Introduction
Hereditary collagen (connective tissue) diseases are genetic disorders affecting structural proteins such as collagen, elastin and fibrillin, which give strength and elasticity to skin, ligaments, bones and vessels. This topic covers osteogenesis imperfecta, Ehlers–Danlos syndrome and Marfan syndrome, with their genetic and clinical characteristics, diagnosis and management, and a comparison of EDS and Marfan syndrome.
Osteogenesis imperfecta (OI)
OI, "brittle bone disease", is a group of genetic connective tissue disorders and one of the most common inherited bone disorders. It is characterized by bone fragility with multiple fractures, defective connective tissue (abnormal type I collagen) and extraskeletal features (hearing loss, dentinogenesis imperfecta, blue sclerae).
Molecular basis
- Defective synthesis of type I collagen, the major structural protein of bone, dentin, sclera and ligaments.
- Mutations most commonly in COL1A1 and COL1A2 give abnormal α chains of collagen type I.
- Inheritance: mostly autosomal dominant; recessive and de novo cases are also reported.
- Pathogenesis: collagen is quantitatively reduced or structurally abnormal, giving a weak bone matrix, reduced tensile strength and systemic connective tissue fragility.
Classification (Sillence, major types)
- Type I (mild): the most common and mildest form; normal stature; fractures in childhood (fewer after puberty); blue sclerae (thin sclera, underlying choroid visible); hearing loss (otosclerosis of the middle ear bones); normal life expectancy.
- Type II (perinatal lethal): the most severe form, usually lethal in utero or shortly after birth; multiple fractures, skeletal deformities, extremely fragile bones, underdeveloped lungs.
- Type III (severe, progressively deforming): severe bone fragility, frequent fractures, progressive deformities; short stature, kyphoscoliosis, barrel-shaped chest; normal sclera (sometimes blue at birth, white with age); wheelchair-dependent, reduced life expectancy.
- Type IV (moderate): severity between types I and III; fractures, mild to moderate bone deformity; normal sclerae; may have dentinogenesis imperfecta.
Clinical features
- Skeletal: multiple fractures with minimal trauma; deformities (bowing of long bones, scoliosis, kyphosis); short stature in severe forms; osteopenia/low bone density on imaging.
- Extraskeletal: blue sclerae (type I); dentinogenesis imperfecta (discoloured, weak, translucent teeth prone to wear and breakage); hearing loss from abnormal ossicles or otosclerosis (adult onset); joint laxity and hypermobility; cardiovascular involvement (mitral valve prolapse, aortic root dilatation, less common).
Diagnosis
- Clinical: history of fractures, skeletal deformity, family history.
- Radiology: generalized osteopenia, multiple fractures at different healing stages.
- Genetic testing: mutations in COL1A1/COL1A2.
- Bone biopsy: abnormal collagen fibril formation (rarely needed).
- Differential diagnosis: rule out child abuse in pediatric cases.