2. The correct answer is E: DoxycyclineReferencesExplanation/Literature ReviewThe clinical photo is showing onycholysis of multiple fingernails. Out of the drugs listed, doxycycline is the most likely to cause onycholysis via a phototoxic effect. Doxorubicin, 5-fluorouracil, and zidovudine can result in longitudinal, transverse, or generalized melanonychia. Hydrochlorothiazide can cause a phototoxic and photo-lichenoid skin reaction but does not typically affect the nails.Onycholysis occurs when the nail plate separates from the nail bed and can result from a number of factors including inflammatory disease, medications, trauma, or infection. Drug-induced photo-onycholysis results from ingestion of an exogenous photosensitizing medication coupled with exposure to ultraviolet radiation. The photo-onycholysis can occur alone or be accompanied by a phototoxic skin reaction. Onychodynia can precede the onycholysis by several weeks. Nail bed splinter hemorrhage can result in dark red discoloration of the nails. The nails will gradually normalize after stopping the offending medications. Doxycycline is a common cause of photo-onycholysis given its widespread use in medicine. Other medications that can cause photo-onycholysis are psoralens, chloramphenicol, oral contraceptives, chlorpromazine, thiazide diuretics, and griseofulvin.References1. Chandran NS and Aw DC. Drug-induced photo-onycholysis: an often-neglected phenomenon. Intern Med J 2013;43(12): 1349-1350.3. The correct answer is C: The pathogenesis of this patient’s underlying disease is due to an LDL receptor defect.Explanation/Literature ReviewThe clinical picture shows plane xanthomas of the palmar creases. Based on the characteristic rash and clues from the question stem (hypercholesterolemia, family history of heart disease), a diagnosis of familial dysbetalipoproteinemia (Type III hyperlipoproteinemia) should be suspected.Familial dysbetalipoproteinemia (also known as remnant removal disease or broad beta disease) is an inherited disease of lipid metabolism. Dysbetaliproteinemia is inherited in an autosomal dominant fashion. The pathophysiology of this condition is due to a deficiency of normal apo E in lieu of an isoform, apo E2, which has a much lower affinity for the apo E receptor. Reduced binding to this receptor results in impaired hepatic clearance of chylomicron and VLDL remnants and ultimately leads to increased levels of serum cholesterol and triglycerides. Dysbetaliproteinemia is typically diagnosed in adulthood and is characterized by premature onset coronary artery disease and peripheral vascular disease.Xanthomas, particularly plane, tuberous, and tendinous, are characteristic and present in 80% of patients with familial dysbetaliproteinemia. Plane xanthomas of the palmar and finger creases, known as xanthoma striatum palmare, are pathognomonic for this disease and present in two-thirds of patients. Biopsy of one of these skin lesions would show foam cells (macrophages with lipidized cytoplasm) in the superficial to mid-dermis.The main differential diagnosis for plane xanthomas of the palm is familial hypercholesterolemia (type II hyperlipoproteinemia), which is due to a dysfunction in the LDL receptor leading to poor clearance of LDL cholesterol and significantly elevated serum LDL. Patients with homozygous familial hypercholesterolemia present much earlier in life (usually in the first decade) with tuberous, tendinous, and plane xanthomas, as well as widespread and early onset atherosclerosis. Unlike the xanthomas found within the creases of dysbetaliproteinemia, the pathognomonic plane xanthomas of familial hypercholesterolemia are found in the interweb spaces.References1. Massengale WT, Hodari KT, Boh EE, and Nesbitt LT. Xanthomas. In: Bolognia, JL, Jorizzo JL, and Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012. 2. Parker F. Xanthomas and hyperlipidemias. J Am Acad Dermatol 1985;13(1): 1-30.