Immune Deficiency, Variable, with Centromeric Instability of Chromosomes 1, 9, and 16

Immune deficiency, variable, with centromeric instability of chromosomes 1, 9, and 16 is better known as ICF syndrome (Immunodeficiency–Centromeric instability–Facial anomalies). It is a very rare inherited primary immunodeficiency. Children are usually born looking well but start to have repeated chest, ear, and gut infections in the first years of life. Their immune system does not make enough working antibodies (panhypogammaglobulinemia), so they cannot fight germs properly. Under the microscope, the middle parts (centromeres) of chromosomes 1, 9, and 16 look unstable or “open,” which is a hallmark of this disease. PMC+2Orpha+2

Immune deficiency with centromeric instability of chromosomes 1, 9, and 16 is usually called ICF syndrome (Immunodeficiency–Centromeric Instability–Facial anomalies syndrome). It is a very rare genetic disease. A child is born with a weak immune system, special changes in some chromosomes in their white blood cells, and often mild but typical changes in the face. The disease is inherited in an autosomal recessive way, which means both parents quietly carry one faulty gene and the child gets both copies.Orpha+1

ICF syndrome is an autosomal recessive disease. This means a child gets one faulty copy of a gene from each parent. The main genes are DNMT3B (ICF1), ZBTB24 (ICF2), CDCA7 (ICF3), and HELLS (ICF4). These genes control DNA methylation, a chemical “tag” on DNA that helps switch genes on and off. When these genes do not work, some DNA around the centromeres is not methylated correctly, so chromosomes 1, 9, and 16 become unstable in dividing lymphocytes. This instability seems to disturb the development and survival of B and T cells, leading to immune deficiency. Science+3PMC+3Nature+3

Children with this immune deficiency can also have facial differences such as wide-set eyes, a flat nasal bridge, and epicanthic folds, plus growth delay and sometimes learning difficulties. The most serious problems come from infections like pneumonia, chronic sinusitis, chronic diarrhea, and sometimes virus-related cancers such as Epstein–Barr virus (EBV)–driven lymphomas. Without good treatment, repeated infections and organ damage can limit life expectancy, so early diagnosis and careful long-term care are very important. eLife+3OUP Academic+3Frontiers+3

In ICF syndrome the immune system does not work properly, so the body cannot make enough good antibodies (immunoglobulins). This makes the person get many infections, especially of the chest and gut. Blood tests show low IgG, IgA or IgM, even though B cells are present.Primary Immune+1

The “centromeric instability” part means that, when doctors look at the chromosomes under the microscope after special stimulation, the centromere regions of chromosomes 1, 9 and 16 look broken or branched. These strange shapes are a key sign of this disease.MalaCards

ICF syndrome happens because of faults in genes that control DNA methylation and chromatin (chromosome) structure, such as DNMT3B, ZBTB24, CDCA7, and HELLS. These genes help switch other genes on and off. When they do not work, many genes are wrongly controlled, especially near the centromere, and immune cells cannot develop normally.Primary Immune+2Nature+2

Because of the weak immune system, people with ICF syndrome often have repeated, long-lasting infections, may not grow well, and may have trouble with learning or development. Without treatment, serious infections can be life-threatening, so early diagnosis and specialist care (for example immunoglobulin replacement and sometimes stem cell transplant) are very important.Bentham Direct+1

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Other Names and Types

This condition has several names in the medical literature. All describe the same basic disease group:

• ICF syndrome (short common name).Wikipedia

• Immunodeficiency–Centromeric Instability–Facial anomalies syndrome (full English name).Wikipedia

• Immunodeficiency, centromeric region instability and facial anomalies syndrome (slightly different wording used in some papers).PMC+1

• Sometimes it is called “immunodeficiency with centromeric instability of chromosomes 1, 9 and 16”, to stress the special chromosome finding.MalaCards

Doctors now describe four main genetic types of ICF syndrome:

• ICF type 1 (ICF1) – caused by mutations in the DNMT3B gene. This is the classic and most common form, first recognized and best studied.PMC+1

• ICF type 2 (ICF2) – caused by mutations in ZBTB24, another gene that helps regulate DNA and immune cell development.Primary Immune+1

• ICF type 3 (ICF3) – caused by mutations in CDCA7. This type also shows the typical chromosome 1, 9 and 16 problems.NCBI+1

• ICF type 4 (ICF4) – caused by mutations in HELLS (also called LSH), a gene linked to chromatin remodeling and DNA methylation.MalaCards+1

All four types share the same basic features (immune deficiency, chromosome changes, facial features), but the age at diagnosis, infection pattern, and severity can be different from person to person and between types.JACI in Practice+1

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Causes

1. Autosomal recessive inheritance
   ICF syndrome happens when a child receives one faulty copy of an ICF-related gene from each parent. The parents are usually healthy “carriers,” but the child’s two faulty copies cause the disease.Orpha+1

2. Mutations in the DNMT3B gene (ICF1)
   In many patients, changes in DNMT3B, a DNA methyltransferase enzyme, lead to abnormal DNA methylation patterns. This especially affects centromeric regions and disrupts normal immune cell development.PMC+1

3. Mutations in the ZBTB24 gene (ICF2)
   Some patients have harmful changes in ZBTB24, a transcription factor that helps control many genes. This causes a similar immune deficiency and chromosome instability as DNMT3B defects.Primary Immune+1

4. Mutations in the CDCA7 gene (ICF3)
   Faults in CDCA7 can weaken the process of DNA repair called non-homologous end joining and disturb centromeric chromatin. This helps explain why chromosomes 1, 9 and 16 become unstable.NCBI+1

5. Mutations in the HELLS gene (ICF4)
   Changes in HELLS, a chromatin-remodeling ATPase, also disturb DNA methylation around centromeres. This leads to the same multi-branched chromosome pattern and immune defects.Nature+1

6. Abnormal DNA methylation of heterochromatin
   In ICF syndrome, sections of DNA that are usually heavily methylated near centromeres become hypomethylated. This makes the chromatin open and fragile, causing breaks and rearrangements especially on chromosomes 1, 9 and 16.PMC+1

7. Centromeric chromatin instability
   Because of wrong DNA methylation and chromatin changes, the centromere region cannot keep its normal tight structure. During cell division this area can form multibranched or stretched chromosomes, which is the hallmark of ICF.MalaCards

8. Impaired B-cell maturation
   ICF patients usually have naïve B cells but very few memory B cells or plasma cells. This means B cells cannot mature fully and cannot keep long-term antibody responses, causing repeated infections.Frontiers+1

9. Defective class-switch recombination
   The genetic changes interfere with the ability of B cells to switch from making IgM to IgG, IgA, or IgE. This helps explain the low IgG and IgA levels seen in many patients.Frontiers+1

10. Low serum immunoglobulin levels (hypogammaglobulinemia)
    Many patients have very low levels of IgG and sometimes IgM and IgA. This is a direct result of the gene defects and B-cell problems and is a major cause of their recurrent infections.Wikipedia+1

11. Variable combined immunodeficiency
    Some patients also have T-cell dysfunction in addition to B-cell problems. This “combined” immunodeficiency increases the risk and severity of viral, fungal and parasitic infections.PubMed+1

12. Genetic background and consanguinity
    ICF is more often reported in families where parents are related (for example, cousins), because this raises the chance that both carry the same rare gene mutation.Nature+1

13. Founder mutations in some populations
    In certain regions, the same DNMT3B or ZBTB24 mutation appears in several unrelated families, suggesting a founder effect that increases disease risk in that population.Nature+1

14. Genome-wide gene expression changes
    Because DNA methylation is disturbed, hundreds of genes in immune cells may be abnormally turned on or off. This global gene dysregulation contributes to immune dysfunction and other body problems.Nature+1

15. Impaired DNA repair pathways
    Studies show that mutations in CDCA7 and HELLS disturb DNA repair processes. This adds to chromosome breaks and instability during cell division.NCBI+1

16. Developmental effects on the face and brain
    The same genetic and epigenetic problems affect cells that form the face and nervous system. This explains the facial anomalies and possible developmental delay in many patients.Nature+1

17. Growth hormone and metabolic disturbances
    Chronic infection, poor nutrition due to illness, and global gene regulation problems can all reduce growth, leading to short stature and failure to thrive.Primary Immune+1

18. Chronic infection load
    Repeated chest and gut infections further weaken the body, damage lungs and liver, and create a vicious circle where poor immunity and chronic disease keep feeding each other.Frontiers+1

19. Possible autoimmune complications
    Some reports suggest that abnormal immune regulation can also give autoimmune problems in a few patients, where the immune system mistakenly attacks the body’s own cells.Bentham Direct+1

20. Delay in diagnosis and treatment
    Because ICF is very rare and symptoms can be variable, many children are diagnosed late. Without early immunoglobulin replacement or stem cell transplantation, ongoing infections and organ damage worsen their condition and outcomes.Bentham Direct+1

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Symptoms

1. Recurrent respiratory infections
   The most common problem is frequent chest and airway infections, such as repeated pneumonia, bronchitis and sinus infections. These happen because the body cannot make strong antibodies against respiratory germs.Primary Immune+1

2. Recurrent ear infections
   Many children have repeated otitis media (middle ear infections), ear discharge and hearing problems. The ear is an easy target when germ protection is weak.immunodeficiency+1

3. Gastrointestinal infections and diarrhea
   Some patients suffer from chronic or repeated diarrhea and gut infections. The weakened immune system cannot clear viruses, bacteria or parasites in the intestines as it should.Frontiers+1

4. Prolonged or severe infections
   Infections can last longer than usual and may be more serious, sometimes needing hospital care and strong antibiotics or antivirals.Frontiers+1

5. Failure to thrive
   Many infants and young children with ICF do not gain weight or grow as expected. Frequent illness, poor appetite and increased energy use during infections all play a role.Primary Immune+1

6. Growth retardation (short stature)
   Over time, children may stay shorter and smaller than their peers because of both chronic disease and underlying genetic effects.Primary Immune+1

7. Characteristic facial features
   Doctors often notice small but typical facial differences: widely spaced eyes (hypertelorism), flat nasal bridge, epicanthal folds, low-set ears, and sometimes a large tongue (macroglossia). These clues can point toward ICF.Primary Immune+1

8. Developmental delay or intellectual disability
   Some patients have slower motor or language development and may have learning difficulties. This is thought to arise from the genetic and epigenetic effects on brain development.Primary Immune+1

9. Psychomotor retardation
   In more severe cases, both thinking and movement can be slow, and milestones such as walking or talking may be delayed.Primary Immune+1

10. Low serum immunoglobulin levels
    Blood tests show low IgG, and sometimes low IgA and IgM. This is not a symptom that the patient feels, but it is an important lab sign explaining their infections.Wikipedia+1

11. Lymph node and spleen enlargement in some patients
    Repeated infections and immune system activation can enlarge lymph nodes or the spleen, although findings vary between people.Bentham Direct+1

12. Anemia or low blood counts
    Some case reports describe anemia, neutropenia or other low blood counts, possibly from chronic infection or bone marrow involvement.IJPediatrics+1

13. Chronic cough and lung damage
    Long-term, repeated chest infections can lead to chronic cough and sometimes lung damage such as bronchiectasis if not well treated.PMC+1

14. Liver problems in some cases
    A few patients develop chronic liver disease, likely from repeated infections, immune problems or treatment-related effects.ResearchGate+1

15. High risk of serious infection-related death
    Without proper management, many patients may die young from severe infections. This is why early diagnosis and treatment are so important.PLOS+1

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Diagnostic Tests

Physical examination (bedside checks)

1. General physical examination
   The doctor looks at the whole child: weight, height, body proportions, vital signs, breathing pattern and signs of acute or chronic illness. This gives the first clue that there may be a primary immune deficiency and growth problem.Primary Immune+1

2. Facial feature assessment
   The clinician checks for hypertelorism (wide-set eyes), flat nasal bridge, epicanthal folds, low-set ears and large tongue. Finding this pattern together with infections suggests ICF syndrome.Primary Immune+1

3. Examination of lymph nodes, liver and spleen
   The doctor feels the neck, armpit and groin nodes, and the abdomen, to look for enlarged lymph nodes, liver or spleen, which may appear because of repeated infections or immune activation.Bentham Direct+1

4. Skin and mucous membrane examination
   Skin, mouth and throat are checked for recurrent infections, ulcers, thrush, or poor wound healing, which are common in people with immune deficiency.Frontiers+1

Manual / clinical bedside tests

5. Growth chart plotting
   Height and weight are plotted over time on standardized growth charts. A pattern showing the child falling away from normal curves helps document failure to thrive and chronic illness.Orpha+1

6. Developmental milestone assessment
   Doctors or psychologists ask about and test things like sitting, walking, speaking and learning skills. Delays support the suspicion of a syndromic condition such as ICF.Primary Immune+1

7. Detailed infection history checklist
   A structured history of how often infections happen, how long they last, and what treatments are needed helps show that the pattern fits a primary immunodeficiency rather than normal childhood infections.Primary Immune+1

8. Family pedigree analysis
   Building a family tree with information on consanguinity and affected relatives helps confirm autosomal recessive inheritance and guides genetic testing.Nature+1

Laboratory and pathological tests

9. Complete blood count (CBC) with differential
   A CBC checks red cells, white cells and platelets. In ICF syndrome, results may show anemia, neutropenia or lymphocyte changes, and help rule out other causes of recurrent infections.IJPediatrics+1

10. Serum immunoglobulin levels (IgG, IgA, IgM)
    This is a core test. Most ICF patients have low IgG and sometimes low IgA and IgM. These findings support the diagnosis of a humoral immunodeficiency.Wikipedia+1

11. Vaccine antibody titers
    Blood levels of antibodies after routine vaccines (such as tetanus or pneumococcal) are measured. Poor responses show that the immune system cannot create or maintain protective antibodies.Bentham Direct+1

12. Lymphocyte subset immunophenotyping
    Flow cytometry counts T cells, B cells and NK cells. In ICF, B-cell numbers may be present but memory B cells are very low, and sometimes T-cell abnormalities are seen, showing combined immunodeficiency.Frontiers+1

13. Lymphocyte proliferation tests
    Special lab tests use mitogens or antigens to see how well lymphocytes (especially T cells) divide in response to stimulation. Reduced proliferation suggests broader immune dysfunction.JACI in Practice+1

14. Cytogenetic karyotyping with PHA stimulation
    Lymphocytes are grown with phytohaemagglutinin (PHA) and chromosomes are examined at metaphase. In ICF, chromosomes 1, 9 and 16 often show multibranched or stretched centromeric regions, which is a classic diagnostic sign.MalaCards

15. DNA methylation studies
    Tests that measure methylation levels in satellite repeats and other pericentromeric DNA show characteristic hypomethylation in ICF patients. This supports the diagnosis and reflects the underlying defect in methylation.PMC+1

16. Targeted or panel genetic testing for ICF genes
    Sequencing of DNMT3B, ZBTB24, CDCA7, and HELLS can confirm which genetic type (ICF1–4) the patient has. This is now the gold standard to make a precise diagnosis and help with family counseling.Nature+1

17. Bone marrow examination (when needed)
    A bone marrow aspirate or biopsy may be done to rule out other causes of immunodeficiency or cytopenias and to study how blood cells are developing. Some reports describe variable marrow findings in ICF.Bentham Direct+1

Electrodiagnostic tests

18. Electroencephalogram (EEG)
    If a patient has seizures or marked developmental delay, an EEG may be used to check the brain’s electrical activity. It does not diagnose ICF directly but helps evaluate neurological involvement and manage symptoms.PMC+1

19. Electrocardiogram (ECG)
    An ECG is sometimes done to monitor heart rhythm and function in seriously ill patients or before major treatments like stem cell transplantation. Again, it is supportive, not specific for ICF.PMC+1

Imaging tests

20. Chest imaging (X-ray or CT scan)
    Chest X-rays, and sometimes CT scans, are very important to look for pneumonia, bronchiectasis or other lung damage in patients with repeated chest infections. Imaging helps judge how badly the lungs have been affected and guides treatment.PMC+1

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Non-pharmacological treatments

Non-drug treatments for this immune deficiency focus on infection prevention, good nutrition, development support, and family education. They do not replace medicines like immunoglobulin or antibiotics, but they make them work better and may reduce complications. Many of these measures come from general guidelines for primary immunodeficiency care and from case series of ICF patients. IJPediatrics+3Orpha+3PMC+3

1. Infection control education
Families are taught clear, simple infection-control habits: frequent handwashing, using alcohol hand rub, covering coughs, and avoiding close contact with people who are sick. The purpose is to reduce the number of viruses and bacteria that reach the child. The mechanism is simple: fewer germs on hands and surfaces means fewer infections entering the nose, mouth, or lungs, which is vital for children whose immune system cannot clear infections well. Primary Immune+1

2. Avoiding high-risk environments
Parents are often advised to limit time in very crowded, poorly ventilated spaces, especially during peak infection seasons. The purpose is to lower exposure to respiratory viruses and bacteria. The mechanism is behavioral: by changing daily routines (for example, shorter visits to busy markets or avoiding contact with people who have obvious infections), the total “germ load” the child meets is reduced, lowering the chance of pneumonia or severe bronchiolitis. Primary Immune+1

3. Vaccination planning for household contacts
The patient’s family members and close contacts are encouraged to stay up to date on inactivated vaccines such as influenza and COVID-19 vaccines when recommended locally. The purpose is called “cocooning”: protecting the vulnerable person by making those around them less likely to bring infections home. The mechanism is population level: when contacts have strong immunity, they shed fewer viruses, so the child with ICF is less exposed. Live vaccines must follow specialist advice. Primary Immune+1

4. Nutrition counseling and growth monitoring
Dietitians help design a high-calorie, high-protein diet with enough vitamins and minerals to support growth and immune function, because many ICF patients have failure to thrive. The purpose is to prevent malnutrition, which further weakens immunity. Mechanistically, good nutrition supports immune cell production in bone marrow, antibody synthesis, and healing of tissues after infection or surgery. Orpha+1

5. Respiratory physiotherapy
When infections damage the lungs, chest physiotherapy (such as breathing exercises and postural drainage) helps clear mucus, improves ventilation, and reduces risk of bronchiectasis. The purpose is to protect long-term lung function. The mechanism is mechanical: tapping, controlled breathing, and position changes move mucus from small airways to larger airways where it can be coughed out, lowering bacterial load and inflammation. PMC+1

6. Regular dental and oral hygiene care
Frequent dental checks and careful brushing with supervision help prevent tooth decay, gum infections, and mouth ulcers, which can be severe in immunodeficiency. The purpose is to remove bacterial “biofilm” from teeth and gums. The mechanism is local: a clean mouth has fewer bacteria that can enter the bloodstream or spread to the lungs in children who already have low antibody levels. Primary Immune+1

7. Skin care and wound protection
Gentle daily skin care, prompt cleaning of cuts, and early treatment of rashes help prevent skin infections. The purpose is to keep the skin barrier strong, because it is one of the first defenses against germs. Mechanistically, moisturizing and protecting the skin maintain the outer layer, while quick cleaning of injuries prevents bacteria from growing and invading deeper tissues. Primary Immune+1

8. Developmental and educational support
Because some children with ICF have developmental delay or learning difficulties, early access to speech therapy, physiotherapy, occupational therapy, and special education plans is important. The purpose is to maximize cognitive and physical potential. The mechanism is brain plasticity: regular, tailored exercises and teaching help build new neural pathways, improve communication skills, and support independence. Orpha+1

9. Psychological counseling for child and family
Living with a chronic, rare immune deficiency is stressful. Counseling or support groups can reduce anxiety, depression, and caregiver burnout. The purpose is emotional resilience and healthy coping. Mechanistically, therapy offers a safe place to express worries, learn stress-management skills, and build realistic hope, which indirectly supports treatment adherence and quality of life. Orpha+1

10. Genetic counseling
Because ICF is autosomal recessive, families may want information about risk in future pregnancies and other relatives. Genetic counselors explain inheritance patterns, carrier testing, and prenatal or preimplantation options where available. The purpose is informed choices. The mechanism is educational: clear risk estimates and explanation of testing steps allow parents to plan early detection and prepare medical care sooner for any affected children. Nature+1

11. Structured fever and infection action plan
Families receive a written plan stating when to measure temperature, when to start oral antibiotics (if prescribed), and when to go straight to hospital. The purpose is to avoid dangerous delays. The mechanism is simple: clear instructions transform uncertainty into quick, decisive action, so serious infections are treated early and sepsis risk is reduced. PMC+1

12. Regular follow-up in an immunology center
Routine clinic visits allow doctors to track infections, adjust immunoglobulin dosing, and screen for complications such as chronic lung or liver disease. The purpose is proactive rather than reactive care. Mechanistically, repeated assessments and lab tests catch slow changes in organ function and immune markers so treatment can be adjusted before a crisis occurs. PMC+1

13. Home monitoring tools
Some families are taught to use home pulse oximeters, peak flow meters, or weight charts. The purpose is early detection of respiratory worsening or poor growth. Mechanistically, numbers like oxygen saturation or weight curves show trends that may not be obvious day to day, prompting earlier medical review and preventing severe deterioration. PMC+1

14. Infection-safe schooling strategies
Plans may include part-time school attendance, distance learning during high-risk seasons, or seating the child away from classmates with coughs. The purpose is to balance social development with safety. The mechanism is environmental control: changing where and how the child learns changes the pattern of contact with infection sources, lowering serious infection risk without total isolation. Primary Immune+1

15. Hospital infection-control precautions
When admitted, children with ICF may need protective isolation, strict hand hygiene, and screening for hospital-acquired germs. The purpose is to avoid picking up dangerous infections in hospital. Mechanistically, barrier precautions (gowns, masks, limited visitors) reduce pathogen transmission in a setting where many people are sick and antibiotic-resistant bacteria are common. CDC+1

16. Physiotherapy and exercise for muscle strength
Gentle, regular physical activity tailored to the child’s energy level helps maintain muscle strength, bone health, and lung function. The purpose is to keep the body as fit as possible to handle infections and treatment. Mechanistically, muscle activity improves blood flow, supports bone density, and enhances breathing mechanics, all of which indirectly support immune health. PMC+1

17. Social work and financial support
Because this disease often requires frequent hospital visits and expensive treatments, social workers can assist with transport, insurance, or disability benefits. The purpose is to reduce financial stress that could limit access to care. The mechanism is practical: when families get help with costs and logistics, they are more able to keep appointments and follow treatment plans. Orpha+1

18. Telemedicine follow-up
Video or phone visits with immunologists can be useful between in-person appointments, especially for families living far from specialist centers. The purpose is ongoing expert support with fewer travel burdens. Mechanistically, telemedicine allows real-time review of symptoms, lab results, and treatment side effects, so small problems can be managed early at home or flagged for in-person review. Primary Immune+1

19. Comprehensive vaccination review (under specialist guidance)
Even though the patient’s own antibody response may be poor, specialists review which inactivated vaccines are still beneficial and which live vaccines should be avoided. The purpose is to get as much safe protection as possible. The mechanism is immune priming in areas where response still exists, plus population-level protection when many people around the child are vaccinated. Primary Immune+1

20. Emergency card or medical alert information
Families may carry an emergency card listing the diagnosis, usual treatments (such as immunoglobulin), and emergency contact details for the immunology team. The purpose is fast, correct care in unfamiliar hospitals. Mechanistically, the card speeds communication, so doctors immediately know the child has severe immunodeficiency and needs urgent antibiotics and careful infection control. PMC+1

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Drug treatments

For “immune deficiency, variable, with centromeric instability of chromosomes 1, 9, and 16,” there is no single FDA-approved drug that cures ICF syndrome itself. Treatment focuses on replacing missing antibodies, preventing infections, and using allogeneic hematopoietic stem cell transplantation (HSCT) in selected patients. Many drugs come from standard primary immunodeficiency care and HSCT protocols, and their detailed prescribing information is available in FDA labels on accessdata.fda.gov. IJPediatrics+4PMC+4FDA Access Data+4

Important safety note: All drug choices, doses, and schedules must be decided by a specialist doctor. The information below is educational only, not a guide for self-treatment.

1. Intravenous immunoglobulin (IVIG)
IVIG (for example “Immune Globulin Intravenous (Human)” products) is the core treatment for many ICF patients with panhypogammaglobulinemia. It is given by vein every 3–4 weeks to replace missing antibodies and reduce infections. The dose is usually calculated in grams per kilogram of body weight, adjusted by the immunologist according to infection rate and IgG levels. Mechanistically, pooled IgG from healthy donors supplies ready-made antibodies against many common bacteria and viruses, giving passive immunity. FDA Access Data+2PMC+2

2. Subcutaneous immunoglobulin (SCIG)
SCIG products like Hizentra or Xembify are similar to IVIG but infused under the skin more often in smaller volumes, sometimes at home. The purpose is steady IgG levels with fewer hospital visits. The mechanism is slow absorption of IgG into the bloodstream, providing continuous antibody coverage. FDA labeling describes their use in primary immunodeficiency; in ICF syndrome, they serve the same role as IVIG when suitable. FDA Access Data+2FDA Access Data+2

3. Prophylactic trimethoprim-sulfamethoxazole (TMP-SMX)
Low-dose TMP-SMX may be prescribed to prevent infections like Pneumocystis jirovecii pneumonia or recurrent bacterial infections, especially in very immunocompromised patients or around HSCT. Doses are based on weight and kidney function. The mechanism is inhibition of folate synthesis in bacteria, stopping them from multiplying. This reduces life-threatening chest infections in people whose immune systems cannot fight them. Frontiers+2PMC+2

4. Broad-spectrum oral antibiotics (for example amoxicillin-clavulanate)
Doctors often prescribe early, broad-spectrum antibiotics at the first sign of bacterial infection such as ear pain, sinus pain, or productive cough. The purpose is rapid infection control before bacteria spread to blood or lungs. The mechanism depends on the drug class (for example, beta-lactams block bacterial cell wall synthesis), leading to bacterial death. Treatment length is usually longer than in healthy children because the immune system needs more support. PMC+2Frontiers+2

5. Intravenous antibiotics for severe infections
When infection is serious (for example, sepsis or pneumonia with low oxygen), intravenous antibiotics like third-generation cephalosporins or carbapenems are used. The purpose is to deliver high drug levels directly into the blood. Mechanistically, IV administration ensures rapid distribution to tissues and higher, more reliable blood levels, which is vital when the patient’s own immune response is weak. PMC+2Frontiers+2

6. Antiviral therapy (e.g., acyclovir, ganciclovir)
ICF patients may have severe or chronic viral infections, including herpes viruses and EBV-related disease. Antivirals such as acyclovir (for herpes simplex) or ganciclovir (for CMV) may be used. They work by interfering with viral DNA replication, slowing or stopping viral multiplication. The purpose is to reduce viral load, shorten illness, and prevent organ damage, especially before or after HSCT. JACI in Practice+2PMC+2

7. Antifungal drugs (e.g., fluconazole, voriconazole)
Because immune-deficient patients can develop serious fungal infections, azole antifungals such as fluconazole or voriconazole may be given preventively or as treatment. The mechanism is inhibition of fungal ergosterol synthesis, weakening the fungal cell membrane. The purpose is to protect lungs, blood, and other organs from invasive fungal disease that the damaged immune system cannot control. Frontiers+2Frontiers+2

8. HSCT conditioning chemotherapy (e.g., busulfan, cyclophosphamide, fludarabine)
For patients selected for hematopoietic stem cell transplantation, combinations of chemotherapy such as busulfan, cyclophosphamide, and fludarabine are used to “empty” the bone marrow and suppress the immune system before donor stem cells are infused. The purpose is to make space and prevent rejection of the graft. Mechanistically, these drugs kill dividing cells, including the patient’s own bone marrow cells, so donor stem cells can engraft and rebuild the immune system. Frontiers+3PMC+3PMC+3

9. Immunosuppressants for graft-versus-host disease (GVHD) prevention
After HSCT, drugs like cyclosporine, tacrolimus, and methotrexate are used to prevent donor immune cells from attacking the patient’s tissues (GVHD). The purpose is to protect skin, liver, and gut from inflammation. The mechanism is suppression of T-cell activation and proliferation, balancing control of GVHD with the need for some graft-versus-infection effect. PMC+2Springer Link+2

10. Broad antiviral prophylaxis post-transplant (e.g., acyclovir)
During the early period after HSCT, prophylactic antivirals may be continued to prevent reactivation of herpes viruses while the new immune system is still weak. The purpose is to lower the risk of life-threatening viral disease. Mechanistically, a constant small dose of antiviral blocks early steps in viral replication, keeping virus copies low until immune reconstitution improves. PMC+1

11. Broad antifungal prophylaxis post-transplant
Similarly, antifungals such as fluconazole or posaconazole may be given to prevent invasive fungal infections after HSCT. The purpose is infection prevention during profound neutropenia. The mechanism is inhibition of fungal growth while the donor immune system is just starting to recover and cannot yet respond vigorously. PMC+1

12. Broad antibacterial prophylaxis post-transplant
Some centers also use prophylactic oral antibiotics after HSCT. The purpose is to reduce bacterial infections when neutrophils and barriers (like gut and skin) are damaged by chemotherapy. Mechanistically, continuous low-dose antibiotics reduce colonization and early invasion by susceptible bacteria, complementing IVIG and strict hygiene. PMC+2CDC+2

13. Granulocyte colony-stimulating factor (G-CSF, e.g., filgrastim)
If a patient with ICF and HSCT has profound neutropenia, G-CSF may be used to stimulate the bone marrow to produce neutrophils faster. The purpose is to shorten the duration of very low white-cell counts. Mechanistically, G-CSF binds to receptors on myeloid precursors, driving their proliferation and maturation into neutrophils, which helps fight bacterial and fungal infections. PMC+1

14. Immunoglobulin prophylaxis post-transplant
Even after a successful HSCT, some patients receive IVIG to support immunity until their own B cells and antibody production recover. The purpose is to bridge the gap in humoral immunity. Mechanistically, donor stem cells take time to mature into functioning B cells; pooled IgG provides passive antibodies during this window. PMC+2CDC+2

15. Antipyretics and analgesics (e.g., paracetamol)
Simple drugs like paracetamol help control fever and pain in infections or after procedures. The purpose is symptom relief and comfort; they do not treat the immune defect itself. The mechanism is inhibition of prostaglandin production in the brain’s temperature center, lowering fever and easing pain. Doctors balance their use with the need to monitor for serious infection. CDC+1

16. Anti-diarrheal and gut-protective medications (with caution)
Some ICF patients have chronic diarrhea or gut infections. Doctors may use oral rehydration solutions, zinc, and sometimes anti-diarrheal medicines along with targeted antibiotics. The purpose is to prevent dehydration and malnutrition. The mechanism differs by drug, but often includes slowing gut movement or improving absorption. Because diarrhea can signal serious infection, these medications are used only under close medical supervision. Orpha+2OUP Academic+2

17. Inhaled bronchodilators and corticosteroids (for chronic lung disease)
If repeated infections cause asthma-like symptoms or obstructive lung disease, inhaled bronchodilators and low-dose inhaled steroids may be used. The purpose is to open airways and reduce inflammation. Mechanistically, bronchodilators relax smooth muscle in airways, and steroids dampen local inflammation, improving breathing and exercise tolerance. They do not fix the immune deficiency but help manage complications. PMC+1

18. Immunosuppressants for autoimmune complications
Some primary immunodeficiencies show autoimmune problems (e.g., autoimmune cytopenias), and similar issues might appear in ICF. In such cases, short courses of corticosteroids or other immunosuppressants may be used. The purpose is to calm the immune system when it mistakenly attacks the patient’s own cells. The mechanism is broad suppression of immune cell activity, which must be carefully balanced against infection risk. PMC+1

19. Anticancer chemotherapy for malignancies
ICF has been linked to EBV-driven lymphomas and other malignancies in some patients. Standard chemotherapy protocols and sometimes rituximab are used when cancers appear. The purpose is to kill malignant cells and achieve remission. Mechanistically, cytotoxic drugs damage rapidly dividing cancer cells, while monoclonal antibodies like rituximab target CD20 on B cells to deplete them. JACI in Practice+2OUP Academic+2

20. Clinical-trial or off-label therapies
Because ICF is ultra-rare, some treatments may be offered only in research settings, such as tailored HSCT conditioning or future gene-therapy approaches based on evolving understanding of DNMT3B, ZBTB24, CDCA7, and HELLS pathways. The purpose is to test whether correcting underlying mechanisms improves survival and quality of life. Mechanistically, these strategies aim to repair or replace defective immune and hematopoietic cells at the genetic or stem-cell level. eLife+4PMC+4Nature+4

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Dietary molecular supplements

There is no supplement proven to cure ICF syndrome, but some nutrients support general immune function and may help prevent deficiency states. Any supplement plan must be checked by the treating doctor, especially around HSCT or other major therapy. Orpha+1

1. Vitamin D – Supports innate and adaptive immunity and bone health; low vitamin D is common in chronically ill children. Supplements are usually given in daily or weekly doses within safe limits. Mechanism: vitamin D receptors on immune cells help regulate inflammatory responses and antimicrobial peptide production. Primary Immune+1

2. Vitamin C – Acts as an antioxidant and supports white blood cell function, especially neutrophils and lymphocytes. Typical doses are within recommended daily allowances; very high self-medication is not advised. Mechanism: vitamin C helps immune cells generate reactive oxygen species to kill microbes and protects tissues from oxidative stress during infections. CDC+1

3. Zinc – Essential for lymphocyte development and normal antibody responses. Supplementation at appropriate doses can correct deficiency, but too much zinc can disturb copper balance. Mechanism: zinc acts as a cofactor for many enzymes involved in DNA replication and immune cell signaling. Primary Immune+1

4. Selenium – Important for antioxidant enzymes such as glutathione peroxidase. Adequate selenium supports antiviral defenses but excess can be toxic. Mechanism: selenium-dependent enzymes reduce oxidative damage in immune cells and tissues under infection stress. CDC+1

5. Folate (vitamin B9) – Needed for DNA synthesis and cell division. Folate deficiency can worsen problems in tissues where cells divide quickly, such as bone marrow. Mechanistically, folate supports synthesis of nucleotides used to build DNA in developing immune cells. ScienceDirect+1

6. Vitamin B12 – Works with folate in DNA synthesis and helps keep nerves healthy. Inadequate B12 can cause anemia and further weaken immunity. Mechanism: B12 is required for folate recycling and methylation reactions, processes already disturbed in ICF due to DNMT3B and related gene defects. PMC+2Nature+2

7. Iron (if deficient) – Iron supplements may be needed if blood tests show iron-deficiency anemia from chronic illness or poor intake. Mechanistically, iron is vital for hemoglobin and many enzymes, but excess iron can feed infections, so dosing must be careful and guided by lab results. IJPediatrics+1

8. Omega-3 fatty acids – Found in fish oil or algae-based supplements, omega-3s can help modulate inflammation and may support heart and brain health. Mechanism: omega-3 fatty acids are incorporated into cell membranes and converted into less inflammatory lipid mediators, which may gently balance over- or under-active immune responses. CDC+1

9. Probiotics (selected strains) – Certain probiotic bacteria may help gut barrier function and local immune responses, but they must be chosen carefully in severe immunodeficiency because of rare infection risk. Mechanistically, probiotics interact with gut immune cells and compete with harmful bacteria. CDC+1

10. Protein and amino acid supplements (e.g., whey, glutamine) – When oral intake is low, extra protein can help maintain muscle and immune cell production. Mechanism: amino acids are building blocks for antibodies, cytokines, and structural proteins in immune cells and tissues. Orpha+2Primary Immune+2

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

These options relate mainly to bone marrow support and stem-cell–based strategies. For ICF syndrome they are usually used only in hospital settings or research.

1. Filgrastim (G-CSF) – Used to boost neutrophil counts in severe neutropenia, especially around HSCT. Dose is weight based and adjusted according to blood counts. Mechanism: G-CSF binds to receptors on myeloid precursors in the bone marrow, speeding their maturation into neutrophils and improving resistance to bacterial and fungal infections. PMC+1

2. Plerixafor (stem-cell mobilizer) – In some transplant settings, plerixafor is used to move stem cells from bone marrow into the blood before collection from donors. Mechanism: it blocks CXCR4–SDF-1 interactions, loosening stem cells so they circulate and can be harvested. This indirectly helps ICF patients by improving donor stem-cell yields for HSCT. PMC+1

3. Erythropoiesis-stimulating agents (e.g., erythropoietin) in selected cases – If anemia and low red cell production occur after HSCT or during chronic illness, erythropoietin may be used. Mechanism: it stimulates red blood cell precursors in the marrow, improving oxygen delivery to tissues. This is supportive, not disease-specific. PMC+1

4. Thrombopoietin receptor agonists (e.g., eltrombopag) – In broader bone marrow failure and thrombocytopenia, eltrombopag stimulates platelet production. While not specific for ICF, similar ideas may be considered in complex cases. Mechanistically, it activates TPO receptors on megakaryocyte precursors, increasing platelet counts and reducing bleeding. FDA Access Data+1

5. Mesenchymal stromal cell infusions (experimental) – In some HSCT programs, mesenchymal stromal cells are used experimentally to treat severe GVHD or support engraftment. Mechanism: they may modulate immune responses and secrete growth factors that help tissue repair. Their role in ICF is not yet defined and remains research-based. PMC+2Secondary Immunodeficiency+2

6. Future gene-therapy or genome-editing approaches – Research into DNMT3B, ZBTB24, CDCA7, and HELLS suggests that correcting these genes in hematopoietic stem cells could one day treat ICF at its source. Mechanism: viral vectors or gene-editing tools (like CRISPR-based systems) would introduce a working gene copy into stem cells, which could then rebuild a healthier immune system after re-infusion. At present, this remains experimental and not a standard clinical option. Science+3PMC+3Nature+3

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Surgeries and invasive procedures

Surgery in ICF syndrome is usually reserved for supporting treatments or treating complications, not for the immune defect itself.

1. Hematopoietic stem cell transplantation (HSCT) – Technically a medical procedure rather than a classic “operation,” HSCT is the only treatment that can potentially correct the underlying immune defect by replacing the bone marrow with stem cells from a healthy donor. It involves central line placement, stem-cell infusion, and a long hospital stay. It is done to rebuild the immune system and reduce life-threatening infections. Frontiers+3PMC+3PMC+3

2. Central venous catheter insertion – Many ICF patients need frequent IVIG infusions, antibiotics, or chemotherapy. A central line or port may be surgically placed into a large vein. It is done to provide reliable long-term access for blood draws and infusions, reducing repeated needle sticks and allowing safe delivery of IV treatments. PMC+1

3. Ear, nose, and sinus surgery (e.g., adenoidectomy, sinus drainage) – Chronic ear infections or sinusitis that do not respond to medicine may need surgical drainage or removal of adenoids. The aim is to clear trapped infected fluid and improve airflow and drainage pathways, lowering the frequency of further infections. PMC+1

4. Lung surgery in severe bronchiectasis (rare) – In very advanced localized bronchiectasis, surgeons may remove the most damaged lung segments. This is done only in selected cases when repeated infections come from one badly scarred area. The mechanism is anatomical: removing the chronically infected segment may reduce bacterial reservoirs and improve overall lung function. PMC+1

5. Gastrostomy tube placement – If swallowing is difficult or nutrition is very poor, a feeding tube may be surgically placed into the stomach. It is done to secure long-term nutritional support, ensure enough calories and protein, and simplify giving medicines and feeds. Adequate nutrition then helps the immune system and supports growth. Orpha+2OUP Academic+2

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Prevention strategies

1. Early diagnosis and referral to an immunology specialist center. Orpha+1

2. Regular immunoglobulin replacement to prevent bacterial and viral infections. PMC+1

3. Consistent infection-control habits at home and school (hand hygiene, cough etiquette). Primary Immune+1

4. Timely vaccines for family members and inactivated vaccines for the patient when advised. Primary Immune+1

5. Prompt treatment of even “small” infections to prevent serious complications. PMC+1

6. Regular monitoring for lung, liver, gut, and growth problems, with early interventions. Orpha+2PMC+2

7. Careful planning and timing of HSCT in suitable patients before irreversible organ damage develops. PMC+2Springer Link+2

8. Avoidance of unnecessary live vaccines and strong immunosuppressive drugs unless clearly needed. Primary Immune+1

9. Education of teachers, relatives, and caregivers about the condition and emergency steps. Primary Immune+1

10. Participation in registries and follow-up studies to improve global understanding and care standards. Springer Link+1

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When to see a doctor

Someone with immune deficiency and centromeric instability should see a doctor regularly for routine follow-up, but certain warning signs need urgent care:

• Fever that is high or lasts more than a day, especially with chills or breathing problems. PMC+1

• Fast breathing, chest pain, wheezing, or blue lips, which may signal serious lung infection. PMC+1

• Repeated vomiting or diarrhea causing poor drinking, less urine, or lethargy. OUP Academic+1

• Unusual bruising, nosebleeds, or tiny red spots (petechiae) that could suggest blood problems. Orpha+1

• Severe headache, confusion, seizures, or changes in behavior. OUP Academic+1

• Any sudden worsening soon after HSCT, such as severe rash, jaundice, or bloody diarrhea, which may signal GVHD or serious infection. PMC+2Springer Link+2

If any of these occur, the safest option is to contact the immunology team or go to the nearest emergency department immediately.

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Diet: what to eat and what to avoid

Helpful foods to include

1. High-protein foods like eggs, fish, poultry, beans, and lentils to support immune cell and antibody production. Orpha+1

2. Colorful fruits and vegetables for vitamins, minerals, and antioxidants that help immune cells work better. Primary Immune+1

3. Whole grains (brown rice, oats, whole-wheat bread) for sustained energy and gut health. CDC+1

4. Healthy fats from nuts, seeds, and olive or canola oil to support cell membranes and hormone balance. CDC+1

5. Safe dairy or fortified alternatives for calcium, protein, and, when fortified, vitamin D, important for bone and immune health. CDC+1

Foods and habits to avoid or limit

6. Raw or undercooked animal products such as raw eggs, sushi, undercooked meat, and unpasteurized milk, which can carry dangerous germs. CDC+1

7. Unwashed raw fruits and vegetables; they should be washed well, and in very immunocompromised periods some centers suggest peeling or cooking. CDC+1

8. Buffet or street foods kept warm for a long time, as bacteria can multiply quickly in these dishes. CDC+1

9. Sugary drinks and ultra-processed snacks that add calories but few nutrients, which can worsen fatigue and weight issues. CDC+1

10. Smoking and second-hand smoke exposure, which damages lungs and weakens local defenses, especially dangerous in immunodeficient patients. PMC+2Frontiers+2

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Frequently asked questions

1. Is immune deficiency with centromeric instability of chromosomes 1, 9, and 16 the same as ICF syndrome?
Yes. This long description refers to ICF syndrome, which stands for Immunodeficiency–Centromeric instability–Facial anomalies. The unstable chromosomes 1, 9, and 16 and the immune deficiency are key features that define the condition. PMC+2Orpha+2

2. What causes this disease?
ICF syndrome is caused by inherited changes in genes like DNMT3B, ZBTB24, CDCA7, or HELLS, which control DNA methylation and chromatin structure. When these genes do not work, certain DNA regions near centromeres lose methylation, leading to chromosomal instability and problems making normal immune cells. Science+3PMC+3Nature+3

3. How is it inherited in a family?
Most cases follow an autosomal recessive pattern: both parents carry one faulty gene copy but are usually healthy. When two carriers have a child together, each pregnancy has a 25% chance that the child will have ICF, a 50% chance the child will be a carrier, and a 25% chance of having no faulty copy. Nature+1

4. What are the main symptoms?
The main problems are recurrent chest infections, ear infections, sinusitis, and gut infections, along with low levels of antibodies in the blood. Many children also have facial differences, poor growth, and sometimes developmental delays or learning difficulties. Serious complications can include chronic lung disease and, in some cases, malignancies. IJPediatrics+3Orpha+3OUP Academic+3

5. How is the diagnosis confirmed?
Doctors use blood tests showing low immunoglobulins, lymphocyte studies, and chromosome analysis showing centromeric instability of chromosomes 1, 9, and 16 in stimulated lymphocytes. Genetic testing then identifies mutations in one of the ICF-related genes, confirming the diagnosis. IJPediatrics+3PMC+3PMC+3

6. Is there a cure for this immune deficiency?
Supportive care with immunoglobulin and antibiotics greatly improves quality and length of life, but does not correct the genetic cause. Allogeneic HSCT is currently the only treatment that can rebuild a near-normal immune system and may be considered a potential “curative” option for the immunodeficiency component, although it has significant risks. Frontiers+3PMC+3PMC+3

7. Why are immunoglobulin infusions so important?
Because patients cannot make enough functional antibodies, immunoglobulin infusions provide ready-made antibodies from healthy donors. These infusions help prevent and control infections, reduce hospitalizations, and protect organs. For many ICF patients, this is a lifelong therapy, adjusted to infection patterns and IgG levels. FDA Access Data+2PMC+2

8. What is the role of HSCT in ICF syndrome?
HSCT replaces the patient’s bone marrow with stem cells from a healthy donor. Studies report that HSCT can correct the immune deficiency and reduce infections, although it does not always reverse developmental issues or all organ damage. It is a complex decision, weighing transplant risks against the severity of disease. ResearchGate+4PMC+4PMC+4

9. How serious is this condition?
ICF syndrome is serious because of repeated infections and the risk of organ damage or malignancy. In older reports, many patients died in childhood; more recent series show better survival thanks to early diagnosis, immunoglobulin replacement, and HSCT in selected cases. Prognosis still varies by individual and by access to expert care. eLife+4PMC+4Orpha+4

10. Can children with this condition go to school?
Yes, many can attend school with appropriate infection-control measures and flexible attendance plans. Collaboration between parents, healthcare teams, and teachers is essential to create a safe environment and support learning while minimizing exposure to infections, especially during high-risk seasons. Primary Immune+1

11. Are routine vaccines safe for these patients?
Inactivated (killed) vaccines are generally safer than live vaccines, but because antibody responses may be weak, benefit varies. Live vaccines (like some measles or polio vaccines, depending on country) may be risky and should only be given if immunologists judge them safe. Household contacts should be well vaccinated to form a protective “cocoon.” Primary Immune+1

12. Can this condition affect adulthood and fertility?
With improved treatments, more patients now survive into adulthood, but data are still limited because the disease is very rare. Some adults with ICF have been reported. Fertility effects are not fully defined and may depend on individual gene variants and treatment history, especially if HSCT and chemotherapy were used. PMC+2OUP Academic+2

13. What is the difference between this condition and “common variable immunodeficiency” (CVID)?
Both ICF and CVID show low antibodies and recurrent infections, but ICF has characteristic chromosomal instability at centromeres and is linked to specific epigenetic genes. CVID does not show these chromosomal changes, and the genetic causes are different. Also, facial anomalies and centromeric instability are hallmarks of ICF but not CVID. ScienceDirect+3PMC+3Orpha+3

14. What research is going on for this disease?
Current research focuses on understanding how DNMT3B, ZBTB24, CDCA7, and HELLS regulate DNA methylation and chromatin, and why their defects mainly harm immune cells. International cohorts of ICF patients are being studied to refine HSCT approaches and outcomes. Future directions may include targeted epigenetic therapies or gene-based treatments. Science+5PMC+5Nature+5

15. What is the most important thing families should remember?
The key message is that early diagnosis, regular specialist follow-up, and strict infection prevention can make a big difference. While ICF syndrome is complex and serious, modern care with immunoglobulin replacement, smart use of antibiotics and antivirals, non-pharmacological support, and, in some cases, HSCT can significantly improve quality of life and survival. Families are not alone: rare-disease and primary immunodeficiency networks can provide information, support, and connection with expert centers. IJPediatrics+4Orpha+4PMC+4

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: December 19, 2025.