genetic diseases

Achondroplasia

Generality

Achondroplasia is a cartilage disease that is one of the main causes of disproportionate dwarfism: in affected individuals, the upper and lower limbs are shorter than normal while the trunk is normal.

Achondroplasia, therefore, is a disease of skeletal development.

The causes of achondroplasia are genetic: causing the onset is the mutation of the FGFR3 gene, located on chromosome 4.

In addition to determining short stature and an absence of proportionality between limbs and trunk, achondroplasia is the reason for other clinical signs, including: short fingers, varus or valgus knee, large head and with prominent forehead, etc.

At present, there are no specific therapies for achondroplasia. The latter, therefore, is an incurable condition.

A brief review of what chondropathy is

Condropatia is the non-specific term by which doctors indicate any cartilage disease, either this cartilage belonging to the hyaline type, the elastic type or the fibrous type.

In the table below, the reader can review the types of cartilage tissue present in the human body and their main location.

Types of cartilage in the human bodyLocation (examples)Features
Hyaline cartilageRibs, nose, trachea, bronchi and larynxBluish white in color, it is the most common type of cartilage in the human body.

It is not present in the joints.

Elastic cartilageAuricles, Eustachian tube and epiglottisMatt yellow in color, it has remarkable elasticity.
Fibrous cartilageIntervertebral discs, knee menisci and pubic symphysisOf whitish color, it is particularly resistant to mechanical stress.

It is richly present in the joints.

What is achondroplasia

Achondroplasia is one of the most common genetic diseases of skeletal development that cause disproportionate dwarfism (or disproportionate dwarfism ).

For disproportionate dwarfism, doctors mean a serious defect in stature, combined with an absence of proportionality between the trunk - which has dimensions close to normality - and the lower and upper limbs - which are instead shorter than normal. According to medical manuals, the maximum height values ​​of those suffering from dwarfism are: 131 centimeters, for men, and 125 centimeters, for women.

Achondroplasia is included in the list of congenital diseases ; a congenital disease is a morbid condition present since birth.

WHY IS IT A CONDROPATHY?

Premise: during fetal development and for the first years of life, most of the human skeleton is composed of cartilaginous tissue. With growth, most of the cartilage present becomes bone.

Achondroplasia is a cartilage disease - hence a chondropathy - because, in those who carry it, the natural process of transforming cartilage into bone does not take place.

Epidemiology

According to reports from the Columbia University Medical Center (CUMC), achondroplasia would affect an individual born alive every 25, 000 or so.

Studies of the spread of achondroplasia in both sexes have shown that the disease affects men and women equally.

Causes

Achondroplasia arises due to a mutation of the FGFR3 gene .

Located on chromosome 4, the FGFR3 gene expresses a protein, known as receptor 3 of the fibroblast growth factor .

The fibroblast growth factor receptor 3 plays the role of a negative regulator of bone growth ; in other words, it blocks the development of bones.

Under normal conditions, the activity of FGFR3 is such that the long bones of the upper and lower limbs grow proportionally to the trunk.

In the presence of mutations against him, however, FGFR3 expresses such high levels of fibroblast growth factor receptor 3 that the development of long bones is strongly impaired.

To better understand what has been said, think of two situations:

  • In a first case, FGFR3 and the resulting protein act in a finely controlled manner. This guarantees the long bones of the limbs a development appropriate to the size of the rest of the body.

    This situation reflects normality.

  • In a second case, FGFR3 acts in an uncontrolled manner and the resulting protein is overactive. The hyperactivity of the fibroblast growth factor receptor 3 blocks the growth of long bones.

    This other situation reflects what happens in the presence of achondroplasia.

IS ACONDROPLASIA A HEREDITARY DISEASE?

According to the National Human Genome Research Institute (NHGRI), in more than 80% of cases, achondroplasia is a non-hereditary genetic disease . This means that the mutation responsible for the condition in question is spontaneous and takes place, for unknown reasons, during the first moments of embryonic development.

In light of this, the share of hereditary cases of achondroplasia is around 20% .

Based on several genetic studies, hereditary mold achondroplasia has all the characteristics of a dominant inherited inherited disease .

Meaning of hereditary disease with dominant transmission

Each human gene is present in two versions, called alleles. An allele has maternal origins - that is, it comes from the mother - and an allele has paternal origins - that is, it comes from the father.

Having said this, the presence of an inherited dominantly transmitted disease has several implications, including:

  • The disease and its symptoms are also manifested in the presence of only one mutated gene allele (it does not matter whether it comes from the mother or the father), since the latter is dominant over the healthy one.
  • A parent carrying the mutation is sufficient to have the disease in part of the offspring.
  • The probability that a sick child will be born, from a couple where only one of the two components carries the mutation, is 50%.

RISK FACTORS

The only attested risk factor for achondroplasia is a family history of this bone development disease.

To subjects belonging to families with one or more cases of achondroplasia, doctors recommend a genetic test that evaluates the individual chromosomal profile and highlights any genetic mutations.

Symptoms and Complications

Generally, achondroplasia has negative repercussions only on the physical plane; in fact, the patients' intellectual level is generally normal.

The characteristic physical signs of achondroplasia are:

  • Significantly lower stature than average (NB: the comparison obviously concerns individuals of the same age and same sex);
  • Short and disproportionate arms and legs with respect to the size of the trunk, which is instead normal. This is the main feature of disproportionate dwarfism;
  • Short fingers and trident hands ;
  • Big head, compared to the rest of the body, and with a prominent front ;
  • Middle area of ​​the face of reduced (or poorly developed) size and flat nasal bridge ;
  • Varus knee or valgus knee ;
  • Accurate spinal kyphosis (spinal hypercyphosis) or lumbar hyperlordosis .

NB: physical changes, such as the varus or valgus knee, spinal hyperciphosis and lumbar hyperlordosis, appear as the patient grows and ages.

HEALTH PROBLEMS

The presence of achondroplasia coincides with various health problems.

In childhood, the most common health problems are:

  • Moments of apnea, ie periods of time in which the patient breathes more slowly or does not breathe at all. The moments of apnea are particularly frequent at night (sleep apnea syndrome);
  • Hydrocephalus;
  • Motor delays (eg: the patient develops skills such as walking, running, etc. late);
  • Spinal stenosis. Spinal (or vertebral) stenosis is the pathological narrowing of one or more areas of the vertebral (or spinal) canal, the canal within which the spinal cord resides.

    In those suffering from achondroplasia, spinal stenosis tends to worsen with age.

During childhood, adolescence and adulthood, instead, the most classic health problems consist of:

  • Difficulty bending the elbows;
  • Overweight or obesity;
  • Recurrent ear infections (otitis), favored by anatomical abnormalities of the ear canal;
  • Disorders related to the presence of varus or valgus knee, spinal hyperciphosis and lumbar hyperlordosis.

Diagnosis

At one time, doctors diagnosed achondroplasia only after birth, observing the patient's physical characteristics.

Today, thanks to modern diagnostic techniques, they are able to identify the disease even before birth, when the affected subject is still in the maternal womb.

PRENATAL DIAGNOSIS

In general, prenatal diagnosis of achondroplasia is based on an obstetric ultrasound, which shows some suspicious signs (eg: hydrocephalus or particularly large head), and on a genetic test on a sample of amniotic fluid, which is the liquid that surrounds the fetus inside the uterus.

It is important to point out that from obstetric ultrasound imaging alone it is impossible to conclude that it is achondroplasia: in fact, there are other congenital diseases that cause hydrocephalus, a very large head, etc.

POST-CHRISTMAS DIAGNOSIS

As a rule, the post-natal diagnosis of achondroplasia occurs through: observation of the child's physical characteristics (proportionality between limbs and trunk, etc.), measurement of the bones of the arms and legs, through an X-ray examination, and, finally, through an evaluation of the genetic profile .

GENETIC TEST

A genetic test is positive for achondroplasia when it shows the presence of a mutation of the FGFR3 gene, located on chromosome 4.

By analyzing the various genetic profiles of the patients analyzed, the scientists observed that there are different types of FGFR3 mutations, capable of triggering achondroplasia.

For obvious reasons, genetic testing is the most reliable diagnostic test.

Treatment

At present, unfortunately, there is no specific treatment for achondroplasia . The latter, therefore, is an incurable condition.

The presence of certain health problems, such as otitis or spinal stenosis, requires medical intervention: the therapies adopted in these circumstances - it is important to point out - are not aimed at treating achondroplasia, but at treating symptoms or related complications.

EXAMPLES OF SYMPTOMATIC TREATMENTS

  • The presence of infectious otitis requires the planning of an antibiotic therapy, to combat bacterial colonization, responsible for the disorder.
  • Severe spinal stenosis requires laminectomy surgery.
  • Repeated episodes of apnea could make it necessary: ​​the use of the nasal mask for CPAP, tonsillectomy, adenoidectomy and tracheostomy. The purpose of these therapies is to clear the airways and remedy respiratory problems.

DO THE GROWTH HORMONES HAVE EFFECT?

In the past, doctors and scientists have tried to subject patients with achondroplasia to hormone-based therapies based on growth hormones, in an attempt to recover the statural defect.

The pharmacological tests carried out were unsuccessful, as they did not bring any benefit to the growth in height.

Prognosis

According to the National Human Genome Research Institute (NHGRI), individuals with achondroplasia have a life expectancy comparable to that of healthy people.