A 7-month-old boy is brought in to his pediatrician’s office due to concern for recurrent infections. The parents state that over the last 3-4 months, the boy has had multiple viral respiratory infections, along with a fungal pneumonia requiring hospitalization. Currently he is without complaints; however, the parents are concerned that he continues to have loose stools and is falling off of his growth curve. Newborn screening is not recorded in the patient’s chart. On exam, the patient’s temperature is 98.4°F (36.9°C), blood pressure is 108/68 mmHg, pulse is 90/min, and respirations are 12/min. The patient is engaging appropriately and is able to grasp, sit, and is beginning to crawl. However, the patient is at the 20th percentile for length and weight, when he was previously at the 50th percentile at 3 months of age. Further screening suggests that the patient has an autosomal recessive immunodeficiency associated with absent T-cells. Which of the following is also associated with this disease?

Nonfunctional common gamma chain

Mutation in ATM DNA repair gene

Negative nitroblue-tetrazolium test

Which of the following patient presentations would be expected in an infant with defective LFA-1 integrin (CD18) protein on phagocytes, in addition to recurrent bacterial infections?

Skin infections with absent pus formation, delayed umbilicus separation

Cardiac defects, hypoparathyroidism, palatal defects, and learning disabilities

Chronic diarrhea, oral candidiasis, severe infections since birth, absent thymic shadow

Progressive neurological impairment and cutaneous telangiectasia

You are seeing a 4-year-old boy in clinic who is presenting with concern for a primary immune deficiency. He has an unremarkable birth history, but since the age of 6 months he has had recurrent otitis media, bacterial pneumonia, as well as two episodes of sinusitis, and four episodes of conjunctivitis. He has a maternal uncle who died from sepsis secondary to H. influenza pneumonia. If you drew blood work for diagnostic testing, which of the following would you expect to find?

Abnormally low number of B cells

Abnormally low number of T cells

Abnormally high number of B cells

Abnormally high number of T cells

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 5-year-old girl is brought to the emergency department by her mother with seizures. The blood glucose is 94 mg/dl and the serum calcium is 5.3 mg/dl; however, the PTH levels are low. The medical history includes a delay in achieving developmental milestones. Her mother also says she needs frequent hospital visits due to recurrent bouts with the flu. The cardiovascular examination is within normal limits. What is the most likely cause underlying this presentation?

Deletion of the chromosome 22q11

Lysosomal trafficking regulator gene defect

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

A 28-year-old man presents for severe abdominal pain and is diagnosed with appendicitis. He is taken for emergent appendectomy. During the procedure, the patient has massive and persistent bleeding requiring a blood transfusion. The preoperative laboratory studies showed a normal bleeding time, normal prothrombin time (PT), an INR of 1.0, and a normal platelet count. Postoperatively, when the patient is told about the complications during the surgery, he recalls that he forgot to mention that he has a family history of an unknown bleeding disorder. The postoperative laboratory tests reveal a prolonged partial thromboplastin time (PTT). Which of the following is the most likely diagnosis in this patient?

Thrombotic thrombocytopenic purpura

Primary immunodeficiencies for USMLE Step 1: High-Yield Pathology Lessons

Primary Immunodeficiencies - The Body's Defense Gaps

B-cell: X-Linked Agammaglobulinemia (Bruton): ↓ Ig of all classes. Defect in BTK.
T-cell: DiGeorge Syndrome: 22q11 deletion. Thymic aplasia. ↓ T-cells.
Combined: SCID: Defective T-cells; B-cell dysfunction is secondary. Multiple gene defects (e.g., IL-2R gamma chain, ADA).
Phagocytic: Chronic Granulomatous Disease (CGD): Defect in NADPH oxidase.

⭐ Absent thymic shadow on newborn chest X-ray is a classic sign of SCID.

B-Cell Blues - Antibody Production Problems

X-Linked Agammaglobulinemia (Bruton's):
- BTK gene defect → no B-cell maturation.
- Recurrent encapsulated bacterial infections after 6 months.
- Labs: ↓ all Igs, absent CD19+ B cells.
- Anatomy: Scanty tonsils/lymph nodes.
Selective IgA Deficiency:
- Most common primary immunodeficiency; isolated ↓ IgA.
- Mostly asymptomatic; may have sinopulmonary/GI infections, atopy.
- ⚠️ Anaphylaxis risk with blood products.
Common Variable Immunodeficiency (CVID):
- Defective B-cell differentiation; late onset (20s-40s).
- Labs: ↓ plasma cells, ↓ IgG & ↓ IgA/IgM.
- ↑ risk of autoimmune disease & lymphoma.

⭐ Patients with Selective IgA Deficiency can develop severe anaphylaxis when transfused with blood containing IgA, as their immune system recognizes it as foreign.

T-Cell Troubles - Cellular Immunity Collapse

Thymic Aplasia (DiGeorge Syndrome)
- 22q11.2 deletion → failed 3rd/4th pharyngeal pouch development.
- 📌 CATCH-22: Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia.
- Labs: ↓ T-cells, ↓ PTH, ↓ Ca²⁺. Absent thymic shadow on CXR.
IL-12 Receptor Deficiency
- ↓ Th1 response → disseminated mycobacterial & fungal infections; ↓ IFN-γ.
Hyper-IgE Syndrome (Job Syndrome)
- STAT3 mutation → impaired Th17 cells.
- 📌 FATED: coarse Facies, cold staph Abscesses, retained primary Teeth, ↑ IgE, Dermatologic (eczema).

⭐ Patients with DiGeorge syndrome often present with congenital heart defects like Tetralogy of Fallot or truncus arteriosus.

Combined Chaos - When B & T Cells Fail

Severe Combined Immunodeficiency (SCID)
- Most severe form; multiple genetic defects (e.g., IL-2R gamma chain, ADA deficiency).
- Presents with failure to thrive, chronic diarrhea, and severe recurrent infections.
- Key finding: Absent thymic shadow on chest X-ray.
Ataxia-Telangiectasia
- Defect in ATM gene; failure to repair DNA double-strand breaks.
- Triad: Ataxia, Angiomas (telangiectasias), IgA deficiency.
- Lab finding: ↑ alpha-fetoprotein.
Wiskott-Aldrich Syndrome (WAS)
- X-linked recessive; defect in WASp gene.
- 📌 WATER mnemonic: Wiskott-Aldrich: Thrombocytopenia, Eczema, Recurrent infections.

⭐ In Ataxia-Telangiectasia, the DNA repair defect leads to an increased risk of lymphoma and leukemia.

Phagocyte Phails - Cleanup Crew on Strike

Chronic Granulomatous Disease (CGD): Defect in NADPH oxidase → impaired respiratory burst.
- Recurrent infections by catalase-positive organisms (e.g., S. aureus, Aspergillus).
- Diagnosis: ↓ Dihydrorhodamine (DHR) flow cytometry test.
Leukocyte Adhesion Deficiency (LAD-1): Defective CD18 (LFA-1 integrin) → impaired leukocyte adhesion & migration.
- Presents with delayed umbilical cord separation, recurrent skin infections without pus.
Chédiak-Higashi Syndrome: LYST gene defect → impaired phagosome-lysosome fusion.
- Features: Recurrent pyogenic infections, partial albinism, peripheral neuropathy.

⭐ In Leukocyte Adhesion Deficiency (LAD), infections are notably non-purulent (lack pus) because neutrophils can't extravasate to the site of inflammation.

Neutrophil defects in primary immunodeficiencies

X-linked agammaglobulinemia (XLA) features a BTK gene defect, leading to no B-cell maturation and recurrent bacterial infections after 6 months.

DiGeorge syndrome (22q11.2 deletion) causes T-cell deficiency from thymic aplasia, plus hypocalcemia and cardiac defects.

Severe Combined Immunodeficiency (SCID) shows absent T and B-cell function, requiring an urgent bone marrow transplant.

Wiskott-Aldrich syndrome is an X-linked disorder with a triad of thrombocytopenia, eczema, and recurrent infections.

IgA deficiency is the most common PID, often asymptomatic but with a risk of anaphylaxis to blood products.

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