Table 5.

Monogenic dyslipidemias: clinical features

Condition	Clinical features and comorbidities	Comments
Group 1: Monogenic hypercholesterolemia: severely elevated LDL-C
Familial hypercholesterolemia	Xanthomas: tendinous (mainly) rarely periosteal, intracranial, peripatellar, digital web spaces	HDL-C can be depressed;
	Xanthelasmas, corneal arcus	Lp(a) can be very elevated;
	Early ASCVD: angina, acute coronary syndrome, myocardial infarction, stroke, transient ischemic attack, peripheral arterial disease, claudication, arterial bruits	Untreated biallelic (ie, homozygous) form can express clinical features in childhood while monoallelic (ie, heterozygous) form expresses clinical features in early adulthood
	Aortic valve disease
Autosomal recessive hypercholesterolemia	As above	Parents have normal lipids
		Affected children are indistinguishable from homozygous FH
Sitosterolemia	Xanthomas: tendinous, cutaneous, tuberous	↑ plasma beta-sitosterol, campesterol stigmasterol are diagnostic, as is positive genetic sequencing showing biallelic mutations
	Splenomegaly
	Early ASCVD: angina, myocardial infarction, stroke, transient ischemic attack, claudication, arterial bruits
	Hemolysis/ hemolytic anemia
	Impaired platelet aggregation with easy bruising or bleeding
Lysosomal acid lipase deficiency	Nausea, vomiting, diarrhea/steatorrhea	↑ TG frequently
	Protuberant abdomen	Transaminase elevations
	Hepatosplenomegaly, hepatic fibrosis, cirrhosis	Lipid infiltration of liver is cholesterol not TG
	Xanthomatous infiltration of adrenal, spleen, lymph nodes, bone marrow, small intestine, lungs, and thymus	Calcified adrenal gland on imaging
		Aliases: Wolman syndrome in infants and cholesterol ester storage disease (somewhat milder presentation)
Group 2: Monogenic hypocholesterolemia
Abetalipoproteinemia	Failure to thrive, steatorrhea	Acanthocytosis on peripheral blood smear
	Night blindness, atypical retinitis pigmentosa, retinal degeneration	Complete absence of apo B containing lipoproteins; HDL-C normal
	Osteomalacia, osteoporosis	Undetectable levels of fat-soluble vitamins
	Ataxia, peripheral neuropathy, posterior column signs, deep tendon reflex loss
Hypobetalipoproteinemia	Biallelic (ie, homozygous) form is clinically identical to abetalipoproteinemia	Monoallelic (ie, heterozygous) form has mainly biochemical features (ie, low but not absent apo B-containing lipoproteins) plus susceptibility to fatty liver (typical hepatosteatosis) and protection from ACSCVD
Chylomicron retention (Anderson) disease	Similar to abetalipoproteinemia	Distinguished biochemically from abetalipoproteinemia and homozygous hypobetalipoproteinemia by normal TG levels
	Systemic features are less severe; no erythrocyte abnormalities
Familial combined hypolipidemia	No defining clinical features	Biallelic form: profound deficiency of all lipoproteins
	Probable protection from ASCVD	Monoallelic form: normal HDL-C; low apo B-containing lipoproteins
Group 2A: Monogenic hyperalphalipoproteinemia: extremely elevated HDL-C
CETP deficiency	No defining clinical features	Biallelic form: extreme high HDL-C
	Possible protection from ASCVD, although this is controversial	Monoallelic form: moderately elevated HDL-C
Hepatic lipase deficiency	Associated with accelerated ASCVD	Increases in both HDL-C and apo B-containing lipoproteins;
	Eruptive or palmar xanthomas sometimes	Managed according to LDL-C targets
SR-B1 deficiency	No defining clinical features	Biallelic form: extremely high HDL-C
	Possible protection from ASCVD, although this is controversial	Monoallelic form: moderately elevated HDL-C
Group 2B: Monogenic hypoalphalipoproteinemia: severely depressed HDL-C
Apolipoprotein A-I deficiency (familial hypoalphalipoproteinemia)	Xanthomatosis: cutaneous, interdigital web spaces	Biallelic form: absent HDL-C and apo A-I
	Predisposition to early ASCVD	Monoallelic form: moderately depressed HDL-C and apo A-I
Tangier disease	Hepatosplenomegaly	Biallelic form: absent HDL-C and apo A-I with clinical features plus stomatocytes on peripheral blood film
	Corneal opacities	Monoallelic form: moderately depressed HDL-C and apo A-I with no clinical features
	Enlarged orange tonsils
	Dry/brittle skin/hair/nails
	CE deposition in lymph nodes, bone marrow, liver, spleen, tonsils
	Demyelinating sensory, autonomic, and motor neuropathies
	Often premature coronary disease, angina, carotid bruits, claudication
Familial LCAT deficiency	Corneal lipid deposits and opacities	Low HDL-C, plasma esterified cholesterol, apo A-I and A-II
	Foam cells in bone marrow and renal glomeruli	High plasma free cholesterol, TG,
	Proteinuria, renal failure	Alias: fish eye disease for severe LCAT deficiency
	Anemia
Group 3A: Monogenic hypertriglyceridemia: severely elevated TG
Familial chylomicronemia syndrome	Nausea, vomiting, failure to thrive, abdominal pain, pancreatitis risk	Biallelic form is associated with early onset (often childhood)
	Lipemic plasma	Relatives with mono-allelic form express extremely heterogeneous phenotypes ranging from normal TG to severe HTG
	Hepatosplenomegaly, lipemia retinalis, eruptive xanthomas, jaundice
Infantile HTG, transient	Short stature	Elevated TG ± cholesterol and liver enzymes normalize with age
	Hepatosplenomegaly	High urinary dicarboxylic acid
	Hepatic steatosis/fibrosis
Dysbetalipoproteinemia	Tuberoeruptive xanthomas, palmar crease xanthomas	Remnant lipoproteins, termed IDL and beta-VLDL, persist abnormally
	Premature atherosclerosis	APOE E2/E2 homozygotes are predisposed but expression requires a second genetic abnormality
Secondary dyslipidemias
Partial lipodystrophies	Distinctive patterns of regional lipoatrophy associated with simultaneous lipohypertrophy in unaffected areas	Elevated TG which can be severe in 10%-20% of cases
	Insulin resistance
	Recurrent pancreatitis
Generalized lipodystrophies	Absence of subcutaneous fat in subcutaneous tissues	Elevated TG, which can be severe in majority of cases
	Insulin resistance	Elevated liver enzymes
	Recurrent pancreatitis
	Hepatosplenomegaly

Abbreviations: apo, apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; CE, cholesterol ester; E2, binding defective isoform of apo E; FH, familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; HTG, hypertriglyceridemia; IDL, intermediate-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); TG, triglyceride; TTG, ; VLDL, very low-density lipoprotein.