poor immune activation can also cause thin enamel, no sweat, and other ectodermal signs. [17]

18. Mutations causing congenital myopathy
    Skeletal muscle cells also need calcium signaling. Defective CRAC function in muscle contributes to low muscle tone and weakness seen in many patients, and this muscle problem is part of the same genetic cause. [18]

19. Mutations predisposing to autoimmunity and lymphoproliferation
    In some STIM1-deficient patients, the broken calcium signaling also disturbs immune tolerance, leading to autoimmune destruction of blood cells and enlarged lymph organs. The same gene mutations that cause infection risk can also lead to autoimmunity. [19]

20. Environmental exposure unmasking the genetic defect
    Infections, live vaccines, or common community germs do not cause the mutation, but they reveal the disease. Because T-cells cannot react properly, ordinary viruses, bacteria, or fungi cause severe illness instead of mild disease. This is why symptoms often appear soon after birth. [20]

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Symptoms

People with combined immunodeficiency due to CRAC channel dysfunction can have many different symptoms. Not everyone has all of them, but the pattern of severe infections plus muscle and skin/teeth problems is typical. [1]

1. Recurrent severe bacterial infections
   Children often have repeated pneumonia, sepsis, skin infections, or bone infections. These infections may be caused by germs that usually do not make healthy children very sick, because their T-cells cannot coordinate a strong immune response. [1]

2. Serious viral infections
   Viruses like cytomegalovirus (CMV), herpes viruses, or common respiratory viruses can lead to long-lasting, dangerous illness. A normal immune system can usually clear these, but in this disease, viral control is poor. [2]

3. Opportunistic and fungal infections
   Fungi (for example, Candida) and other opportunistic germs that mostly affect people with weak immunity may cause thrush, lung infections, or systemic disease. This is another sign that the T-cell arm of the immune system is not working well. [3]

4. Mycobacterial infections
   Some patients develop infections with mycobacteria, including BCG vaccine strain or environmental mycobacteria. This happens because T-cell-mediated immunity, which is crucial to control these germs, is severely impaired. [4]

5. Chronic diarrhea
   Persistent diarrhea is common and may be caused by repeated gut infections or inflammation. Ongoing diarrhea leads to poor nutrient absorption, weight loss, and failure to thrive in infants. [5]

6. Failure to thrive and poor weight gain
   Because of infections, diarrhea, and high energy needs, many babies do not gain weight or grow as expected. This “failure to thrive” is a classic sign in severe primary immunodeficiency disorders. [6]

7. Recurrent pneumonia and chronic lung disease
   Frequent chest infections can damage the lungs over time, leading to chronic cough, breathing problems, and bronchiectasis (permanent widening of airways). [7]

8. Meningitis or severe central nervous system infections
   Some children develop infections in the brain and spinal cord (meningitis or encephalitis), which can cause seizures, developmental delay, or long-term neurological problems. [8]

9. Muscular hypotonia and weakness
   Many patients have floppy muscles, delayed motor milestones, and general weakness, because the same calcium pathway is important for muscle function. This is often present from birth. [9]

10. Ectodermal dysplasia (skin, hair, sweat problems)
    Some patients do not sweat normally (anhidrosis) and may have abnormal hair or skin. They can over-heat easily and may show dry or scaly skin changes. [10]

11. Dental enamel defects (amelogenesis imperfecta)
    Teeth may have very soft enamel that chips or wears away quickly. This causes early cavities, tooth pain, and cosmetic problems, often noticed in early childhood. [11]

12. Autoimmune cytopenias (low blood counts from autoimmunity)
    In some STIM1-deficient patients, the immune system attacks red blood cells or platelets, causing anemia or easy bruising and bleeding. This shows that tolerance (the ability not to attack self) is also disturbed. [12]

13. Lymphoproliferation (enlarged lymph nodes, spleen, liver)
    Some patients have big lymph nodes, large spleen, or liver due to chronic immune stimulation and abnormal cell survival. This can cause abdominal discomfort or fullness. [13]

14. Skin rashes and eczema-like changes
    Recurrent infections, immune dysregulation, or ectodermal problems can lead to chronic rashes, eczema, or other inflammatory skin lesions. [14]

15. General fatigue and low exercise tolerance
    Because of chronic infections, muscle weakness, and anemia or heart strain, many patients feel tired, short of breath with activity, and cannot keep up with peers. [15]

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Diagnostic tests

Doctors use a mix of physical examination, simple bedside checks, blood and tissue tests, nerve and muscle studies, and imaging to diagnose this disease. A final diagnosis usually needs both functional immune tests and genetic testing. [1]

Physical exam tests

1. Full physical examination and growth chart review
   The doctor carefully checks weight, height, and head size over time. Slow growth, small size for age, and signs of chronic illness (like thin limbs or big belly) suggest an underlying immune problem. The doctor also looks for scars, rashes, enlarged organs, and signs of repeated hospital stays. [1]

2. Skin and hair examination
   The doctor looks for dry skin, missing sweat, abnormal hair texture, or other signs of ectodermal dysplasia. These outward features can be an important clue that the CRAC pathway is faulty in both the immune system and the skin. [2]

3. Oral and dental examination
   Teeth are checked for soft enamel, rapid wear, many cavities, and delayed eruption. Finding enamel defects together with severe infections points strongly toward a syndrome such as ORAI1 or STIM1 deficiency. [3]

4. Respiratory examination
   Using a stethoscope, the doctor listens for crackles, wheezes, or reduced air entry in the lungs. Frequent or chronic pneumonia in a young child is a warning sign for combined immunodeficiency. [4]

5. Abdominal and lymph node examination
   The doctor feels for an enlarged liver, spleen, or lymph nodes. Big organs can reflect infections, lymphoproliferation, or autoimmune problems, which are all part of the disease picture in some patients. [5]

Manual tests and bedside checks

6. Manual muscle strength testing
   The clinician gently resists the child’s movements and rates strength, often using a standard scale. Low muscle tone and weakness support the idea of a congenital myopathy linked to CRAC channelopathy, especially when combined with infections. [6]

7. Developmental and motor milestone assessment
   Simple tasks like sitting, standing, walking, or grasping objects are observed. Delay in these milestones, along with hypotonia and infections, suggest a syndromic condition rather than a simple, isolated infection problem. [7]

Laboratory and pathological tests

8. Complete blood count (CBC) with differential
   This routine blood test measures white cells, red cells, and platelets. In CRAC channelopathy, numbers of lymphocytes may be normal, but there may be anemia, low platelets from autoimmunity, or signs of chronic infection. CBC is a basic starting test. [8]

9. Lymphocyte subset analysis (flow cytometry)
   Special machines count T-cells, B-cells, and NK cells. In this disease, the counts can look normal, but function is poor. This pattern (normal numbers, bad function) guides doctors to think about signaling defects like ORAI1 or STIM1 deficiency. [9]

10. Serum immunoglobulin levels (IgG, IgA, IgM, IgE)
    Blood tests measure antibody levels. These may be low, normal, or sometimes unusual, but in the context of serious infections they help classify the combined immunodeficiency and rule out some other forms of SCID. [10]

11. T-cell proliferation and activation assays
    In the lab, T-cells are exposed to stimulants (such as mitogens or anti-CD3 antibodies). Healthy cells divide strongly, but in CRAC channelopathy they show very poor proliferation and cytokine production, reflecting the broken calcium signaling. [11]

12. Calcium flux / store-operated calcium entry (SOCE) testing
    Researchers load T-cells with a dye that changes brightness when calcium enters. After emptying the internal calcium stores, they measure how much calcium enters from outside. Near-absent SOCE is a hallmark of ORAI1/STIM1-related disease. [12]

13. Genetic testing for ORAI1 and STIM1 mutations
    DNA is sequenced to look for pathogenic variants in ORAI1 and STIM1. Finding two harmful mutations in one of these genes confirms the diagnosis and helps with family counseling and future pregnancy planning. [13]

14. Bone marrow examination (when needed)
    Sometimes doctors take a small sample of bone marrow to rule out other causes of low blood counts or immune problems. In CRAC channelopathy, marrow cell development may look relatively normal, supporting the idea that the main defect is activation, not production. [14]

Electrodiagnostic tests

15. Nerve conduction studies
    Electrodes measure how fast electrical signals travel along nerves. This helps to rule out other neuromuscular disorders and to better understand the cause of weakness or low tone in affected children. [15]

16. Electromyography (EMG)
    A thin needle electrode records electrical activity in muscles. EMG can show patterns of congenital myopathy seen in some patients with ORAI1 or STIM1 mutations, supporting the diagnosis of a multi-system CRAC channelopathy. [16]

Imaging tests

17. Chest X-ray
    A simple chest X-ray can show pneumonia, enlarged heart, or early lung damage. Repeated abnormal chest films in a young child with infections raise concern for primary immunodeficiency. [17]

18. High-resolution CT scan of the chest
    CT provides detailed pictures of the lung tissue and airways. It can reveal bronchiectasis or chronic lung changes caused by repeated infections, information that helps guide treatment and long-term care. [18]

19. Brain MRI
    If there have been seizures, meningitis, or developmental concerns, MRI of the brain may be done to look for injury from infections or other structural problems. This does not diagnose the immunodeficiency directly but shows complications that need attention. [19]

20. Dental radiographs (X-rays)
    Dental X-rays show the structure of teeth and enamel, as well as root and bone health. In CRAC channelopathy, they can help document enamel defects and guide proper dental treatment, while also supporting the overall syndrome diagnosis. [20]

Non-pharmacological treatments (20 options)

1. Strict infection-prevention lifestyle – Careful hand-washing, regular use of alcohol hand rub, masking in crowded places and avoiding contact with people who are clearly unwell reduce exposure to germs. These simple habits lower the chance that bacteria or viruses will reach a vulnerable immune system, which is crucial because even “mild” infections can become serious in combined immunodeficiency. 5

2. Household “cocooning” vaccination – Family members and close contacts should receive all recommended inactivated vaccines (e.g., influenza, COVID-19, pneumococcal) so they are less likely to bring infections home. This “cocoon” approach indirectly protects the patient, who may have a weaker vaccine response and must avoid live vaccines. 6

3. Protective isolation in high-risk periods – During local outbreaks or when the patient is severely immunosuppressed (for example, around HSCT), doctors may advise temporary “protective isolation.” This can include single hospital rooms with filtered air and visitor restrictions, or reduced exposure to crowded schools and malls at home. The goal is to lower pathogen exposure while immune defences are at their weakest. 7

4. Early-fever action plan – Families are trained to treat any fever or new symptom as an emergency and to contact the immunology team or visit hospital very quickly. Written emergency plans help ensure that blood cultures, basic labs and broad-spectrum antibiotics are started without delay, which is key to preventing sepsis in primary immunodeficiency. 8

5. Specialised dental and oral care – Because enamel is often thin or abnormal, children are at high risk of cavities and tooth fracture. Regular reviews with dentists familiar with genetic enamel defects, fluoride treatments, sealants and early repairs help preserve teeth and reduce dental infections, which might otherwise spread and become systemic. 9

6. Chest physiotherapy and breathing exercises – Physiotherapists can teach airway-clearance techniques, postural drainage and breathing exercises to help remove mucus and reduce pneumonia risk. For children with recurrent chest infections or bronchiectasis, regular physiotherapy can improve lung function and quality of life. 10

7. Nutrition counselling and growth support – Chronic infections and diarrhoea may cause poor weight gain. Dietitians can suggest high-calorie, high-protein diets, oral supplements or tube feeding if needed. Good nutrition supports immune cell production, wound healing and muscle strength, and is especially important before major procedures like HSCT. 11

8. Physiotherapy and rehabilitation for myopathy – Because many patients have muscle weakness, gentle strength training, stretching and tailored exercise programmes help maintain mobility and function. Therapy is usually low-impact to avoid fatigue, and aims to support activities of daily living rather than build athletic performance. 12

9. Skin and sweat-management routines – Reduced sweating and altered skin barrier function can cause overheating and dryness. Simple measures like lukewarm showers, fragrance-free moisturisers and breathable clothing help protect the skin, while planning outdoor activities for cooler parts of the day reduces heat stress. 13

10. Avoidance of live vaccines in the patient – Live vaccines (such as oral polio, some measles–mumps–rubella and varicella formulations) can cause disease in people with severe T-cell defects. Immunologists usually recommend inactivated alternatives when available and design personalised vaccine schedules, balancing protection with safety. 14

11. Environmental mould and dust control – Keeping the home free of damp patches, visible mould and heavy dust loads lowers exposure to fungal spores that can cause severe disease in immunocompromised people. Dehumidifiers, HEPA filters and good ventilation are often helpful, especially in bedrooms. 15

12. Psychological and social support – Living with a life-threatening rare disease is stressful for patients and families. Access to counselling, peer-support groups and school-based psychological support can reduce anxiety, improve adherence to complex treatment plans and support healthy coping. 16

13. Genetic counselling for the family – Because this is an autosomal recessive condition, specialist genetic counselling helps relatives understand carrier status, recurrence risks in future pregnancies and options such as prenatal or preimplantation genetic testing. This information supports informed reproductive decisions. 17

14. Regular specialist monitoring – Scheduled visits with clinical immunologists, infectious-disease physicians and other specialists allow early detection of lung damage, autoimmune complications, growth failure or treatment side effects. Routine blood tests, imaging and lung function tests guide when to step up or change therapy. 18

15. Home nursing and infusion training – Some families are trained to give subcutaneous immunoglobulin or certain antibiotics at home under supervision. Home-care nurses check technique, monitor for side effects and reduce the need for long hospital stays, which also lowers exposure to hospital-acquired infections. 19

16. Hospital infection-control precautions – When hospitalisation is needed, staff use strict hand hygiene, protective gowns, masks and sometimes positive-pressure rooms. These measures aim to shield the patient from multi-drug resistant hospital bacteria and viruses which could cause severe, difficult-to-treat infections. 20

17. Heat and sun-exposure management – Due to reduced sweating, patients can overheat quickly. Planning rest breaks, avoiding midday sun, staying hydrated and using fans or air conditioning when possible help prevent heat exhaustion and related complications. 21

18. Patient-held emergency information – Carrying an emergency card or digital record that explains the diagnosis, key medications and the need for urgent antibiotics in case of fever helps emergency doctors act fast, even if they have never seen CRAC channelopathy before. 22

19. School and workplace accommodations – Adjusted timetables, permission to wear masks, flexible attendance and remote-learning options reduce exposure to infection and allow rest after procedures. Clear plans with school staff help balance safety with social and educational needs. 23

20. Sleep, stress and general wellness strategies – Good sleep, regular gentle activity, stress-reduction techniques and avoiding tobacco smoke support overall health and may reduce the frequency and severity of infections. While they cannot fix the genetic defect, they make the body more resilient. 24

Drug treatments – infection control and immune support (20 approaches)

Important: All medicines must be prescribed and dosed individually by a specialist. The descriptions below are educational, not instructions for self-treatment.

1. Intravenous immune globulin (IVIG) replacement – IVIG is a pooled human antibody product, given through a vein every 3–4 weeks to replace missing antibodies and reduce serious bacterial infections in primary immunodeficiency. Several FDA-approved products (such as immune globulin infusion for primary immunodeficiency) are used in this way. 25

2. Subcutaneous immune globulin (SCIG) replacement – SCIG uses similar antibody products given under the skin in smaller, more frequent doses, often at home. This provides steadier IgG levels, fewer systemic reactions and more flexible scheduling, using devices specifically cleared for subcutaneous immunoglobulin infusion. 26

3. Trimethoprim–sulfamethoxazole (TMP-SMX) prophylaxis – The antibiotic combination TMP-SMX is widely used to prevent Pneumocystis pneumonia and some bacterial infections in immunocompromised patients. FDA labels emphasise using it only when infection risk is significant and adjusting dose for age, kidney function and weight. 27

4. Macrolide antibiotics (e.g., azithromycin) – Azithromycin is a macrolide antibiotic with broad respiratory coverage and convenient once-daily dosing. In some immunodeficiency settings, it is used for prophylaxis or early treatment of chest infections, with dosing guided by FDA-approved labelling and local resistance patterns. 28

5. Oral beta-lactam antibiotics (e.g., amoxicillin or amoxicillin–clavulanate) – These drugs treat common bacterial infections of the ears, sinuses and lungs. In combined immunodeficiency, doctors often start treatment earlier and may use longer courses than in healthy children to ensure full bacterial clearance. 29

6. Parenteral cephalosporins (e.g., ceftriaxone) – For high fever, pneumonia or sepsis, hospital teams frequently use broad-spectrum intravenous cephalosporins to provide rapid, high-level antibacterial cover while awaiting cultures. Doses are weight-based and adjusted for kidney and liver function. 30

7. Carbapenem antibiotics (e.g., meropenem, ertapenem) – When resistant Gram-negative bacteria are suspected or proven, carbapenems may be used as powerful “last-line” intravenous antibiotics. Devices cleared for carbapenem infusion underline their use in serious infections under strict hospital supervision. 31

8. Fluconazole prophylaxis or treatment – Fluconazole is an oral or IV triazole antifungal used to treat or prevent Candida and some other fungal infections. FDA labels describe tablet and oral-suspension strengths and stress dose adjustment in kidney impairment and careful monitoring of liver tests. 32

9. Posaconazole for high-risk fungal prophylaxis – Posaconazole (Noxafil) is a broad-spectrum triazole antifungal used to prevent invasive Aspergillus and Candida infections in profoundly immunocompromised patients. FDA prescribing information details loading and maintenance doses and link dosing duration to recovery from neutropenia or immunosuppression. 33

10. Voriconazole for invasive mould infections – Voriconazole is another triazole antifungal indicated for invasive aspergillosis and serious fungal disease. Labels provide weight-based IV and oral dosing and highlight important drug–drug interactions and liver-function monitoring. 34

11. Amphotericin B formulations – Lipid-complex or liposomal amphotericin B is used when fungal infection is severe or resistant to azoles. It binds fungal cell membranes and is usually given IV with close monitoring of kidney function and electrolytes. 35

12. Topical antifungals (e.g., nystatin, clotrimazole) – For oral thrush or skin Candida infections, topical antifungals can reduce fungal load without systemic toxicity. They are often used alongside systemic agents in patients with combined immunodeficiency. 36

13. Acyclovir and related antivirals – Acyclovir, available as IV, oral and topical formulations, is used to treat and sometimes prevent herpesvirus infections such as HSV and VZV in immunocompromised hosts. FDA labels emphasise dose adjustment in renal impairment and careful hydration. 37

14. Influenza antivirals during outbreaks – Neuraminidase inhibitors (such as oseltamivir) may be used promptly if the patient is exposed to or develops influenza, because flu can be much more severe in immunodeficiency. Dosing and duration follow official labelling and public-health guidance. 38

15. High-dose IVIG as immunomodulation – Beyond replacement dosing, IVIG at higher doses can be used to treat autoimmune haemolytic anaemia or immune thrombocytopenia that sometimes accompany CRAC channelopathy, helping to dampen abnormal autoantibodies and stabilise blood counts. 39

16. Systemic corticosteroids for autoimmune complications – Short courses of steroids may be used to control autoimmune cytopenias, inflammatory lung disease or other immune dysregulation. They are powerful and must be balanced against additional infection risk, so are tapered as soon as safely possible. 40

17. Rituximab or other targeted immunosuppressants – In severe, steroid-refractory autoimmune complications, B-cell–depleting therapies such as rituximab can be considered. These drugs further weaken host defence, so they are reserved for carefully selected cases in expert centres. 41

18. Broad-spectrum peri-transplant anti-infective regimens – Around HSCT, patients typically receive multi-drug prophylaxis against bacteria, fungi and viruses, adjusted as counts and graft status evolve. These regimens are based on transplant guidelines and clinical-trial data and are tailored to local resistance patterns. 42

19. Electrolyte and fluid management for severe diarrhoea – While not “immune drugs,” oral rehydration solutions and IV fluids plus zinc supplementation help manage chronic diarrhoea and prevent kidney injury and shock during infections, supporting overall survival. 43

20. Symptomatic medicines (antipyretics, antiemetics, pain relief) – Paracetamol, certain antiemetics and other supportive drugs are used carefully to control symptoms like fever, nausea and pain, improving comfort and allowing patients to maintain nutrition and sleep while definitive anti-infective therapy works. 44

Dietary molecular supplements (10)

Always discuss supplements with the treating team; doses below are typical adult study ranges, not personal recommendations.

1. Vitamin D – Vitamin D supports innate and adaptive immunity and bone health. Typical supplemental doses in deficiency are in the hundreds to low thousands of IU per day, adjusted for blood levels. In combined immunodeficiency, correcting deficiency may reduce respiratory infections and support muscle and bone strength. 45

2. Vitamin C – Vitamin C is an antioxidant that participates in collagen synthesis and supports neutrophil function. Supplemental doses are often in the 200–1000 mg/day range, divided, and are used to support general immunity, especially during acute infections. 46

3. Zinc – Zinc is essential for T-cell development and function. Mild deficiency is common in chronic illness; typical supplement doses are 5–20 mg elemental zinc per day for children, adjusted with medical advice. Repletion can improve growth and reduce diarrhoeal episodes. 47

4. Selenium – Selenium is involved in antioxidant enzymes and immune regulation. Low doses (for example, 25–100 micrograms/day in adults) are used when deficiency is documented, as excess can be toxic. Adequate selenium status may help modulate viral infection outcomes. 48

5. Omega-3 fatty acids – Marine omega-3 fats (EPA/DHA) have anti-inflammatory effects and may help balance chronic inflammation. Typical supplemental amounts are a few hundred milligrams per day, taken with food to improve absorption. 49

6. Probiotic preparations – Carefully selected, non-live or well-characterised probiotic products may help stabilise gut microbiota and reduce antibiotic-associated diarrhoea. In severe immunodeficiency, only products considered safe by the specialist team should be used, because live bacteria can rarely translocate. 50

7. Glutamine – Glutamine is a fuel for rapidly dividing cells, including gut and immune cells. Under dietitian supervision, supplemental glutamine may be used during periods of high metabolic stress (such as HSCT) to support gut integrity and nitrogen balance. 51

8. Arginine – Arginine is involved in nitric oxide production and lymphocyte function. It has been studied as part of immunonutrition formulas in critical illness; use in rare primary immunodeficiencies is extrapolated and should be individualised. 52

9. B-complex vitamins (including folate and B12) – Adequate B-vitamin status helps red-blood-cell production and energy metabolism. Supplements are used when laboratory tests show deficiency, especially in patients with chronic diarrhoea or poor intake. 53

10. Multinutrient formulas for malnourished patients – In children with failure to thrive, specialised oral or tube-feeding formulas that provide balanced macro- and micronutrients may be used to achieve adequate growth before major procedures like HSCT. 54

Immunity-boosting / regenerative and stem-cell-related drugs (6)

1. Granulocyte colony-stimulating factor (G-CSF, e.g., filgrastim) – G-CSF stimulates bone marrow to produce and release neutrophils, shortening the duration of neutropenia during severe infections or after HSCT. Doses are weight-based and adjusted to avoid extreme leukocytosis or bone pain. 55

2. Granulocyte–macrophage colony-stimulating factor (GM-CSF, e.g., sargramostim) – GM-CSF can boost monocyte and neutrophil function and is sometimes used post-transplant or in specific infection settings. It is given subcutaneously or intravenously under close monitoring for fever, capillary-leak and other side effects. 56

3. Eltrombopag (thrombopoietin-receptor agonist) – Eltrombopag (Promacta) is an oral drug that stimulates platelet production and is FDA-approved for chronic immune thrombocytopenia. In the context of immune dysregulation and thrombocytopenia, it may be considered to reduce bleeding risk once infections are under control. 57

4. Other thrombopoietin-receptor agonists (e.g., romiplostim) – Similar agents can be used to support platelet counts in selected patients with severe thrombocytopenia, especially around HSCT, but require expert haematology oversight because of potential thrombotic and marrow effects. 58

5. Stem-cell-mobilising agents (e.g., G-CSF plus plerixafor) – In donors or patients undergoing HSCT, combinations of G-CSF and other mobilising drugs can increase the number of hematopoietic stem cells collected for transplantation, improving graft success. 59

6. Experimental gene and cell-based therapies – In future, gene therapies that correct ORAI1 or STIM1 defects or engineered immune-cell infusions may become options, similar to approaches already used in other forms of SCID. At present, such strategies remain research-only and are not standard care. 60

Surgical and procedural treatments (5)

1. Hematopoietic stem cell transplantation (HSCT) – HSCT is currently the only potentially curative treatment, replacing the patient’s defective immune system with donor stem cells that can form functional lymphocytes. It involves conditioning chemotherapy, infusion of donor cells and long-term follow-up for graft-versus-host disease and infection. 61

2. Central venous catheter placement – Many patients need long-term central lines for IV medications, blood sampling and parenteral nutrition. Surgical insertion and meticulous line care are essential, because line infections can be life-threatening in this population. 62

3. Feeding-tube placement (e.g., gastrostomy) – If oral intake is insufficient due to chronic illness or procedures, a gastrostomy tube may be placed to provide reliable nutrition and medications, supporting growth and preparing for HSCT. 63

4. Dental rehabilitation and restorative procedures – Because enamel defects and tooth fragility are part of CRAC channelopathy, patients may need crowns, implants or other restorative dental surgeries to maintain function and prevent chronic infection. These are planned with antibiotic cover and close immunology input. 64

5. Selected procedures for complications (e.g., lung surgery) – In rare cases of severe, localised bronchiectasis or structural lung damage, surgical options may be considered, though they are uncommon and carefully weighed against operative risks in immunodeficient patients. 65

Prevention strategies (10 key points)

1. Avoid close contact with people who have coughs, colds or stomach bugs whenever possible. 66

2. Ensure all household members keep vaccines up to date with inactivated vaccines as advised. 67

3. Follow meticulous hand hygiene before meals, after toilet visits and after touching public surfaces. 68

4. Use safe food and water practices (well-cooked meat, pasteurised dairy, safe drinking water). 69

5. Avoid live vaccines in the patient unless an immunologist specifically advises otherwise. 70

6. Keep up with regular dental, eye and skin checks to spot early problems. 71

7. Follow all prophylactic medication plans exactly as prescribed; do not stop without medical advice. 72

8. Maintain good baseline fitness and nutrition to increase resilience during infections. 73

9. Prepare early for HSCT evaluation when recommended, as outcomes are usually better before severe organ damage occurs. 74

10. Keep clear written emergency plans and contact numbers easily accessible at home and on mobile devices. 75

When to see doctors

People with CRAC channelopathy should stay closely linked to a specialist immunology team and seek medical care quickly whenever anything changes. Any fever, breathing difficulty, new rash, persistent diarrhoea, mouth ulcers, severe fatigue or behavioural change should trigger urgent review, because infections can progress very fast when T-cell activation is impaired. Families are usually advised to treat fevers as emergencies, so that blood tests and IV antibiotics can be started promptly. Regular planned visits are also important to adjust immunoglobulin dosing, review prophylactic medicines, check growth and development, and monitor for autoimmune complications or organ damage. 76

What to eat and what to avoid (10 practical points)

1. Emphasise a balanced diet rich in fruits, vegetables, whole grains and lean proteins to support growth and immune cell production. 77

2. Include safe sources of healthy fats (like vegetable oils and fish) to help absorb fat-soluble vitamins and provide extra calories. 78

3. Choose pasteurised milk and dairy products to avoid exposure to harmful bacteria. 79

4. Eat well-cooked meat, poultry and eggs; avoid raw or undercooked animal products that may carry Salmonella or other pathogens. 80

5. Prefer freshly prepared foods and avoid buffets or foods left at room temperature for long periods. 81

6. Limit very sugary drinks and snacks, which can worsen dental problems in the setting of enamel defects. 82

7. Avoid unpasteurised juices, raw sprouts and unwashed fruits or vegetables, which can harbour bacteria. 83

8. Discuss any herbal products or high-dose supplements with the medical team first, because some can interact with antifungals, antivirals or transplant drugs. 84

9. Maintain adequate fluid intake, especially during fevers or diarrhoea, to prevent dehydration and support kidney function. 85

10. If appetite is poor, use small, frequent meals and high-energy snacks or prescribed formulas under dietitian guidance. 86

Frequently asked questions (15)

1. Is CRAC channelopathy the same as classic SCID?
   No. It is a form of combined immunodeficiency where lymphocyte numbers may be near normal, but calcium signalling and activation are severely impaired. The infection risk is similar to some SCID forms, but there are additional muscle and enamel problems. 87

2. What causes this condition?
   It is usually caused by autosomal recessive mutations in the ORAI1 or STIM1 genes, which encode key components of the CRAC calcium channel. Both parents are usually healthy carriers. 88

3. How is the diagnosis confirmed?
   Doctors combine clinical features, immunological tests, genetic sequencing of ORAI1/STIM1 and functional assays showing absent store-operated calcium entry in patient cells. This pattern is typical for CRAC channelopathy. 89

4. Can children with this condition receive vaccines?
   Most can receive inactivated vaccines according to individual plans, but live vaccines are generally avoided because T-cell function is impaired. Household members should be fully vaccinated to protect the patient. 90

5. Is there a cure?
   HSCT can potentially cure the immune defect by providing a new, functional immune system. However, HSCT does not always fix non-immune features like enamel defects or muscle weakness, and it carries its own risks. 91

6. What is life expectancy?
   Without aggressive treatment, life expectancy can be severely shortened because of recurrent severe infections. With modern supportive care and successful HSCT, some patients can survive long term, but numbers are still small and long-term data are limited. 92

7. Can affected children attend school?
   Many do, with adjustments such as reduced class size, remote learning during outbreaks and strict infection-control measures. Decisions are individual and depend on infection history, treatment stage and local infection rates. 93

8. Are there specific “best” antibiotics or antifungals for this disease?
   There is no single “CRAC-channelopathy drug.” Doctors use combinations of standard FDA-approved antibiotics, antifungals and antivirals, chosen based on likely or proven organisms, organ function and drug interactions. 94

9. Does diet alone fix the immune problem?
   No. Diet and supplements can support general health but cannot correct the underlying calcium-channel defect. Core treatments are immunoglobulin replacement, infection prophylaxis and, when possible, HSCT. 95

10. Can siblings be tested?
    Yes. Once a family mutation is known, siblings can be tested for carrier or affected status, and newborns can be screened early so that treatment begins before severe infections develop. 96

11. Is pregnancy possible in affected individuals?
    Data are very limited. If survival to adulthood occurs, pregnancy would require extremely close monitoring by high-risk obstetric and immunology teams because of infection and treatment issues. 97

12. Are there new treatments in research?
    Research is ongoing into better understanding of store-operated calcium entry, potential small-molecule modulators and gene-therapy strategies. At present, care relies on optimised versions of existing SCID and HSCT protocols. 98

13. Can this condition recur after HSCT?
    The genetic defect remains in non-haematopoietic tissues, but if the graft is successful, the immune defect usually does not “recur” in blood and immune cells. However, graft failure or chronic graft-versus-host disease can still cause long-term problems. 99

14. Do patients always have muscle weakness and enamel defects?
    Many reported patients do, but the exact combination and severity of features can vary with the specific mutation. Some individuals show mainly immune problems, while others have prominent muscle and ectodermal signs. 100

15. What is the most important message for families?
    Even though CRAC channelopathy is very rare and serious, early diagnosis, strong partnership with specialised centres, strict infection-prevention measures and timely consideration of HSCT can greatly improve outcomes. Families should never feel they are “over-reacting” when seeking urgent care for fever or new symptoms. 101

Non-pharmacological treatments

1. Strict infection-prevention lifestyle – Careful hand-washing, regular use of alcohol hand rub, masking in crowded places and avoiding contact with people who are clearly unwell reduce exposure to germs. These simple habits lower the chance that bacteria or viruses will reach a vulnerable immune system, which is crucial because even “mild” infections can become serious in combined immunodeficiency. 5

2. Household “cocooning” vaccination – Family members and close contacts should receive all recommended inactivated vaccines (e.g., influenza, COVID-19, pneumococcal) so they are less likely to bring infections home. This “cocoon” approach indirectly protects the patient, who may have a weaker vaccine response and must avoid live vaccines. 6

3. Protective isolation in high-risk periods – During local outbreaks or when the patient is severely immunosuppressed (for example, around HSCT), doctors may advise temporary “protective isolation.” This can include single hospital rooms with filtered air and visitor restrictions, or reduced exposure to crowded schools and malls at home. The goal is to lower pathogen exposure while immune defences are at their weakest. 7

4. Early-fever action plan – Families are trained to treat any fever or new symptom as an emergency and to contact the immunology team or visit hospital very quickly. Written emergency plans help ensure that blood cultures, basic labs and broad-spectrum antibiotics are started without delay, which is key to preventing sepsis in primary immunodeficiency. 8

5. Specialised dental and oral care – Because enamel is often thin or abnormal, children are at high risk of cavities and tooth fracture. Regular reviews with dentists familiar with genetic enamel defects, fluoride treatments, sealants and early repairs help preserve teeth and reduce dental infections, which might otherwise spread and become systemic. 9

6. Chest physiotherapy and breathing exercises – Physiotherapists can teach airway-clearance techniques, postural drainage and breathing exercises to help remove mucus and reduce pneumonia risk. For children with recurrent chest infections or bronchiectasis, regular physiotherapy can improve lung function and quality of life. 10

7. Nutrition counselling and growth support – Chronic infections and diarrhoea may cause poor weight gain. Dietitians can suggest high-calorie, high-protein diets, oral supplements or tube feeding if needed. Good nutrition supports immune cell production, wound healing and muscle strength, and is especially important before major procedures like HSCT. 11

8. Physiotherapy and rehabilitation for myopathy – Because many patients have muscle weakness, gentle strength training, stretching and tailored exercise programmes help maintain mobility and function. Therapy is usually low-impact to avoid fatigue, and aims to support activities of daily living rather than build athletic performance. 12

9. Skin and sweat-management routines – Reduced sweating and altered skin barrier function can cause overheating and dryness. Simple measures like lukewarm showers, fragrance-free moisturisers and breathable clothing help protect the skin, while planning outdoor activities for cooler parts of the day reduces heat stress. 13

10. Avoidance of live vaccines in the patient – Live vaccines (such as oral polio, some measles–mumps–rubella and varicella formulations) can cause disease in people with severe T-cell defects. Immunologists usually recommend inactivated alternatives when available and design personalised vaccine schedules, balancing protection with safety. 14

11. Environmental mould and dust control – Keeping the home free of damp patches, visible mould and heavy dust loads lowers exposure to fungal spores that can cause severe disease in immunocompromised people. Dehumidifiers, HEPA filters and good ventilation are often helpful, especially in bedrooms. 15

12. Psychological and social support – Living with a life-threatening rare disease is stressful for patients and families. Access to counselling, peer-support groups and school-based psychological support can reduce anxiety, improve adherence to complex treatment plans and support healthy coping. 16

13. Genetic counselling for the family – Because this is an autosomal recessive condition, specialist genetic counselling helps relatives understand carrier status, recurrence risks in future pregnancies and options such as prenatal or preimplantation genetic testing. This information supports informed reproductive decisions. 17

14. Regular specialist monitoring – Scheduled visits with clinical immunologists, infectious-disease physicians and other specialists allow early detection of lung damage, autoimmune complications, growth failure or treatment side effects. Routine blood tests, imaging and lung function tests guide when to step up or change therapy. 18

15. Home nursing and infusion training – Some families are trained to give subcutaneous immunoglobulin or certain antibiotics at home under supervision. Home-care nurses check technique, monitor for side effects and reduce the need for long hospital stays, which also lowers exposure to hospital-acquired infections. 19

16. Hospital infection-control precautions – When hospitalisation is needed, staff use strict hand hygiene, protective gowns, masks and sometimes positive-pressure rooms. These measures aim to shield the patient from multi-drug resistant hospital bacteria and viruses which could cause severe, difficult-to-treat infections. 20

17. Heat and sun-exposure management – Due to reduced sweating, patients can overheat quickly. Planning rest breaks, avoiding midday sun, staying hydrated and using fans or air conditioning when possible help prevent heat exhaustion and related complications. 21

18. Patient-held emergency information – Carrying an emergency card or digital record that explains the diagnosis, key medications and the need for urgent antibiotics in case of fever helps emergency doctors act fast, even if they have never seen CRAC channelopathy before. 22

19. School and workplace accommodations – Adjusted timetables, permission to wear masks, flexible attendance and remote-learning options reduce exposure to infection and allow rest after procedures. Clear plans with school staff help balance safety with social and educational needs. 23

20. Sleep, stress and general wellness strategies – Good sleep, regular gentle activity, stress-reduction techniques and avoiding tobacco smoke support overall health and may reduce the frequency and severity of infections. While they cannot fix the genetic defect, they make the body more resilient. 24

Drug treatments

Important: All medicines must be prescribed and dosed individually by a specialist. The descriptions below are educational, not instructions for self-treatment.

1. Intravenous immune globulin (IVIG) replacement – IVIG is a pooled human antibody product, given through a vein every 3–4 weeks to replace missing antibodies and reduce serious bacterial infections in primary immunodeficiency. Several FDA-approved products (such as immune globulin infusion for primary immunodeficiency) are used in this way. 25

2. Subcutaneous immune globulin (SCIG) replacement – SCIG uses similar antibody products given under the skin in smaller, more frequent doses, often at home. This provides steadier IgG levels, fewer systemic reactions and more flexible scheduling, using devices specifically cleared for subcutaneous immunoglobulin infusion. 26

3. Trimethoprim–sulfamethoxazole (TMP-SMX) prophylaxis – The antibiotic combination TMP-SMX is widely used to prevent Pneumocystis pneumonia and some bacterial infections in immunocompromised patients. FDA labels emphasise using it only when infection risk is significant and adjusting dose for age, kidney function and weight. 27

4. Macrolide antibiotics (e.g., azithromycin) – Azithromycin is a macrolide antibiotic with broad respiratory coverage and convenient once-daily dosing. In some immunodeficiency settings, it is used for prophylaxis or early treatment of chest infections, with dosing guided by FDA-approved labelling and local resistance patterns. 28

5. Oral beta-lactam antibiotics (e.g., amoxicillin or amoxicillin–clavulanate) – These drugs treat common bacterial infections of the ears, sinuses and lungs. In combined immunodeficiency, doctors often start treatment earlier and may use longer courses than in healthy children to ensure full bacterial clearance. 29

6. Parenteral cephalosporins (e.g., ceftriaxone) – For high fever, pneumonia or sepsis, hospital teams frequently use broad-spectrum intravenous cephalosporins to provide rapid, high-level antibacterial cover while awaiting cultures. Doses are weight-based and adjusted for kidney and liver function. 30

7. Carbapenem antibiotics (e.g., meropenem, ertapenem) – When resistant Gram-negative bacteria are suspected or proven, carbapenems may be used as powerful “last-line” intravenous antibiotics. Devices cleared for carbapenem infusion underline their use in serious infections under strict hospital supervision. 31

8. Fluconazole prophylaxis or treatment – Fluconazole is an oral or IV triazole antifungal used to treat or prevent Candida and some other fungal infections. FDA labels describe tablet and oral-suspension strengths and stress dose adjustment in kidney impairment and careful monitoring of liver tests. 32

9. Posaconazole for high-risk fungal prophylaxis – Posaconazole (Noxafil) is a broad-spectrum triazole antifungal used to prevent invasive Aspergillus and Candida infections in profoundly immunocompromised patients. FDA prescribing information details loading and maintenance doses and link dosing duration to recovery from neutropenia or immunosuppression. 33

10. Voriconazole for invasive mould infections – Voriconazole is another triazole antifungal indicated for invasive aspergillosis and serious fungal disease. Labels provide weight-based IV and oral dosing and highlight important drug–drug interactions and liver-function monitoring. 34

11. Amphotericin B formulations – Lipid-complex or liposomal amphotericin B is used when fungal infection is severe or resistant to azoles. It binds fungal cell membranes and is usually given IV with close monitoring of kidney function and electrolytes. 35

12. Topical antifungals (e.g., nystatin, clotrimazole) – For oral thrush or skin Candida infections, topical antifungals can reduce fungal load without systemic toxicity. They are often used alongside systemic agents in patients with combined immunodeficiency. 36

13. Acyclovir and related antivirals – Acyclovir, available as IV, oral and topical formulations, is used to treat and sometimes prevent herpesvirus infections such as HSV and VZV in immunocompromised hosts. FDA labels emphasise dose adjustment in renal impairment and careful hydration. 37

14. Influenza antivirals during outbreaks – Neuraminidase inhibitors (such as oseltamivir) may be used promptly if the patient is exposed to or develops influenza, because flu can be much more severe in immunodeficiency. Dosing and duration follow official labelling and public-health guidance. 38

15. High-dose IVIG as immunomodulation – Beyond replacement dosing, IVIG at higher doses can be used to treat autoimmune haemolytic anaemia or immune thrombocytopenia that sometimes accompany CRAC channelopathy, helping to dampen abnormal autoantibodies and stabilise blood counts. 39

16. Systemic corticosteroids for autoimmune complications – Short courses of steroids may be used to control autoimmune cytopenias, inflammatory lung disease or other immune dysregulation. They are powerful and must be balanced against additional infection risk, so are tapered as soon as safely possible. 40

17. Rituximab or other targeted immunosuppressants – In severe, steroid-refractory autoimmune complications, B-cell–depleting therapies such as rituximab can be considered. These drugs further weaken host defence, so they are reserved for carefully selected cases in expert centres. 41

18. Broad-spectrum peri-transplant anti-infective regimens – Around HSCT, patients typically receive multi-drug prophylaxis against bacteria, fungi and viruses, adjusted as counts and graft status evolve. These regimens are based on transplant guidelines and clinical-trial data and are tailored to local resistance patterns. 42

19. Electrolyte and fluid management for severe diarrhoea – While not “immune drugs,” oral rehydration solutions and IV fluids plus zinc supplementation help manage chronic diarrhoea and prevent kidney injury and shock during infections, supporting overall survival. 43

20. Symptomatic medicines (antipyretics, antiemetics, pain relief) – Paracetamol, certain antiemetics and other supportive drugs are used carefully to control symptoms like fever, nausea and pain, improving comfort and allowing patients to maintain nutrition and sleep while definitive anti-infective therapy works. 44

Dietary molecular supplements

Always discuss supplements with the treating team; doses below are typical adult study ranges, not personal recommendations.

1. Vitamin D – Vitamin D supports innate and adaptive immunity and bone health. Typical supplemental doses in deficiency are in the hundreds to low thousands of IU per day, adjusted for blood levels. In combined immunodeficiency, correcting deficiency may reduce respiratory infections and support muscle and bone strength. 45

2. Vitamin C – Vitamin C is an antioxidant that participates in collagen synthesis and supports neutrophil function. Supplemental doses are often in the 200–1000 mg/day range, divided, and are used to support general immunity, especially during acute infections. 46

3. Zinc – Zinc is essential for T-cell development and function. Mild deficiency is common in chronic illness; typical supplement doses are 5–20 mg elemental zinc per day for children, adjusted with medical advice. Repletion can improve growth and reduce diarrhoeal episodes. 47

4. Selenium – Selenium is involved in antioxidant enzymes and immune regulation. Low doses (for example, 25–100 micrograms/day in adults) are used when deficiency is documented, as excess can be toxic. Adequate selenium status may help modulate viral infection outcomes. 48

5. Omega-3 fatty acids – Marine omega-3 fats (EPA/DHA) have anti-inflammatory effects and may help balance chronic inflammation. Typical supplemental amounts are a few hundred milligrams per day, taken with food to improve absorption. 49

6. Probiotic preparations – Carefully selected, non-live or well-characterised probiotic products may help stabilise gut microbiota and reduce antibiotic-associated diarrhoea. In severe immunodeficiency, only products considered safe by the specialist team should be used, because live bacteria can rarely translocate. 50

7. Glutamine – Glutamine is a fuel for rapidly dividing cells, including gut and immune cells. Under dietitian supervision, supplemental glutamine may be used during periods of high metabolic stress (such as HSCT) to support gut integrity and nitrogen balance. 51

8. Arginine – Arginine is involved in nitric oxide production and lymphocyte function. It has been studied as part of immunonutrition formulas in critical illness; use in rare primary immunodeficiencies is extrapolated and should be individualised. 52

9. B-complex vitamins (including folate and B12) – Adequate B-vitamin status helps red-blood-cell production and energy metabolism. Supplements are used when laboratory tests show deficiency, especially in patients with chronic diarrhoea or poor intake. 53

10. Multinutrient formulas for malnourished patients – In children with failure to thrive, specialised oral or tube-feeding formulas that provide balanced macro- and micronutrients may be used to achieve adequate growth before major procedures like HSCT. 54

Immunity-boosting / regenerative and stem-cell-related drugs

1. Granulocyte colony-stimulating factor (G-CSF, e.g., filgrastim) – G-CSF stimulates bone marrow to produce and release neutrophils, shortening the duration of neutropenia during severe infections or after HSCT. Doses are weight-based and adjusted to avoid extreme leukocytosis or bone pain. 55

2. Granulocyte–macrophage colony-stimulating factor (GM-CSF, e.g., sargramostim) – GM-CSF can boost monocyte and neutrophil function and is sometimes used post-transplant or in specific infection settings. It is given subcutaneously or intravenously under close monitoring for fever, capillary-leak and other side effects. 56

3. Eltrombopag (thrombopoietin-receptor agonist) – Eltrombopag (Promacta) is an oral drug that stimulates platelet production and is FDA-approved for chronic immune thrombocytopenia. In the context of immune dysregulation and thrombocytopenia, it may be considered to reduce bleeding risk once infections are under control. 57

4. Other thrombopoietin-receptor agonists (e.g., romiplostim) – Similar agents can be used to support platelet counts in selected patients with severe thrombocytopenia, especially around HSCT, but require expert haematology oversight because of potential thrombotic and marrow effects. 58

5. Stem-cell-mobilising agents (e.g., G-CSF plus plerixafor) – In donors or patients undergoing HSCT, combinations of G-CSF and other mobilising drugs can increase the number of hematopoietic stem cells collected for transplantation, improving graft success. 59

6. Experimental gene and cell-based therapies – In future, gene therapies that correct ORAI1 or STIM1 defects or engineered immune-cell infusions may become options, similar to approaches already used in other forms of SCID. At present, such strategies remain research-only and are not standard care. 60

Surgical and procedural treatments

1. Hematopoietic stem cell transplantation (HSCT) – HSCT is currently the only potentially curative treatment, replacing the patient’s defective immune system with donor stem cells that can form functional lymphocytes. It involves conditioning chemotherapy, infusion of donor cells and long-term follow-up for graft-versus-host disease and infection. 61

2. Central venous catheter placement – Many patients need long-term central lines for IV medications, blood sampling and parenteral nutrition. Surgical insertion and meticulous line care are essential, because line infections can be life-threatening in this population. 62

3. Feeding-tube placement (e.g., gastrostomy) – If oral intake is insufficient due to chronic illness or procedures, a gastrostomy tube may be placed to provide reliable nutrition and medications, supporting growth and preparing for HSCT. 63

4. Dental rehabilitation and restorative procedures – Because enamel defects and tooth fragility are part of CRAC channelopathy, patients may need crowns, implants or other restorative dental surgeries to maintain function and prevent chronic infection. These are planned with antibiotic cover and close immunology input. 64

5. Selected procedures for complications (e.g., lung surgery) – In rare cases of severe, localised bronchiectasis or structural lung damage, surgical options may be considered, though they are uncommon and carefully weighed against operative risks in immunodeficient patients. 65

Prevention strategies

1. Avoid close contact with people who have coughs, colds or stomach bugs whenever possible. 66

2. Ensure all household members keep vaccines up to date with inactivated vaccines as advised. 67

3. Follow meticulous hand hygiene before meals, after toilet visits and after touching public surfaces. 68

4. Use safe food and water practices (well-cooked meat, pasteurised dairy, safe drinking water). 69

5. Avoid live vaccines in the patient unless an immunologist specifically advises otherwise. 70

6. Keep up with regular dental, eye and skin checks to spot early problems. 71

7. Follow all prophylactic medication plans exactly as prescribed; do not stop without medical advice. 72

8. Maintain good baseline fitness and nutrition to increase resilience during infections. 73

9. Prepare early for HSCT evaluation when recommended, as outcomes are usually better before severe organ damage occurs. 74

10. Keep clear written emergency plans and contact numbers easily accessible at home and on mobile devices. 75

When to see doctors

People with CRAC channelopathy should stay closely linked to a specialist immunology team and seek medical care quickly whenever anything changes. Any fever, breathing difficulty, new rash, persistent diarrhoea, mouth ulcers, severe fatigue or behavioural change should trigger urgent review, because infections can progress very fast when T-cell activation is impaired. Families are usually advised to treat fevers as emergencies, so that blood tests and IV antibiotics can be started promptly. Regular planned visits are also important to adjust immunoglobulin dosing, review prophylactic medicines, check growth and development, and monitor for autoimmune complications or organ damage. 76

What to eat and what to avoid

1. Emphasise a balanced diet rich in fruits, vegetables, whole grains and lean proteins to support growth and immune cell production. 77

2. Include safe sources of healthy fats (like vegetable oils and fish) to help absorb fat-soluble vitamins and provide extra calories. 78

3. Choose pasteurised milk and dairy products to avoid exposure to harmful bacteria. 79

4. Eat well-cooked meat, poultry and eggs; avoid raw or undercooked animal products that may carry Salmonella or other pathogens. 80

5. Prefer freshly prepared foods and avoid buffets or foods left at room temperature for long periods. 81

6. Limit very sugary drinks and snacks, which can worsen dental problems in the setting of enamel defects. 82

7. Avoid unpasteurised juices, raw sprouts and unwashed fruits or vegetables, which can harbour bacteria. 83

8. Discuss any herbal products or high-dose supplements with the medical team first, because some can interact with antifungals, antivirals or transplant drugs. 84

9. Maintain adequate fluid intake, especially during fevers or diarrhoea, to prevent dehydration and support kidney function. 85

10. If appetite is poor, use small, frequent meals and high-energy snacks or prescribed formulas under dietitian guidance. 86

Frequently asked questions

1. Is CRAC channelopathy the same as classic SCID?
   No. It is a form of combined immunodeficiency where lymphocyte numbers may be near normal, but calcium signalling and activation are severely impaired. The infection risk is similar to some SCID forms, but there are additional muscle and enamel problems. 87

2. What causes this condition?
   It is usually caused by autosomal recessive mutations in the ORAI1 or STIM1 genes, which encode key components of the CRAC calcium channel. Both parents are usually healthy carriers. 88

3. How is the diagnosis confirmed?
   Doctors combine clinical features, immunological tests, genetic sequencing of ORAI1/STIM1 and functional assays showing absent store-operated calcium entry in patient cells. This pattern is typical for CRAC channelopathy. 89

4. Can children with this condition receive vaccines?
   Most can receive inactivated vaccines according to individual plans, but live vaccines are generally avoided because T-cell function is impaired. Household members should be fully vaccinated to protect the patient. 90

5. Is there a cure?
   HSCT can potentially cure the immune defect by providing a new, functional immune system. However, HSCT does not always fix non-immune features like enamel defects or muscle weakness, and it carries its own risks. 91

6. What is life expectancy?
   Without aggressive treatment, life expectancy can be severely shortened because of recurrent severe infections. With modern supportive care and successful HSCT, some patients can survive long term, but numbers are still small and long-term data are limited. 92

7. Can affected children attend school?
   Many do, with adjustments such as reduced class size, remote learning during outbreaks and strict infection-control measures. Decisions are individual and depend on infection history, treatment stage and local infection rates. 93

8. Are there specific “best” antibiotics or antifungals for this disease?
   There is no single “CRAC-channelopathy drug.” Doctors use combinations of standard FDA-approved antibiotics, antifungals and antivirals, chosen based on likely or proven organisms, organ function and drug interactions. 94

9. Does diet alone fix the immune problem?
   No. Diet and supplements can support general health but cannot correct the underlying calcium-channel defect. Core treatments are immunoglobulin replacement, infection prophylaxis and, when possible, HSCT. 95

10. Can siblings be tested?
    Yes. Once a family mutation is known, siblings can be tested for carrier or affected status, and newborns can be screened early so that treatment begins before severe infections develop. 96

11. Is pregnancy possible in affected individuals?
    Data are very limited. If survival to adulthood occurs, pregnancy would require extremely close monitoring by high-risk obstetric and immunology teams because of infection and treatment issues. 97

12. Are there new treatments in research?
    Research is ongoing into better understanding of store-operated calcium entry, potential small-molecule modulators and gene-therapy strategies. At present, care relies on optimised versions of existing SCID and HSCT protocols. 98

13. Can this condition recur after HSCT?
    The genetic defect remains in non-haematopoietic tissues, but if the graft is successful, the immune defect usually does not “recur” in blood and immune cells. However, graft failure or chronic graft-versus-host disease can still cause long-term problems. 99

14. Do patients always have muscle weakness and enamel defects?
    Many reported patients do, but the exact combination and severity of features can vary with the specific mutation. Some individuals show mainly immune problems, while others have prominent muscle and ectodermal signs. 100

15. What is the most important message for families?
    Even though CRAC channelopathy is very rare and serious, early diagnosis, strong partnership with specialised centres, strict infection-prevention measures and timely consideration of HSCT can greatly improve outcomes. Families should never feel they are “over-reacting” when seeking urgent care for fever or new symptoms. 101

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

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

Last Updated: February 13, 2025.