Osteogenesis imperfecta

Classification according to ICD-10
Q78.0	Osteogenesis imperfecta
ICD-10 online (WHO version 2019)

Osteogenesis imperfecta (abbreviation OI ; Greek οστέον ostéon , German 'bone' , γένεσις génesis 'origin' and Latin imperfecta 'imperfect' ) is colloquially referred to as a glass bone disease , as the bones are easily fragile and have a glassy structure in the X-ray image. The OI is a rare genetic disease , for the predominantly autosomal - dominant , more rarely, autosomal recessive described modes of inheritance. The main feature of OI is the modified type I collagen , which leads to an abnormally high level of bone fragility with various clinical pictures.

The term “vitreous bone disease” tends to be rejected by those affected, as OI is more of a disability than a disease for them. In this context, one speaks of “having glass bones”.

Cause of collagen malformation and frequency

Type I collagen is the main component of connective tissue and therefore the most important protein for building up the bone matrix. It is composed of three left-handed alpha-tropocollagen chains to form a right-handed helix .

The cause of the OI is a point mutation in the genetic information , which codes for collagen type I and is on chromosomes 7 and 17 . By replacing the most important amino acid of collagen ( glycine , which is relatively small in size) with another - larger - amino acid, the synthesis of collagen is reduced. In addition, the correct “twisting” of the triple collagen helix is hindered, which leads to a loss of stability.

The inheritance is predominantly autosomal dominant . In the specialist literature, the recessive inheritance is also described for individual forms. If neither of the parents is affected, it is a spontaneous mutation .

The frequency of the disease is estimated worldwide for all forms together at approx. 4–7 cases per 100,000 inhabitants, so that in the Federal Republic of Germany it is assumed that around 2,500–4500 people are affected.

Symptoms

Blue sclera in osteogenesis imperfecta

Since type I collagen makes up around 90% of the bone matrix, the main characteristic of OI is an abnormally high level of bone fragility. The synonym glass bone describes very graphically both the mechanical properties of the bone, which is easily fragile like glass, and the appearance of the bones on X-rays. Since the OI only contains insufficient shadow-giving bone substance, the X-ray transparency increases so that the bone is often shown as a faded structure similar to frosted glass.

In addition, a number of other symptoms can occur, which are listed below:

extreme bone fragility
blue sclera
Hearing loss
Short stature
skeletal deformities
Curvature of the spine ( scoliosis and kyphosis )
overstretchable joints
weak muscles
Heart valve malformations with leaks ( insufficiency )
open ventricular septum (VSD)
heavy sweating
Tendency to hernias
myopia
Rubber head (soft skull)
wide fontanelles (connective tissue between the cranial sutures)

Glass bone disease has no effect on cognitive abilities.

Historical overview

Medically, OI has been known since the end of the 17th century, albeit only roughly anatomically, as we know from writings by Malebranche (1684), Bordenave (1763), Henckel (1772) or Sandifort (1793).

In 1833, the Strasbourg anatomist Johann Friedrich Lobstein (1777-1835) published a study of the fragility of bones in adults in his textbook on pathological anatomy . With the designation of "idiopathic osteopsathyrosis", into which he also incorporated symptoms of age-related osteoporosis ( "Osteopsathyrosis is observed particularly at the two border marks of life in childhood and in old age." ), He coined the term " maladie de Lobstein ” .

In 1849, the Dutch anatomist Willem Vrolik succeeded in describing the case of a newborn with a soft skull and numerous old and fresh fractures, to distinguish congenital fragility of bones from rickets fetalis. For the first time he sharply differentiated the disease from the previous collective name of rickets foetalis, to which all fetal development disorders of the bones were classified at that time, and gave it the name osteogenesis imperfecta .

But the different forms of OI in adults and newborns were still considered to be two very different diseases, and it took almost another sixty years before Emil Looser was able to provide final proof with his investigations in 1906 that the different cases were a and the same clinical picture with different characteristics is involved. After Looser had succeeded in establishing this etiological relationship, he then introduced the terms Osteogenesis imperfecta congenita (formerly Vrolik type) for the form that can be determined from birth and Osteogenesis imperfecta tarda (formerly Lobstein type) for the form that can only be recognized later in life.

At the turn of the century, thanks to further diagnostic progress, the subject area in the description of OI expanded. If previous publications referred solely to the bone system, at the beginning of the 20th century the authors increasingly dealt with descriptions of extrasceletal peculiarities, such as the appearance of blue sclera (Adair-Dight, 1912; Gutzeit 1921), hearing loss in early adulthood ( Fischer, 1921), tooth formation disorders up to dentinogenesis imperfecta (Biebl, 1924).

Mostly, however, the authors limited their publications to the description of individual symptoms or characteristics of osteogenesis imperfecta. Only the dissertation of the Danish doctor Knud Stakemann Seedorff , published in 1949 , which goes beyond the purely medical aspects, set a scientific milestone in the extensive description of the OI. In addition to a medically detailed anamnestic part, which he supplemented with radiological images, Seedorff also described the professional and social background of the 180 OI sufferers he examined very extensively. For the first time he made a statement about the frequency of OI: ". In this country every year a child is born with this disorder" .

Gradient forms

The 4-type classification introduced in 1979 by the Australian doctor and geneticist David Sillence was expanded in 2000 by the Montreal scientific group around Francis H. Glorieux to include OI types V, VI and VII. Due to the high expression variability , however, the affected one of these OI types can not always be clear after the extended Sillence classification assigned.

OI type I (formerly Osteogenesis imperfecta tarda, type Lobstein)

This is the mildest form of OI. It is therefore often only recognized when the child learns to walk and thereby develops fractures. OI is often not diagnosed in these affected persons until the middle of the third decade of life, for example if the treating doctor has a bone density measurement due to degenerative symptoms or if the mother is also examined in an infant with OI. The physique is usually normal and bone deformations are minimal or completely absent. Muscle strength is reduced and the muscles are often hypotonic. Due to the weak ligaments, the joints often tend to overstretch. The sclera can vary from white to bluish to deep blue. From the age of 20, hearing problems can occur more often due to calcification of the stapes. A stapes plastic almost completely eliminates the hearing loss. The most difficult time is probably puberty (usually between the ages of 13 and 18), but at the beginning of the age of 20 the bones usually become more stable.

OI type II

It is the most severe form of OI. Even if this OI type has so far been described in the literature as fatal, i.e. not viable, due to the underdeveloped lung function, a high susceptibility to fractures and its severe deformations, the prognosis has improved greatly thanks to medical developments in recent years.

OI type III (formerly Osteogenesis imperfecta congenita, type Vrolik, or also Vrolik syndrome)

Those affected of this type are short . With the smallest body size and the greatest tendency towards deformities and fractures of the bones, they belong to the extreme form among those affected by OI in the type II classification, which often requires the use of a wheelchair. In addition to the extremities, the skull, the chest and the spine can be deformed to different degrees, which can also lead to problems with breathing.

OI type IV

Those affected by this type are also short, but mostly more easily affected than with type III and are therefore more frequent pedestrians. The sclera are normal to slightly bluish. The tendency to fractures and deformities of the bones is often less than with type III. A wheelchair is not absolutely necessary.

OI type V

Type V OI in an adult; X-ray of the arms

Those affected of this type tend to have the rare phenomenon of the so-called hyperplastic callus ( callus luxurians ), a spontaneously excessive callus formation without the usual fracture and subsequent ossification. Due to the storage of calcium salts in the connective tissue structures ( syndesmoses ) between the two forearm bones ulna and radius as well as the lower leg bones tibia and fibula (calcification of the membranes interosseae antebrachii et cruris), the inward and outward rotation ( pronation / supination ) of the forearm or the The lower leg of the affected person is significantly blocked, which is helpful for clinical differential diagnosis , provided that the restricted mobility is not due to deformities of the corresponding bones or joints.

OI type VI

Although those affected by this type of OI show classic clinical symptoms of OI, no mutation in the collagen genes known for this has yet been detected. The sclera are normal to slightly bluish. No dentinogenesis imperfecta. The blood level of alkaline phosphatase (an enzyme that describes osteoblast activity) is slightly increased.

OI type VII

In type VII OI, the proximal extremities , i.e. the upper arms and thighs, are shortened in relation to the distal extremities (forearms and thighs). This peculiarity, known as rhizomelia , has so far only occurred in OI-affected people from an Indian tribe in Québec .

Treatment methods

Therapy pillars of the OI

Since OI is a genetic disorder, the possible forms of therapy are limited to purely symptomatic treatment methods.

These include in particular:

intramedullary nailing
the physiotherapy
bisphosphonate therapy

Intramedullary nailing

When nailing the curved bone is first multiple osteotomy , then pearl necklace-like to thread the individual bone segments back to the intramedullary nail. Initially, rigid nails were used for this. In the growing bone, however, these nails had to be replaced again and again, because the bone eventually became longer than the nail and the nail could no longer support the bone. The result was fractures in these unprotected areas. That is why the two orthopedic surgeons Bailey and Dubrow constructed a telescopic intramedullary nail in 1963. As the bone grows, the two nail segments pull apart like a telescope and so “grow” with them.

In addition to frequent fractures of the same bone, indications for intramedullary nailing are pseudarthroses and moderate to severe malpositions with functional impairment of the limbs.

Contraindications include a poor general condition, cardiorespiratory insufficiency or the lack of anchoring options for the nail in the bone due to insufficient bone substance.

physical therapy

Since the early 1970s, physiotherapy has been playing an increasingly important role in OI treatment. In previous years, attempts had been made to immobilize them and try not to provoke any fractures, but now they knew that immobilization leads to increased bone loss. The treatment methods for OI sufferers were also adapted to this knowledge, albeit slowly, in the following years, and those affected were encouraged to be more active. There is currently no standardized physiotherapeutic treatment concept for OI. In 1997 , the German Society for Osteogenesis Imperfecta Affected People published the Glasfit exercise program developed by Willy Hagelstein in order to provide help to both those affected and the therapists .

Bisphosphonate therapy

The youngest of the three pillars of therapy is the pillar of drug treatment with bisphosphonates . The first publications on the therapy of OI sufferers with bisphosphonates were published at the 6th International Scientific Conference on OI in Holland in 1996. Although all scientific groups were able to measure significant bone growth, the question remained whether the increased bone density would also be accompanied by a reduced fracture rate. In a very extensive study in 1998, the Montreal doctor and scientist Francis H. Glorieux and his colleagues succeeded in showing the connection between an increase in bone density and a decrease in the fracture rate. In the meantime, drug therapy with bisphosphonates has become part of the state of the art in the treatment of OI.

Differential diagnosis

A distinction must be made between the rare idiopathic juvenile osteoporosis , achondrogenesis type II and type II as well as achondrogenesis type IA and achondrogenesis type IB .