Chédiak-Higashi Syndrome (CHS)

• Chédiak-Higashi Syndrome (CHS) is a genetic disorder resulting from mutations in the LYST gene.
• LYST gene mutations disrupt the function of lysosomes, affecting their structure and function in cells throughout the body.
• A dysfunctional immune system results from these mutations, leaving patients susceptible to infections.
• CHS is a rare disorder, with about 200 cases reported worldwide.
• Without treatment, most children with CHS enter an accelerated phase, leading to abnormal bleeding, infections, and organ failure.
• CHS damages the immune system and increases susceptibility to infections.
• Oculocutaneous albinism is a characteristic of CHS, causing vision problems, involuntary eye movements, and photophobia.
• CHS is also known as ocular cutaneous albinism with leukocyte defect.
• Abnormal lysosome-like structures inside platelets can cause abnormal bruising and bleeding in CHS patients.
• Albinism is a non-contagious, congenital condition marked by a reduction or complete lack of pigmentation in hair, skin, and eyes.
• Melanin subtypes range in color from black to red to yellow; the relative quantity and rate at which they're metabolized define a person's skin color.
• Melanin acts as a natural sunscreen, dissipating UVB light to prevent DNA damage in skin cells.
• Albinism results from a recessive gene mutation affecting enzymes needed for melanin production, reducing the amount of melanin produced.
• Albinism can occur with mutations in proteins responsible for tyrosine or linosome transport.
• CHS is linked to hypopigmentation, recurrent infections, mild coagulation defects, and varying neurological problems.
• Symptoms of albinism include reduced pigmentation, white hair, milky white skin, and light blue or translucent irises.
• Absence of melanin in the eyes can lead to vision problems, ranging from focusing and depth perception to nystagmus and amblyopia.
• Lack of melanin can cause freckles, moles, and lentigines to form on the skin, increasing the risk of skin cancers.
• Diagnosis is initially made clinically, but a skin biopsy or hair wool test can confirm the presence of melanin; genetic testing can give a definitive diagnosis.
• Treatment for albinism focuses on preventing additional ailments from lack of melanin, such as wearing tinted glasses or sunscreen.

Etiology of CHS

• Caused by mutations in the LYST (Lysosomal Trafficking Regulator) gene.
• The LYST gene encodes a protein crucial for lysosomal trafficking and function.
• Mutations disrupt lysosomal function, affecting their size, structure, and ability to process materials.
• These mutations lead to defects in immune cells, platelets, and pigmentation.

Epidemiology of CHS

• An extremely rare genetic disorder, with about 200 reported cases worldwide.
• Inherited in an autosomal recessive manner, requiring two copies of the mutated gene for the disease to develop.
• Untreated children often develop an accelerated phase characterized by abnormal bleeding, recurrent infections, and organ failure.

Abnormal Bleeding

• Platelet dysfunction can cause abnormal bleeding
• Platelets contain dense granules that store and release molecules important for clot formation.
• CHS involves lysosome-related organelle dysfunction, including platelet dense granules.
• Granules are abnormally large and dysfunctional, impairing platelet aggregation and causing prolonged bleeding times and increased bruising.

Recurrent Infections

• Immune dysfunction can cause recurrent infections
• Neutrophils and phagocytes rely on lysosomes to degrade pathogens.
• CHS neutrophils have defective phagolysosome fusion, leading to inefficient destruction of bacteria and frequent infections.
• Natural killer (NK) cells and cytotoxic T cells require proper lysosomal function to release lytic granules.
• Their dysfunction results in poor viral defense.

Organ Failure

• Lysosomal defects affecting multiple tissues can cause organ failure
• CHS patients have defective phagolysosome fusion, impairing pathogen destruction by macrophages, neutrophils, and cytotoxic T cells.
• This leads to chronic infections and immune activation, potentially triggering hemophagocytic lymphohistiocytosis (HLH).
• HLH leads to overactive macrophages that engulf healthy blood cells, causing bone marrow failure, uncontrolled cytokine release, systemic inflammation, and tissue damage.
• Excessive immune cell infiltration in organs leads to hepatosplenomegaly and multi-organ failure.
• Giant lysosome accumulation can damage the nervous system, leading to neurological decline, weakness, and ataxia.

Pathogenesis of CHS

• CHS primarily affects the immune system and pigmentation through dysfunctional lysosomes.
• Melanosomes, responsible for melanin storage and transport, are lysosome-related organelles (LROs).
• Mutations in the LYST gene disrupt melanosome formation and transport, leading to partial albinism (hypopigmentation).
• The immune system is compromised, increasing susceptibility to infections.
• CHS is associated with oculocutaneous albinism, causing vision problems, photophobia, and nystagmus.
• Platelet abnormalities lead to excessive bruising and bleeding disorders.

What is Albinism?

• A genetic condition caused by mutations in genes responsible for melanin production.
• Melanin protects against UV radiation in the skin, hair, and eyes.
• Individuals with albinism have very light skin, white or light-colored hair, and light-colored or translucent irises.
• Lack of melanin can cause nystagmus.
• Underdeveloped fovea can lead to poor visual acuity and nystagmus
• Albinism can cause amblyopia.
• Misrouting of optic nerve fibers can lead to abnormal binocular vision
• Albinism can cause photophobia.
• The retinal pigment epithelium (RPE) relies on melanin to absorb light

Skin Layers

• Epidermis is the outermost layer with keratinocytes for protection.
• Dermis contains hair follicles, nerves, and blood vessels.
• Hypodermis is the deepest layer, anchoring the skin to muscles.
• Melanocytes in the basal layer of the epidermis produce melanin using tyrosine.
• Albinism disrupts melanin production, leading to hypopigmentation.
• Melanin absorbs and scatters UVB light, protecting DNA.

CHS Relation to Albinism

• CHS is sometimes called "oculocutaneous albinism with leukocyte defect".
• CHS disrupts melanosomes, leading to albinism-like features.

CHS & Albinism Diagnosis

• Diagnosis is made based on clinical signs such as hypopigmentation and recurrent infections.
• Confirmation tests include microscopic examination of white blood cells, genetic testing for LYST mutations, and skin/hair bulb biopsy.

CHS & Albinism Treatments

• Treatment options include managing immune dysfunction, bleeding disorders, and albinism symptoms.
• Immune dysfunction can be managed with antibiotics and bone marrow transplants.
• Bleeding disorders can be managed with platelet transfusions and avoiding risky activities.
• Albinism symptoms can be managed with tinted glasses, sunscreen, and low-vision aids.
• Gene therapy and enzyme replacement therapy are potential future therapies.

Recap On CHS

• Caused by LYST gene mutations, leading to lysosomal dysfunction.
• Immune system is severely compromised, resulting in frequent infections.
• Linked to albinism, leading to pale skin and vision problems.
• Bone marrow transplants can improve immune function; supportive treatments manage symptoms.
• Early diagnosis is crucial for managing CHS and improving quality of life.

Foveal Hypoplasia & Nystagmus Mechanism

• Reduced melanin impairs the development of the fovea, leading to poor visual acuity and subsequent involuntary eye movements as the brain struggles to focus.

Melanin's Role in Skin Cell Protection Mechanism

• Melanin absorbs and scatters UVB light, protecting DNA from damage; its absence increases susceptibility to DNA mutations and skin cancer.

Consequences of Giant Lysosomes Accumulation Mechanism

• The dysfunctional lysosomes impair critical cellular processes, leading to energy depletion and cellular dysfunction, ultimately resulting in organ damage.

Melanosomes Role in Pathogenesis of Albinism Mechanism

• Melanosomes are responsible for storing and transporting melanin, and their formation and transport are disrupted in CHS, leading to hypopigmentation.

CHS vs Other Albinism Mechanism

• CHS is characterized by defective lysosomal function affecting melanosome formation and immune cell function, while other forms of albinism primarily involve mutations in genes directly related to melanin production.

HLH's Role in the Accelerated Phase of CHS Mechanism

• HLH leads to uncontrolled cytokine release and overactive macrophages engulfing healthy blood cells, resulting in systemic inflammation, organ damage, and bone marrow failure.

Adult Immunity Considerations

• As a person ages, there is a weakening of the immune system
• Immunity from childhood vaccinations wanes over time
• Changes in environment and genetics can alter an individual’s risk for certain diseases.
• Widespread vaccination has significantly reduced the morbidity and mortality of many infectious diseases.
• Epidemiological factors like birth rates, aging populations, and vaccination adherence influence disease patterns.
• Ongoing research guides recommendations for new and existing adult vaccines.

Current CDC Adult Vaccine Recommendations

• COVID-19 Vaccine is essential for preventing severe illness.
• Influenza (Flu) Vaccine is recommended annually to prevent seasonal flu outbreaks.
• Td or Tdap Vaccine provides protection against tetanus, diphtheria, and pertussis.
• Additional vaccines may be recommended based on individual factors, Such as chronic health conditions, Occupation, and Travel history.

What Physicians Should Evaluate

• patient’s overall health
• age-based recommendations
• special medical circumstances
• contraindications and precautions

Specific Vaccine Guidelines

• COVID-19 Vaccine is recommended for everyone 5 years and older, with a 3-dose series in most cases.
• Influenza Vaccine is recommended annually for everyone 6 months and older.
• Tdap Vaccine should be administered if not received in adolescence, followed by a Td booster every 10 years.
• Pneumococcal Vaccine is recommended for adults 65+ and for younger adults with certain chronic illnesses.
• Shingles Vaccine is recommended for adults 50+, as the risk of shingles increases with age.

Tdap, Pneumonia & Shingles Vaccines

• Tdap can protect children from whooping cough
• Pneumonia and Shingles vaccinations may also be recommended

Considerations for Chronic Illnesses

• Chronic conditions like asthma, diabetes, and heart disease increase susceptibility to complications from vaccine-preventable diseases.

Real World Impact From Vaccines

• By getting the Tdap vaccine, adults protect both themselves and the children they work with.
• Staying up to date with essential vaccines helps prevent severe illness in at-risk populations.

Preventative Health

• Vaccination is an essential part of preventive healthcare.
• Adults should regularly review their vaccination status with their healthcare provider.
• Continue learning and discussing key vaccine concepts to enhance public health awareness.

Influenza Vaccine Types

• IIV4 (Inactivated Influenza Vaccine, Quadrivalent) / RIV4 (Recombinant Influenza Vaccine, Quadrivalent) is recommended for pregnancy and immunocompromised patients