Generality
Imperfect osteogenesis is a congenital genetic disease, unrelated to sex, responsible for a certain bone fragility and a marked tendency to fracture .
Symptoms of imperfect osteogenesis are numerous; generally, they consist of: bone weakness, high tendency to bone fractures, presence of blue, gray or purple eye sclerae, presence of bone deformities or other skeletal alterations, triangular face, dental fragility, etc.
In general, for a correct diagnosis of imperfect osteogenesis the following are fundamental: physical examination, medical history, diagnostic imaging tests, a type I collagen evaluation test and a genetic test.
Unfortunately, currently, the only treatments available to patients with imperfect osteogenesis are symptomatic. The illness in question, in fact, is incurable.
What is imperfect osteogenesis?
Imperfect osteogenesis is a genetic disease that makes a person's bones suffer weaker and prone to fractures .
In reality, with the term imperfect osteogenesis, doctors refer to a heterogeneous group of genetic diseases, characterized by a certain degree of bone fragility . Therefore, there are more forms (or types) of imperfect osteogenesis, some much more serious than others.
IT IS A CONGENITAL DISEASE
In people who are affected, imperfect osteogenesis is a disease present from birth. Therefore it can be defined, for all purposes, a congenital disease .
IS IT SEXED?
Imperfect osteogenesis is not a genetic sex-related disease, such as haemophilia or Klinefelter syndrome .
Epidemiology
According to some statistical research, the incidence of imperfect osteogenesis would be equal to one case every 15, 000-20, 000 births. This means that every 15, 000-20, 000 newborns have one suffering from imperfect osteogenesis.
Other statistical studies have shown that imperfect osteogenesis affects males and females equally, and that it has no preference for a race or a particular ethnic group.
Life span is an extremely variable parameter, which depends on the form of imperfect osteogenesis.
Causes
Imperfect osteogenesis almost always results from a qualitative and quantitative alteration of type I collagen production.
Type I collagen is essential for strengthening bones and maintaining healthy connective tissues that make up cartilage, tendons, skin, ocular sclera, etc.
Therefore, an alteration in the production of type I collagen affects the strength of the bones and the good health of the connective tissues present in the human body.
WHAT ABOUT COLLAGEN PRODUCTION?
A genetic disease is a condition that arises due to a mutation of one or more genes constituting cellular DNA .
In the case of imperfect osteogenesis, the causes of the latter are to be found, almost always, in the mutation of one or both genes COL1A1 (located on chromosome 17) and COL1A2 (located on chromosome 7).
Under normal conditions, COL1A1 and COL1A2 regulate the normal production of type I collagen; in the presence of mutations against them, they fail in their regulatory function.
Important: which other genes, if mutated, cause imperfect osteogenesis?
In addition to the COL1A1 and COL1A2 mutations, mutations in the IFITM5, SERPINF1, CRTAP and LEPRE1 genes are potential causes of imperfect osteogenesis.
The aforementioned genes cover functions different from COL1A1 and COL1A2 - therefore they do not control the production of type I collagen - but they still have an influence on the strength and resistance of the bones of the human skeleton.
WHAT KIND OF GENETIC ILLNESS IS?
Imperfect osteogenesis is an autosomal genetic disease .
The term autosomal, associated with a genetic disease, indicates that the condition in question is due to genetic mutations based on autosomal and not sexual chromosomes.
Readers are reminded that the human being possesses a chromosome set of 23 pairs of total chromosomes, in which 22 pairs are of the autosomal type and only a couple is of a sexual nature. The pair of sex chromosomes affects the sex of the individual.
The imperfect osteogenesis following mutations of COL1A1, COL1A2 and IFITM5 has all the characteristics of an autosomal dominant disease . When instead it is due to mutations in the SERPINF1, CRTAP and LEPRE1 genes, it has the characteristics of an autosomal recessive disease .
TYPES
Currently, doctors believe that there are 8 types (or forms) of imperfect osteogenesis. To distinguish the various types, they thought of using Roman numeration, to be precise the first eight Roman numerals.
The table below shows the 8 forms of imperfect osteogenesis, the mutations that cause them and other characteristics.
Guy | Mutated gene | Type of genetic disease |
THE | COL1A1 | Autosomal dominant |
II | COL1A1 and COL1A2 | Autosomal dominant |
III | COL1A1 and COL1A2 | Autosomal dominant |
IV | COL1A1 and COL1A2 | Autosomal dominant |
V | IFITM5 | Autosomal dominant |
YOU | SERPINF1 | Autosomal recessive |
VII | CRTAP | Autosomal recessive |
VIII | LEPRE1 | Autosomal recessive |
* NB: obviously, the mutations in COL1A1 and COL1A2, which cause the first four forms of imperfect osteogenesis, are genetic alterations with slightly different characteristics. Otherwise, it would make no sense to distinguish one from the other.
Symptoms, signs and complications
All types of imperfect osteogenesis are responsible for a weakening of the bones, such that the subject suffering from the disease presents a particular predisposition to fractures . The degree of weakening of the bones varies according to the forms; for some of these, this weakening is greater than for others.
Having said this, it is necessary to point out that every form of imperfect osteogenesis presents itself with its own symptomatological framework, which for some may recall the symptomatological picture of other forms.
SYMPTOMS AND POSSIBLE SIGNS
The possible symptoms and signs of imperfect osteogenesis include:
- Presence of bone malformations;
- Presence of a body (intended as a trunk) short and small;
- Joint problems (eg: loose joints);
- Muscle weakness;
- Blue, purple or gray eye sclera;
- Triangular face;
- Barrel chest;
- Morphological abnormalities of the spine;
- Dental fragility;
- Total hearing loss or loss;
- Respiratory problems;
- Problems related to the absence or low presence of type 1 collagen.
Imperfect Osteogenesis: note the blue color of the sclerae and the bone deformations that characterize the disease. From wikipedia.org
WHAT ARE THE MOST SERIOUS FORMS OF IMPERFECT OSTEOGENESIS?
The doctors classify the symptomatological severity of the various types of imperfect osteogenesis on a scale of 3 degrees, which are: the mild degree, the moderate degree and the severe degree.
Only one form belongs to the "mild degree" category: the imperfect osteogenesis of type I; to the category "moderate degree" belong 4 forms of imperfect osteogenesis: the IV, the V and the VI; finally, to the category "severe grade" belong 3 forms: the II, the III, the VII and the VIII.
TYPE I: CHARACTERISTICS
Most common and least severe form of all, type I imperfect osteogenesis has the following characteristics:
- It causes fractures especially before puberty;
- It has almost no influence on stature, so patients usually have a normal height;
- Causes joint problems and muscle weakness;
- It is responsible for blue, purple or gray sclera;
- It causes a triangular face and abnormalities in the spine;
- It almost never causes bone deformities. If it provokes them, they are minimal;
- It can cause dental fragility and / or hearing loss (the latter usually occurs in adulthood);
- It is associated with the presence of normal type I collagen in quality, but abnormal in quantity (it is scarcer than normal).
TYPE II: CHARACTERISTICS
Type II imperfect osteogenesis is characterized by:
- Being a cause of death at birth or shortly thereafter. Respiratory problems are almost always the cause of death;
- Presence of considerable bone fragility and severe bone deformities;
- Short stature and underdeveloped lungs;
- Blue, purple or gray sclera;
- Presence of quantitative and qualitative abnormalities of type I collagen.
TYPE III: CHARACTERISTICS
Type III imperfect osteogenesis has the following characteristics:
- Despite being very serious, it does not frequently cause death in the neonatal period;
- It is associated with a high bone fragility;
- It is responsible for short stature, joint problems, muscle weakness (especially in the legs and arms), barrel chest, triangular face and abnormal curvature of the spine;
- It causes blue, purple or gray sclera;
- May cause respiratory problems, dental fragility and hearing loss;
- It is frequently responsible for bone deformities;
- It is associated with qualitative and quantitative abnormalities of type I collagen.
TYPE IV: CHARACTERISTICS
Type IV osteogenesis is characterized by:
- A degree of bone fragility between forms II and III and form I;
- Lower than average height;
- Blue, purple or gray sclera;
- Bone deformities of mild / moderate severity, slight abnormalities of the spine and barrel thorax;
- Triangular face;
- Possible presence of dental fragility and hearing loss;
- Presence of type I collagen abnormalities.
TYPE V: CHARACTERISTICS
The imperfect type V osteogenesis resembles, in some ways, the imperfect osteogenesis of type IV. However, it has some peculiarities, which are:
- Sclera of normal color;
- Absence of dental fragility;
- Formation of abnormal bony calluses, during the healing processes of fractured bones;
- Calcification of the interosseous membrane that resides between radius and ulna. This compromises the mobility of the forearm.
TYPE VI: CHARACTERISTICS
Even the imperfect type VI osteogenesis is similar to the IV form. To distinguish it from the latter are some peculiarities, including high blood levels of alkaline phosphatase and the presence, on some bones, of lamellae (bones) similar to fish spines.
TYPE VII: CHARACTERISTICS
From a symptomatological point of view, the imperfect osteogenesis of type VII may resemble, in some circumstances, type IV while, in other circumstances, type II.
The peculiarities of this serious pathological form include:
- The short stature;
- The presence of an extremely short humerus (arm bone) and a femur (thigh bone);
- The frequent presence of a hip deformity, known as coxa vara.
TYPE VIII: CHARACTERISTICS
Imperfect osteogenesis of type VIII is very reminiscent of forms II and III.
Among its peculiar characteristics, the following stand out: the severe growth deficit, the severe skeletal hypomineralization and the absence (or poor presence) of the enzyme prolyl 3-hydroxylase.
Diagnosis
In general, the diagnostic procedure to which patients with a suspected form of imperfect osteogenesis are subjected begins with an accurate physical examination and a careful medical history ; then it continues with an analysis of the patient's family history and with a series of diagnostic imaging tests (X-rays, CT scans, etc.); finally, it ends with a quantitative and qualitative evaluation of type I collagen and a genetic test .
Today, there is the possibility of diagnosing imperfect osteogenesis even in the prenatal phase, subjecting an expectant mother to an ultrasound scan.
THE IMPORTANCE OF THE OBJECTIVE EXAM AND THE ANAMNESIS
A doctor who is an expert in imperfect osteogenesis is very often able to diagnose the aforementioned disease even by means of physical examination and medical history. This means that these diagnostic tests have no negligible relevance.
ASSESSMENT OF TYPE I COLLAGEN PRODUCTION
As a rule, the qualitative and quantitative evaluation of type I collagen is a very reliable test, as, as stated, the majority of cases of imperfect osteogenesis are characterized by mutations of genes that control the production of type 1 collagen.
To assess, in an individual, the quantity and quality of type I collagen, present at the cellular level, doctors can rely on a skin biopsy or a particular blood test .
Both of these evaluative tests are quite complex and the patient (or his parents) may have to wait several weeks to know the results.
GENETIC TEST
Through a genetic test that scans the entire DNA of the individual under examination, the doctors are able to definitively determine the characteristics of the genetic mutation present.
Generally, the execution of a genetic test on all the cellular DNA is foreseen when the evaluation of the type I collagen has not provided the desired results, or when it is not a mutation of COL1A1 or COL1A2 to cause the imperfect osteogenesis.
PRENATAL DIAGNOSIS
Prenatal ultrasound is very useful in identifying imperfect osteogenesis type II and type III.
Therapy
Currently there is no specific cure for imperfect osteogenesis. In other words, people suffering from imperfect osteogenesis are destined to live with this condition, until death; death which is often due to the consequences of the disease itself.
The lack of specific therapy does not exclude that other forms of treatment exist. In fact, among the therapeutic possibilities of a patient with imperfect osteogenesis, there are several symptomatic therapies ; for symptomatic therapies we mean treatments able to alleviate the symptoms, slow down the course of the disease and prevent (or at least postpone) the most serious consequences.
POSSIBLE SYMPTOMATIC TREATMENTS
In the list of possible symptomatic treatments for imperfect osteogenesis, the following stand out:
- Surgical insertion, inside longer bones (NB: the most prone to fractures), of nails that provide greater resistance to fractures and deformities. This operation is called intramedullary rodding ;
- Conservative or surgical treatment of fractures and / or bone deformities;
- Dental care, to safeguard tooth health;
- Pain relief therapies, in the case of very painful multiple fractures;
- Physiotherapy, for stretching and muscle strengthening. An elastic and tonic muscle apparatus helps prevent falls that could lead to several bone fractures;
- The use of supports for locomotion, including the wheelchair, guardians, crutches etc.
BENEFITS OF MOVEMENT
To subjects with imperfect osteogenesis, doctors recommend the constant practice of physical exercise and movement in general, as both these activities contribute to the strengthening of the skeletal and muscular apparatus.
Recommended sports include: swimming, as it is a low-impact physical activity on the skeletal system, and walking.
BENEFITS FROM A HEALTHY LIFESTYLE
Leading a healthy life, avoiding smoking, drinking excess alcohol, eating too much and badly, etc., has more than decent health benefits for patients with imperfect osteogenesis, since it slows down the progression of the disease and reduces bone fragility.
SYMPTOMATIC TREATMENTS DURING EXPERIMENTATION
Currently, doctors and researchers are evaluating the effectiveness of some symptomatic treatments, including a growth hormone treatment and an intravenous and oral bisphosphonate-based therapy.
For the moment, the results provided by the aforementioned treatments in the experimental phase give hope to the entire medical community.
Prognosis
Imperfect osteogenesis is a disease with a negative prognosis, as it is incurable, drastically compromises the quality of life and, in some cases, causes the premature death of the affected subject.
However, it is good to point out that, also thanks to modern symptomatic treatments, many individuals with a non-severe form of imperfect osteogenesis are able to lead a pleasant and fulfilling life.
Prevention
Currently, unfortunately, there is no preventive measure against imperfect osteogenesis.
