In a 14‑year‑old African‑American girl with new hyperpigmentation of the proximal and distal interphalangeal joints, what are the differential diagnoses and the recommended evaluation and management?

Hyperpigmentation of PIP and DIP Joints in a 14-Year-Old African-American Girl

The most likely diagnosis is vitamin B12 deficiency presenting as isolated knuckle hyperpigmentation, which should be evaluated with serum B12 and methylmalonic acid levels before irreversible neurological complications develop. 1

Primary Differential Diagnoses

Vitamin B12 Deficiency (Most Likely)

• Knuckle hyperpigmentation can be an early isolated cutaneous sign of B12 deficiency, appearing before hematological or neurological manifestations. 1
• This presentation is particularly important to recognize because it enables treatment before irreversible neurological complications occur. 1
• The hyperpigmentation specifically targets the knuckles (PIP and DIP joints) and responds to oral B12 supplementation. 1
• In adolescents, nutritional deficiency is common, especially in those with restricted diets (vegetarian/vegan), malabsorption, or pernicious anemia. 1

Postinflammatory Hyperpigmentation (PIH)

• PIH occurs after various dermatoses, exogenous stimuli, and dermatologic procedures, with chronic and unpredictable clinical course. 2
• However, PIH typically follows a known inflammatory event or dermatologic condition, which should be evident in the history. 2
• The localization specifically to PIP and DIP joints without preceding trauma or inflammation makes this less likely as the primary diagnosis. 2

Acanthosis Nigricans

• Consider insulin resistance and metabolic syndrome, particularly given the patient's age and demographic. 3, 4
• However, acanthosis nigricans typically affects flexural areas (neck, axillae, groin) rather than specifically targeting PIP and DIP joints. 3

Addison's Disease

• Adrenal insufficiency causes diffuse hyperpigmentation with accentuation in pressure points, palmar creases, and knuckles. 4
• This would be accompanied by systemic symptoms including fatigue, weight loss, hypotension, and salt craving. 4

Recommended Evaluation

Initial Laboratory Workup

• Serum vitamin B12 level (first-line test) 1
• Methylmalonic acid and homocysteine levels (if B12 is borderline or to confirm tissue deficiency) 1
• Complete blood count with peripheral smear (to evaluate for megaloblastic anemia or pancytopenia) 1
• Fasting glucose and hemoglobin A1c (to exclude insulin resistance) 3
• Morning cortisol and ACTH stimulation test (if Addison's disease is suspected based on systemic symptoms) 4

Clinical Assessment Points

• Document the exact distribution of hyperpigmentation (isolated to joints vs. involving palmar creases, mucous membranes, or other areas) 4
• Assess for systemic symptoms: fatigue, weakness, paresthesias, gait disturbances, cognitive changes, weight loss, or orthostatic symptoms 1, 4
• Dietary history: vegetarian/vegan diet, restrictive eating patterns, or gastrointestinal symptoms suggesting malabsorption 1
• Medication history: metformin, proton pump inhibitors, or H2 blockers that impair B12 absorption 1
• Family history: pernicious anemia, autoimmune conditions, or endocrinopathies 4

Management Approach

If Vitamin B12 Deficiency is Confirmed

• Oral vitamin B12 supplementation (1000-2000 mcg daily) is effective for nutritional deficiency and can reverse the hyperpigmentation. 1
• Intramuscular B12 (1000 mcg weekly for 4-8 weeks, then monthly) is reserved for malabsorption or severe deficiency with neurological symptoms. 1
• Monitor for resolution of hyperpigmentation over 2-3 months as a marker of treatment response. 1
• Repeat B12 levels after 3 months to confirm normalization. 1

If Postinflammatory Hyperpigmentation

• First, identify and treat any underlying inflammatory condition to prevent progression. 2
• Once inflammation is controlled, consider topical depigmenting agents (hydroquinone, tretinoin, or combination therapy). 2
• Chemical peels, cryotherapy, or laser therapy are second-line options for resistant cases. 2

If Other Diagnoses are Suspected

• Refer to endocrinology if Addison's disease is confirmed (requires lifelong glucocorticoid and mineralocorticoid replacement). 4
• Address insulin resistance with lifestyle modifications and metformin if acanthosis nigricans is present with metabolic syndrome. 3

Critical Clinical Pearls

• Knuckle hyperpigmentation in an adolescent should prompt immediate evaluation for B12 deficiency, as this may be the only early sign before irreversible neurological damage occurs. 1
• The distribution pattern (PIP and DIP joints specifically) is highly characteristic of B12 deficiency rather than other pigmentation disorders. 1
• African-American patients may have more prominent hyperpigmentation due to higher baseline melanin content, making early recognition even more important. 3, 4
• Unlike PIH, B12-related hyperpigmentation appears without preceding inflammation or trauma. 2, 1
• Do not delay treatment while waiting for confirmatory tests if clinical suspicion is high—B12 supplementation is safe and can prevent neurological complications. 1