bone fragility with contractures, arterial rupture, and deafness

Bone fragility with contractures, arterial rupture, and deafness is an inherited connective-tissue disorder that affects many body systems, especially the skeleton, joints, eyes, skin, and blood vessels. The condition results from pathogenic variants in the PLOD3 gene, which encodes lysyl hydroxylase 3, an enzyme essential for proper collagen formation. Symptoms usually begin before birth or in early infancy and affect males and females equally. Fewer than one in a million people worldwide are thought to have this condition, making it extremely rare. Because collagen is found throughout the body, the clinical picture is complex and varies widely between individuals.

Severity and symptoms vary widely between individuals, but several features are considered characteristic. Skeletal issues dominate early life: many babies are born with club foot, shortened long bones, and joint contractures of the elbows, fingers, and other large joints. Progressive scoliosis, osteopenia, and frequent fractures reflect the underlying bone fragility, while platyspondyly (flattened vertebral bodies) may be seen on spinal imaging. Connective-tissue weakness also affects soft tissues. Skin may blister easily, hair can be coarse or irregularly distributed, and palmar creases are often reduced. Hypoplastic nails and thenar muscle wasting further illustrate the widespread impact on the musculoskeletal system. Eye involvement includes severe myopia and early-onset cataracts, sometimes accompanied by a flat retina. Hearing loss is sensorineural, bilateral, and usually detected in childhood. Facial features such as a flat midface, shallow orbits, low-set ears, short upturned nose, and down-turned corners of the mouth can provide diagnostic clues. Serious vascular complications emerge later. The walls of large arteries are fragile, predisposing affected individuals to spontaneous arterial ruptures, and dilation of cerebral arteries may lead to life-threatening events. Diaphragmatic weakness is another hallmark, occasionally resulting in respiratory difficulties. Not all individuals experience all features, and new symptoms can develop over time, underscoring the importance of lifelong monitoring.

The disorder is caused by pathogenic variants in the PLOD3 gene. PLOD3 provides instructions for making lysyl hydroxylase 3, an enzyme that modifies collagen molecules so they can form strong, stable fibers. When the enzyme is missing or does not work correctly, collagen remains under-hydroxylated, weakening bones, blood-vessel walls, and other connective tissues. The condition is inherited in an autosomal recessive pattern. An individual must receive one altered copy of PLOD3 from each parent in order to be affected, while carriers with a single variant usually have no symptoms. Each pregnancy between two carriers carries a 25 percent chance of producing a child with the condition, a 50 percent chance of a carrier child, and a 25 percent chance of an unaffected, non-carrier child. Because this ultra-rare condition requires two copies of the same rare variant, it is more common when parents share a common ancestor, since relatives are more likely to carry the same genetic change. Carrier testing and genetic counseling are strongly recommended for family members who may be at risk.

Currently, management focuses on supportive care and symptom management. Treatment is tailored to the individual and typically involves a multidisciplinary team that may include orthopedic surgeons, physiotherapists, audiologists, ophthalmologists, cardiologists or vascular surgeons, dermatologists, and genetic counselors. Orthopedic care addresses fractures, scoliosis progression, and joint contractures. Bracing, physiotherapy, and in some cases surgical correction help maintain mobility and reduce pain. Hearing aids or cochlear implants improve communication for those with significant deafness. Regular ophthalmologic assessments allow timely treatment of cataracts or progressive myopia, while dermatologic care helps manage skin fragility. Long-term management includes regular surveillance for potential complications. Annual vascular imaging may be recommended to detect arterial dilatations before rupture, and pulmonary evaluations monitor diaphragmatic function. Bone-density monitoring guides interventions to minimize fracture risk. These monitoring schedules help detect problems early when intervention is most effective. Because no disease-specific therapy exists, research into enzyme replacement or gene-based approaches continues. Patients should discuss management strategies with their healthcare team and consider enrolling in natural-history studies when available.

Outcomes depend on the number and severity of complications each person experiences, and individual experiences with this condition differ significantly. Many children survive into adolescence and adulthood, but quality of life can be affected by recurrent fractures, progressive scoliosis, hearing impairment, and anxiety surrounding potential vascular events. Early diagnosis, coordinated specialist care, and proactive surveillance can reduce morbidity by allowing preventive surgeries or interventions before severe complications arise. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialist centers and genetic counselors who can guide surveillance plans and discuss family-planning options.