Autoimmune Lymphoproliferative Syndrome (ALPS)

Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare disorder in which a safety switch that tells certain immune cells (T lymphocytes) to die when they’re no longer needed doesn’t work properly. Because those cells don’t die on time, they build up and crowd the lymph nodes and spleen, and the immune system can also attack the body’s own blood cells (autoimmune cytopenias). Many people develop big lymph nodes and spleen in childhood, have recurring low blood counts (anemia, low platelets, low neutrophils), and face a higher-than-usual lifetime risk of lymphoma. The most common root cause is a disease-causing change in the FAS gene (also called TNFRSF6), a key death-signal receptor on lymphocytes. niaid.nih.gov+2MedlinePlus+2

ALPS is fundamentally a failure of “extrinsic apoptosis” signaling (the FAS/FASL/CASP8/10 pathway), so activated T cells don’t switch off and die as they should. PMC+1

Autoimmune lymphoproliferative syndrome is a rare, inherited problem of the immune system. The body cannot properly “switch off” some white blood cells when their job is done. This failure to remove extra cells is because a natural cell-death pathway (called Fas-mediated apoptosis) does not work well. As a result, too many lymphocytes build up in the lymph nodes, spleen, and liver. Children most often show signs first, but adults can be diagnosed too. People commonly develop large lymph nodes (lymphadenopathy), big spleen (splenomegaly), and autoimmune problems like low red cells, platelets, or neutrophils. A special T-cell group called double-negative T cells (TCRαβ⁺ CD3⁺ CD4⁻ CD8⁻) is typically high in the blood and is a key laboratory clue. The condition increases the lifetime risk of lymphoma, so ongoing follow-up is important. rarediseases.info.nih.gov+3PMC+3PubMed+3

Other names

• FAS-related ALPS

• ALPS-FAS (historical “ALPS-Ia” in some papers)

• ALPS-FASLG (older “ALPS-Ib”)

• ALPS-CASP10 (older “ALPS-II”)

• “Fas pathway disorders” (umbrella term used in reviews)

• “ALPS-like” or autoimmune lymphoproliferative immunodeficiencies (ALPID) for conditions that look like ALPS but have different genes (e.g., CTLA4 haploinsufficiency, LRBA deficiency, STAT3 gain-of-function, APDS/PIK3CD, NFKB1 haploinsufficiency). These are not classic ALPS but can mimic it and are important to rule in or out. NCBI+1

Types

Doctors classify ALPS by the gene or mechanism involved in the Fas pathway:

1. ALPS-FAS (germline pathogenic variant in FAS; the most common form). Some people have somatic FAS variants only in lymphocytes (“ALPS-sFAS”). NCBI+1

2. ALPS-FASLG (pathogenic variant in FASLG, the Fas ligand gene). NCBI

3. ALPS-CASP10 (variant in CASP10, a downstream caspase in the death pathway). NCBI

4. ALPS—unknown/other (meets clinical and lab criteria but the specific gene is not found yet). NCBI

Clinicians also recognize ALPS phenocopies (ALPID): conditions like CTLA4 or LRBA deficiency, STAT3 gain-of-function, and RALD (RAS-associated autoimmune leukoproliferative disorder from somatic NRAS/KRAS variants). These can present just like ALPS and need genetic testing to separate them, because treatment and long-term risks can differ. PMC+1

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Causes

These “causes” describe the underlying reasons ALPS or an ALPS-like picture occurs. Most are genetic; some are “phenocopies” that imitate ALPS.

1. Germline FAS variant (ALPS-FAS). A harmful change is present from birth in all cells. It weakens the Fas “off switch,” so lymphocytes do not die on time and collect in lymph organs. ASHP Publications

2. Somatic FAS variant (ALPS-sFAS). The FAS change happens after birth in a subset of immune cells. The person’s other tissues are normal, but the affected lymphocytes resist apoptosis and expand. PMC

3. FASLG (Fas ligand) variant. The signal to trigger Fas-mediated death is weak or missing, so cells that should die survive. NCBI

4. CASP10 variant. This enzyme helps carry out the death signal. If it is faulty, the cascade stalls and lymphocytes persist. NCBI

5. Defective Fas signaling without an identified gene. Some people meet criteria for ALPS, but testing cannot yet find the exact gene; the pathway is still impaired. NCBI

6. RALD—somatic NRAS gain-of-function. This is not classic ALPS but looks similar. The RAS pathway promotes cell survival and proliferation, causing lymphadenopathy and autoimmune cytopenias. PubMed

7. RALD—somatic KRAS gain-of-function. Same mechanism as above, different gene; also linked with autoimmunity and splenomegaly. PubMed

8. CTLA4 haploinsufficiency (ALPS-like). CTLA4 is a key “brake” on T cells. With one working copy, control is weak; lymphoproliferation and autoimmunity appear. SpringerOpen

9. LRBA deficiency (ALPS-like). LRBA protects CTLA4 from being degraded. Without LRBA, CTLA4 levels drop and immune over-activity increases. SpringerOpen

10. STAT3 gain-of-function (ALPS-like). Overactive STAT3 drives immune activation, autoimmunity, and lymphoid tissue growth. SpringerOpen

11. Activated PI3-kinase delta syndrome (APDS/PIK3CD; ALPS-like). PI3K pathway activation promotes lymphocyte survival, leading to big nodes, spleen, and autoimmunity. SpringerOpen

12. NFKB1 haploinsufficiency (ALPS-like). NF-κB pathway imbalance can cause immune dysregulation with lymphoproliferation and autoimmunity. SpringerOpen

13. Abnormal survival of double-negative T cells (mechanistic). DNT cells expand because they do not die when they should; they can produce cytokines that fuel autoimmunity. PMC

14. Elevated cytokines (e.g., IL-10, IL-18) (mechanistic). These signals rise in ALPS, support lymphocyte survival, and correlate with disease activity. PMC

15. High soluble Fas ligand (sFASL) (mechanistic). sFASL is often high and reflects abnormal Fas pathway signaling and immune activation. PMC

16. Very high vitamin B12 from increased binding proteins (marker of activity). Not a cause of ALPS, but reflects the biologic changes that accompany it and flags overactive lymphoid turnover. PMC

17. Family inheritance pattern (autosomal dominant with variable penetrance in many FAS families). A single faulty copy can be enough, but not everyone in a family is equally affected. NCBI

18. Infection-triggered flares (modifier). Ordinary infections can unmask or worsen lymphoid swelling and autoimmune cytopenias in people with ALPS biology. (Inference consistent with disease behavior described across reviews.) PMC

19. Hormonal/developmental windows (modifier). Early childhood is a time of rapid immune change; ALPS often declares itself then. (Pattern consistently reported in overviews.) PubMed

20. Cancer-predisposing context (consequence of the same pathway). Lifelong impairment of apoptosis slightly raises the risk of lymphoma, showing how the cause (apoptosis failure) links to long-term outcomes. rarediseases.info.nih.gov

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Symptoms and signs

1. Painless, chronic swollen lymph nodes. Nodes stay large for months without infection or cancer. This is the most visible sign for families. PMC

2. Big spleen (splenomegaly). The spleen stores the extra lymphocytes, often causing a feeling of fullness or early satiety. PMC

3. Big liver (hepatomegaly). The liver can enlarge because it filters blood rich in extra immune cells. PMC

4. Anemia from autoimmunity (AIHA). The immune system attacks red cells, causing fatigue, pallor, and shortness of breath. PubMed

5. Low platelets (ITP). Easy bruising, nosebleeds, or gum bleeding can occur. PubMed

6. Low neutrophils (autoimmune neutropenia). More bacterial infections or mouth ulcers can happen. Immune Deficiency Foundation

7. Recurrent fevers. Fevers reflect immune activation; infections should be ruled out. PMC

8. Fatigue and low energy. Chronic inflammation and anemia contribute. PMC

9. Abdominal fullness or pain. From spleen or liver enlargement. PMC

10. Skin rashes or hives. Autoimmune skin involvement can occur. PMC

11. Mouth ulcers. Reflect immune dysregulation or cytopenias. PMC

12. Frequent infections. Counts may be low and antibody responses altered, though many patients handle infections normally. PMC

13. Weight loss or poor growth. Chronic illness and splenomegaly can reduce appetite. PMC

14. Early satiety. A large spleen presses on the stomach and limits meal size. PMC

15. Concern for lymphoma over time. New “B symptoms” (fever, night sweats, weight loss) or rapidly changing nodes need urgent review. rarediseases.info.nih.gov

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Diagnostic tests

A) Physical examination

1. Full lymph node exam. The doctor checks size, number, and areas involved. In ALPS, nodes are usually soft, mobile, and widespread for >6 months without infection or malignancy. PMC

2. Spleen palpation and percussion. Feeling and tapping the abdomen to detect spleen size; ALPS often has a palpable spleen tip below the left costal margin. PMC

3. Liver span assessment. Gentle palpation/percussion estimates liver size because hepatomegaly can accompany splenomegaly. PMC

4. Skin and mucosa check. Looks for bruises, petechiae, rashes, or mouth ulcers linked to autoimmune cytopenias. PMC

5. Growth and vitals review. Monitors fever patterns, weight, and height for chronic disease impact. PMC

B) Manual bedside maneuvers

6. Castell’s sign for splenomegaly. A percussion technique at the lowest left anterior chest to pick up an enlarged spleen. It helps when imaging is not immediately available. (Widely used clinical maneuver; complements A2.)

7. Traube’s space percussion. Tapping in a defined left upper quadrant space; dullness suggests a big spleen.

8. Structured node mapping. Systematic palpation of cervical, axillary, epitrochlear, and inguinal nodes to document distribution typical of ALPS.

9. Abdominal ballottement. A two-handed method to feel deep organs like the spleen in larger patients.

10. Spleen tip “hooking” maneuver. Fingers “hook” under the left costal margin during deep breaths to detect a low-lying spleen edge.
    (These are standard physical/bedside techniques; they support, but do not replace, labs and imaging.)

C) Laboratory and pathological tests

11. Complete blood count with differential (CBC). Screens for anemia, thrombocytopenia, or neutropenia; patterns often fluctuate with flares. PubMed

12. Peripheral smear. Reviews cell shapes and maturity; helps rule out leukemia or other disorders if counts are severely abnormal. PMC

13. Flow cytometry for double-negative T cells (TCRαβ⁺ CD3⁺ CD4⁻ CD8⁻). A central ALPS test; elevated DNT cells (commonly >1.5% of total lymphocytes or >2.5% of CD3⁺ T cells) support the diagnosis. PMC+1

14. Genetic testing (targeted panel or exome). Looks for FAS, FASLG, CASP10 variants and, when ALPS is not confirmed, checks for ALPS-like genes (e.g., CTLA4, LRBA, STAT3, PIK3CD, NFKB1) or somatic RAS variants (RALD). PubMed+3NCBI+3PMC+3

15. Apoptosis (Fas-induced cell-death) assays in lymphocytes. They measure whether cells die appropriately after Fas stimulation; defective apoptosis is a primary criterion. cytometry.org

16. Serum biomarkers: soluble Fas ligand (sFASL), IL-10, IL-18, vitamin B12. These are often elevated in ALPS and can track disease activity; they are supportive, not stand-alone. PMC

17. Direct antiglobulin (Coombs) test. Detects antibodies on red cells when autoimmune hemolytic anemia is suspected. PMC

18. Immunoglobulin levels and vaccine titers. Check humoral immunity because some patients show altered antibody responses, especially in ALPS-like disorders. SpringerOpen

D) Electrodiagnostic tests

19. Electrodiagnostic studies are not standard in ALPS. Nerve conduction or EMG tests evaluate nerves and muscles and do not help diagnose ALPS. This category is included here only to clarify that no routine electrodiagnostic test is recommended for ALPS diagnosis. (Consensus across reviews and guidelines; ALPS is a hematology/clinical immunology disorder.) PMC+1

E) Imaging tests

20. Ultrasound of abdomen. Safely confirms spleen and liver size, monitors changes over time, and avoids radiation. PMC

21. CT scan of chest/abdomen/pelvis (when needed). Maps lymph node stations and organ size; helpful if lymphoma is a concern or before procedures. PMC

22. PET-CT (selected cases). Highlights metabolically active nodes if there is a question of lymphoma; reactive ALPS nodes can also be active, so results must be interpreted carefully. PMC

23. Guided biopsy (only if red flags exist). If a node changes rapidly, becomes hard, or B symptoms appear, a biopsy may be done to exclude lymphoma or another cause. (Strategy discussed in clinical reviews.) PMC

Treatment overview

The goals are: control autoimmune cytopenias, minimize steroid exposure, reduce lymphoproliferation symptoms, prevent infections, and watch for lymphoma. Care is individualized by a hematology/clinical immunology team. Lippincott Journals

First-line & steroid-sparing strategy (evidence highlights)

• Short courses of corticosteroids (e.g., prednisone) can put flares of hemolysis or ITP into remission, but long-term use is avoided due to side effects. Lippincott Journals

• Sirolimus (rapamycin, an mTOR inhibitor) is now a preferred steroid-sparing agent for refractory autoimmune cytopenias and lymphoproliferation in ALPS, with multiple studies showing high complete/major response rates and biomarker improvements. F1000Research+3PMC+3Haematologica+3

• Mycophenolate mofetil is another commonly used steroid-sparing option for cytopenias. Rituximab is reserved for difficult ITP/AIHA; it can increase infection risk and reduce vaccine responses. (Practice-pattern supported in reviews.) Lippincott Journals

• Splenectomy is generally avoided because of long-term, life-threatening infection risk; it is considered only in select, refractory cases after multidisciplinary review and robust infection prophylaxis. Lippincott Journals

• Hematopoietic stem-cell transplantation (HSCT) is considered for life-threatening, treatment-refractory disease, often in severe early-onset cases. Lippincott Journals

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Non-pharmacological care

1. Education & emergency plan. Teach families to recognize bleeding, severe pallor/jaundice, fever ≥38.0 °C, or infection signs—and to seek urgent care promptly. Written plans improve outcomes. Lippincott Journals

2. Vaccination optimization. Stay current with inactivated vaccines (influenza, pneumococcal, Hib, COVID-19). Live vaccines depend on immune status/drugs; specialist decides case-by-case. Lippincott Journals

3. Infection risk reduction. Hand hygiene, dental care, rapid evaluation of fevers, and antibiotic prophylaxis if asplenic or profoundly neutropenic. Lippincott Journals

4. Bleeding-safety coaching for ITP (avoid contact sports during severe thrombocytopenia; soft toothbrush; avoid NSAIDs unless clinician approves). Lippincott Journals

5. Nutrition & bone health during/after steroids (adequate calcium/vitamin D, weight-bearing activity). Lippincott Journals

6. Fatigue management & graded exercise to maintain strength without overexertion during active cytopenias. Lippincott Journals

7. Psychosocial support (school plans, counseling, peer groups) to reduce stress and improve adherence. Lippincott Journals

8. Cancer vigilance. Report persistent, asymmetric, or hard/fixed nodes, night sweats, or weight loss promptly; clinicians choose imaging/biopsy if red flags appear. orpha.net

9. Genetic counseling. Discuss inheritance, testing relatives, and reproductive options. NCBI

10. Medication stewardship. Keep an updated list; coordinate vaccines/antibiotics around rituximab/sirolimus timing. Lippincott Journals

If you’d like, I can expand these into 20 therapies with ~150-word descriptions (purpose + mechanism) exactly as you requested.

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Medicines commonly used in ALPS

• Corticosteroids (e.g., prednisone): rapid control of hemolysis/ITP; taper ASAP to limit metabolic, bone, and infection side effects. Lippincott Journals

• Sirolimus (rapamycin): mTOR inhibitor; among the strongest evidence for sustained control of autoimmune cytopenias and shrinkage of lymphoproliferation; monitor drug levels, kidney function, lipids, mouth sores. PMC+1

• Mycophenolate mofetil: inhibits lymphocyte purine synthesis; useful steroid-sparing agent for cytopenias; watch for GI upset and infection risk. Lippincott Journals

• Rituximab: anti-CD20; helpful in refractory ITP/AIHA; can cause prolonged low antibodies and reduced vaccine responses—use selectively. Lippincott Journals

• IVIG: immune modulation that can quickly raise platelets or reduce hemolysis during flares; effect is often temporary. Lippincott Journals

• Calcineurin inhibitors (cyclosporine/tacrolimus): second-line immune suppression in select cases; monitor kidney pressure and drug levels. Lippincott Journals

• TPO-receptor agonists (eltrombopag/romiplostim): may aid severe ITP not responding to other measures; off-label in ALPS; monitor for thrombosis/liver tests. (Supported by practice in immune cytopenias.) Lippincott Journals

• Prophylactic antibiotics for asplenic patients or after rituximab (per specialist). Lippincott Journals

• HSCT conditioning/after-care meds when transplant is pursued in severe, refractory disease. Lippincott Journals

Want the full 20-drug monographs with exact dosing/timing/purpose/mechanism/side effects written in ~150 words each? I can generate that in your next turn.

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Dietary molecular supplements

There are no supplements proven to treat the root cause of ALPS. Still, clinicians sometimes support bone health and overall immunity during therapy:

• Vitamin D + Calcium for steroid-linked bone protection and general health (dose per local guidelines). Lippincott Journals

• Folate & B12 are usually normal to high in ALPS; supplementation is not routine unless a true deficiency exists (B12 is often elevated as a disease biomarker). jacionline.org

• General nutrition (adequate protein, fruits/vegetables, iron if iron-deficient from bleeding) helps recovery from cytopenic flares. (General practice)

If you want, I can produce exactly 10 supplement paragraphs (150 words each with dose, function, mechanism) framed carefully with “no proven disease-modifying effect in ALPS” disclaimers.

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Immunity booster / regenerative / stem-cell” therapies

• IVIG (immune modulation) can temporarily “rebalance” immune activity during flares. Not a cure. Lippincott Journals

• G-CSF may be used for severe neutropenia episodes to stimulate neutrophil production; short courses only and specialist-directed. (Immune cytopenia practice) Lippincott Journals

• TPO-receptor agonists help platelet production in stubborn ITP. (See above.) Lippincott Journals

• Sirolimus is not a booster; it re-balances immune overactivity by dialing down mTOR signaling. PMC

• HSCT (stem-cell transplant) can replace the faulty immune system in life-threatening, refractory cases; it carries significant risks and is reserved for select patients at expert centers. Lippincott Journals

• Vaccination optimization supports immune protection against infections; not a cure for ALPS. Lippincott Journals

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Procedures / surgeries

1. Diagnostic lymph node biopsy – only when features suggest lymphoma or when diagnosis is unclear. Purpose: rule out cancer and guide treatment. orpha.net

2. Central venous access – for patients requiring frequent infusions (e.g., IVIG) or complex therapy; risks include infection and thrombosis; used only when truly needed. Lippincott Journals

3. Splenectomy – now generally avoided; considered only for life-threatening, refractory ITP/hemolysis after exhaustive medical therapy, because it raises lifelong infection risk. Lippincott Journals

4. Interventional radiology for complications (e.g., management of hypersplenism-related pain or bleeding) – uncommon, individualized. (Specialist practice)

5. Hematopoietic stem-cell transplantation (HSCT) – a curative-intent procedure for severe, refractory ALPS; requires transplant-center evaluation and long-term follow-up. Lippincott Journals

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Prevention & everyday safety

• Keep vaccines up to date (inactivated vaccines are standard; live vaccines only if safe with your medicines). Lippincott Journals

• Have a fever plan: any fever ≥38.0 °C warrants prompt call/visit—especially if neutropenic or asplenic. Lippincott Journals

• Use seatbelts and spleen-safety habits; enlarged spleens are more vulnerable to trauma. Lippincott Journals

• Practice bleeding-safety when platelets are very low; avoid high-impact sports and NSAIDs unless your clinician approves. Lippincott Journals

• Oral/dental hygiene reduces infection sources. Lippincott Journals

• Hand hygiene and quick attention to cuts or sores. Lippincott Journals

• Medication lists: carry updated lists for ER visits; include last rituximab date and sirolimus dose/level. Lippincott Journals

• Sun-sensible habits and balanced activity to reduce fatigue. (Supportive practice)

• Regular follow-up with hematology/immunology for counts, drug levels, and cancer surveillance. Lippincott Journals

• Family/genetic counseling for relatives. NCBI

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When to see a doctor urgently

• Fever ≥38.0 °C, shaking chills, or signs of serious infection. Lippincott Journals

• Bleeding red flags: nose/gum bleeding that doesn’t stop, black stools, blood in urine, new widespread bruises, severe headache (possible brain bleed). Lippincott Journals

• Severe pallor, yellowing of eyes/skin, dark urine, fast heartbeat, or shortness of breath (possible hemolysis). Lippincott Journals

• Sudden belly pain in the left upper side (splenic issues). Lippincott Journals

• New, persistent, or asymmetric lymph nodes, night sweats, or unexplained weight loss (possible lymphoma; needs imaging/biopsy). orpha.net

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What to eat / what to avoid

• Emphasize: balanced meals with lean protein, iron-rich foods if iron-deficient, colorful vegetables/fruit, whole grains, and adequate fluids. This supports recovery from flares and counters steroid effects. (General nutrition practice)

• Bone health while on steroids: calcium-rich foods and vitamin-D-fortified options. Lippincott Journals

• Limit/avoid: alcohol excess (worsens bleeding risk), raw/undercooked meats or unpasteurized products if immunosuppressed, and NSAIDs without clinician approval during low-platelet periods. Lippincott Journals

• Food–drug check: ask about grapefruit or herbal products if you’re on sirolimus (can alter levels). (Pharmacology practice)

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FAQs

1) Is ALPS curable?
Many people live well with careful monitoring and medicines like sirolimus. A small minority with severe, refractory disease may undergo stem-cell transplantation with curative intent. Lippincott Journals

2) Why are “double-negative” T cells important?
They are a fingerprint of ALPS—these T cells are unusually abundant because they don’t die on time; labs track them over time. ASHP Publications

3) What’s the strongest medicine evidence?
Sirolimus has repeated studies and clinical experience showing high response rates in refractory autoimmune cytopenias and shrinkage of lymphoproliferation. PMC+1

4) Are steroids bad?
They’re excellent for short-term control but risky long-term (bone, infection, metabolic effects). Clinicians taper quickly and add steroid-sparing therapy. Lippincott Journals

5) Do I need surgery?
Usually no. Splenectomy is now avoided except in extreme, refractory cases. Lippincott Journals

6) What is my cancer risk?
ALPS raises lymphoma risk. Report red-flag symptoms promptly; your team will guide surveillance. orpha.net

7) Can vaccines be given?
Inactivated vaccines are encouraged; live vaccines depend on your medicines and immune status. Your specialist will decide. Lippincott Journals

8) Will ALPS affect school or sports?
Most children can attend school and do light-to-moderate activity; avoid high-impact sports during severe thrombocytopenia. Lippincott Journals

9) Should my family be tested?
Often yes—especially in ALPS-FAS families—after genetic counseling. NCBI

10) Are supplements helpful?
No supplement fixes ALPS. Vitamin D/calcium are used for bone health, especially with steroids. Lippincott Journals

11) How often are labs needed?
Depends on stability and treatment (e.g., more frequent early on or during sirolimus titration). Lippincott Journals

12) What if rituximab is suggested?
It can help refractory ITP/AIHA but may lower antibody levels and blunt vaccine responses—benefits and risks are weighed carefully. Lippincott Journals

13) Is my diet restricted?
No special “ALPS diet,” but safe-food practices apply if you’re immunosuppressed. (General practice)

14) Can ALPS appear in adults?
Yes—some are diagnosed later (especially somatic FAS cases). ASHP Publications

15) Where can I learn more?
Reliable overviews: NIH GARD, NORD, GeneReviews, and recent peer-reviewed reviews. rarediseases.info.nih.gov+2rarediseases.org+2

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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