Ehlers–Danlos syndrome

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133 Ehlers–Danlos syndrome

Instruction

Do a general examination.

Examine this patient’s joints.

Salient features

History

• Family history (JAMA 1997;278:1284–5)

• Hypermobile joints (Fig. 133.1)

• Fragile skin with impaired wound healing

• Bleeding diathesis.

Fig. 133.1 Manoeuvres that may establish clinically significant joint laxity.

Examination

Skin

• The skin over the neck, axillae and groin is smooth and elastic (Fig. 133.2). It can be stretched and, when released, it returns immediately to its normal position. Late in the disease it becomes lax, wrinkled and hangs in folds.

Fig. 133.2 The skin over the neck, axillae and groin is smooth and elastic; it can be stretched and, when released, it returns immediately to its normal position. Late in the disease it becomes lax, wrinkled and hangs in folds.

Proceed as follows:

• Look at bony prominences for bruising, haematomas and gaping wounds. Wounds heal forming tissue-paper or papyraceous or ‘cigarette-paper’ scars. Haematomas heal forming pseudotumours or nodules.

Diagnosis

This patient has hypermobile joints (lesion) caused by Ehlers–Danlos syndrome (aetiology).

Advanced-level questions

What are the gastrointestinal manifestations of this syndrome?

• Marked tendency to herniate

• Achalasia cardia

• Eventeration of the diaphragm

What are the cardiovascular manifestations?

• Mitral valve prolapse

• Aortic dissection.

What precautions would you take in managing skin wounds?

As the skin wounds tend to be gaping, they should be approximated with care; removable sutures are usually left in place for twice the usual time.

What do you know about Ehlers–Danlos syndrome?

It comprises a group of heterogeneous disorders that result from defects in collagen synthesis and vary genetically and clinically from one another (Science 1973;182:298). Some molecular defects are known.

Type VI (kyphoscoliotic type). The most common and autosomal recessive form of inheritance. There is a defect in the enzyme lysyl hydroxylase, which is necessary for hydroxylation of lysyl residues during collagen synthesis. Only collagen types 1 and 3 are affected, and collagen types 2, 4 and 6 are normal. The predominant clinical features are ocular fragility with rupture of the cornea and retinal detachment. Some of these patients respond to ascorbic acid.

Type IV (‘vascular type’). This is caused by a defect in the structural gene for collagen type 3 (COL3A1) and is inherited as an autosomal dominant trait. As type 3 collagen is present largely in blood vessels and intestines, the typical features of this syndrome include easy bruising; thin skin with visible veins; characteristic facial features; rupture of the large arteries, uterus or colon; and reduced life expectancy. This is the most severe form of Ehlers–Danlos syndrome (N Engl J Med 2000;342:673–80). Loeys–Dietz syndrome overlaps with this type.

Type VII. A defect in the conversion of procollagen to collagen, caused by the mutation that affects one of the two type 1 collagen genes (COL1A1 and COL1A2). Although in the single mutant allele, only 50% of type 1 collagen chains are affected, heterozygotes manifest the syndrome because these abnormal chains interfere with the formation of normal collagen helices.

Type IX. This is caused by a defect in copper metabolism, with high levels of copper in the cells but low levels of serum copper and caeruloplasmin. Because the gene influencing copper metabolism is on the X chromosome, it is inherited as an X-linked recessive trait. This disease illustrates how copper metabolism can affect connective tissue.

Classical or types I and II. Null alleles of the COL5A1 gene encoding type V collagen are a cause of the classical form. A single base mutation in COL5A2 causes type II. Mutations in a gene that encodes tenascin-X, which is neither a collagen nor a collagen-modifying protein, can result in a variation of the classic form of the Ehlers–Danlos syndrome.

Patients with type I, II and IV disease are often investigated for bleeding diathesis before the correct diagnosis is made. Because of joint instability and laxity, many patients with types I, II, III, VI and VII disease are investigated for developmental delay before it is recognized that they have this syndrome.

Over 35 collagen genes have now been identified and these encode the chains of >20 types of collagen: types 1, 2 and 3 are the interstitial or fibrillar collagen whereas types 4, 5 and 6 are amorphous and are present in the interstitial tissue and basement membranes.

In which other condition is there a defect in collagen metabolism?

Osteogenesis imperfecta.

What are the criteria for diagnosis of joint hypermobility?

Beighton’s nine-point scoring for joint hypermobility assigns two points for each of the following four paired manoeuvres (Ann Rheum Dis 1973;32:413–18):

• Hyperextension of the fifth metcarpophalangeal joint to 90 degrees

• Apposition of the thumb to the volar aspect of the forearm

• Hyperextension of the elbow beyond 10 degrees

• Hyperextension of the knee to beyond 10 degrees.

One point is assigned for the ability to place the palms of the hands on the floor with the knees extended.

It is not unusual to find extreme laxity in small joints and less laxity in large joints. Laxity decreases with age, so the dominant nature of most of these syndromes may not be appreciated when examining older family members.

Is hypermobility advantageous to musicians?

Lax fingers and wrists are good for flutists and string players, but lax knees and spines are bad for tympanists and others who stand while they play (N Engl J Med 1993;329:1079).

Further reading

Asociación Sindromes de Ehlers-Danlos e Hiperlaxitud (www.asedh.org): Spanish patient support group.

Association Francaise des Syndromes d’Ehlers-Danlos (www.afsed.com): French patient support group.

Ehlers-Danlos Foundation of New Zealand (www.edfnz.org.nz): New Zealand patient support group.

Ehlers-Danlos National Foundation (www.ednf.org): US patient support group.

Ehlers-Danlos Support Group (www.ehlers-danlos.org): UK patient support group.

Edvard Ehlers (1863–1937), a Danish dermatologist, and HA Danlos, a French dermatologist, described this condition independently in 1901 and 1908, respectively. Tschernogobow in Moscow first described this syndrome in 1892 (N Engl J Med 2000;342:730)

It is widely believed that the outstanding virtuosity of the violionist Niccolò Paganini (1782–1840) was the result of remarkable flexibility of the joints of his left hand: he could span three octaves with little effort (Arthritis Rheum 1982;25:1385–6).

Robert James Gorlin (1923–2006) described Gorlin’s sign, which is the ability to touch the tip of the nose with the tongue in Ehlers–Danlos syndrome.

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