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Heritable connective tissue disorders


In the proposal for a CA, submitted in 1989 to the EC, it was argued that a European NETWORK linking clinical centres and laboratories:

a) could solve the problems connected with the low prevalence of the individual disorders in every country and of high genetic heterogeneity and clinical variability of the HCTD
b) would be an adequate means of reaching a double goal, ie, the scientific unravelling of pathogenetic mechanisms in HCTD and the improvement in clinical application of research results in particular: clinical and laboratory diagnosis, prevention by genetic counselling and prenatal diagnosis and also prophylactic treatment of the severely disabling or life threatening complications.
A network linking 61 European clinical centres and connective tissue laboratories, set up for collaborative research projects, has allowed considerable progress in the scientific understanding and medical management of heritable connective tissue disorders (HCTD). As each of the connective tissue (CT) disorders are individually rare, pooling of samples from different geographic areas allowed for an appropriate amount of clinical material for research on specific CT disorders or particular CT proteins or genes. The elucidation of mutational mechanisms and biochemical defects concerned especially those HCTD connected with collagen and fibrillin defects (ie Osteogenesis Imperfecta (OI) (brittle done disease), Ehlers-Damlos Syndrome (EDS), Marfan Syndrome and Pseudoxanthoma Elasticum (PXE)). Their clinical symptomatology is overlapping and similar types of mutations have been found in different disease groups: the types of mutations in collagen type II (chondrodysplasia) and in collagen type III (EDS IV) reflect those found in collagen type I genes (OI) in Marfan syndrome, and the molecular characterization of the spectrum of mutations is just beginning.
Molecular genetics studies in OI provided information not only about normal and abnormal collagen, but also about the genetic transmission of dominant traits (ie their variable penetrance and expression and the unexpected recurrences in children of normal parents (germinal mosaicism).
The EB research studies have widened the understanding of normal skin functions and helped discern the mechanisms leading to acquired diseases of the dermoepidermal juction, such as autoimmune blistering disorders or disturbances of epithelialization and wound healing.
Research on the single gene HCTD has opened the way for the investigation of the fundamental mechanisms of the ageing process and the common chronic CT disorders of aged people in which inheritance is less obvious.

Special clinics have been set up to aid HCTD patients and families. When people at risk are recognized, modern treatments (medical and surgical) can postpone disabling complications and prolonge life (eg in Marfan Syndrome).
HCTD are a wide range of disorders which affect bones, skin, ligaments, blood vessels, eyes and teeth. The clinical features are multifold and vary from very mild to crippling and life threatening manifestations, such as multiple fractures, severe skeletal deformities, spontaneous bleedings, vascular ruptures, cardiac insufficiency, severe visual impairment and various cutaneous problems (inesthetic scarring, blistering, etc). HCTD are caused by mutations in structural genes or enzymes controlling the biosynthesis or degradation of one or more connective tissue matrix components (collagens, elastin, fibrillin, fibronectin, decorin, etc).

These components form distinct suprastructures (eg fibrils and microfibrils, beaded filaments, basement membranes or other supramolecular aggregates) which make interacting networks responsible for the stability, elasticity and resilience of CT and which provide a scaffold for normal organ development, differentiation and repair.

HCTD are clinically and genetically heterogeneous. Each disorder has variable phenotypic manifestations and there are overlapping clinical signs between the different groups and subgroups.

Many different types of mutations are found within the numerous genes involved. Moreover the phenotypic expression of a particular CT defect is modulated by interactions between the different matrix components.

The main problem in mutation identification in HCTD is the fact that each mutation is unique to a particular family and that therefore analysis is both labour intensive and time consuming.

HCTD have a great socio-economic impact: the great majority are 'familial' (dominant or recessive) disorders that may affect several relatives in the same and/or successive generations.

In 1988 the idea of the desirability of a Concerted Action (CA) on HCTD arose amongst a few European medical geneticists because:
- on the one hand, clinical knowledge about these disorders was insufficient, sample referral for biochemical and molecular diagnosis inadequate and prevention by genetic counselling almost inexistent.
- on the other hand, each of the disorders being individually rare, pooling of samples from different geographic areas would allow for an appropriate amount of clinical material for research on specific CT disorders or particular CT proteins or genes.

Funding Scheme

CON - Coordination of research actions


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