Immunological Pathologies Flashcards
What disorder involves the triad of recurrent infections with encapsulated organisms, eczema and purpura?
Wiskott-Aldrich syndrome
A congenital (x-linked recessive, only occurring in males) immunodeficiency that is characterized by the classic triad of eczema, thrombocytopenic purpura, and recurrent opportunistic infections (otitis media).
Caused by a mutation in the WAS gene, which results in impaired signaling to actin cytoskeleton reorganization and therefore impaired T-cell function and thrombocytopenia
Leads to low T Cell counts, normal B cell counts, and low platlets.
Which antibodies are decreased in Wiskott-Aldrich syndrome (WAS)?
IgG and IgM
can be low or normal values.
Which antibodies are elevated in Wiskott-Aldrich syndrome (WAS)?
IgE and IgA
In patients with WAS, the rate of IgA synthesis is significantly increased.
What gene leads to the x-linked recessive immunodeficiency that is characterized by the classic triad of eczema, thrombocytopenic purpura, and recurrent opportunistic infections?
Caused by a mutation in the WAS gene, on the X chromosome, which is inherited in an X-linked recessive manner.
Mutations result in impaired signaling to actin cytoskeleton reorganization and therefore impaired T-cell function and thrombocytopenia.
Diagnosis is confirmed with genetic analysis of the mutated WAS gene.
WATER:
Wiskott-Aldrich:
Thrombocytopenia (purpura)
Eczema
Recurrent (pyogenic) infections
Wiskott-Aldrich syndrome (WAS) will show what on a peripheral blood smear?
microthromocytes in low amounts (thrombocytopenia).
What is the appropriate treatment for the disease causing thrombocytopenia, eczema, and recurring opportunistic infections?
Treatment for Wiskott-Aldrich syndrome:
• IV immunoglobulin therapy
• Prophylactic antibiotics
• Platelet transfusions
• Stem cell transplantation (curative)
What must be avoided with Wiskott-Aldrich syndrome?
Live attenuated vaccines
A group of vaccines containing a modified virus or bacterium that are no longer pathogenic but are able to replicate within the host’s body. These vaccines trigger a humoral and cellular immune response that usually provides lifelong immunity. Contraindicated in pregnancy and immunocompromised patients because of the risk of reverting to virulent forms. Examples include vaccines against mumps-measles-rubella, varicella, zoster, rotavirus, yellow fever, influenza (intranasal), typhoid (oral), smallpox, and adenovirus.
What is the prognosis ofWiskott-Aldrich syndrome?
Death in the first year with no treatment.
Even with treatment, patients usually have a shortened life expectancy.
Increased risk of autoimmune diseases and hematological malignancies
(e.g., lymphoma, leukemia).
Which immunodeficiencies are associated with anaphylaxis during blood transfusion?
Selective IgA deficiency, Common Variable Immunodeficiency (CVID), Bruton’s agammaglobulinemia, and Hyper-IgM syndrome.
These conditions may lead to anaphylaxis due to the development of anti-IgA antibodies (common in IgA deficiency and CVID) or exposure to foreign immunoglobulins not native to the host.
What is the most common cause for the most common primary immune deficiency?
Selective IgA deficiency is the most common primary immune deficiency.
The cause is unknown.
What is the prevalence of selective IgA deficiency?
It is the most common primary immunodeficiency, with a prevalence of approximately 1 in 300–1,500 individuals, varying by population.
What are the hallmark features of selective IgA deficiency?
IgA is low or completely absent (<7 mg/dL) with normal levels of IgG and IgM, increasing susceptibility to mucosal infections (e.g., respiratory, gastrointestinal).
Most patients are ASYMPTOMATIC. Clinical manifestations are highly variable and range from asymptomatic to recurrent sinopulmonary (mostly caused by encapsulated bacteria, e.g., S. pneumoniae, H. influenzae) and GI infections (due to Giardia lamblia), as secretory IgA antibodies are a crucial part of mucosal defense.
Atopic diseases.
Sprue-like conditions (gluten-sensitive enteropathy) and fat malabsorption (chronic diarrhea).
Autoimmune diseases.
Anaphylaxis to blood products.
Why are nosebleeds common with Selective IgA deficiency?
These patients have an increased risk for developing other autoimmune issues like ITP, which can cause ITP (among other autoimmune issues), leading to bleeding diathesis. Additionally, they tend to have increased irritation in their mucosa due to atopy, infection, and inflammation. Combined, this all increases risk for nosebleeds (epistaxis).
What differentiates CVID from selective IgA deficiency in the context of transfusion reactions?
Both conditions may lead to anti-IgA antibodies, but CVID involves low levels of multiple immunoglobulins (IgG, IgA, and/or IgM), whereas selective IgA deficiency affects only IgA.
What must be done while testing for Celiac disease in a patient with selective IgA deficiency?
Test with IgG because the condition can cause false-negative celiac disease test, which normally uses IgA antibodies.
Selective IgA deficiency is associated with an increased risk of having which comorbidities?
Increased risk of:
- inflammatory bowel disease
- gluten sensitive enteropathy
- vitiligo
- thyroiditis
- RA
- immune thrombocytopenia
What lab test tends to be falsely positive with selective IgA deficiency?
Positive pregnancy tests.
Presumably due to heterophile antibodies interference with β-hCG tests
How should blood transfusions be managed in immunodeficient patients at risk of anaphylaxis?
Use IgA-depleted blood products or washed red blood cells to prevent exposure to IgA.
What laboratory test is used to confirm the presence of anti-IgA antibodies?
Enzyme-linked immunosorbent assay (ELISA) or other serological tests specifically for anti-IgA antibodies.
Decreased serum IgA levels (< 7 mg/dL)
Normal IgG and IgM levels
What is the primary treatment for anaphylaxis during transfusion in these patients?
Immediate administration of epinephrine.
Follow EPI with supportive care (oxygen, antihistamines, corticosteroids).
Why is anaphylaxis following transfusion more common in IgA-related deficiencies than other immunodeficiencies?
The absence of IgA allows the immune system to produce anti-IgA antibodies, which react to transfused IgA, triggering an allergic or anaphylactic reaction.
Why are anti-IgA antibodies formed in selective IgA deficiency?
The immune system recognizes IgA as foreign due to its absence in the body and produces IgE-mediated or other antibodies against it, which can trigger anaphylaxis upon re-exposure.
How is the management of transfusion anaphylaxis different in IgA deficiency vs. allergic transfusion reactions in general?
In IgA deficiency: Use IgA-depleted products.
For allergic transfusion reactions: Pre-medicate with antihistamines and/or corticosteroids.
How is selective IgA deficiency managed?
Treat infection(s)
Prophylactic antibiotics
Intravenous infusion of IgA is not recommended because of the risk of anaphylactic reactions (caused by the production of anti-IgA antibodies).
To prevent transfusion reactions, IgA-deficient patients must be given washed blood products without IgA or obtain blood from an IgA-deficient donor.
Which broader immunodeficiency syndrome can also involve anaphylaxis to transfusion and includes selective IgA deficiency?
Common Variable Immunodeficiency (CVID).
CVID patients may develop anti-IgA antibodies if they are IgA-deficient, similar to those with isolated IgA deficiency.
Why should patients with CVID or IgA deficiency avoid live vaccines?
These patients are immunocompromised and at risk for uncontrolled infections due to their inability to mount an adequate immune response.
What is the primary defect in CVID?
CVID involves low serum levels of all immunoglobulin classes due to B cells being phenotypically normal but unable to differentiate into immunoglobulin-producing cells.
Total protein will be low as it is a composite of albumin and immunoglobulins.
Patients have normal lymph tissue.
At what age does CVID typically present?
CVID usually presents later than other B-cell defects, typically between 20-40 years of age.
May present in childhood but usually diagnosed after puberty.
Does CVID affect females more than males?
No.
CVID affects male and female patient populations equally.
Is there a genetic component to CVID?
The occurrence is sporadic.
The pathogenesis of autoimmunity is poorly understood. Findings include an increase of CD21-/low cells in patients with CVID, which is thought to be linked to autoimmune reactions. In addition, defects of regulatory immune responses and tolerance to self-antigens have been found in patients with CVID as well as genetic mutations associated with autoimmunity.
What are the most common infections in CVID?
Recurrent pyogenic respiratory infections, including sinopulmonary infections.
What malignancies are associated with CVID?
Patients are at high risk of developing lymphoma and gastric cancer.
What pulmonary issues are associated with CVID?
Bronchiectasis.
Pneumonia.
What GI issue is associated with CVID?
Chronic diarrhea.
What autoimmune issues are associated with CVID?
- rheumatoid arthritis
- autoimmune hemolytic anemia
- pernicous anemia
- immune thrombocytopenia
How is CVID diagnosed?
Diagnosis involves:
- Low immunoglobulin levels (IgG, IgA, IgM).
- Decreased number of plasma cells.
- Poor response to immunizations.
- Flow cytometry showing subsets of normal B and T cells.
What is the treatment for CVID?
- Treat active infections.
- IV immunoglobulin (IVIG) to replace deficient immunoglobulins.
- Prophylactic antibiotics to prevent infections.
Why are patients with CVID poor responders to vaccines?
Due to defective antibody production despite normal B-cell numbers.
Patients with CVID have an increased chance of developing what malignancy?
non-Hodgkin lymphoma.
What is Transient Hypogammaglobulinemia of Infancy (THI)?
THI is an age-related delay in immunoglobulin production despite normal B-cell levels, which typically resolves by 2-6 years of age.
What is the typical onset age for THI?
Onset is after 6 months of age, as maternal IgG wanes.
What are the common clinical features of THI?
- Recurrent infections: sinopulmonary infections, otitis media, bronchitis, tonsillitis, diarrhea.
- Atopic manifestations: asthma, food allergies.
- Failure to thrive or developmental delay (in severe cases).
How is THI diagnosed?
- Low IgG levels (≥2 SD below age-appropriate levels).
May also have low IgA and IgM levels.
Presence of specific post-exposure or post-immunization IgG antibodies.
Flow cytometry showing normal B and T-cell subsets.
What are the treatments for THI?
- Prophylactic antibiotics for recurrent infections.
IVIG for severe or invasive infections.
Routine immunizations remain appropriate.
What are the complications of severe THI?
Rare complications include meningitis and bacteremia.
How can THI be differentiated from CVID?
THI resolves spontaneously by 2-6 years of age, whereas CVID persists into adulthood and involves autoimmune and malignant complications.
Can patients with SCID experience transfusion-related reactions?
Yes, SCID patients are at risk of graft-versus-host disease (GVHD) from transfused lymphocytes but are less commonly linked to anti-IgA antibody-mediated anaphylaxis.
What is the underlying defect in SCID?
SCID is caused by mutations leading to defective development of functional B cells and T cells.
What is the most common genetic mutation associated with SCID?
The X-linked recessive mutation in the gene encoding the common gamma chain (IL-2R gamma chain), linked to JAK3.
Name three common genetic causes of SCID besides the IL-2R gamma chain mutation.
Autosomal recessive mutations:
- Adenosine deaminase (ADA) deficiency, which causes toxic metabolite accumulation (e.g., dATP).
- Janus-associated kinase 3 (JAK3) deficiency independent of IL-2R.
- RAG mutations that affect V(D)J recombination.
What is the subtype of SCID caused by mutations in the RAG or ILRA7 gene?
Omenn syndrome.
What are common clinical features of SCID?
Normal at birth.
Severe recurrent infections (bacterial, viral, fungal, protozoal).
Chronic diarrhea.
Failure to thrive.
Absent lymph nodes and tonsils.
What are the characteristic clinical features of Omenn syndrome?
Onset before 3 months of age.
Erythroderma, adenopathy, and hepatosplenomegaly.
Severe recurrent infections.
Failure to thrive.
What infections are most frequently seen in SCID patients?
Bacterial diarrhea.
Oral thrush (chronic candidiasis).
Viral and protozoal infections.
How is Omenn syndrome diagnosed?
Oligoclonal T cells.
Eosinophilia.
Elevated IgE levels.
How is SCID typically diagnosed in newborns?
Quantitative PCR for T-cell receptor excision circles (TRECs), used in newborn screening.
Flow cytometry: Absent T cells.
Chest X-ray: Absent thymic shadow.
Lymph node biopsy: Absent germinal centers.
Why are lymph nodes and tonsils absent in SCID?
These structures rely on the presence of functional B and T cells, which are deficient in SCID.
What are the findings on imaging and biopsy in SCID?
Chest X-ray: Absent thymic shadow.
Lymph node biopsy: No germinal centers.
What is a major medical intervention that must be avoided with SCID?
Avoidance of live vaccines.
How does ADA deficiency in SCID affect purine metabolism?
ADA deficiency leads to:
Accumulation of toxic metabolites (e.g., deoxyadenosine and dATP).
dATP accumulation inhibits ribonucleotide reductase, impairing the generation of deoxynucleotides.
What laboratory finding is essential for newborn screening of SCID?
T-cell receptor excision circles (TRECs) are absent or low.
What is the treatment for SCID?
IV immunoglobulins (IVIG) for antibody replacement.
PCP prophylaxis (e.g., trimethoprim-sulfamethoxazole).
Bone marrow transplant or stem cell transplantation (curative).
What is the prognosis of SCID without treatment?
Fatal in the first year of life if untreated.
How can Hyper-IgM syndrome lead to transfusion-related anaphylaxis?
Patients with Hyper-IgM syndrome often have low IgA and IgG levels, predisposing them to form anti-IgA antibodies. Exposure to IgA-containing blood products can result in hypersensitivity reactions.
What is the underlying defect in Hyper-IgM syndrome?
A defect in CD40 ligand (CD40L) on T helper cells, which leads to impaired interaction with B cells, which have the CD40 molecule (receptor) and prevents class switching of immunoglobulins.
What is the most common inheritance pattern of Hyper-IgM syndrome?
X-linked recessive.
What is the most common mutation associated with Hyper-IgM syndrome?
CD40L deficiency.
Why are germinal centers absent in Hyper-IgM syndrome?
The absence of CD40-CD40L interaction prevents B-cell activation and formation of germinal centers in lymph nodes.
What are the hallmark clinical features of Hyper-IgM syndrome?
Recurrent severe pyogenic infections starting in childhood.
Opportunistic infections: Pneumocystis jirovecii pneumonia (PCP), Histoplasma infections, Cryptosporidium enteritis, which may lead to biliary disease, cirrhosis, and cholangiocarcinoma, and CMV hepatitis.
Failure to thrive.
What is the clinical picture of CMV hepatitis?
Common symptoms are prolonged malaise and fever.
Mild transaminitis (increased LFTs)
Elevated lactate dehydrogenase (LDH)
Normal to elevated bilirubin
How does Hyper-IgM syndrome predispose to biliary and liver complications?
Cryptosporidium infections can cause chronic inflammation of the biliary tree, leading to biliary disease, cirrhosis, or cholangiocarcinoma.
Which opportunistic infections are unique complications in Hyper-IgM syndrome compared to other immunodeficiencies?
Cryptosporidium enteritis, which can progress to biliary complications.
Fungal infections like Histoplasma and Pneumocystis jirovecii.
What are the diagnostic immunoglobulin levels in Hyper-IgM syndrome?
↓↓↓ IgG, IgA, IgE.
Normal or ↑ IgM.
What lymph node biopsy finding is associated with Hyper-IgM syndrome?
Absent germinal centers due to impaired B-cell activation and class-switching.
What supportive therapies are used in Hyper-IgM syndrome?
IV immunoglobulin (IVIG) replacement.
Prophylactic antibiotics to prevent infections.
Recombinant human granulocyte-colony stimulating factor for neutropenia.
What is the definitive treatment for Hyper-IgM syndrome?
Stem cell transplantation.
What distinguishes Hyper-IgM syndrome from other hypogammaglobulinemias?
Normal or elevated IgM levels due to impaired class-switching.
Specific susceptibility to opportunistic infections
(e.g., Pneumocystis jirovecii, Cryptosporidium).
How does Hyper-IgM syndrome differ from Bruton’s agammaglobulinemia?
Hyper-IgM syndrome involves normal or elevated IgM with low IgG, IgA, and IgE levels due to defects in class-switch recombination. Bruton’s involves low levels of all immunoglobulin classes due to a defect in B-cell maturation.
What is the immunoglobulin profile in Bruton’s agammaglobulinemia?
Profoundly low or absent IgG, IgA, and IgM levels due to a defect in B-cell maturation caused by mutations in the BTK gene.
What is the genetic defect in X-linked agammaglobulinemia (XLA)?
A mutation in the Bruton tyrosine kinase (BTK) gene, which is required for B-cell maturation.
X-linked recessive, meaning it primarily affects boys.
How does Bruton’s agammaglobulinemia affect B cells and immunoglobulins?
Results in absent mature B cells in the blood.
Low levels of all immunoglobulin classes (IgG, IgA, IgM).
At what age do symptoms of XLA typically begin, and why?
Symptoms begin between 3 and 6 months of age when maternal IgG wanes.
Suspect XLA in any male infant with recurrent bacterial infections (enteroviral) after 6 months of age.
What types of infections are common in Bruton’s agammaglobulinemia?
Recurrent, severe pyogenic infections, including pneumonia, otitis media, and sinusitis caused by encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
Enteroviral infections like hepatitis virus and enterovirus (e.g., Coxsackievirus).
Why are encapsulated bacteria a major concern in XLA?
Patients lack antibodies (specifically IgG) required for opsonization and clearance of encapsulated organisms.
What physical findings might suggest Bruton’s agammaglobulinemia?
Hypoplasia of lymphoid tissue (e.g., absent or small tonsils and lymph nodes).
Absent germinal centers and primary follicles in lymph node biopsy.
How is Bruton’s agammaglobulinemia diagnosed?
Flow cytometry: Absent or low B cells (marked by CD19, CD20, and CD21), leading to low levels of all immunoglobulins.
Absent lymphoid tissue, i.e., no germinal centers and primary follicles.
Normal or elevated T-cell levels.
Family history consistent with X-linked recessive inheritance.
Why do patients with Bruton’s agammaglobulinemia have normal T-cell function?
The defect is specific to B-cell maturation; T cells are unaffected and remain functional.
What infections should you suspect in a patient with recurrent enteroviral infections?
Bruton’s agammaglobulinemia, as enteroviral infections (e.g., Hepatitis and Coxsackievirus) are common due to poor mucosal immunity.
What is the cornerstone of treatment for Bruton’s agammaglobulinemia?
IV immunoglobulin (IVIG) therapy to replace missing antibodies.
Prophylactic antibiotics to prevent infections.
Are live vaccines contraindicated in Bruton’s agammaglobulinemia?
Yes, live vaccines (e.g., MMR, varicella) are contraindicated because these patients cannot mount an adequate immune response.
What is the manner by which a patient inherited the disorder that causes late separation (>30 days) of umbilical cord, absent pus, dysfunctional neutrophils recurrent skin and
mucosal bacterial infections?
Autosomal recessive inheritance
Absence of the β2-integrin leukocyte adhesion surface molecule LFA-1 (CD18) prevents leukocytes from migrating to tissues during infection or inflammation.
Causes a defect in LFA-1 integrin (CD18) protein on phagocytes leads to impaired migration and chemotaxis by C5a, IL-8, and leukotriene B4
Flow cytometry will show absent CD18, CD11a, CD11b, and CD11c.
Key Clinical Clues for Leukocyte Adhesion Deficiency (LAD)
Recurrent bacterial skin & mucosal infections
Absent pus despite severe infection
Leukocytosis with neutrophilia
(increased neutrophils in blood and an absence of neutrophils at infection sites with impaired wound healing)
Delayed umbilical cord separation (>30 days after birth).
What is the underlying developmental defect in DiGeorge syndrome?
A 22q11 microdeletion leads to the failure of development of the third and fourth pharyngeal pouches, leading to hypoplastic thymus and parathyroids.
What are the characteristic craniofacial anomalies in DiGeorge syndrome?
Prominent nasal bridge.
Ocular hypertelorism
Hypoplastic wing of the nose.
Dysplastic ears.
Micrognathia (small lower jaw) and/or retrognathia.
What additional anomalies seen on radiographic imaging is commonly seen in DiGeorge syndrome?
Absent thymic shadow on chest X-ray (also seen in SCID).
Additional features are: Cleft palate, flat cheek bones, wide set eyes, epicanthal folds, micrognathia, dysplastic ears, prominent nasal bridge, Developmental delay or intellectual disability, renal agenesis, and anal atresia, and other congenital GI abnormalities.
What is the mnemonic “CATCH-22” used for in DiGeorge syndrome?
Cardiac (conotruncal) anomalies.
Abnormal facies.
Thymic aplasia/hypoplasia.
Cleft palate.
Hypocalcemia.
22: Chromosome 22 deletion.
What is the inheritance pattern of Job Syndrome?
Autosomal dominant (STAT3), but sometimes autosomal recessive (DOCK8).
The autosomal dominant form (STAT3) is in many cases a de novo mutation.
Most patients have unaffected parents.
What are the characteristic clinical features of Job Syndrome?
Coarse facial features.
Recurrent cold abscesses (typically caused by Staphylococcus aureus and Candida).
Retained primary teeth (failure of normal exfoliation).
Hyper-IgE (with associated eosinophilia).
Dermatologic features (severe eczema).
Bone fragility, with increased risk of fractures due to decreased bone density.
Other than retained primary teeth, what other orthodontic issue is seen in Hyper-IgE (Job Syndrome)?
Gingival hypertrophy is also commonly associated.
Retained primary teeth is the more known orthodontic issue accompanying Job Syndrome.
What is the mnemonic FATED used for in Job Syndrome?
Facies (coarse facial [Leonine] features).
Abscesses (cold, recurrent).
Teeth (retained primary teeth).
Eosinophilia/Hyper-IgE.
Dermatologic findings (eczema).
Why are the abscesses in Job Syndrome described as “cold”?
They lack typical signs of inflammation (e.g., warmth, redness) because of defective neutrophil chemotaxis and cytokine signaling.
Cold abscesses are pathognomonic for Job Syndrome and differentiate it from other primary immunodeficiencies.
What dermatologic findings are common in Job Syndrome?
Severe eczema, often present from infancy.
What are the long-term complications of Job Syndrome?
Chronic lung disease (e.g., bronchiectasis and pneumatoceles).
Skeletal abnormalities (fractures and scoliosis).
Recurrent infections leading to significant morbidity.
What is the underlying defect in IPEX syndrome?
Dysfunctional regulatory T cells due to a mutation in the FOXP3 transcription factor, leading to unchecked T-cell activation and autoimmunity.
What dermatologic features are associated with IPEX syndrome?
Severe eczema.
Possible co-occurrence of other autoimmune dermatoses.
What are the common clinical features of CGD?
Recurrent severe infections involving:
Respiratory tract (most common manifestation is pneumonia).
GI and GU tract.
Granulomas in the skin, GI tract and urinary tract (leading to obstructions).
Apthous ulcers and inflammation of the nares with purulent material.
Lymphadenopathy.
Chronic inflammatory symptoms.
Skin, Lymph nodes (e.g., suppurative lymphadenitis), and Bones (osteomyelitis).
A 6-year-old boy is brought to the clinic by his parents due to recurrent infections and progressive weakness. Over the past year, he has had multiple episodes of otitis media, pneumonia, and skin abscesses. On examination, the child has partial albinism with silvery hair, hepatosplenomegaly, and generalized lymphadenopathy. Neurologic examination reveals decreased deep tendon reflexes and muscle weakness in the lower extremities.
The peripheral blood smear demonstrates neutrophils with large cytoplasmic granules. Laboratory tests show normal total leukocyte and platelet counts.
Which of the following is the most likely underlying cause of this child’s condition?
A) Deficiency in NADPH oxidase
B) Impaired phagosome-lysosome fusion
C) Mutation in STAT3 affecting Th17 cells
D) Impaired respiratory burst
E) Mutation in FOXP3 leading to loss of regulatory T cells
This child presents with the classic features of Chediak-Higashi Syndrome (CHS), an autosomal recessive disorder caused by a mutation in the LYST gene, leading to defective lysosomal trafficking and impaired phagosome-lysosome fusion in neutrophils and other cells.
Key features include:
- Progressive neurodegeneration: Manifesting as peripheral neuropathy and neurologic decline (e.g., weakness, decreased reflexes).
- Lymphohistiocytosis: Can lead to hepatosplenomegaly and lymphadenopathy due to an overactive inflammatory response.
- Albinism: Partial albinism (silvery hair, light skin) due to defective melanosome trafficking.
- Recurrent pyogenic infections: Particularly with Staphylococcus aureus and Streptococcus pyogenes, due to impaired neutrophil function.
- Peripheral neuropathy: Seen in advanced disease stages.
What is the genetic defect in Chediak-Higashi Syndrome (CHS)?
Autosomal recessive mutation in the LYST gene.
Microtubule polymerization dysfunction.
Leads to defective:
- Lysosomal trafficking
- Impaired phagosome-lysosome fusion
- Chemotaxis (neutropenia)
- serotinin and platelet defects
What is the hallmark pathophysiology of CHS?
Defective phagosome-lysosome fusion, causing impaired killing of ingested pathogens and the formation of giant granules in neutrophils and other cells.
Pancytopenia
Mild coagulation defects
What is the mnemonic to remember the key features of CHS?
ALPINe:
Albinism (partial, light-colored skin, silvery hair).
Lymphohistiocytosis (hepatosplenomegaly, lymphadenopathy).
Infections (recurrent pyogenic).
Neuropathy (progressive peripheral neuropathy and decreased reflexes).
Progressive neurodegeneration.
Neutropenia.
What is the pathognomonic finding on a peripheral blood smear in CHS?
Giant cytoplasmic granules in neutrophils and other white blood cells.
Diagnostic.
How is CHS diagnosed?
Peripheral smear: Shows giant granules in neutrophils.
Genetic testing: Confirms mutation in the LYST gene.
Immune function testing shows impaired intracellular pathogen killing.
A 7-year-old boy is brought to the pediatrician for evaluation of poor coordination and frequent infections. His parents note that he started walking later than expected and has progressively developed an unsteady gait. Physical examination reveals conjunctival telangiectasias, difficulty with tandem walking, and multiple scars from frequent respiratory infections. Laboratory studies show elevated alpha-fetoprotein (AFP) and decreased levels of IgA, IgG, and IgE.
Which of the following is the most likely underlying cause of this patient’s condition?
A) Defective phagosome-lysosome fusion
B) Mutation in STAT3 affecting Th17 cells
C) Impaired DNA repair due to an ATM gene defect
D) Defective respiratory burst in neutrophils
E) FOXP3 mutation causing loss of regulatory T cells
This child has Ataxia-Telangiectasia (AT), a rare autosomal recessive disorder caused by mutations in the ATM gene. The ATM protein is crucial for detecting DNA damage and halting the cell cycle for repair. Mutations result in: DNA instability, Increased risk of malignancies (e.g., lymphoma, leukemia), Immunodeficiency due to lymphopenia and reduced immunoglobulins.
Clinical features include:
- Cerebellar ataxia (progressive unsteady gait).
- Telangiectasias (spider-like blood vessels on the skin and conjunctiva).
- Immunodeficiency (frequent infections, low IgA, IgG, IgE).
- Increased alpha-fetoprotein (AFP).
- Hypersensitivity to ionizing radiation.
What portion of the cerebellum deteriorates with Ataxia-Telangiectasia?
Vermis
What physical examination findings are typical in Ataxia-Telangiectasia?
Cerebellar ataxia (unsteady gait, difficulty with coordination).
Telangiectasias (visible on conjunctiva and skin).
Spider Angiomas.
