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Inherited defects of connective tissue: Ehlers–Danlos syndrome, Marfan’s syndrome, and pseudoxanthoma elasticum 

Inherited defects of connective tissue: Ehlers–Danlos syndrome, Marfan’s syndrome, and pseudoxanthoma elasticum

Chapter:
Inherited defects of connective tissue: Ehlers–Danlos syndrome, Marfan’s syndrome, and pseudoxanthoma elasticum
Author(s):

N.P. Burrows

DOI:
10.1093/med/9780199204854.003.2002_update_002

July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

Clinical subtypes of EDS updated to include two new recently identified types.

Newly recognized genotype-phenotype described in the role of fibrillin 1.

Recommendation for Marfan’s syndrome treatment updated following results of losartan study.

Updated on 29 May 2014. The previous version of this content can be found here.
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date: 25 March 2017

The inherited disorders of connective tissue are all conditions in which structural defects in collagen or other extra cellular matrix proteins lead to its fragility, with the commonest sites of involvement being the skin, ligaments and vasculature.

Ehlers–Danlos syndrome (EDS)

EDS is a heterogeneous group of disorders resulting from abnormalities in collagen synthesis and processing, or of other extracellular matrix proteins. They can be classified on the basis of descriptive clinical phenotype and/or underlying molecular cause. Most cases are autosomal dominant, but 30 to 50% may be sporadic.

Clinical features—the cardinal manifestations are cutaneous hypextensibility, soft texture (‘doughy consistency’) and fragility, ligamentous laxity, and easy bruising. (1) Classical EDS (types I and II)—commonly caused by mutations in COL5A1; notable features include epicanthic folds and blue sclerae. (2) Hypermobile EDS (type III)/benign joint hypermobility syndrome—the commonest subtype of EDS; caused by haploinsufficiency of tenascin-X in some cases; manifest with joint hypermobility but minimal skin changes; persistent arthralgia may be difficult to treat. (3) Vascular EDS (type IV)—mutations in COL3A1 lead to reduction of collagen III in blood vessels and bowel in this life threatening condition; about half of arterial ruptures involve medium/large thoracic or abdominal arteries, but any site can be affected; most bowel perforations affect the sigmoid colon; significant risk of uterine rupture in pregnancy. (4) Kyphoscoliotic EDS (type VI)—may be due to defective function of a post-translational modification enzyme, lysyl hydroxylase. (5) Arthrochalasis EDS (type VIIA and B)—due to deficient processing of collagen I; characterised by severe joint hypermobililty, congenital bilateral hip dislocations and recurrent subluxations. (6) Dermatosparaxis (type VIIC)—mutations in ADAMTS2 leads to extreme skin fragility and laxity. More recent subtypes have been characterised; (7) Tenascin-X deficiency—an autosomal recessive EDS type but with absence of scars due to truncating mutations or deletions in TNXB. (8) Spondylocheiro dysplastic type—due to mutations in the zinc transporter gene SLC39A13; present with EDS features and mild skeletal dysplasia. (9) D4ST1-deficient EDS—mutations in CHST14 result in a phenotype of EDS with distinct craniofacial features and congenital contractures. (10) Kyphoscoliosis with myopathy and deafness—an autosomal recessive variant with typical skin features in addition to muscle hypotonia at birth, progressive kyphoscoliosis and sensorineural hearing loss due to mutations in FKBP14. (11) Progeroid EDS arises due to defective glyscosaminoglycans synthesis (XGPT1/B4GALT7 mutations). A phenotype due mutations in B3GALT6 gives overlapping features of progeroid EDS, kyphoscoliosis and spondyloepimetaphaseal dysplasia.

Marfan’s syndrome

Marfan’s syndrome is caused by autosomal dominant mutations in the human fibrillin-1 (FBN1) gene, with de novo mutations occurring in about 25% of cases. Criteria for diagnosis include aortic root dilatation, aortic dissection, lens dislocation, dural ectasia, and the presence of skeletal features including pectus carinatum, pectus excavatum requiring surgery, reduced upper to lower segment ratio or arm span to height ratio >1.05, wrist and thumb signs, scoliosis or spondylolisthesis, reduced extensions at the elbows, pes planus, and protrusio acetabulae. The main causes of death in Marfan’s syndrome are cardiovascular complications, in particular aortic rupture (see Chapters 16.11 and 16.14.1). It is possible that early treatment with angiotensin II receptor blockade will prevent this by slowing the progression of aortic root dilatation, and it may also help other noncardiovascular complications.

Pseudoxanthoma elasticum (PXE)

PXE is caused by molecular defects in the transporter gene (ABCC6) that lead to calcification of elastic fibres and manifestation with complications including (1) cutaneous—yellowish papules appear in flexures, leading to a ‘plucked chicken’ or ‘gooseflesh’ appearance; (2) ocular—fundoscopy reveals mottled peau d’orange pigmentation, progressing to breaks in Bruch’s membrane when angioid streaks are seen; retinal haemorrhages, neovascularization and chorioretinitis can all lead to loss of central vision; and (3) cardiovascular—calcification of arterial elastic media and intima affects predominantly peripheral arteries; intermittent claudication is the commonest symptom.

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