A 6-year-old child presents for evaluation of a medical condition associated with recurrent infections. After reviewing all of the medical history, gene therapy is offered to treat a deficiency in adenosine deaminase (ADA). ADA deficiency is the most common autosomal recessive mutation in which of the following diseases?

Severe Combined Immunodeficiency

A 24-year-old woman comes to the clinic complaining of headache and sinus drainage for the past 13 days. She reports cold-like symptoms 2 weeks ago that progressively got worse. The patient endorses subjective fever, congestion, sinus headache, cough, and chills. She claims that this is her 5th episode within the past year and is concerned if “there’s something else going on.” Her medical history is significant for asthma that is adequately controlled with her albuterol inhaler. Her laboratory findings are shown below: Serum: Hemoglobin: 16.2 g/dL Hematocrit: 39 % Leukocyte count: 7,890/mm^3 with normal differential Platelet count: 200,000/mm^3 IgA: 54 mg/dL (Normal: 76-390 mg/dL) IgE: 0 IU/mL (Normal: 0-380 IU/mL) IgG: 470 mg/dL (Normal: 650-1500 mg/dL) IgM: 29 mg/dL (Normal: 40-345 mg/dL) What is the most likely diagnosis?

Common variable immunodeficiency

A 2-year-old girl presents with high fever, restlessness, and a generalized papulovesicular rash. Past medical history is significant for varicella pneumonia and disseminated cytomegalovirus infection during the 1st year of her life. She was delivered vaginally to a primigravid 22-year-old woman from an uncomplicated pregnancy and was breastfed up to 9 months of age. She is up to date with her vaccines and is meeting all developmental milestones. The vital signs include blood pressure 70/45 mm Hg, heart rate 110/min, respiratory rate 27/min, and temperature 38.0°C (100.4°F). Physical examination demonstrates a generalized papulovesicular rash without a tendency to fuse. The rest of the physical examination is unremarkable for any pathological findings. Disseminated herpes virus infection is suspected. The child is also assessed for primary immunodeficiency. Flow cytometry reveals the absence of CD56 positive cells. Which of the following is true regarding these cells in this patient?

They have cell surface receptors for detecting MHC 1 on other cells

They differentiate from the myeloid progenitor

These cells also express the T cell receptor

They are the part of adaptive immunity

They need MHC class 1 to be expressed on the cell to eliminate it

A 9-month-old girl is brought in by her father for a scheduled check-up with her pediatrician. He states that over the past 4-5 months she has had multiple ear infections. She was also hospitalized for an upper respiratory infection 2 months ago. Since then she has been well. She has started to pull herself up to walk. Additionally, the patient’s medical history is significant for eczema and allergic rhinitis. The father denies any family history of immunodeficiencies. There are no notable findings on physical exam. Labs are remarkable for low IgG levels with normal IgA, IgE, and IgM levels. Which of the following is the most likely etiology for the patient’s presentation?

Delayed onset of normal immunoglobulins

Failure of B-cell differentiation

Defect in Bruton tyrosine kinase

A 6-month-old baby boy presents to his pediatrician for the evaluation of recurrent bacterial infections. He is currently well but has already been hospitalized multiple times due to his bacterial infections. His blood pressure is 103/67 mm Hg and heart rate is 74/min. Physical examination reveals light-colored skin and silver hair. On examination of a peripheral blood smear, large cytoplasmic vacuoles containing microbes are found within the neutrophils. What diagnosis do these findings suggest?

Leukocyte adhesion deficiency-1

Common variable immunodeficiency

Acquired immunodeficiency syndrome

A 1-year-old infant is brought to the emergency department by his parents because of fever and rapid breathing for the past 2 days. He had a mild seizure on the way to the emergency department and developed altered sensorium. His mother states that the patient has had recurrent respiratory infections since birth. He was delivered vaginally at term and without complications. He is up to date on his vaccines and has met all developmental milestones. His temperature is 37.0°C (98.6°F), pulse rate is 200/min, and respirations are 50/min. He is lethargic, irritable, and crying excessively. Physical examination is notable for a small head, an elongated face, broad nose, low set ears, and cleft palate. Cardiopulmonary exam is remarkable for a parasternal thrill, grade IV pansystolic murmur, and crackles over both lung bases. Laboratory studies show hypocalcemia and lymphopenia. Blood cultures are drawn and broad-spectrum antibiotics are started, and the child is admitted to the pediatric intensive care unit. The intensivist suspects a genetic abnormality and a fluorescence in situ hybridization (FISH) analysis is ordered which shows 22q11.2 deletion. Despite maximal therapy, the infant succumbs to his illness. The parents of the child request an autopsy. Which of the following findings is the most likely to be present on autopsy?

Hypertrophy of Hassall's corpuscles

Absent follicles in the lymph nodes

Immunodeficiency disorders for USMLE Step 1: High-Yield Pathology Lessons

B-Cell Deficiencies - Antibody Factory Shutdown

X-Linked Agammaglobulinemia (Bruton):
- Defect in BTK gene → no B-cell maturation.
- Presents after 6 months as maternal IgG wanes.
- Recurrent bacterial infections (encapsulated), especially sinopulmonary & GI.
Selective IgA Deficiency:
- Most common primary immunodeficiency.
- Usually asymptomatic; may have recurrent sinopulmonary/GI infections.
⭐ Risk of anaphylaxis during blood transfusion due to anti-IgA antibodies.
Common Variable Immunodeficiency (CVID):
- Defective B-cell differentiation, presents 20-40 years old.
- ↓ Plasma cells, ↓ immunoglobulins.
- Increased risk of autoimmune disease & lymphoma.

B-cell development pathway with immunodeficiency defects

T-Cell Deficiencies - General Under Attack

Presentation: Recurrent infections with intracellular pathogens (viruses, fungi, protozoa), particularly opportunistic ones.
Key Pathogens: Candida, Pneumocystis jirovecii (PJP), CMV, EBV, JC virus, VZV.
Lab Findings: ↓ T-cell count (lymphopenia), ↓ CD4+ or CD8+ cells. Absent/reduced thymic shadow on CXR in some syndromes.
⚠️ Warning: Avoid all live vaccines (MMR, varicella, rotavirus, intranasal influenza).
Examples: DiGeorge Syndrome, IL-12R Deficiency, Job Syndrome, Chronic Mucocutaneous Candidiasis.

⭐ T-cell defects primarily impair immunity against intracellular microbes and increase risk for malignancy due to poor tumor surveillance.

Combined B & T-Cell - Total System Failure

Severe Combined Immunodeficiency (SCID)
- Most common: IL-2R gamma chain defect (X-linked).
- Also: Adenosine Deaminase (ADA) deficiency (AR).
- Presents with failure to thrive, chronic diarrhea, thrush, and recurrent severe infections (viral, fungal, protozoal).
- Lab findings: Absent T-cells, no thymic shadow on CXR.
Ataxia-Telangiectasia
- Defect in the ATM gene, which repairs DNA double-strand breaks.
- 📌 Triad: cerebellar defects (Ataxia), spider Angiomas (telangiectasias), IgA deficiency.
- Labs: ↑ AFP.
Wiskott-Aldrich Syndrome (XLR)
- 📌 WATER: Wiskott-Aldrich, Thrombocytopenia, Eczema, Recurrent infections.

⭐ In SCID, the absence of a thymic shadow on a newborn chest X-ray is a classic diagnostic clue, indicating a lack of T-cell development.

Chest X-ray: Absent Thymic Shadow in SCID Newborn

Phagocyte & Complement - Cleanup Crew Chaos

Leukocyte Adhesion Deficiency (LAD-1)
- Defect in LFA-1 integrin (CD18 subunit).
- Features: Delayed separation of umbilical cord (>30 days), recurrent skin/mucosal infections without pus, marked neutrophilia.
Chédiak-Higashi Syndrome
- Mutation in LYST gene; impaired phagolysosome fusion.
- Features: Giant granules in granulocytes, partial albinism, progressive neurodegeneration, recurrent pyogenic infections.
Chronic Granulomatous Disease (CGD)
- Defective NADPH oxidase; ↓ respiratory burst.
- Recurrent infections with catalase-positive organisms (S. aureus, Aspergillus).
- Dx: Abnormal dihydrorhodamine (DHR) test.

Phagocyte function and respiratory burst in immunity

⭐ Terminal Complement Deficiency (C5-C9) Patients present with recurrent infections by encapsulated bacteria, especially Neisseria spp. (gonorrhea or meningitis).

X-linked agammaglobulinemia: BTK gene defect. No B-cells. Recurrent bacterial infections after 6 months.

CVID: Low immunoglobulins in adults. High risk of autoimmune disease & lymphoma.

DiGeorge Syndrome: 22q11 deletion. T-cell deficiency (no thymus), hypocalcemia, cardiac defects.

SCID: Defective T and B cells. Severe recurrent infections. Requires stem cell transplant.

Wiskott-Aldrich: X-linked triad: Thrombocytopenia, Infections, Eczema (TIE).

Ataxia-Telangiectasia: ATM gene defect. Triad: Ataxia, Telangiectasias, IgA deficiency.

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