Brief overview
- Description: rare genetic disorder associated with a more or less pronounced bone fragility
- Types: four main types, which differ mainly in severity. Type 2 has the most severe course.
- Life expectancy: Depends on the type of disease. Some affected individuals die in the womb, others have a normal life expectancy.
- Symptoms: Frequent bone fractures, deformation of bones, often blue eyeballs, hearing loss, short stature.
- Cause: Genetic defects that usually affect the formation of collagen (a component of bone and connective tissue).
- Diagnosis: taking medical history, radiological examinations (such as X-rays), genetic examinations
- Treatment: individually tailored therapy with physiotherapy, orthopedic measures, surgery, medication
What is brittle bone disease?
Brittle bone disease (osteogenesis imperfecta, or OI for short) is a congenital, genetic disease. In the vast majority of those affected, the production of collagen is disturbed. This is an important structural protein of bones and connective tissues (such as tendons, ligaments, sclera = the “white” in the eye).
In all cases, however, the bones break more easily than normal. In addition, those affected usually have blue eyeballs and are often hard of hearing.
In individual cases, the exact symptoms depend on the type and severity of the disease. The same applies to life expectancy: some children with brittle bone disease die around birth, while others have a normal life expectancy.
There is no cure for brittle bone disease yet. However, with the right treatment, symptoms can be alleviated and the quality of life of those affected can be improved.
Brittle bone disease: Types
Classically, experts distinguish four main types of osteogenesis imperfecta. This classification (according to Sillence, 1979) is based on clinical appearance and radiological findings (such as body stature, bone deformities, etc.). It was later found that these four main types are due to alterations (mutations) in one of two genes that contain the blueprint for type I collagen.
Osteogenesis imperfecta type 1
Brittle bone disease type 1 is mild. Affected individuals often have only blue sclerae (the “whites” in the eyes).
In about half of the cases, hearing loss is also present. Rarely, the formation of teeth is disturbed in this form of vitreous bone disease. Affected individuals also show few or minor bone deformities (deformities). The body stature is normal.
Osteogenesis imperfecta type 2
Brittle bone disease type 2 takes the most severe course. Affected children die shortly before, during or shortly after birth (perinatal).
Bone fractures already in the womb, deformed as well as shortened bones (and thus short stature) are typical for this form of the disease. In addition, affected individuals have bluish sclerae.
Osteogenesis imperfecta type 3
Brittle bone disease type 3 takes a severe course. The bones of affected individuals are already deformed at birth, and the deformities continue to progress. Typically, severe scoliosis and short stature are observed, as well as a very large number of bone fractures.
Osteogenesis imperfecta type 4
Brittle bone disease type 4 is mild to moderately severe. Affected individuals have mild to moderate bone deformities and a high rate of fractures. They are usually short in stature, although the severity of short stature is variable. The sclerae may be slightly bluish at birth but lighten with age. Sometimes the disease is associated with hearing loss.
Vitreous Bone Disease: Life Expectancy and Course of the Disease
The life expectancy of people with brittle bone disease depends on the type and severity of the disease. Some types of osteogenesis imperfecta do not limit life expectancy. On the other hand, there are also forms in which affected babies die in the womb or soon after birth.
How the brittle bone disease will progress in individual affected persons can only be predicted to a very limited extent. The most severe symptom manifestations generally appear during puberty and the growth phases. In adulthood, patients with some forms of the disease can lead a largely “normal” life.
Brittle bone disease and pregnancy
Fertility per se is not affected by osteogenesis imperfecta. However, the question of a possible pregnancy in women with brittle bone disease must be answered individually. It is important that the bone structure, especially in the pelvis, is stable enough to carry a child to term.
Brittle bone disease: symptoms
Symptoms in brittle bone disease differ depending on the type of disease and severity.
Bone fractures: in general, bone fractures (breaks) almost always occur in clusters, especially in childhood. Because bones generally break much more easily than in people without osteogenesis imperfecta, even small amounts of force are often enough to cause a fracture.
Bone deformities: Long long bones can become deformed in brittle bone disease. This mainly affects the extremities, i.e. legs and arms. These may also be shortened. Therefore, people with brittle bone disease are often short or even small in stature.
Hearing loss: Often, brittle bone disease is also accompanied by hearing loss.
Hernias and muscle pain: Because of weaker connective tissue, people with brittle bone disease are often prone to hernias.
Joints are often hyperextensible and more mobile than normal, which promotes muscle pain.
Effects on internal organs: sometimes vitreous bone disease also affects the connective tissue of the lungs or heart. In the latter case, this can mean that the heart valves do not close properly. This affects the blood supply to the body. Affected people then feel listless and tired. Their performance decreases.
Brittle bone disease: Cause
Brittle bone disease is a genetic disorder. It results from pathological changes (mutations) in genes that are important for bone metabolism (formation and breakdown).
In the vast majority of cases of osteogenesis imperfecta, the COL1A1 and COL1A2 genes are affected. These contain the blueprint for type 1 collagen. As a result of the gene changes, the body produces the structural protein, which is important for bones and connective tissue, in a defective form or in insufficient quantities.
In other cases, the disease is caused by defects in genes involved in the development (differentiation) of bone-building cells – so-called osteoblasts – or in the mineralization of bone.
How brittle bone disease is inherited
Those who have brittle bone disease can inherit the underlying genetic defect to their offspring.
Autosomal dominant inheritance
In most cases, this is an autosomal dominant inheritance. Autosomal means that the underlying genetic defect is located on one of the autosomes. This is the name given to all chromosomes that are not sex chromosomes.
Dominant means: It is sufficient if one parent carries the responsible genetic defect and passes it on to the child (this risk is 50 percent), so that the child is also born with brittle bone disease. This is the case with the main types of the disease (with mutations in the two type 1 collagen genes).
Such an autosomal dominant genetic defect can also be inherited from one parent with a genetic mosaic. This term is used when not all germ cells and/or somatic cells of a person have the same genetic makeup.
However, if one of the sperm or eggs with the genetic defect leads to a pregnancy, the child may develop the full-blown disease – sometimes even with a fatal outcome.
Autosomal recessive inheritance
The less common forms of brittle bone disease are generally inherited in an autosomal recessive manner. A child must then inherit the mutated gene – located on an autosome – from both parents to be born with brittle bone disease. There is a 25 percent chance of this happening.
If only one parent passes on the mutation, but the second parent passes on a healthy variant of this gene, the disease does not break out in the child.
X-linked inheritance
A few years ago, scientists also discovered for the first time a (rare) form of brittle bone disease that is inherited X-linked:
The causative gene defect here is found on the female sex chromosome (X chromosome). It is inherited recessively. This means that boys are usually more severely affected by this form of brittle bone disease because they only have one X chromosome.
New onset of brittle bone disease
Even parents who do not have brittle bone disease themselves can have a child with this genetic disorder. The underlying gene mutation has then newly (spontaneously) arisen at or around conception.
This is often the case with the main types of brittle bone disease, which are caused by mutations in the genes for type 1 collagen.
Brittle bone disease: examinations and diagnosis
Doctors diagnose brittle bone disease primarily on the basis of the clinical picture. This means that the typical cluster of symptoms in a patient is crucial for the diagnosis of osteogenesis imperfecta.
Medical history
Taking a patient’s medical history (anamnesis) during the first interview with a patient or parents is therefore very important for physicians. The physician asks in particular about frequent bone fractures and similar events within the family.
Imaging procedures
Depending on the type of disease, doctors can detect brittle bone disease in unborn babies in the womb using ultrasound examinations.
Genetic testing
In addition, physicians often perform genetic testing to confirm the diagnosis. Blood samples in particular are used to analyze the genetic material of affected individuals. Not only can the brittle bone disease itself be reliably determined, but also the type of osteogenesis imperfecta. At the same time, other possible diseases can be excluded as the cause of the symptoms.
Knowing what form of the disease it is is particularly important for subsequent pregnancies. This is because doctors can then assess the risk of recurrence and further inheritance.
However, genetic testing does not allow a reliable statement to be made about the viability and quality of life of an affected person.
Brittle bone disease: treatment
This can be achieved by combining various measures. The therapy plan is therefore made up of various building blocks and is individually tailored to the person affected.
Ideally, treatment for brittle bone disease is carried out by a multidisciplinary team (orthopedists, surgeons, physiotherapists, etc.) in a specialized center.
Physiotherapy
A very important component of therapy for brittle bone disease is regular physiotherapy. It aims to strengthen muscles, tendons, ligaments and bones, as well as to correct any bone deformities. On the one hand, this is intended to prevent bone fractures and, on the other, to improve mobility – those affected should be able to manage their daily lives as independently as possible.
Physiotherapy is also essential after operations (see below) as part of the rehabilitation process. It is about reducing the fear of movement (and thus further bone fractures) and trying out new movement patterns. In addition to improving mobility, this can also improve the quality of life of those affected.
Surgical-orthopedic therapy
Sometimes, however, surgery is necessary, for example in the case of a displaced fracture. Likewise, pronounced bone deformities (e.g., severe scoliosis) usually require surgical treatment.
For example, a telescopic nail can be inserted into long tubular bones (e.g., femur) – either to stabilize the bone after a fracture or to straighten a severe deformity. The telescopic nail can grow with the bone, so it does not hinder the growth of the child’s bones.
Medication
In the case of moderate or severe brittle bone disease, those affected are often given so-called bisphosphonates. These drugs increase bone mass and bone strength. This should make the bones less likely to break.
Apart from bisphosphonates, other drugs are often used in osteogenesis imperfecta. These include preparations containing calcium and vitamin D. These substances are essential for the mineralization of the bones. A deficiency can therefore aggravate the reduced bone density (osteopenia) in brittle bone disease.
The administration of calcium and vitamin D supplements is therefore advisable when patients have or are at risk of such a deficiency (e.g., because they have limited mobility and spend too little time outdoors to produce sufficient vitamin D by means of sunlight).
An overdose of vitamin D must be avoided at all costs! This is because calcium is then increasingly dissolved out of the bones. In addition, a vitamin D overdose can damage the kidneys, among other things.
Research into further therapies
Scientists are researching further treatment options for people with osteogenesis imperfecta.