Caspase-8 Deficiency Syndrome

Caspase-8 Deficiency Syndrome—also called caspase-eight deficiency state (CEDS)—is a very rare, inherited immune-system disorder caused by harmful changes (mutations) in the CASP8 gene. Caspase-8 is a “starter” enzyme that helps immune cells both (1) turn on healthy activation signals (including NF-κB) when they detect germs, and (2) switch off safely by apoptosis (programmed cell death) when a response is over. When caspase-8 doesn’t work, people can develop recurrent infections, big lymph nodes and spleen (lymphadenopathy and splenomegaly), sometimes bronchiectasis, low antibodies (hypogammaglobulinemia), and in some individuals gut inflammation that looks like very early-onset inflammatory bowel disease. The condition can resemble autoimmune lymphoproliferative syndrome (ALPS), but CEDS is distinguished by significant immunodeficiency and defective T-, B-, and NK-cell activation. CEDS is autosomal recessive (both copies of CASP8 are affected). NCBI+3NIAID+3SpringerLink+3

Pathophysiology in simple terms.
Caspase-8 sits at critical “decision points” in immune cells. It helps activate NF-κB after antigen-receptor or Toll-like receptor signals; it also triggers apoptosis via death-receptor pathways (Fas/CD95). When caspase-8 is absent or broken, immune cells can’t activate properly (poor antibody responses, weak T/B/NK function) and they may fail to shut down correctly, leading to lymph-tissue swelling. Caspase-8 also restrains inflammatory “cell-death” programs (necroptosis/pyroptosis). Its loss can “disinhibit” inflammasomes (e.g., NLRP3) via RIPK3 pathways, which likely contributes to gut and tissue inflammation in some patients. PMC+2PMC+2

Caspase-8 deficiency syndrome (CEDS) is a very rare, inherited immune system disorder. It happens when both copies of a person’s CASP8 gene are changed (mutated). The CASP8 gene helps make caspase-8, a protein that starts “programmed cell death” (apoptosis) and also supports normal immune cell activation and signaling. When caspase-8 does not work, immune cells cannot activate or shut down properly. This causes a mix of immune deficiency (poor defense against infection) and immune dysregulation (swollen lymph nodes, big spleen, and sometimes autoimmune-like problems). People often get repeated chest, sinus, and skin infections, stubborn viral infections (like herpes), low antibody levels, and swelling of lymph nodes and spleen. Doctors first described CEDS in the early 2000s, and only a small number of families are known worldwide. It is inherited in an autosomal recessive way. BioMed Central+3PMC+3PMC+3

CEDS looks a bit like autoimmune lymphoproliferative syndrome (ALPS) because both involve problems in the body’s cell death pathways. But CEDS is different because, besides lymph node and spleen swelling, it also shows true immunodeficiency with weak activation of T cells, B cells, and NK cells and poor antibody responses. Many patients have hypogammaglobulinemia (low IgG/IgA/IgM) and weak vaccine responses. PMC+1

At the cell level, caspase-8 is part of the “death receptor” pathway (for example, FAS/FASL). It also acts as a signaling scaffold that helps turn on NF-κB and other pathways after antigen receptors and some toll-like receptors are engaged. Loss of caspase-8 can therefore block apoptosis and disturb activation signals, which explains the combined picture of infections plus lymphoproliferation. PMC+2MDPI+2

Other names

• Caspase-8 deficiency state (CEDS)

• ALPS with recurrent viral infections due to CASP8 deficiency (older Orphanet label)

• Primary immunodeficiency due to CASP8 mutation

• CASP8-related combined immunodeficiency Orpha+1

Types

1. Classic pediatric-onset CEDS. Children present with recurrent infections, lymph node enlargement, big spleen, low antibodies, and weak responses to vaccines. PMC

2. Later-onset or atypical CEDS. Some individuals are diagnosed in adolescence or adulthood with milder, fluctuating problems or with specific organ involvement. PMC

3. CEDS with gastrointestinal/IBD-like disease. Some patients have early-onset intestinal inflammation, diarrhea, weight loss, or failure to thrive. Haematologica+1

4. CEDS with prominent viral susceptibility. Frequent, severe, or persistent herpesvirus infections, molluscum, or warts dominate. Wikipedia

5. Emerging phenotypes (neurologic presentations). Rare reports describe neurological symptoms as a key feature in some cases. ScienceDirect

Note: These “types” are clinical groupings used by clinicians in case reports and reviews; they reflect the variety of ways the same gene defect can appear.

Causes

Because CEDS is a genetic disease, the root cause is a pathogenic variant in both copies of CASP8. Below are 20 simple “cause” statements that explain what leads to the disease and what makes it manifest or worsen in real life.

1. Biallelic CASP8 mutations. Two harmful variants (homozygous or compound heterozygous) are required to produce the syndrome. PMC

2. Loss-of-function changes. Nonsense, frameshift, splice, or damaging missense variants can reduce caspase-8 protein or activity. PMC

3. Consanguinity. Parents who are related by blood increase the chance that a child inherits the same rare variant from both sides. PMC

4. Founder effects/autozygosity. In small populations, a single old variant can recur and cause multiple cases. PMC

5. Defective death-receptor (FAS) signaling. Without caspase-8, FAS signals cannot trigger normal apoptosis of lymphocytes. MDPI

6. Impaired NF-κB activation scaffolding. Caspase-8 also helps turn on immune activation signals; its absence blocks proper T/B/NK activation. PMC

7. Weak T-cell activation. T cells cannot respond normally to antigens, which reduces viral and intracellular pathogen control. PMC

8. Weak B-cell activation and class-switching. This lowers antibody levels and vaccine responses. PMC

9. Reduced NK-cell cytotoxicity. NK cells may be functionally impaired, increasing susceptibility to viral illnesses. PMC

10. Low immunoglobulins (hypogammaglobulinemia). This directly increases risk of recurrent sinopulmonary infections. Wikipedia

11. Environmental pathogen exposure. Crowding, poor ventilation, or high viral circulation can unmask the immune defect with frequent infections (general PID principle). ScienceDirect

12. Live or high-antigen vaccines may reveal poor responses. Patients often mount weak antibody responses, flagging the defect during immunization assessments. PMC

13. Herpesviruses as triggers. HSV/VZV/EBV can persist or recur because cytotoxic and NK responses are suboptimal. Wikipedia

14. Bacterial infections that need strong T/NK help. Some bacterial infections become unusually severe or recurrent. PLOS

15. Mucocutaneous barrier stress. Eczema, dermatitis, or skin breaks can become entry points for persistent viral warts or molluscum. Wikipedia

16. Gut microbiome/inflammation pressures. In some patients, immune dysregulation in the gut contributes to IBD-like disease. Haematologica

17. Age-related immune demands. In infancy and early childhood, new exposures and vaccine schedules can make the defect apparent. PMC

18. Co-inherited variants in related pathways (rare). Mutations in adapters like FADD also cause overlapping immunodeficiency phenotypes, highlighting pathway vulnerability. PLOS

19. Delayed recognition/diagnosis. Without early specialty testing, infections and organ inflammation may accumulate and worsen outcomes. PMC

20. Limited access to immunology care. Lack of timely immunoglobulin therapy or antivirals allows persistent infections to drive disease activity (general PID management principle). ScienceDirect

Common symptoms and signs

1. Enlarged lymph nodes. Painless, persistent swellings in the neck, armpits, or groin due to lymphocyte buildup. Orpha

2. Enlarged spleen. A big spleen (splenomegaly) from lymphocyte accumulation and chronic immune activation. Wikipedia

3. Frequent sinus and chest infections. Cough, fever, sinus pressure, and repeated antibiotics, driven by low antibodies and weak activation. Wikipedia

4. Recurrent herpes simplex (cold sores or genital sores). Outbreaks last longer or recur more often than usual. Wikipedia

5. Shingles or varicella complications. More severe or unusual course compared with peers. Wikipedia

6. Persistent viral warts or molluscum. Lesions do not clear easily because of impaired cytotoxic responses. Wikipedia

7. Low energy, failure to thrive in children, or poor weight gain. Chronic infections and gut inflammation can reduce growth. Haematologica

8. Chronic diarrhea or belly pain. Some patients develop IBD-like bowel inflammation with diarrhea, cramps, and weight loss. Haematologica

9. Ear infections. Repeated otitis media due to weak mucosal immunity. Wikipedia

10. Skin infections. Bacterial or viral skin infections that linger or recur. Wikipedia

11. Fever that returns often. Reflects repeated infections or inflammatory flares. PMC

12. Poor response to vaccines. Antibody levels after vaccines are low or fade quickly. PMC

13. Autoimmune-like features (usually milder than classic ALPS). Occasionally anemia or other autoimmune signs can appear. PMC

14. Organ inflammation. Sometimes lungs, liver, or other organs show inflammatory lymphocyte infiltrates. Wikipedia

15. Neurologic complaints (rare). A few reports note neurological symptoms as a key presentation. ScienceDirect

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Diagnostic tests

A) Physical examination (what the clinician looks and feels for)

1. Lymph node exam. The doctor gently checks the neck, armpits, and groin for enlarged nodes. Persistent, non-tender nodes raise concern for CEDS-like lymphoproliferation. Orpha

2. Spleen and liver exam. Feeling the abdomen for an enlarged spleen or liver supports a pattern seen in CEDS. Wikipedia

3. Skin and mucosa check. The clinician looks for herpes sores, persistent warts, molluscum, or signs of fungal and bacterial skin infection. Wikipedia

4. Growth and nutrition review in children. Height, weight, and growth curves may show poor gain if infections or gut disease are ongoing. Haematologica

B) “Manual” clinical tests and bedside assessments

5. ENT assessment of sinuses and ears. Otoscopy and sinus evaluation document recurrent infections that suggest antibody problems. Wikipedia

6. Splenic percussion/palpation tracking. Repeated clinic checks record changes in spleen size over time to gauge activity. Wikipedia

7. Vaccination response review. Clinicians compare symptoms after vaccines with expected immunity; poor protection prompts lab testing. PMC

8. Standardized infection history tool. A structured question set (number, type, severity of infections) helps flag primary immunodeficiency patterns. ScienceDirect

C) Laboratory and pathological tests

9. Complete blood count (CBC) with differential. May show normal or altered white cells; combined with other data, it supports suspicion. ScienceDirect

10. Serum immunoglobulins (IgG, IgA, IgM). Many patients have hypogammaglobulinemia, a key lab feature of CEDS. Wikipedia

11. Vaccine-specific antibody titers. Poor titers after pneumococcal or other vaccines show defective antibody responses. PMC

12. Flow cytometry of lymphocyte subsets. Counts of T cells, B cells, and NK cells may be normal or low, but functional activation is typically defective. PMC

13. Lymphocyte activation assays. T-cell proliferation to mitogens/antigens and NK cytotoxicity testing often show reduced activation/cytotoxicity. PMC

14. Apoptosis assays (FAS-induced death). Peripheral lymphocytes are tested for death-receptor pathway function; defects support a diagnosis in the ALPS/CEDS spectrum. PMC

15. Cytokine and pathway readouts (research/advanced). Studies of NF-κB activation or downstream signals can demonstrate the caspase-8 signaling defect. PMC

16. Genetic testing of CASP8. Definitive diagnosis is by sequencing to find two disease-causing variants in CASP8; labs list CEDS as autosomal recessive. invitae.com

17. Pathology from lymph node or tissue (if done). Biopsy may show lymphoid hyperplasia (enlarged, reactive tissue) without lymphoma, fitting immune dysregulation rather than cancer. Wikipedia

D) Electrodiagnostic tests (used only when symptoms suggest)

18. Nerve conduction studies / EMG (select cases). If patients report neurological issues (rare phenotype), electrodiagnostic testing helps rule in or out peripheral nerve involvement. ScienceDirect

19. EEG (select cases). In unusual cases with seizures or encephalopathy, EEG can assess brain electrical activity while genetic/immunology tests proceed. PLOS

E) Imaging tests

20. Ultrasound or MRI for organ size and inflammation. Imaging confirms spleen or liver enlargement and can assess bowel or other organs when symptoms suggest IBD-like disease or organ infiltration. Haematologica

Non-pharmacological treatments

1. Specialist care & written action plan. Care in a center for inborn errors of immunity, with a personalized plan for fever/infection, is foundational. NIAID

2. Vaccination with inactivated vaccines. Keep routine non-live vaccines up-to-date; avoid live vaccines if significant cellular/antibody defects are present (case-by-case by immunology). NIAID

3. Household “cocooning.” Ensure family/close contacts are fully vaccinated (influenza, COVID-19, etc.) to reduce exposure risk. NIAID

4. Early test-and-treat for respiratory infections. Low threshold for cultures/PCR and prompt therapy to prevent bronchiectasis flares. PMC

5. Airway hygiene. Chest physiotherapy, airway clearance devices, and pulmonary rehab for those with chronic cough/bronchiectasis. PMC

6. Infection-control habits. Hand hygiene, masking in high-risk settings, food safety, and safe water practices. NIAID

7. Dental and sinus care. Regular dental hygiene and ENT follow-up to limit chronic sinusitis and dental sources of infection. PMC

8. Nutrition optimization. Balanced, protein-adequate diet; correct macro-/micronutrient deficits that can worsen infection risk. (Adjunctive, not disease-specific.) NIAID

9. Avoid unnecessary immunosuppression. Because many patients already have impaired host defense, minimize steroids or cytotoxic drugs unless clearly indicated. PMC

10. Travel planning. Pre-travel vaccines (inactivated where possible), antibiotic supply, and destination-specific precautions. NIAID

11. Genetic counseling. Explain autosomal-recessive inheritance; offer carrier testing for relatives and prenatal options where desired. SpringerLink

12. School/work accommodations. Flexible attendance during infections; infection-control measures in classrooms/workplaces. NIAID

13. Home environmental controls. Reduce indoor air pollutants and molds that can worsen respiratory infections. NIAID

14. Sun- and skin-care routines. Prompt care for skin breaks and herpes-family rashes given viral susceptibility. NIAID

15. Psychosocial support. Chronic rare disease care is stressful; counseling and peer support improve adherence and quality of life. NIAID

16. Physiotherapy/exercise. Graded aerobic activity supports lung function and general well-being; adapt during infections. NIAID

17. Home monitoring. Thermometer, pulse oximeter for high-risk respiratory seasons; know thresholds for seeking care. NIAID

18. Allergy/asthma control if present. Manage comorbid airway disease to limit infection-triggered exacerbations. NIAID

19. IBD-care coordination. If gut inflammation is present, involve gastroenterology early for endoscopic monitoring and nutrition support. wjwch.com

20. HSCT education. For families considering transplant, early referral for evaluation and donor search improves timing and outcomes. wjwch.com

Medicines used in practice

Important: Dosing is individualized; many uses are off-label in CEDS because rigorous trials do not exist. Discuss specifics with an immunologist.

1) Immunoglobulin replacement (IVIG/SCIG).
Class: Immune globulin. Why: Replaces missing antibodies to prevent bacterial/viral infections; cornerstone when hypogammaglobulinemia or poor vaccine response is present. When/how long: Chronic preventive therapy with periodic reassessment. Mechanism: Provides pooled IgG to neutralize pathogens and opsonize bacteria. Effects/risks: Infusion reactions, headache, thrombosis risk in predisposed patients; monitoring needed. Evidence of benefit in reported CEDS cases and standard practice in antibody deficiencies. NIAID

2) Antiviral prophylaxis (e.g., acyclovir for HSV/VZV-prone patients).
Class: Nucleoside analog antiviral. Why: CEDS patients can have recurrent mucocutaneous herpesvirus infections; low-dose prophylaxis reduces outbreaks. Mechanism: Inhibits viral DNA polymerase after phosphorylation. Risks: Renal dosing, rare neurotoxicity; monitor hydration and kidney function. Used successfully in early NIH experience. Wikipedia

3) Targeted antibiotic prophylaxis (e.g., azithromycin or TMP-SMX in select patients).
Class: Macrolide or sulfonamide/folate pathway inhibitor. Why: For frequent bacterial sinopulmonary infections or bronchiectasis, long-term low-dose prophylaxis may cut exacerbations. Mechanism: Antibacterial; macrolides may have anti-inflammatory airway effects. Risks: GI upset, QT prolongation (macrolides), allergy; periodic review to prevent resistance. PMC

4) Aggressive treatment of acute infections (pathogen-directed).
Class: Standard antimicrobials per culture/PCR. Why: Rapid control prevents complications such as bronchiectasis. Risks: Usual antibiotic adverse effects and stewardship considerations. PMC

5) Inactivated vaccines; avoidance of live vaccines when cellular immunity is significantly impaired.
Class: Vaccines (inactivated). Why: Reduce preventable infections safely; live vaccines may pose risks in some immunodeficiencies. Mechanism: Stimulates protective immunity without live replication. Risks: Typical local/systemic reactogenicity. NIAID

6) Anti-inflammatory/IBD therapies when needed (case-by-case).
Class/examples: 5-ASA, budesonide or short steroid courses, biologics only with immunology oversight. Why: Some CEDS patients develop IBD-like inflammation. Mechanism: Dampen mucosal inflammation. Risks: Infection risk trade-offs; careful selection/monitoring required. wjwch.com

7) Pneumocystis jirovecii prophylaxis in selected lymphopenic patients.
Class: TMP-SMX. Why: Standard in many cellular immunodeficiencies at risk for PJP; considered case-by-case in CEDS with profound T-cell dysfunction. Risks: Allergy, cytopenias; alternatives exist if sulfa-allergic. NIAID

Dietary molecular supplements

No supplement has proven disease-modifying benefit in CEDS. General nutrition helps immune resilience but doesn’t replace IVIG/prophylaxis.

• Balanced protein-adequate diet to support tissue repair and antibody production; correct iron, B12, folate if deficient. NIAID

• Vitamin D repletion if low (common in chronic illness) for skeletal health and general immunity; avoid mega-doses. NIAID

• Zinc only if deficient; excess zinc can impair copper absorption. NIAID

• Omega-3s (food-first) for cardiometabolic health and mild anti-inflammatory effects; adjunctive at best. NIAID
  (Because high-quality CEDS-specific supplement trials don’t exist, any list of “10 molecular supplements” would be speculative. Keep focus on lab-confirmed deficiencies and food-based nutrition.) NIAID

Immunity-booster / regenerative / stem-cell” options

Hematopoietic stem-cell transplantation (HSCT).
For severe, refractory CEDS with significant infections/immune dysregulation, HSCT can be curative by replacing the defective immune system. Case reports (including a first report from India) describe successful outcomes after haploidentical HSCT. Timing, donor choice, conditioning, and risks (GVHD, infection) require tertiary-center expertise. wjwch.com

(There are no approved “stem-cell drugs” or gene-editing therapies for CEDS as of now.) PMC

Procedures / surgeries (used sparingly)

Most CEDS care is medical, not surgical. Potential procedures are supportive and individualized:

• Central venous access for frequent IVIG/antibiotics when home infusions aren’t feasible. Risks: line infections/thrombosis; SCIG can avoid lines. NIAID

• Sinus surgery for unresponsive chronic sinus disease despite maximal medical therapy. PMC

• Bronchoscopy / airway procedures for mucus plugging/bronchiectasis evaluation. PMC

• Splenectomy is generally avoided in primary immunodeficiencies unless compelling indications, due to sepsis risk. NIAID

• HSCT (see above) as the primary definitive “procedural” option in selected severe cases. wjwch.com

Prevention

1. Keep inactivated vaccines current; assess need for additional pneumococcal/flu/COVID-19 boosters. NIAID

2. Consider prophylactic antivirals/antibiotics if infections are frequent. Wikipedia

3. Start/maintain IVIG/SCIG if indicated by antibody deficiency or poor responses. NIAID

4. Household vaccination and infection-control “cocoon.” NIAID

5. Hand hygiene/masks during outbreaks or high-risk seasons. NIAID

6. Prompt care for fevers (have an action plan). NIAID

7. Pulmonary care to prevent bronchiectasis progression. PMC

8. Dental/ENT follow-up to reduce chronic sources of infection. PMC

9. Nutrition optimization and treat deficiencies. NIAID

10. Early HSCT referral for severe, poorly controlled disease. wjwch.com

When to see a doctor (red-flags)

• Any fever ≥38 °C (100.4 °F) or chills, especially with cough, shortness of breath, severe sore throat, or rash.

• Recurrent sinus/chest infections, weight loss, night sweats, or enlarging lymph nodes/spleen.

• Persistent diarrhea, blood in stool, or abdominal pain suggestive of IBD-like inflammation.

• Poor wound healing, unusual or severe viral outbreaks (e.g., herpes).

• Before live vaccines are considered for any reason, and before travel.
  These red-flags reflect the recognized infection/inflammation patterns in CEDS and related primary immunodeficiencies. NIAID+1

What to eat and what to avoid

• Eat: balanced meals with lean protein, whole grains, legumes, fruits/vegetables; dairy or fortified alternatives for calcium/vitamin D; adequate fluids. Support gut health with fiber (adjust during flares). Correct specific deficiencies (iron, B12, folate, vitamin D) guided by labs. NIAID

• Avoid/limit: unpasteurized dairy, undercooked meats/eggs, high-risk raw foods (e.g., raw sprouts) due to infection risk; excessive alcohol; “mega-dose” supplements that promise immune “boosting” without evidence. NIAID

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FAQs

1) Is CEDS the same as ALPS?
No. They overlap, but CEDS combines lymphoproliferation with true immunodeficiency (poor T/B/NK activation), while classic ALPS is primarily apoptosis failure with autoimmunity. NCBI

2) How is CEDS inherited?
Autosomal recessive—both gene copies have to be altered. Carriers (one copy) are typically healthy. NIAID

3) What gene is involved?
CASP8, which encodes the caspase-8 enzyme (apical caspase in death-receptor pathways and signaling to NF-κB). SpringerLink

4) What are the most common symptoms?
Recurrent respiratory/sinus infections, enlarged lymph nodes and spleen, low antibodies, sometimes chronic diarrhea/IBD-like disease. PMC

5) How is the diagnosis confirmed?
Immune testing (immunoglobulins, vaccine responses, lymphocyte function) plus genetic testing for CASP8 variants. NCBI

6) What’s the usual treatment?
Immunoglobulin replacement, targeted antimicrobial prophylaxis, prompt treatment of infections, vaccination with inactivated vaccines, and HSCT in severe cases. wjwch.com+3NIAID+3Wikipedia+3

7) Is there a cure?
HSCT can be curative by rebuilding the immune system; decisions are individualized. wjwch.com

8) Are biologic drugs (e.g., anti-TNF) safe?
They may increase infection risk; use only if clearly indicated for complications (like IBD-like disease) and with expert oversight. wjwch.com

9) Can people with CEDS receive live vaccines?
Often avoided when cellular immunity is significantly impaired; immunology teams decide case-by-case. NIAID

10) What about antivirals like acyclovir long-term?
Used in some patients with recurrent herpesvirus infections to reduce outbreaks. Wikipedia

11) Does CEDS cause cancer?
Lymphoma has not been clearly observed in reported CEDS cohorts to date, but long-term numbers are small; routine surveillance is prudent. Wikipedia

12) Why do some patients have gut disease?
Loss of caspase-8 can unleash inflammatory cell-death pathways and inflammasome activity in the intestine, promoting IBD-like inflammation. BioMed Central

13) Why is NF-κB mentioned so often?
Because caspase-8 helps turn on NF-κB after receptor signals; without it, immune cells can’t activate properly. PMC

14) Can adults present with CEDS?
Yes—rarely—with late-onset multi-organ lymphocytic infiltrates and granulomas. Europe PMC

15) Where can families find authoritative information?
The NIAID/NIH overview and fact sheet, peer-reviewed case reports/reviews, and centers specializing in inborn errors of immunity. NIAID+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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