Mendelian connective tissue disorders
The following conditions are the main focus of the Thematic Group Mendelian connective tissue disorders.
Ehlers-Danlos syndromes (EDS)
Ehlers-Danlos syndromes (EDS) form a heterogeneous group of hereditary connective tissue diseases characterized by joint hyperlaxity, cutaneous hyperelasticity and tissue fragility.
There are several types of EDS that may share some symptoms.
These include an increased range of joint movement, stretchy skin, fragile skin that breaks or bruises easily. The different types of EDS are caused by faults in certain genes that make connective tissue weaker. Depending on the type of EDS, the faulty gene may have been inherited from one parent or both parents. Sometimes the faulty gene is not inherited, but occurs in the person for the first time.EDS can affect people in different ways. For some, the condition is relatively mild, while for others their symptoms can be disabling. Some of the rare, severe types can be life threatening.
Cutis laxa (CL)
Cutis laxa (CL) is an inherited or acquired connective tissue disorder characterized by wrinkled, redundant and sagging inelastic skin associated with skeletal and developmental anomalies and, in some cases, with severe systemic involvement. Several different forms of inherited CL have been described, differentiated on the basis of the mode of inheritance and differences in the extent of internal organ involvement, associated anomalies and disease severity. Autosomal recessive types of CL (ARCL) appear to be the most common forms with two subtypes being described:ARCL1 and ARCL2.
ARCL1 is the most severe form of CL with generalised involvement leading to life-threatening complications (lung atelectesias and emphysema, vascular anomalies, and gastrointestinal and genitourinary tract diverticuli).
ARCL2 appears to cover a spectrum of disorders ranging in severity from the wrinkly skin syndrome to more severe disease associated with growth and developmental delay, and skeletal anomalies (classic ARCL2, Debré type). De Barsy syndrome and geroderma osteodysplastica also show significant clinical overlap with ARCL2.
Occipital horn syndrome (X-linked cutis laxa (XRCL) is very similar to ARCL2; however, several patients present a more severe phenotype and systemic involvement. Autosomal dominant CL (ADCL) is generally a mild cutaneous disorder but systemic manifestations (hernias, cardiac valve anomalies, cardiovascular manifestations, gastrointestinal diverticuli and emphysema) have been noted in some cases.
Most cases of CL are inherited, with prevalence at birth being estimated at around 1/1,000,000 and only around 200 families being reported in the literature so far.
Pseudoxanthoma elasticum (PXE)
Pseudoxanthoma elasticum (PXE) is an inherited connective tissue disorder characterized by progressive calcification and fragmentation of elastic fibers in the skin, retina, and arterial walls.
Skin lesions appear during the second decade of life, with a progressive increase in number and severity during adolescence. The disease is clinically heterogeneous, being limited to only one organ in some patients but affecting all three organs in others. The skin lesions consist of yellow papules that may merge to form plaques. They appear mainly in the flexural areas of the neck and elbows, popliteal spaces and umbilical region, and are accompanied by loosening of the skin around the inguinal folds and armpits. Ophthalmological findings include retinal pigment epithelium anomalies, drusen, angioid streaks (fissuring of the Bruch membrane of the retina), and neovascularization and bleeding leading to retinal hemorrhage and, in many patients, loss of visual acuity. Involvement of the macula may lead to patients being declared as legally blind. Cardiovascular manifestations lead to intermittent claudication of the lower and/or upper limbs due to arteriosclerosis of medium-sized arteries with calcified vessel walls. Transitory ischemic events and angina pectoris are less frequent findings. Gastrointestinal hemorrhage occurs in 5% of cases, mostly during adolescence. Although early reports indicated that affected women may encounter difficulties during pregnancy, more recent studies show that pregnancy in PXE patients is not associated with any specific complications.
Prevalence is estimated at between 1/25,000 and 1/100,000.
Buschke-Ollendorff syndrome (BOS)
Buschke-Ollendorff syndrome (BOS) is a benign disorder characterized by the association of osteopoikilosis lesions (“spotted bones”) in the skeleton and connective tissue nevi in the skin.
Onset may occur at any age and expression of the bone and skin lesions is variable. Osteopoikilosis is characterized by small and round spots of increased bone density that are mainly located in the epiphyseal regions of the tubular bones. They are harmless and usually found by chance when radiographs are taken for other purposes, although pain and limited joint mobility have been reported in a minority of patients. The number of lesions can vary from a few to many lesions, usually found in the shoulders, elbows, wrists, pelvis, knees and ankles. The skin lesions encountered in the BOS are connective tissue nevi. These lesions can present as either widely disseminated, skin-colored to yellow small papules or as more localized larger lesions referred to as yellow plaques. In families with BOS, affected individuals can have both bone and skin lesions, or just one of these manifestations. Melorheostosis (see this term) has been described in some patients from BOS families.
The exact prevalence is unknown but BOS is believed to affect around 1 in 20,000 individuals.
Pediatric marfan syndrome
Marfan syndrome is a systemic disease of connective tissue characterized by a variable combination of cardiovascular, musculo-skeletal, ophthalmic and pulmonary manifestations.
Symptoms can appear at any age and vary greatly between individuals even within the same family. Cardiovascular involvement is characterized by 1) progressive dilation of the aorta accompanied by an increased risk of aortic dissection, which affects prognosis; the aortic dilation can result in a leaky aortic valve; and 2) mitral insufficiency, which can be complicated by arythmias, endocarditis or cardiac insufficiency. Skeletal involvement is often the first sign of the disease and can include dolichostenomelia (excessive length of extremities), large size, arachnodactyly, joint hypermobility, scoliotic deformations, acetabulum protrusion, thoracic deformity (pectus carinatum or pectus excavatum), dolichocephaly of the anteroposterior axis, micrognathism or malar hypoplasia. Ophthalmic involvement results in axile myopia, which can lead to retinal detachment and lens displacement (ectopia or luxation are characteristic signs). Ocular complications, particularly lens ectopia, can lead to blindness. Cutaneous signs (vergetures), a risk of pneumothorax and dural ectasia can also occur.