Tendon xanthomata

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173 Tendon xanthomata

Instruction

Look at this patient’s hands.

Salient features

History

• Family history of hyperlipidaemia

• History of premature coronary artery disease.

Examination

• Tendon xanthomata seen on the extensor tendons and becoming more prominent when the patient clenches his fist (Fig. 173.1B)

Fig. 173.1 Clinical manifestations of hyperlipidaemia (A) Achilles tendon xanthoma (heterozygous familial hypercholesterolaemia). (B) Tendon xanthomata on dorsum of hand (heterozygous familial hypercholesterolaemia). (C) Subperiosteal xanthomata (heterozygous familial hypercholesterolaemia). (D) Planar xanthoma in antecubital fossa (homozygous familial hypercholesterolaemia). (E) Striate palmar xanthomata (type III hyperlipoproteinaemia). (F) Tuberoeruptive xanthomata on elbow and extensor surface of arm (type III hyperlipoproteinaemia). (G) Milky plasma from patient with acute abdominal pain (severe hypertriglyceridaemia). (H) Eruptive xanthomata on extensor surface of forearm (severe hypertriglyceridaemia).

(With permission from Durrington 2003.)

Proceed as follows:

• Look at other tendons, particularly the patellar and Achilles tendon (Fig. 173.1A)

• Look at the eyes for xanthelasmata (see Fig. 170.1) and corneal arcus

• Tell the examiner that you would like to:

• check fasting lipids, in particular for an increase in cholesterol level

• screen family members for hypercholesterolaemia

• examine the heart for aortic valve stenosis caused by lipid deposition (N Engl J Med 2003;349:717).

Diagnosis

This patient has tendon xanthomata (lesion) caused by hypercholesterolaemia (aetiology).

Questions

In which condition are these seen?

Familial hypercholesterolaemia, an autosomal dominant trait with an excess of LDL or β-lipoprotein in the blood. It occurs in 1 in 200–500 of the population.

Advanced-level questions

What is the basic defect?

Autosomal dominant familial hypercholesterolaemia is caused by mutations either in the gene encoding the LDL receptor or in the gene encoding apolipoprotein B (the protein in LDL cholesterol that is recognized by the LDL receptor).

Recessive familial hypercholesterolaemia arises from mutations in the gene encoding an adapter protein involved in the internalization of the LDL receptor.

Another variant of familial hypercholesterolaemia with dominant inheritance and an identical phenotype to the other forms is associated with missense mutations in PCSK9, encoding protease proprotein convertase subtilisin/kexin type 9.

At what age do these patients manifest the condition?

Homozygotes usually have xanthomata at birth or as children. They have a predisposition to ischaemic heart disease, which usually results in death before the age of 30 years. About 50% of heterozygotes also present by the same age.

What are xanthomata?

Xanthomata are tumour-like collections of foamy histiocytes within the dermis. There are five types of xanthoma:

• Eruptive xanthoma (seen in types I, IIb, III, IV, V)

• Tuberous xanthoma (types IIa, III, rarely IIb, IV)

• Tendon xanthoma (types IIa, III, rarely IIIb)

• Palmar xanthoma (types III, IIa, associated with primary biliary cirrhosis)

• Xanthelasma (types IIa, III; also without lipid abnormalities).

Is there any treatment for familial hypercholesterolaemia?

One view is that statin treatment should be started in these patients when boys are in their late teens and women from their late twenties. However, if the family history is particularly adverse then there is an increasing tendency for pediatricians to commence treatment (Lancet 2001;357:574). The Simvastatin in Children Study Group reported that, in such children, LDL cholesterol was reduced by 41% after 48 weeks of treatment with simvastatin and no safety issues were evident. With the exception of small decreases in dehydroepiandrosterone sulfate, there were ‘no significant changes from baseline in adrenal, gonadal or pituitary hormones in the children given simvastatin. There are no adverse effects on growth or pubertal development.’ Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins (Lancet 2010;375:998–1006).

What do you know about phytosterolaemia?

Phytosterolaemia is caused by increased intestinal absorption of dietary sterols (not only cholesterol, but also plant sterols) and decreased biliary excretion of sterols. As a consequence, large amounts of plant sterols accumulate in most tissues, and xanthomas and premature cardiovascular disease develop. It is an autosomal recessive condition caused by mutations in the genes encoding the family of ATP-binding cassette transporters (ABCG5 and ABCG8), which pump sterols out of intestinal cells in the lumen of the gut.

Michael S Brown (b. 1941) and Joseph L Goldstein (b. 1940), both of the University of Texas Health Science Centre in Dallas, were awarded the 1983 Nobel Prize for their discoveries concerning the regulation of cholesterol metabolism.

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