Xanthomas

Question 1

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Which xanthoma subtype is not associated with lipid abnormalities and often occurs in the oral mucosa or genital areas?

Answer 1

Verruciform Xanthoma

Question 2

Which lipid-lowering therapy is best suited for LDL receptor–negative patients with homozygous familial hypercholesterolemia?

Answer 2

ANGPTL3 inhibitor

ANGPTL3 inhibitors (e.g., evinacumab) bypass the LDL receptor pathway:

🧬 Enhance lipase activity
✅ Lower LDL-C, TG, and HDL independently of LDL receptor presence
📌 Only effective option in receptor-negative HoFH patients

Question 3

Which condition is almost pathognomonic when xanthomas are found in the interdigital web spaces?

Answer 3

Homozygous familial hypercholesterolemia

Inherited as an autosomal dominant trait with absent or defective LDL receptors
LDL-C levels often >700–1000 mg/dL
Presents with early-onset atherosclerosis and multiple xanthoma subtypes

Question 4

What is the most typical histologic feature seen in tendinous xanthomas?

Answer 4

• Show large aggregates of foam cells (lipid-laden macrophages)
• Often contain cholesterol clefts (may be seen as clear spaces due to lipid dissolution)
• May show mild surrounding fibrosis
• Commonly occur in the Achilles tendon and extensor tendons of the hands

📌 Seen in familial hypercholesterolemia, especially the heterozygous form.

Question 5

Which xanthoma subtype is most classically associated with extremely elevated triglyceride levels (>3000 mg/dL) and may have an early inflammatory halo?

Answer 5

Eruptive xanthoma

Question 6

Tuberous xanthomas typically resolve rapidly once triglyceride levels normalize.
True or False?

Answer 6

False

• Caused by cholesterol-rich lipoprotein accumulation, not triglyceride excess
• Associated with familial hypercholesterolemia and dysbetalipoproteinemia
• ❗ Regression is slow, even with effective lipid-lowering therapy

May take months to years to resolve due to long-standing deposition and fibrosis

Question 7

What is the specific apoprotein defect in dysbetalipoproteinemia and how does it affect lipid metabolism?

Answer 7

Apolipoprotein E2 (Apo E2)
– In dysbetalipoproteinemia, patients are homozygous for Apo E2, an isoform that:

Has poor affinity for the apo B-100/E receptor

Leads to impaired hepatic uptake of chylomicron remnants and VLDL remnants

Results in elevated total cholesterol and triglycerides

📌 Clinically associated with:
* Tuberous/tuberoeruptive xanthomas
* Plane xanthomas of palmar creases (xanthoma striatum palmare)

Question 8

Xanthelasma is nearly always a sign of severe hyperlipidemia.
True or False?

Answer 8

False - 50% of patients with xanthelasma have normal lipids

Xanthelasma Palpebrarum:
* Most common form of plane xanthoma
* Appears as yellowish plaques on the eyelids
* More likely to signal hyperlipidemia in:
* ``Younger patients
* Those with a family history of dyslipidemia
* 📌 Should still trigger a lipid panel, but is not diagnostic of dyslipidemia.

Question 9

What is the typical histologic hallmark of plane xanthomas, such as xanthelasma?

Answer 9

Foam cells = lipid-laden macrophages/histiocytes
Contain vacuolated cytoplasm due to lipid content

Located in the superficial dermis
Minimal inflammation or fibrosis

In xanthelasma, other clues include:
Thin epidermis
Fine vellus hairs
Striated muscle fibers (from eyelid anatomy)

📌 Foam cells may be subtle early, so lipid-specific stains (e.g. adipophilin) can be helpful.

Question 10

Verruciform xanthomas commonly indicate underlying hypertriglyceridemia.

Answer 10

False

Verruciform Xanthomas are NOT associated with lipid disorders

Typically normolipemic
Often arise due to epithelial damage or chronic inflammation
Seen in oral mucosa, anogenital areas, acral skin

Associated with lichen planus, GVHD, CHILD syndrome, etc.
Histologically mimic warts, but contain foamy macrophages in dermal papillae

📌 Don’t assume lipid abnormality when you see these.

Question 11

What genetic mutation is responsible for xanthomas seen in CHILD syndrome, and what enzyme does it affect?

Answer 11

Gene: NSDHL
(NAD(P) dependent steroid dehydrogenase-like)
Enzyme affected: 3β-hydroxysteroid dehydrogenase

🧬 This enzyme is involved in cholesterol biosynthesis
Mutation → lipid accumulation → foamy histiocytes → xanthoma-like skin lesions

📌 CHILD = Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects

Question 12

Plane xanthomas involving the palmar creases are almost diagnostic of dysbetalipoproteinemia

Answer 12

True

Question 13

Patients with sitosterolemia accumulate cholesterol-rich lipoproteins.
True or False?

Answer 13

False - Patients do not accumulate cholesterol.

Instead, they absorb and retain plant sterols (e.g., sitosterol, campesterol).

Caused by mutations in ABCG5 or ABCG8 (plant sterol transporters).

Leads to:
Tendinous and tuberous xanthomas
Normal or only mildly elevated LDL/TC levels
Increased risk of premature atherosclerosis

📌 Diagnosis requires specialized testing for non-cholesterol sterols

Question 14

What topical therapy has shown benefit in treating CHILD syndrome–associated xanthomas?

Answer 14

Topical Lovastatin/Cholesterol Ointment:

Used successfully in CHILD syndrome

Mechanism:
Lovastatin: Inhibits cholesterol synthesis
Cholesterol: Replenishes deficient barrier lipid

Targets the underlying NSDHL enzyme defect in cholesterol biosynthesis

Question 15

What two xanthoma subtypes are most strongly associated with familial hypercholesterolemia?

Answer 15

Tendinous Xanthomas
📍 Achilles tendon, extensor tendons
Highly specific for heterozygous FH

Plane Xanthomas in Web Spaces
📍 Finger web spaces
Pathognomonic for homozygous FH

Question 16

Foam cells in eruptive xanthomas are typically found in the papillary dermis.
True or False?

Answer 16

False

Foam cells are primarily located in the reticular dermis, not the papillary dermis.

Early lesions may show:
* Sparse foam cells
* Mixed neutrophilic and lymphocytic infiltrate

As the lesion matures:
* Foam cells increase
* Extracellular lipid clefts may appear due to dissolved triglycerides

📌 The papillary dermis is more typical for plane xanthomas and verruciform xanthomas

Question 17

What is the mechanism by which PCSK9 inhibitors lower LDL cholesterol?

Answer 17

PCSK9 normally binds to the LDL receptor and promotes its degradation within lysosomes.
PCSK9 inhibitors (e.g., alirocumab, evolocumab) are monoclonal antibodies that:
Bind to circulating PCSK9
Prevent it from degrading LDL receptors
⬆️ Result: More LDL receptors recycled to the hepatocyte surface → increased LDL clearance
📌 Result: 40–60% reduction in LDL-C

Question 18

A 33-year-old man presents to dermatology with multiple firm, smooth nodules over both Achilles tendons and the extensor tendons of his hands. He is otherwise healthy, but reports that his father had a myocardial infarction at age 42.

What is the most likely diagnosis?
What is the genetic defect involved?
Name two additional xanthoma types that may be seen in this condition.

Answer 18

Tendinous Xanthoma secondary to Heterozygous Familial Hypercholestrolaemia

Most commonly: LDL receptor gene mutation → ↓ LDL clearance
Less commonly: mutations in Apo B-100 (defective receptor binding) or PCSK9 gain-of-function

Additional xanthoma types:

1. Plane xanthomas: e.g., in finger web spaces (especially in homozygous FH)
2. Tuberous xanthomas: extensor surfaces, elbows, knees

Question 19

A 45-year-old woman presents with yellowish macules and plaques on her eyelids and upper eyelid folds. She is concerned about cosmetic appearance but has no pruritus or systemic symptoms. Her past medical history is unremarkable, and she is not on any medications. She denies alcohol use, diabetes, or family history of heart disease.

What is the most likely diagnosis?
Is this condition always associated with hyperlipidemia?
What are two treatment options for this condition?

Answer 19

Xanthelasma palpebrarum - a form of plane xanthoma

50% of patients have normal lipid profiles

Treatment:
- CO2 laser ablation
- Electrosurgery
- Cryotherapy
- Surgical excision
- Chemical cautery (TCA)

📌 ⚠️ Recurrence is common, regardless of method
📌 Cosmetic treatment—often patient-driven

Question 20

What is the near - pathopneumonic sign of Dysbetalipoproteinemia?

Answer 20

Plane xanthomas of the palmar creases - Xanthoma striatum palmare

Question 21

What are the subtypes of Xanthomas?

Answer 21

Eruptive - ass with hypertriglyceridaemia
Tuberous - ass with hypercholestrolaemia (familial and dysbetalipoproteineaemia)
Tendinous - ass with hypercholestrolaemia (familial hypercholestrolaemia)
Plane Xanthomas - ass with hypercholestrolaemia (Dysbetalipoproteinemia, homozygous FH, paraproteinemias, cholestasis)
Verrucous - often no underlying lipid issue

Question 22

How do you treat Tuberous Xanthomas?

Answer 22

Treat the underlying hypercholesterolemia to reduce lipid accumulation and prevent cardiovascular disease.

Specific First-Line Medications:

HMG-CoA Reductase Inhibitors (Statins)
First-line pharmacologic choice
↓ LDL by 25–45%
Proven to reduce cardiovascular risk

+/- Ezetimibe
Often added if statin effect is insufficient
↓ LDL by ~15%

+/- PCSK9 Inhibitors (e.g., alirocumab, evolocumab)
Considered in familial hypercholesterolemia or high CV risk
↓ LDL by 40–60%

Niacin or Fibrates
Sometimes used adjunctively, especially in mixed dyslipidemia
Less common now due to side effect profiles

Question 23

Plane xanthomas in paraproteinemia are typically associated with elevated cholesterol levels.

Answer 23

False

Plane xanthomas in paraproteinemia are typically seen in normolipemic patients.

Often linked to monoclonal gammopathies, particularly IgG

Mechanism: IgG binds LDL → forms complexes that are more readily phagocytosed by macrophages
Leads to xanthoma formation without elevated serum cholesterol

Favored locations: neck, upper trunk, flexural folds, periorbital region

📌 Important to screen for plasma cell dyscrasias or lymphoproliferative disease, even if lipids are normal.

Question 24

In cerebrotendinous xanthomatosis, xanthomas develop due to accumulation of plant sterols.

Answer 24

False

Cerebrotendinous xanthomatosis is caused by accumulation of cholestanol, not plant sterols.

Due to mutations in the CYP27A1 gene

Leads to defect in bile acid synthesis

Results in buildup of cholestanol (a bile acid precursor) in tissues

Causes:
Tendinous xanthomas
Neurologic dysfunction (e.g., cerebellar ataxia, dementia)
Cataracts

📌 Contrast with sitosterolemia, which involves plant sterol accumulation.

Question 25

Xanthomas in CHILD syndrome typically follow a bilateral distribution due to its X-linked dominant inheritance.

Answer 25

False Presents with unilateral linear skin lesions, including: Epidermal nevi Ichthyosis Xanthomatous plaques 📌 The unilateral distribution is due to functional mosaicism (i.e., lyonization of X chromosome), not the inheritance pattern itself.

Question 26

Which of the following lipid abnormalities is most commonly associated with eruptive xanthomas? A. Elevated LDL only B. Elevated HDL only C. Elevated chylomicrons and VLDL D. Elevated lipoprotein(a)

Answer 26

C

Question 27

Which gene mutation is responsible for familial defective Apo B-100, leading to clinical features similar to heterozygous familial hypercholesterolemia? A. APOE B. PCSK9 C. APOB D. NSDHL

Answer 27

C

Question 28

Which of the following is most pathognomonic for dysbetalipoproteinemia? A. Tendinous xanthomas B. Xanthoma striatum palmare C. Xanthelasma palpebrarum D. Verruciform xanthoma

Answer 28

B

Question 29

Which of the following drugs does not significantly reduce LDL cholesterol? A. Statins B. Fibrates C. Ezetimibe D. PCSK9 inhibitors

Answer 29

B - Fibrates primarily reduce triglycerides and raise HDL

Question 30

Which rare disorder involves xanthomas due to accumulation of plant sterols? A. Sitosterolemia B. CHILD syndrome C. Cerebrotendinous xanthomatosis D. Dysbetalipoproteinemia

Answer 30

A