Autoimmune Lymphoproliferative Syndrome Caused by Mutation in CASP8

Autoimmune lymphoproliferative syndrome caused by mutation in CASP8/Caspase-8 deficiency is a very rare, inherited problem of the immune system where a gene called CASP8 does not work properly. Caspase-8 is a key “on/off switch” for apoptosis (the safe, natural death of immune cells) in the FAS pathway. When this switch is weak or broken, old or autoreactive lymphocytes are not removed on time. As a result, people can develop chronic swollen lymph nodes (lymphadenopathy), an enlarged spleen (splenomegaly), autoimmune blood problems, and frequent infections. Doctors group these disorders under autoimmune lymphoproliferative syndromes (ALPS). Mutations in CASP8 produce an ALPS-like picture that often includes immunodeficiency (easy infections) and may also involve inflammatory bowel disease (IBD)-like colitis in infants or organ-infiltrating lymphocytes in adults. Treatment is tailored to symptoms and may include immune-modulating medicines; stem-cell transplant is a last resort. PMC+2PMC+2

Autoimmune lymphoproliferative syndrome (ALPS) happens when the immune system can’t switch off old lymphocytes properly; they accumulate and sometimes attack the body’s own blood cells. “Classic” ALPS is usually due to variants in FAS (TNFRSF6), FASLG, or CASP10—all core parts of the “Fas” cell-death pathway. Extremely rarely, mutations in CASP8 (caspase-8) cause a closely related disorder called caspase-8 deficiency state (CEDS). People with CEDS can look “ALPS-like” (big lymph nodes/spleen, higher “double-negative” T cells) but also have true immunodeficiency with frequent infections, because caspase-8 is needed not only for Fas-mediated apoptosis but also for full activation of T, B, and NK cells. In short: CASP8 disease is ALPS-like, not classic ALPS. NCBI+1

Why CASP8 matters biologically:
In healthy lymphocytes, Fas engagement builds a “death-inducing signaling complex” (Fas–FADD–caspase-8/-10) that triggers apoptosis and keeps the immune system in balance. CASP8 loss-of-function weakens Fas apoptosis and also blunts NF-κB signaling after T-cell/B-cell receptor and some Toll-like receptor signals, explaining the combined picture of lymphoproliferation + infections. PMC

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Other names

• Caspase-8 deficiency state (CEDS) or caspase-8 deficiency (CED). Wikipedia

• ALPS—recurrent viral infections due to caspase-8 deficiency (Orphanet label). Orpha

• Historically, some authors placed CASP8 within ALPS IIb in FAS-pathway–based classifications. (Modern papers usually say “ALPS-like due to CASP8.”) Cytometry.org

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Types

1. Early-onset, classic CEDS (biallelic loss-of-function). Babies or young children show swollen nodes/spleen, recurrent viral and sinopulmonary infections, low antibodies, poor vaccine responses, and sometimes very-early-onset IBD-like colitis. PMC

2. Adult-onset, hypomorphic CEDS. Adults with milder activity in caspase-8 can present later, sometimes with multi-organ lymphocytic infiltration, granulomas, pulmonary hypertension, or neurological involvement. PMC

3. Gastrointestinal-predominant CEDS. Children where IBD-like colitis, diarrhea, failure to thrive dominate, with lymphadenopathy/splenomegaly in the background. PMC

4. ALPS-like with immunodeficiency emphasis. Patients meet ALPS clinical features (lymphadenopathy/splenomegaly, autoimmune cytopenias) plus clear T, B, and/or NK-cell signaling/activation defects typical of CASP8 problems. PMC

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Causes

Because this condition is monogenic, the root cause is mutation in CASP8. The points below describe what kinds of mutations and biological effects lead to disease and which modifiers/triggers can worsen it.

1. Homozygous loss-of-function CASP8 mutations. Both copies are altered (often in consanguineous families), blocking caspase-8 activity and FAS-mediated apoptosis → lymphocyte buildup. PMC

2. Missense variants in the catalytic p18 domain (e.g., R307W, Q279R). These reduce enzyme function or stability, weakening the apoptosis switch. PMC

3. Variants that impair procaspase-8 dimerization (e.g., Q524H/Q482H naming differences). Poor dimerization prevents activation of caspase-8 after the death signal. PMC

4. Defective DISC assembly (FAS–FADD–CASP8 complex). If mutant caspase-8 cannot join the complex correctly, the death signal stalls. PMC

5. Impaired Fas-mediated apoptosis of effector T cells. The normal “brake” that clears activated/auto-reactive lymphocytes fails → lymphoproliferation and autoimmunity. PMC+1

6. Reduced NF-κB signaling downstream of TCR/BCR/TLR. Caspase-8 also helps immune-cell activation; reduced signaling causes immunodeficiency and poor control of infections. PMC

7. Skewed cell-death balance (apoptosis↔necroptosis/pyroptosis). Caspase-8 is a central “mode switch”; its loss disrupts inflammatory cell-death checks and may fuel tissue inflammation. PMC+1

8. Accumulation of double-negative T (DNT) cells. Poor apoptosis lets DNT cells rise; they are a hallmark of ALPS biology. PMC

9. Hypogammaglobulinemia and poor vaccine responses. B-cell help/activation is suboptimal when caspase-8 signaling is weak. PMC

10. Recurrent herpesvirus and respiratory infections. Weakened antiviral and B-/NK-cell responses amplify lymphoid stimulation and tissue infiltration. PMC+1

11. Very-early-onset intestinal inflammation. Dysregulated epithelial/innate signaling can drive IBD-like disease. PMC

12. Cytokine milieu that promotes lymphoproliferation (e.g., high IL-10, IL-18). These biomarkers track with ALPS activity and support cell survival. cincinnatichildrens.org+1

13. Genetic background and consanguinity. Increases the chance of inheriting two harmful CASP8 copies. PMC

14. Environmental/pathogen exposures. Ongoing antigen stimulation (frequent infections) pushes lymphocyte expansion when off-switches are weak. (Inference from immunodeficiency + infections pattern.) PMC

15. Autoantibody generation. Survival of autoreactive clones → autoimmune cytopenias. (ALPS mechanism extrapolated to CASP8 ALPS-like.) PubMed

16. Reduced NK-cell numbers/function. Makes viral control harder, sustaining immune activation. PMC

17. Age-related penetrance differences. Hypomorphic variants may present only in adulthood with organ infiltration. PMC

18. Defective apoptosis on ex vivo testing. The functional defect itself is causal and measurable in patient cells. PMC+1

19. Pathway-neighbor gene effects (FAS, FASLG, CASP10, FADD). Not causes of CEDS, but explain how CASP8 sits in the same death-pathway family that produces ALPS when any node fails. PubMed

20. Molecular “switch” role of caspase-8 across death programs. Its central position means even partial loss can ripple across immune control. PMC

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Symptoms and signs

1. Chronic swollen glands (lymphadenopathy)—usually painless, waxing and waning. PMC

2. Enlarged spleen (splenomegaly)—can cause early fullness or left-upper-abdominal discomfort. PMC

3. Enlarged liver (hepatomegaly) in some cases. PMC

4. Autoimmune cytopenias (anemia, low platelets, low neutrophils) causing pallor, bruising, or infections. PMC

5. Frequent respiratory infections (sinus, chest). PMC

6. Recurrent herpes or other viral infections (mouth/skin). PMC

7. Fever of unknown origin during flares. PMC

8. Fatigue from inflammation or anemia. (Common in ALPS activity.) Medscape

9. Diarrhea/IBD-like colitis, sometimes with blood/mucus and poor growth. PMC

10. Failure to thrive/poor weight gain in infants/children. PMC

11. Eczema/allergic symptoms in some pediatric cases. PMC

12. Neurologic problems (rare): cranial nerve palsies from lymphocytic organ infiltration. PMC

13. Pulmonary hypertension or lung involvement (adult cases). PMC

14. Granulomatous lesions in affected organs on biopsy. PMC

15. Generalized inflammation markers (raised ESR/CRP) during active disease. PMC

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Diagnostic tests

A) Physical examination (bedside)

1. Lymph node and spleen exam. Doctors gently feel for persistent, non-tender lymph nodes and an enlarged spleen—classic ALPS features. Medscape

2. Liver exam. Checks for hepatomegaly that can accompany lymphoproliferation. PMC

3. Growth and nutrition checks. Weight/height curves help detect failure to thrive in children with GI involvement. PMC

4. Skin and mucosa review. Looks for eczema, ulcers, or herpes lesions that point to immune weakness. PMC

5. Abdominal exam for tenderness/fullness. Assesses spleen-related discomfort and bowel inflammation signs. PMC

B) “Manual/office” tests (simple point-of-care or clinic-based)

6. Complete blood count (CBC) with differential (finger-stick venous sample). Screens for anemia, thrombocytopenia, or neutropenia from autoimmunity. PMC

7. Peripheral smear review (manual microscopy). Looks for hemolysis clues and abnormal lymphocytes. Medscape

8. Direct antiglobulin (Coombs) test. Detects autoimmune hemolysis—a common ALPS complication. Medscape

9. Stool calprotectin/lactoferrin (rapid assays) when diarrhea is present—supports IBD-like inflammation. PMC

C) Laboratory and pathology (core of the work-up)

10. Quantitative immunoglobulins (IgG/IgA/IgM). Low or low-normal levels with poor responses suggest the CEDS immunodeficiency pattern. PMC

11. Vaccine titers (e.g., pneumococcal). Poor protective titers despite vaccination are typical in CEDS. PMC

12. Flow cytometry lymphocyte subsets. Measures T, B, and NK cells; CEDS may show low B/NK cells, altered CD4:CD8 ratio. PMC

13. Alpha–beta double-negative T cells (DNT, TCRαβ+CD4–CD8–). Elevated DNTs are a hallmark ALPS biomarker (measured by flow cytometry). Mayo Clinic Laboratories+1

14. ALPS serum biomarkers: IL-10, soluble FAS ligand (sFASL), IL-18, and high vitamin B12. Help support ALPS activity and classification. cincinnatichildrens.org+1

15. Fas-mediated apoptosis assay (ex vivo). Functional test of the FAS death pathway in patient blood cells; detects defective apoptosis. PMC+1

16. Targeted or panel-based genetic testing. Confirms pathogenic CASP8 variants and distinguishes CASP8 ALPS-like disease from other ALPS genes (FAS, FASLG, CASP10, FADD, etc.). SpringerLink

17. Caspase-8 protein/activity assessments (specialized labs). Some centers study expression or enzyme function to interpret uncertain variants. PMC

18. Lymph node or organ biopsy (when needed). Shows reactive lymphoid hyperplasia or granulomatous lymphocytic infiltration; rules out lymphoma. PMC

D) Electrodiagnostic (used selectively, when symptoms point to complications)

19. Electrocardiogram (ECG). Helpful if severe anemia or pulmonary hypertension is suspected in adult-onset cases; monitors cardiac strain/rhythm. PMC

E) Imaging

20. Ultrasound/CT/MRI/PET-CT and endoscopy. Ultrasound checks spleen/liver size; CT/MRI/PET-CT map deep lymph nodes and organ infiltration; colonoscopy with biopsy evaluates IBD-like colitis. Medscape+1

Non-pharmacological treatments

Because this disease is rare, most non-drug measures are adapted from ALPS, primary immunodeficiency, and immunosuppression safety guidance.

1. Education & action plans: clear instructions for fever, bleeding, severe fatigue, or new neurologic signs; early care reduces complications. NCBI

2. Vaccination optimization: keep inactivated vaccines up to date; plan timing around immunosuppression; follow ACIP/IDSA principles. Live vaccines depend on immune status—often avoided if severely immunocompromised. CDC+1

3. Household immunization (“cocooning”): fully vaccinate close contacts (e.g., influenza, COVID-19, pertussis) to reduce exposure. CDC

4. Food-safety upgrades: avoid high-risk foods (raw/undercooked meats, unpasteurized dairy, raw sprouts); strict kitchen hygiene. CDC+1

5. Travel & infection-control counseling: mask in crowded indoor spaces during outbreaks; hand hygiene; prompt care for respiratory symptoms. CDC

6. Dental care schedule: regular cleanings and early treatment of mouth infections (common with hypogammaglobulinemia). PMC

7. Activity pacing & physical therapy during recovery from cytopenias or organ infiltration; preserve lung capacity and strength safely. PMC

8. Bone health plan if steroids are used: weight-bearing exercise, fall-prevention, adequate calcium/vitamin D intake; screen for osteoporosis. Frontiers+1

9. Nutrition quality (not “neutropenic diet” by default): aim for balanced, safe foods; strict raw-food bans don’t clearly prevent infections and can worsen nutrition—prioritize food safety over blanket restrictions. PMC+1

10. Sun/skin care to reduce secondary infections from skin breakdown; treat HSV flares early. PMC

11. Stress-sleep management: fatigue and chronic illness improve with consistent sleep and stress reduction—supportive, though nonspecific. NCBI

12. Home pulse-ox or symptom logs when lung involvement was present; alerts earlier decompensation. PMC

13. Oncology surveillance cadence: periodic imaging and biopsy if lymphoma suspected (ALPS framework). NCBI

14. Pregnancy planning with specialists if applicable; some ALPS drugs are teratogenic. NCBI

15. Avoid non-essential splenectomy: high sepsis risk; reserve for last-resort scenarios only. NCBI

16. Pre-splenectomy steps if ever needed: vaccines + antibiotic prophylaxis planning. NCBI

17. Genetic counseling for families (autosomal-recessive patterns often in CASP8). NCBI

18. School/work letters & infection precautions during immunosuppressive phases. CDC

19. Vaccination timing around rituximab/IVIG: plan to maximize responses and avoid neutralization. Infectious Diseases Society of America

20. Multidisciplinary clinic follow-up (immunology/hematology/infectious diseases). NCBI

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Drug treatments

Important: CASP8 disease is ultra-rare; drug choices follow ALPS, immune cytopenia, and primary immunodeficiency practice. Confirm dosing and monitoring locally.

1. Prednisone/prednisolone for acute autoimmune cytopenias (e.g., 1–2 mg/kg/day, taper). Purpose: fast anti-inflammatory effect. Risks: hyperglycemia, infection, osteoporosis. NCBI

2. Sirolimus (rapamycin) for lymphoproliferation and refractory cytopenias (typical trough 5–15 ng/mL). Purpose: T-cell regulation; strong ALPS data. Risks: mouth sores, lipids, cytopenias. NCBI

3. Mycophenolate mofetil (e.g., 600 mg/m² bid in children; 1–1.5 g bid adults). Purpose: steroid-sparing for autoimmunity. Risks: GI upset, leukopenia, teratogenicity. NCBI

4. Rituximab (375 mg/m² weekly × 1–4) for refractory immune cytopenias; use cautiously due to hypogammaglobulinemia risk and infections. NCBI+1

5. Intravenous immunoglobulin (IVIG) (e.g., 400–600 mg/kg q3–4 weeks) for antibody replacement (if low IgG) or for acute AIHA with steroids. Risks: headache, thrombosis (rare). PMC+1

6. G-CSF (filgrastim, variable dosing) for chronic neutropenia to reduce infections. Risks: bone pain, leukocytosis. NCBI

7. Thrombopoietin receptor agonists (eltrombopag, romiplostim) for isolated ITP not responding to first-line therapy. Risks: thrombosis, liver enzyme changes. NCBI

8. Cyclophosphamide (protocol-specific) for severe, refractory lymphoproliferation; potent and immunosuppressive. Risks: cytopenias, infertility, infections. NCBI

9. Antithymocyte globulin (ATG) for life-threatening refractory autoimmunity/lymphoproliferation in specialized centers. Risks: serum sickness, infections. NCBI

10. Alemtuzumab (anti-CD52) as rescue in selected severe cases—specialist only. Risks: profound immunosuppression. NCBI

11. Antimicrobials for active infections tailored to culture/organism; low threshold due to immune dysfunction. PMC

12. HSV antivirals (acyclovir/valacyclovir) for frequent mucocutaneous HSV. Purpose: reduce recurrences. Risks: renal dosing needs. PMC

13. PJP prophylaxis (TMP-SMX) during moderate–high immunosuppression regimens. Risks: cytopenias, allergy. Infectious Diseases Society of America

14. Pneumococcal/meningococcal conjugate vaccines (drug-adjacent but preventive “biologics”) per ACIP; time away from rituximab when possible. CDC

15. Azathioprine (rarely used today) as a steroid-sparing option if MMF/sirolimus not feasible. Risks: myelosuppression. NCBI

16. Tacrolimus/cyclosporine (case-by-case) for autoimmune cytopenias when others fail. Risks: nephrotoxicity, hypertension. NCBI

17. Erythropoiesis-stimulating agents when anemia is multifactorial and marrow reserve is adequate. Risks: thrombosis. NCBI

18. Methotrexate (low-dose) occasionally for autoimmune complications—specialist judgment. Risks: liver toxicity. NCBI

19. Corticosteroid-sparing tapers and bone-protection medicines (bisphosphonates if indicated) during long steroid courses. Frontiers+1

20. HSCT conditioning drugs (see “Surgeries/HSCT”): not routine but curative when used for severe disease; protocols vary by center. NCBI

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Dietary “molecular supplements

Important: No supplement cures CASP8 disease. Use these only to correct deficiency or support specific risks (e.g., steroid-related bone loss), and always with clinician oversight.

1. Vitamin D to maintain sufficiency for bone/muscle health (typical 600–800 IU/day adults; higher if deficient). Mechanism: calcium/phosphate balance; skeletal remodeling support. Office of Dietary Supplements

2. Calcium (diet first; supplement only if intake low) for bone protection when on steroids. Office of Dietary Supplements

3. Protein/energy supplements during weight loss or chronic infection to maintain lean mass (dietitian-guided). MDPI

4. Omega-3 fatty acids (food-first) for general cardiometabolic and anti-inflammatory support; evidence is nonspecific here. Office of Dietary Supplements

5. Zinc only if deficient; excess impairs copper status and immunity. Office of Dietary Supplements

6. Folate if hemolysis or poor intake is documented. Office of Dietary Supplements

7. Iron only for proven iron-deficiency anemia (avoid during active infection without guidance). Office of Dietary Supplements

8. B-complex to correct documented deficiencies (note: B12 can be high in ALPS as a biomarker—don’t supplement unless deficient). PMC

9. Probiotics are not routinely advised in immunocompromised states due to rare bacteremia/fungemia—discuss locally. Infectious Diseases Society of America

10. Electrolyte solutions during febrile illnesses to prevent dehydration; symptomatic support only. CDC

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Immunity-booster/regenerative/stem-cell” drugs

1. Hematopoietic stem-cell transplantation (HSCT) is the only curative approach for ALPS when used, and may be considered for severe, refractory ALPS-like disease; data in CASP8 are limited due to rarity, so decisions are highly individualized in expert centers. NCBI

2. IVIG replacement (see above) is an immune substitute, not a booster; it lowers infections when antibodies are low. PMC

3. G-CSF functionally “boosts” neutrophils when they’re chronically low, cutting bacterial infection risk. NCBI

4. TPO-receptor agonists “boost” platelet production in refractory ITP. NCBI

5. Sirolimus normalizes overactive lymphocyte survival/proliferation—an immune regulator, not a classic booster. NCBI

6. Antiviral prophylaxis (e.g., acyclovir during frequent HSV) reduces viral triggers that stress an already dysregulated immune system. PMC

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Surgeries/procedures

1. HSCT (see above): considered for severe, refractory immune dysregulation or life-threatening complications; intent is cure by replacing the immune system. NCBI

2. Splenectomy: discouraged except as last resort for life-threatening refractory cytopenias/hypersplenism due to high sepsis risk and frequent relapse. NCBI

3. Lymph-node excision biopsy: not curative; used to rule out lymphoma when nodes change or B-symptoms appear. NCBI

4. Central venous access device placement: supports long-term IVIG/therapies in selected patients. NCBI

5. Organ-specific surgeries/transplant (e.g., lung transplant reported in one adult sibling with severe pulmonary disease): case-by-case salvage for irreversible organ damage. PMC

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Preventions

Keep vaccinations up to date (inactivated), use food safety, avoid contact with sick people, hand hygiene, mask in high-risk settings, prompt antibiotics for serious infections per clinician plan, bone protection on steroids, avoid non-essential splenectomy, regular surveillance for lymphoma, and genetic counseling for families. CDC+2CDC+2

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When to see a doctor urgently

Seek care fast for fever, breathlessness, easy bruising/bleeding, confusion/neurologic changes, or rapidly enlarging lymph nodes/spleen. Call the team if a new drug is started (to plan vaccines/prophylaxis), before travel, and well before pregnancy planning. NCBI

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What to eat vs. avoid

Eat: a balanced, fully cooked diet with fruits/vegetables that are well washed (and cooked when neutropenic), safe dairy (pasteurized), lean proteins, whole grains, and adequate calcium/vitamin D if on steroids. Avoid: raw/undercooked meats/eggs/seafood, unpasteurized milk/soft cheeses, raw sprouts, and unwashed produce; be extra careful with leftovers and deli meats (heat thoroughly). The focus is food safety, not blanket produce bans. CDC+2CDC+2

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FAQs

1) Is CASP8 disease the same as ALPS?
No. It’s ALPS-like: overlaps clinically but sits in the ALPS-like category; classic genetic ALPS is FAS/FASLG/CASP10. NCBI

2) Can people have both infections and autoimmunity?
Yes—because caspase-8 is needed for apoptosis and immune activation. PMC

3) What single test “proves” it?
Genetic confirmation of CASP8 plus supportive immune tests (DNTs, apoptosis defect, biomarkers). NCBI

4) Are DNT cells always high?
They can be only marginally elevated in CASP8 disease; high DNTs are more typical in ALPS-FAS. NCBI

5) What blood biomarkers help?
Combinations of sFASL/IL-10/IL-18/vitamin B12 with DNTs raise the probability of Fas-pathway disease. PMC

6) Is sirolimus helpful?
Yes—for cytopenias/lymphoproliferation in ALPS; it’s often preferred over chronic steroids. NCBI

7) Is rituximab safe?
It can work in refractory cytopenias but may cause prolonged low antibodies and infections—use with caution. NCBI+1

8) Will IVIG fix ALPS-like disease?
It replaces antibodies and cuts infections when IgG is low; it does not correct the apoptosis defect. PMC

9) Should I avoid all raw fruits/vegetables?
Not routinely; focus on food safety. Strict “neutropenic diets” don’t clearly reduce infections and can harm nutrition. PMC

10) Can vaccines be given?
Generally yes for inactivated vaccines; be cautious with live vaccines in significant immunodeficiency and time doses around immunosuppression. CDC

11) Is splenectomy recommended?
Usually no; reserve for last-resort emergencies due to sepsis risk and relapse. NCBI

12) Is there a cancer risk?
Classic ALPS (FAS) carries a lymphoma risk; CASP8 risk is unknown given the very small numbers. NCBI

13) Is HSCT curative?
For ALPS, yes; for CASP8, HSCT is considered in severe cases—evidence is limited and decisions are center-specific. NCBI

14) Who manages this?
A clinical immunologist/hematologist with experience in primary immunodeficiency and ALPS-like disorders. NCBI

15) What’s the outlook?
Highly variable; some stabilize with targeted immunosuppression and infection prevention, others need escalated care (including HSCT) if disease is severe. PMC+1

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: September 29, 2025.

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