Osteogenesis Imperfecta (OI)

in Greece

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*** WHAT IS OI ***

Osteogenesis Imperfecta (OI) is a rare heritable disorder of the connective tissue. Literally OI means imperfect bone formation. This refers to the most prominent feature of OI: bone fragility. Without a clear immediate cause the bones of an affected person may fracture. This can happen at any age, even before birth. There are various synonyms for OI in most languages:

In the English Literature OI has been discussed under the following 34 eponyms

· Osteogenesis Imperfecta

· Adair-Dighton disease (syndrome)

· Aplasia periostalis

· Blegvad Haxthausen syndrome

· Blue sclera syndrome

· Blue sclerotics and brittle bones

· Blue scleras and fragilitas ossium

· Brittle bones and blue sclerae

· Dark sclerotics and fragilitas ossium

· Dysplasie pιriostale

· Dystrophie pιriostale

· Eddowes disease (syndrome)

· Ekman syndrome

· Ekman-Lobstein syndrome

· Fetal rickets

· Fragile bones

· Fragilitas vitrea ossium

· Hereditary fibrous osteodysplasia

· Hereditary hypoplasia of the mesenchyme

· Lobstein's disease

· Molities ossium

· Osseous fragility

· Osteogenesis Imperfecta congenita (Vrolik)

· Osteogenesis Imperfecta tarda

· Osteomyopathia

· Osteoporosis foetalis

· Osteopsathyrosis ideopathica (Lobstein)

· Osteopsathyrosis foetalis

· Osteitis parenchymatosa chronica

· Rachitis congenita

· Spurway-Eddowes syndrome

§ § Vrolik disease (syndrome)

· Van der Hoeve - De Kleyn syndrome

People with OI have brittle bones!

Symptoms of OI

Fragility differs widely from person to person, so the number of fractures can vary from a few to over a hundred. All connective tissue is involved, not only that in bone. Besides bone fractures this may cause a variety of symptoms like:

curvature of arms, legs or spine (scoliosis or kyphosis)
deformities of the scull,
triangular face,
small stature,
extreme laxity of the joints,
luxations,
easy bruising (haematoma),
blue sclerae,
hearing loss,
abnormal teeth (dentinogenesis imperfecta),
heart valve insufficiency,
basilar impression,
extreme tiredness,
excessive sweating,
OI can lead to physical disability, requiring the use of crutches or a wheelchair.

It must be stressed that:

an affected person may show some but usually does not show all these symptoms.

Many people are only very lightly affected and show hardly any symptoms at all.

OI expresses itself very individually, it is variable between persons and unpredictable per person.

Classification

In 1979 Sillence proposed a classification of OI in 4 types based on the clinical features. With some minor alterations this classification is still used. It is not always possible to determine the OI type for every individual:

Type IA

- most frequent type
- fragile bones
- widely varying fragility
- blue sclerae
- rarely fractures at birth; onset of fractures often after 1st year of life
- hearing loss with about 50% of patients, usually starting after puberty
- height usually below average,
- deformities usually moderate,
- so called "Wormian Bones" at Birth (Mozaic cranium on X-ray),
- often loose joints,
- heredity, see inheritance (below)

Type IB :Same as Type Ia, but with dental problems (dentinogenesis imperfecta)

Type II (This is also called the lethal form of OI)

- children are often stillborn or die shortly after birth,
- many fractures, often already at or before birth,
- almost no ossification of the skull; soft cranium,
- deformities of the legs, arms and ribs,
- heredity, see inheritance.

Type III

- severe fragility of the skeleton,
- severe growth retardation,
- deformities of the arms, legs and spine,
- often a relatively large head with a characteristic shape
(triangular with broad forehead and pointed chin),
- blue sclerae, later turning white,
- sometimes hearing loss,
- sometimes dentinogenesis imperfecta,
- often leading to physical disability,
- heredity, see inheritance.

Type IVA

- strongly variable in severity
- fragility light to severe
- deformities moderate to severe
- moderate to serious growth retardation
- white sclerae, or blue at first, turning white later
- sometimes hearing loss
- heredity, see inheritance.

Type IVB : Same as type IVA, but with dentinogenesis Imperfecta.

It has been established that in type(s) I the defect causes a reduced production of normal collagen, sometimes resulting in a low bone mineral density (BMD); while in the other types structurally abnormal collagen (sometimes also in a lower amount) is produced, resulting in low quality bone usually with a low BMD. Until now, any further clear correspondence between the clinical types as defined above and the genetical defects causing OI has not been found. Also, the importance of the typing should not be overestimated. In daily life the severity of the condition could be far more important. In the old days OI was classified as OI congenita or OI tarda, meaning that the OI manifested itself before birth or sometime thereafter. These terms have become obsolete.

WARNING:
This classification should not be used for "self diagnosis", always seek the advice of a medical specialist familiar with OI.

*** INHERITANCE ***

O.I. is a genetic disease and, as such, is inheritable. The types I and IV sometime appear in families, through various generations. The mode of inheritance of the disease is dominant: an affected parent has a 50% chance of transmitting his/her altered gene to the offspring, and a 50% chance of transmitting the normal counterpart (we all carry two copies of any given gene, with the exception of genes linked to the sex chromosomes).

Although a certain degree of variability (e.g. the number of fractures) is observed within affected relatives, the clinical type in a given family generally remains the same through generations, since the same basic genetic defect is passed from parent to child. OI on the other hand, is highly heterogeneous in unrelated cases: each individual case may represent a different genetic defect in the collagen genes. OI, as other dominant genetic disorders, can appear also spontaneously. This statement is particularly true for the types III and type II (usually more severe forms of OI), but is also applicable to the other types. When a child with O.I. is born from unaffected parents, we assume that a mutation has occurred in a collagen gene. Mutations are sporadic, unpredictable events which change the DNA informational content. Most likely the mutation occurred in either gamete (ovocite or sperm cell) the merging of which gave origin to the affected baby. In families where a spontaneous OI case occurs, the unaffected siblings do not carry the mutation so they do not have particular genetic risks for their progeny; the affected child, on the contrary, has a 50% risk of transmitting the mutant gene and therefore the disease, to his/her children, starting a new chain of hereditary OI through generations.

In conclution: OI is dominantly inheritable, which means that when one of the parents has OI then for each newborn child the chance to be affected is 50%. In many cases OI is not inherited but is caused by a mutation. In these cases none of the parents shows any sign of OI. The mutation is again dominantly inheritable. The issue is further complicated by the possibility of mosaicism. Because of the complexity of the matter it is recommended to seek personal genetic advice.

*** MOSAICISM***

As for the parents, studies on a wide number of families where unaffected parents had a type II (lethal) OI baby, have shown recurrence of the disease (i.e. another pregnancy with OI) in 5-7% of the cases. This puzzling situation at first was explained erroneously with a different mode of inheritance (autosomal recessive) and can still generate confusion (and wrong genetic advice) with clinicians who are not updated in the OI field. Peter Byers and collaborators (at the University of Seattle- USA) and, subsequently, many other investigators, have demonstrated that the recurrence of OI in families with negative clinical history is due to dominant mutations in either collagen gene (COL1A1 or COL1A2): the causal mutation, instead of involving a single germ cell, is carried only by a certain proportion of the germ cells of a given parent (either mother or father), who therefore runs the risk of generating more than one affected child. This phenomenon is called mosaicism. It is very difficult to recognize mosaic individuals: searching for the mutation in them would be just like to look for a needle in a haystack. Only after the mutation has been identified in the affected child (who carries it in all his/her cells), it is possible to design specific molecular assays to test the parents for the presence of mosaicism (generally detectable in both germ cells and white blood cells) and to try to estimate their hypothetical recurrence risk. Mosaicism can occur for any clinical OI form, but so far it has been documented extensively only for the severest form (type II): its frequency has been estimated empirically to range between 5-7%.

Diagnosis

OI can be quite difficult to diagnose. Many doctors are not familiar with it, and many cases go undetected. It is a myth that all people with OI have blue sclerae. Only a certain percentage of people with OI have blue sclerae. Occasionally child abuse is suspected when the child in fact has OI, this is a particularly frustrating experience for the family involved. If you think that you or your child may have OI ask your national OI society to direct you to a specialist who is familiar with OI.

Cause of OI

In most cases OI is caused by a defect in either of the two genes that code for collagen I, i.e. COL1A1 on chromosome 17 or COL1A2 on chromosome 7. The defect disturbs the production of collagen. In OI type I too little, but normal, collagen is produced. In the other types the collagen is of bad structural quality, while the amount of collagen may be reduced as well.

Treatment

It is not expected that the cause of OI can be eliminated in the near future. Therefore OI can not be cured at the moment. However, careful treatment can alleviate the circumstances. Treatments are aimed at reducing the impact of the consequences and at the prevention of complications. Often this calls for an integral management plan, which may encompass: orthopedic treatment of fractures, hearing improvement, dental intervention, physiotherapy, psychological assistance, genetic counselling and DNA testing, social advisory, ergotherapy with advice on crutches and wheelchairs and other equipment, sometimes also dietary advice. Attention should be given to the prevention of osteoporosis, as people with OI are more vulnerable to this than other people. Recently several types of bisphosphonates have been used as drugs with apparently good results, but it is still too early to draw conclusions.

Prognosis

Because of the individual variability of OI it is impossible to make general statements about the prospects of an affected person. It is recommended to seek personal advice. In many cases fragility diminishes after puberty for reasons still unknown.

Incidence

OI is a rare disorder. Its incidence is estimated at 1:10.000 to 15.000. This estimate is a lower limit because light forms of the disease are quite often not recognised. OI occurs in all races and is independent of gender. Only 0.008% of the world population is affected by OI. This means that at present there are about 0.5 Million persons with OI in the world. Details on the OIFE members can be found on the statistics page.

Life & OI

In spite of the restrictions that OI may impose People with OI can lead a happy life as a valued member of society. Many people with OI live independently and pursue careers (some are even famous). They can be married or living in stable relationships and have children. Mutual support by exchange of experience and information is of prime importance for people with OI and their families. Please contact your national OI society for further information and help.

Theofilos Koupidis

ΜD Biopathologist

tkoupidis@yahoo.gr

Statement on the Importance of adequate first information to parents after the diagnosis of OI

In spite of the combined efforts of medical professionals and patient/parent organizations on OI over the past decades it still happens that the impact of the first information given by the diagnosing doctor to the parents of a newborn child with OI is gravely underestimated. The OI societies are regularly confronted with cases in which parents of an OI child have been given the diagnosis and the first information from a doctor who has little or no knowledge of OI and a lack of sensitivity. Frequently the doctor of first contact mainly describes some possible negative physical symptoms of this rare genetic disorder which would make their child's life miserable and probably cause early death. Usually this doctor was not aware of more knowledgeable colleagues or the existence of an OI society. If parents are suddenly confronted not only with the diagnosis of OI but as well with a prognosis for deficiencies and disabilities, numerous fractures, hearing loss etc. without any offer of hope and concrete helpful information and without any hint as to the more positive aspects it is not difficult to imagine that the impact of such information can be disastrous. It is known that some parents completely lose hope and give up their child immediately (leave it in hospital), because they see no way how to cope with such circumstances. In the opinion of the OIFE this kind of misinformation and its consequences should and could be avoided. The medical professionals need to be aware of the importance of adequate initial information to the parents of their little patients, they should direct parents to specialists and OI societies who are available to offer information and personal support. We call upon you as the medical professionals to discuss with us how we can raise more awareness on this issue and how we can combine our efforts to spread this request and all other relevant information on OI. Further down you will find an example of how adequate, balanced information to new parents could look like.

Copied from www.oife.org

Recommendations for the first information on OI to parents of a recently diagnosed child

Basic facts on Osteogenesis imperfecta (=OI) OI is a rare genetic disorder of connective tissue (collagen), usually caused by new dominant mutations or dominantly inherited mutations. Different types of OI are distinguished which show great diversity in its symptoms, prognosis is difficult, symptoms and development are different from person to person.
Possible symptoms: fractures, loose joints, short stature, blue sclerae, hearing impairment (which normally begins only after puberty or later in life), skeletal deformities and fragile teeth. The number of fractures in cases of OI, the forms and the extent of its symptoms vary greatly. Often fractures occur mainly till puberty. Sometimes there are respiratory problems, but nowadays antibiotics and respiratory physiotherapy can be of great assistance.
Although there has been no officially approved medical treatment yet, new drugs ("bisphosphonates") have been recently found to be successful in some patients, and surgery has greatly been improved for managing fractures. Again, physiotherapy is of great help, especially in children.
It is important that the child has the best possible conditions in a loving family and will get the best treatment available.
For information or individual support please contact your national OI society or the OIFE (Federation of European OI associations).
At the beginning you might have to face some big problems, but very soon you will learn how to cope and be able to manage every kind of emergency: how to immobilise a limb in case of a fracture, how to identify a fracture and sometimes avoid unnecessary surgery and hospitalisation.
OI-children in a supportive environment normally adapt themselves well to their condition. They often start to talk earlier than other children of the same age, socialise easily and are successful with their studies and professional career, even if they have to spend a considerable time in hospitals. They can succeed in many kinds of university studies and find different kinds of jobs they are interested in, provided they do not include too much physical effort.
"If you learn to share the problem of your OI-child with all the members of your family, this challenge can contribute to the union of the family and will give to the other children a better sense for the value of life. They will develop a greater maturity and they will be stronger facing their own life".

Copied from www.oife.org

Fast facts on OI

What is Osteogenesis Imperfecta?

Osteogenesis Imperfecta (OI) is the medical name for brittle bones. `Brittle Bones' refers to a range of conditions resulting from abnormalities in the protein structure of the bones. This causes the bones to break more easily than normal.

What is it like to have brittle bones?

Some children with OI are born with fractures, others have their first injury soon after birth, yet others when they try to walk for the first time. This is obviously a difficult time for the family and a large part of the society's work is to provide the guidance, support and information that they need. In a few cases children with brittle bones are, initially thought to have been injured by their parents. This accusation does great damage to the families and the Society can provide advice and support.

Does it vary in severity?

There are several types of OI and people with the condition may experience only 10 - 20 fractures during their childhood years, others may have 100 or more fractures. All parents have a difficult task stopping their children taking risks but also trying not to be over protective. In fact most people with osteogenesis imperfecta, given the support they need, can lead active and fulfilled lives.

Is it an inherited disorder?

In some cases, mostly milder ones, the disorder passes from one generation to another. In most severe cases it comes `out of the blue' with no signs in either parent.

What can be done to help?

Quite a lot can be done to make life better for those with OI. There is no `cure' but work is progressing into a number of possible drug treatments, however these are still at the stage of clinical trials and are not widely available. Each fracture has to be treated carefully to ensure the bones heal properly and Orthopaedic surgery can be of help in many cases.

Is any special equipment necessary?

Most children with OI can enjoy a high standard of mobility, though some will require the use of very specialised wheelchairs that may not be available through local statutory services. Equipment such as specially adapted keyboards, or other input devices linked to a computer can be of great benefit where people with OI are unable to make full use of their fingers.

Do the children go to ordinary schools?

Most children with OI can be educated in mainstream primary and usually secondary schools. Good education is important because these children are bright and given the right opportunities can lead independent lives.

What is medical research achieving?

Research has shown that brittle bones is not one condition but a group of several hundred all caused by abnormalities in the structure of the protein component of bone known as `collagen'. These abnormalities are caused by defects in the genes that tell the cells how to make collagen. Osteogenesis imperfecta is not caused by a lack of calcium.

Advances in our understanding of these disorders has enabled us to ensure that families get accurate genetic advice. In the future these advances may lead to more effective treatments for brittle bones.

Copied from http://www.brittlebone.org

Story of Christos Koupidis

(child with OI in Greece)

My name is Koupidis Theofilos and I am a medical doctor specialized in laboratory medicine (Biopathologist). I have a son (born on August 16, 2003), who has at least 7 fractures since his birth (one on his left humerus in Sept2003, one on his right femur in Dec2003 , and four in his left femur from Mars 2004 until July 2005). He has not blue sclera, he has not major deformities.

Birth: 3,85 kilos and 50 cm, 50% at chart, cranium perimeter 36cm

6months: 7,1 kilos and 65 cm, 50% at chart, cranium perimeter 43cm

8months: 7.5 kilos & 67 cm, 20% at chart, cranium perimeter 45cm

10 months: 7,950 Kg & 70 cm, 10% at chart, cranium perimeter: 47cm

26 months: 10,700 Kg & 82 cm, 2% at chart, cranium perimeter: 50cm

At the age of 8 months, I examined his blood and I found that : Ht= 35.3 %, Hb=11.4, RBC=4.81x10⁶, PLT= 350.000, ΜCV=73.4, MCH=23.7, MCHC=32.3, RDW=16.8, WBC= 14.450, (G=8%, L=75%, M=12%, E=1%, others=4%) SGOT=40, SGPT=16, GLU= 92, UREA= 15, KRE= 0.33, Ca= 10.9, K= 5.4, P=7.0, Na=142, ALP=206, PTH (intact)=21.5 pg/ml, Vit D=35.7 pg/ml, Zn=90μg/dl, Cu=139μg/dl.