A 19-year-old man presents to his primary care physician for evaluation before going off to college. Specifically, he wants to know how to stay healthy while living outside his home. Since childhood he has suffered severe sunburns even when he goes outside for a small period of time. He has also developed many freckles and rough-surfaced growths starting at the same age. Finally, his eyes are very sensitive and become irritated, bloodshot, and painful after being outside. A defect in a protein with which of the following functions is most likely responsible for this patient's symptoms?

Recognition of chemically dimerized bases

Distinguishing methylated from unmethylated strands

Endonucleolytic removal of bases from backbone

Recognition of mismatched bases

Sister chromatid binding and recombination

A 53-year-old farmer presents to the clinic for evaluation of a pigmented lesion on his arm. He states that he first noticed the lesion last year, but he believes that it has been slowly growing in size. He otherwise does not have any complaints and is generally healthy. Which of the following findings on physical exam would suggest a malignant diagnosis?

Different pigmentation throughout the lesion

Flat lesion with symmetric hyperpigmentation

Hyperpigmented lesion with smooth borders

A 17-year-old Latin American woman with no significant past medical history or family history presents to her pediatrician with concerns about several long-standing skin lesions. She notes that she has had a light-colored rash on her chest and abdomen that has been present for the last 2 years. The blood pressure is 111/81 mm Hg, pulse is 82/min, respiratory rate is 16/min, and temperature is 37.3°C (99.1°F). Physical examination reveals numerous hypopigmented macules over her chest and abdomen. No lesions are seen on her palms or soles. When questioned, she states that these lesions do not tan like the rest of her skin when exposed to the sun. The remainder of her review of systems is negative. What is the most likely cause of these lesions?

Post-viral immunologic reaction

TYR gene dysfunction in melanocytes

A 28-year-old woman presents with progressive darkening of her face that started during pregnancy. The pigmentation is symmetrical and primarily affects her cheeks and forehead. It became more prominent with sun exposure. Examination reveals bilateral, symmetrical brown patches on her face. Which of the following is the most appropriate initial management?

Broad-spectrum sunscreen and sun avoidance

An otherwise healthy 17-year-old girl comes to the physician because of multiple patches on her face, hands, abdomen, and feet that are lighter than the rest of her skin. The patches began to appear 3 years ago and have been gradually increasing in size since. There is no associated itchiness, redness, numbness, or pain. She emigrated from India 2 years ago. An image of the lesions on her face is shown. Which of the following is most likely involved in the pathogenesis of this patient's skin findings?

Autoimmune destruction of melanocytes

Infection with Malassezia globosa

Infection with Mycobacterium leprae

A 50-year-old woman with rheumatoid arthritis on methotrexate develops rapidly progressive painful ulcers on her legs with violaceous undermined borders. Biopsy shows neutrophilic dermal infiltrate with areas of necrosis, but no vasculitis or infection. Wound cultures are negative. Despite debridement, the ulcers worsen. C-ANCA and P-ANCA are negative. Evaluate the diagnosis and determine the management that addresses both the cutaneous condition and systemic disease.

Continue methotrexate, add TNF-alpha inhibitor and systemic corticosteroids

Discontinue all immunosuppression to allow wound healing

Increase methotrexate dose and add wound care

Discontinue methotrexate, start cyclosporine and prednisone

Start broad-spectrum antibiotics and surgical debridement

A 25-year-old woman presents with painful oral ulcers and a pustular rash at venipuncture sites. She has genital ulcers and a history of recurrent uveitis. Skin biopsy from a pustule shows neutrophilic infiltrate in the dermis without vasculitis or infection. HLA-B51 testing is positive. She is planning pregnancy. Evaluate the management strategy considering disease control and pregnancy planning.

Start infliximab, use contraception, then transition to low-risk therapy before conception

Start methotrexate for disease control

Start colchicine monotherapy and proceed with pregnancy

Start high-dose corticosteroids and azathioprine, delay pregnancy

Avoid all immunosuppression and manage symptoms only

Disorders of pigmentation for USMLE Step 1: High-Yield Pathology Lessons

Melanin & Melanocytes - The Pigment Factory

Origin: Neural crest cells.
Location: Stratum basale (basal layer) of the epidermis; 1 melanocyte per 10 basal keratinocytes.
Function: Synthesize melanin within melanosomes and transfer them to adjacent keratinocytes.
Protection: Melanin forms a supranuclear cap over the keratinocyte nucleus, shielding DNA from UV radiation damage.

⭐ The number of melanocytes is roughly the same across all skin phototypes; differences in skin color are due to the activity of melanocytes and the type, size, and distribution of melanosomes.

Hypopigmentation - Fading Away Fast

Vitiligo
- Autoimmune destruction of melanocytes → complete absence of pigment.
- Presents as well-demarcated, chalk-white macules & patches.
- Wood's lamp exam: accentuates lesions, causing them to fluoresce blue-white.
- Associated with other autoimmune disorders (e.g., thyroid disease, pernicious anemia).
Albinism (Oculocutaneous)
- Genetic; typically autosomal recessive.
- Normal melanocyte count, but defective tyrosinase enzyme → ↓ or absent melanin synthesis.
- Presents with white hair, pale skin, and translucent irides.
- ⚠️ High risk for squamous cell carcinoma & basal cell carcinoma due to lack of UV protection.
Pityriasis Alba
- Common in children/adolescents, often with atopic dermatitis history.
- Presents as ill-defined, hypopigmented macules with fine scale, typically on the face.
- Represents post-inflammatory hypopigmentation from a mild dermatitis.

⭐ Vitiligo vs. Albinism: The key distinction is the melanocyte count. In vitiligo, melanocytes are destroyed and absent. In albinism, melanocytes are present but cannot produce melanin.

Hyperpigmentation - The Dark Side

Ephelis (Freckle)
- Cause: ↑ Melanin production by normal-numbered melanocytes.
- Features: Small, light brown macules in sun-exposed areas. Darken with sun exposure, fade in winter.
- Histo: Normal number of melanocytes, but ↑ melanin in basal keratinocytes.
Lentigo Simplex
- Cause: Localized, linear proliferation of melanocytes.
- Features: Sharply demarcated, round/oval brown-to-black macules. Do not darken or fade with sun exposure.
- Histo: Linear, non-nested melanocytic hyperplasia in the basal layer.
Melasma (Chloasma)
- Cause: Hormone-related (pregnancy, OCPs) + UV exposure.
- Features: Symmetrical, blotchy hyperpigmentation on the face ("mask of pregnancy").
- Histo: ↑ Melanin deposition in all epidermal layers; may involve dermis (dermal melasma).

Lentigo Simplex Histology: Melanocytic Hyperplasia

Café-au-Lait Macules
- Features: Well-circumscribed, light-to-dark brown patches with irregular borders.
⭐ Having 6 or more café-au-lait macules larger than 1.5 cm in diameter is a key diagnostic criterion for Neurofibromatosis Type 1 (NF1).

High‑Yield Points - ⚡ Biggest Takeaways

Vitiligo is an autoimmune disorder causing the complete destruction of melanocytes.

Albinism results from normal melanocyte numbers but impaired melanin synthesis, typically due to tyrosinase deficiency.

Melasma appears as facial hyperpigmentation often triggered by pregnancy or OCPs.

Freckles (ephelides) show increased melanin, not melanocytes, and darken with sun exposure.

Acanthosis nigricans, a velvety rash in flexures, signals insulin resistance or an underlying malignancy.

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