A 16-year-old boy is brought to the pediatrician by his mother because she is concerned about the “spots” on his abdomen and back. The patient’s mother reports that there are several “light spots” on the patient’s trunk that have been slowly increasing in number. The lesions are not painful nor pruritic. The patient’s mother is worried because her nephew had vitiligo. The patient reports that he feels “fine,” but reports occasional headaches and increasing difficulty with seeing the board at school. In addition to the patient’s cousin having vitiligo, the patient’s paternal grandfather and uncle have bilateral deafness, and his mother has systemic lupus erythematous. On physical examination, there are multiple, discrete, 2-3 cm hypopigmented macules on the chest, abdomen, back, and posterior shoulders. Which of the following head and neck computed tomography findings is the patient most likely to develop?

Bilateral vestibular schwannomas

An investigator is studying DNA repair processes in an experimental animal. The investigator inactivates a gene encoding a protein that physiologically excises nucleotides from damaged, bulky, helix-distorting DNA strands. A patient with a similar defect in this gene is most likely to present with which of the following findings?

Dry skin and increased photosensitivity

Ataxic gait and facial telangiectasias

Malignant breast and ovarian growths

Leukocoria and a painful bone mass

Colorectal and endometrial cancers

A 75-year-old gentleman is brought to the ED with confusion that started earlier this morning. His family notes that he was complaining of feeling weak last night and also had a slight tremor at the time. He is afebrile and he has no known chronic medical conditions. Physical exam reveals a cooperative but confused gentleman. His mucous membranes are moist, he has no focal neurological deficits, and his skin turgor is within normal limits. His lab results are notable for: Serum Na+: 123 mEq/L Plasma osmolality: 268 mOsm/kg Urine osmolality: 349 mOsm/kg Urine Na+: 47 mEq/L Which of the following malignancies is most likely to be responsible for this patient's presentation?

Esophageal squamous cell carcinoma

Non-seminomatous germ cell tumor

A 75-year-old man comes to his primary care physician because he has been having diarrhea and difficulty breathing. The diarrhea has been intermittent with frequent watery stools that occur along with abdominal cramps. Furthermore, the skin on his face and upper chest feels hot and changes color in episodes lasting from a few minutes to hours. Finally, the patient complains of loss of appetite and says that he has unexpectedly lost 20 pounds over the last two months. Based on clinical suspicion, magnetic resonance imaging is obtained showing a small mass in this patient's lungs. Which of the following is associated with the most likely cause of this patient's symptoms?

Has keratin pearls and intercellular bridges

Most common lung cancer in non-smokers and females

A 40-year-old man presents with a painless firm mass in the right breast. Examination shows retraction of the nipple and the skin is fixed to the underlying mass. The axillary nodes are palpable. Which of the following statements is FALSE regarding the above condition?

Lobular cancer is the most common breast cancer in males

BRCA2 mutations are associated with increased risk

These are positive for estrogen receptor

Endocrine therapy plays an important role in treatment

Gynecomastia may be caused by certain medications

Cancer predisposition syndromes — USMLE Lesson

Neurofibromatosis - Not-So-Funny Bumps

Neurofibromatosis Type 1 (NF1) - von Recklinghausen's
- Autosomal Dominant, NF1 gene mutation on Chromosome 17.
- Diagnosis: ≥2 of the following:
  - ≥6 Café-au-lait macules (>5 mm prepubertal, >15 mm postpubertal).
  - ≥2 Neurofibromas or 1 plexiform neurofibroma.
  - Axillary or inguinal freckling (Crowe's sign).
  - Optic glioma.
  - ≥2 Lisch nodules (iris hamartomas).
  - Sphenoid dysplasia or long bone cortical thinning.
  - First-degree relative with NF1.

Clinical features of Neurofibromatosis Type 1

⭐ Optic pathway gliomas are the most common CNS tumor in children with NF1.

Neurofibromatosis Type 2 (NF2)
- Autosomal Dominant, NF2 gene mutation on Chromosome 22.
- Key feature: Bilateral vestibular schwannomas.

Tumor Suppressor Syndromes - Guardian Genes Asleep

Inherited mutation in one allele of a tumor suppressor gene (TSG). Cancer occurs after a second, somatic "hit" inactivates the other allele (Knudson's Hypothesis).

Syndrome	Gene	Key Associated Cancers
Li-Fraumeni	TP53	Sarcoma, Breast, Leukemia, Adrenal (SBLA)
Retinoblastoma	RB1	Retinoblastoma, Osteosarcoma
NF Type 1	NF1	Neurofibromas, Optic Glioma, Pheochromocytoma
NF Type 2	NF2	Bilateral Acoustic Neuromas (Schwannomas)
Von Hippel-Lindau	VHL	Hemangioblastoma, Renal Cell Ca (clear cell)
Beckwith-Wiedemann	WT2/IGF2	Wilms Tumor, Hepatoblastoma

⭐ In Li-Fraumeni Syndrome (TP53 mutation), there is a very high lifetime risk of developing a wide range of cancers, often at a young age. It's the classic example of a cancer predisposition syndrome.

Knudson Two-Hit Hypothesis: Hereditary vs. Non-Hereditary

Overgrowth Syndromes - Growing Too Fast

Beckwith-Wiedemann Syndrome (BWS):
- Gene: Imprinting defect at 11p15.5 (WT2 locus).
- Features: Macrosomia, macroglossia, omphalocele, hemihyperplasia, ear creases/pits.
- Cancers: ↑ Wilms tumor, hepatoblastoma.
⭐ Screening for BWS: Abdominal ultrasound & serum AFP every 3 months until age 4 (for hepatoblastoma) and renal ultrasound until age 8 (for Wilms tumor).
Sotos Syndrome:
- Gene: NSD1.
- Features: Macrocephaly, advanced bone age, intellectual disability.
Simpson-Golabi-Behmel Syndrome (SGBS):
- Gene: GPC3 (X-linked).
- Features: Coarse "bulldog" facies, organomegaly.
- Cancers: ↑ Wilms tumor, hepatoblastoma.

DNA Repair Defects - Faulty Fix-It Crew

Autosomal recessive disorders with faulty DNA repair, leading to genomic instability.
Common Features: Growth retardation, immunodeficiency, ↑ cancer risk.

Syndrome	Gene Defect	Key Clinical Features	Associated Malignancy
Ataxia-Telangiectasia	ATM	📌 Ataxia, Telangiectasia, Immunodeficiency	Leukemia (ALL), Lymphoma
Xeroderma Pigmentosum	NER pathway	Extreme photosensitivity, freckles	Skin Cancers (BCC, SCC)
Bloom Syndrome	BLM (helicase)	Photosensitive rash, short stature	Leukemia, Lymphoma
Fanconi Anemia	FANCA etc.	Pancytopenia, thumb/radial defects	AML, MDS

⭐ Ataxia-Telangiectasia: Characterized by elevated alpha-fetoprotein (AFP) levels after infancy, a key diagnostic marker. Patients show extreme sensitivity to radiation therapy.

High‑Yield Points - ⚡ Biggest Takeaways

Li-Fraumeni syndrome (p53) is linked to sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma.

Beckwith-Wiedemann syndrome presents with hemihypertrophy and macroglossia, increasing the risk for Wilms tumor and hepatoblastoma.

Down syndrome (Trisomy 21) significantly elevates the risk for both ALL and AML.

Neurofibromatosis type 1 predisposes to optic pathway gliomas.

Fanconi anemia, a DNA repair defect syndrome, is strongly associated with AML.

WAGR syndrome involves a WT1 gene deletion, leading to Wilms tumor and aniridia.

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