26th February 2025

Hereditary connective tissue disorders

Marfan syndrome

Marfan syndrome is caused by a mutation in the Fibrillin-1 gene (FBN1) and is inherited in an autosomal dominant pattern, although 25% of patients have de novo mutations.

Diagnosis of Marfan’s is made using the Ghent criteria, the key components of which are aortic root dilatation, ectopia lentis and FBN1 gene mutation.

Clinical features of Marfan syndrome

Patients have characteristic musculoskeletal findings. Excess growth of the long bones results in greater height than expected for their genetic background and increased arm length and arm-span-to-height ratio. Chest wall deformity is often present, with pectus carinatum more common than excavatum. Arachnodactyly (long, slim fingers) is also seen. There may be a high-arched palate.

The aortic root is often involved in up to 50% of children and 80% of adults. This manifests as aortic root dilation, aortic regurgitation and aortic dissection, which is the most common cause of morbidity and mortality. Other cardiac features are mitral valve prolapse, tricuspid regurgitation and subsequent heart failure. They can have a high risk of pneumothorax due to emphysematous changes and lung bullae in the upper lobes.

Ectopia lentis is another common feature of Marfan’s and is classically an upward dislocation of the lens. Dural ectasia (enlargement of the spinal canal) in the lumbosacral spine is common.

Homocystinuria is a condition that mimics Marfan’s; however, it has some distinguishing features, and differentiating between the two is a common exam question. Homocystinuria is caused by mutations in multiple genes, such as CBS, which encodes the cystathionine beta-synthase enzyme. Homocystinuria causes marfanoid body habitus and also causes ectopia lentis; however, the lens usually dislocates downward. Intellectual disability is commonly present, and there is a high incidence of thrombotic events, neither of which are associated with Marfan’s.

Osteogenesis imperfecta

Osteogenesis imperfecta is a heritable connective tissue disorder caused by type 1 collagen abnormalities, either decreased production or disrupted structure or processing.

Classification of osteogenesis imperfecta

Originally, four subtypes were described, and these are most commonly asked about in MRCP, although the disease is now felt to be a spectrum, and other subgroups have been added. Types I and IV encompass 90% of patients.

Table 7 Clinical features and heritability of osteogenesis imperfecta types I to IV

Clinical features of osteogenesis imperfecta

Other suggestive features include short stature, scoliosis, easy bruising, increased skin laxity and dental abnormalities. Very mild disease can present as premature osteoporosis, particularly postpartum, or accelerated osteoporosis following menopause.

Management is supportive, including physiotherapy, targeted surgical intervention as required, and screening for osteoporosis.

Ehlers-Danlos syndrome (EDS)

This is a heterogeneous group of disorders with common features including hypermobility, soft and ‘stretchy’ skin, bruising and poor wound healing. There are fourteen types, of which thirteen have had a causative gene mutation identified. These mostly occur in genes which code for type I, III or V collagen subunits or relevant enzymes.

EDS can affect any organ or tissue structure and can present with a variety of signs or symptoms, although those mentioned above are classical. It is important to be aware of vascular EDS, which can cause arterial aneurysms or dissections due to vascular fragility.

Diagnosis is difficult, as some features of EDS are common in healthy individuals, and there is considerable overlap with other diseases. Examination of the skin in classical EDS may reveal hyper-extensibility, abnormal scarring, or velvety or ‘doughy’ texture, whereas, in vascular EDS, the skin is usually thin with visible veins. Hypermobility can be assessed using the Beighton scale. In individuals where there is high clinical suspicion, genetic testing is usually undertaken for diagnosis, except for hypermobile EDS, which has no genetic test and, therefore, requires careful clinical assessment alone.

There is no specific treatment for EDS, and management is directed at the patient’s features. In vascular EDS there should be regular screening for asymptomatic aneurysms and dissections.

References

• Beary JF. Osteogenesis imperfecta: An overview [Internet]. Firth HV, TePas E, editors. UpToDate. 2021 [cited 2022 Feb 25]. Available from: https://www.uptodate.com/contents/osteogenesis-imperfecta-an-overview
• Meester JAN, Verstraeten A, Schepers D, Alaerts M, Van Laer L, Loeys BL. Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Annals of Cardiothoracic Surgery [Internet]. 2017 Nov [cited 2022 Jun 1];6(6):582–94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721110/
• Malfait F, Castori M, Francomano CA, Giunta C, Kosho T, Byers PH. The Ehlers–Danlos syndromes. Nature Reviews Disease Primers. 2020 Jul 30;6(1)
• Clunie GPR, Wilkinson N, Nikiphorou E, Deepak Jadon. Oxford handbook of rheumatology. Oxford: Oxford University Press; 2018
• Sacharow SJ, Picker JD, Levy HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency [Internet]. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, et al., editors. PubMed. Seattle (WA): University of Washington, Seattle; 1993 [cited 2022 Jun 3]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1524/