Achondroplasia

Achondroplasia is a bone dysplasia caused by a genetic disorder and the cause of 90% of disproportionately short stature, also known as dwarfism. Its main physical feature is short limbs, while that the trunk is of average size. 75% of cases are new mutations and the remaining 25% are autosomal dominant disorders, that is, inherited from the parents. The disorder consists of a DNA modification that generates alterations in the growth factor receptor 3 of fibroblasts, which in turn generates abnormalities in the formation of cartilage and, therefore, in bone growth.

The picture occurs in one of every 25,000 live newborns. It is the most frequent type of dwarfism and is characterized by short stature at birth and a series of dysmorphia, among which are: macrocephaly, hypoplasia of the region maxilla, shortening of the long bones and fingers, and radiologically, platyspondylia, decreased interpedicular distance of the lumbar spine, deformity of the metaphyso-epiphyseal regions, square iliac bones and markedly decreased height and a narrow foramen magnum, among others. The phenotypic diagnosis is evident at any stage of life, even occasionally during the prenatal period.

People with this genetic mutation have a 50-50 chance of having their own child with this same disorder. If two people with achondroplasia have a child, there is a 50% chance that the child will inherit the abnormality, a 25% chance of having a baby of average height, and a 25% chance that the baby will have what is known as "double dominance" of achondroplasia. The latter is, in all cases, fatal in childhood. Babies born with dual dominance have very small ribs, as well as severe brain abnormalities.

Expected heights for people with achondroplasia are 51.5 inches (131 centimeters) for men and 48.4 inches (123 centimeters) for women; however, the stature can be as short as 62.8 cm (24.7 in). A hallmark of this syndrome is thoracolumbar gibbus in childhood.

Genetic etiology

Don Sebastián de Morra, an acondroplastic dwarf, painted by Velázquez.

The cause of this disorder is a mutation in the gene that codes for receptor 3 of fibroblast growth factor 3 (FGF3), located on chromosome 4. There are two possible mutations that affect this gene: G1138A and G1138C. Both are points, where two complementary DNA base pairs are exchanged:

• G1138A Mutation: in nucleotide number 1138, guanine is replaced by adenine. In 98 % of cases of acondroplasia, this mutation is suffered.
• G1138C Mutation: the change of guanins per cytosine takes place, also in nucleotide 1138. The frequency of this alteration is much lower, only in 2 % of cases.

In both situations, the impact on the amino acid chain of the FGFR3 protein is the same: the change of the amino acid glycine to arginine.

This mutation can occur in two different ways: by autosomal dominant inheritance, when there is a family history of disease (around 10% of cases) and by a de novo mutation, with healthy parents (is the most common cause, in up to 90% of patients).

Genetic inheritance

The inheritance of this disorder is autosomal dominant, which means that, to suffer from it, it is enough to inherit the mutated gene from at least one of the parents. The genotypic possibilities and their phenotypic correspondences are the following:

• Homocigoto (G1138A/G1138A): It is the most serious form of disorder and is usually lethal during the neonatal period. In order to take place, it is necessary that both parents have acondroplasia (heterozygotes, because homozygotes do not survive). It occurs in 25% of children when both parents are acondroplastic.
• Heterozygous (G1138A/normal allele): This genotype can be reached from three possible assumptions.
  • If both parents have acondroplasia, the possibility that the child is heterozygous for the disorder is 50%.
  • If only one parent is acondroplastic, there are also 50% chances of inheriting it.
  • In most heterozygous cases, the disorder is due to a new mutation, so the two parents are normal stature.

New mutation

Around 80% of people with achondroplasia have no family history of the disorder. The reason is spontaneous or de novo mutations (G1138A or G1138C) that affect the paternal germ line. They are, therefore, mutations that occur in the father's gametes (spermatozoa) during spermatogenesis. These alterations occur, as their name indicates, spontaneously, which implies a lack of knowledge of their cause; however, numerous studies seem to confirm a relationship between the de novo mutation and the age of the father at the time of fertilization, in such a way that being over 35-40 years of age seems to be a risk factor for having an achondroplasic child. The frequency of occurrence of achondroplasia is equally distributed among individuals of both sexes and of any race.

Epidemiology

Because achondroplasia is a disease that has similar manifestations to 19 other congenital diseases (osteogenesis imperfecta, late multiple epiphyseal dysplasia, achondrogenesis, osteopetrosis, thanatophoric dysplasia, etc.), estimates of its prevalence are difficult since the Diagnostic criteria are subjective and change over time. An example of this is that a detailed and long-term study in the Netherlands showed that the prevalence determined at birth was only 1.3 per 100,000 live births, while another study carried out at the same time found a rate of 1 per 100,000 live births. per 10,000. The largest European study on the disease found a prevalence of 3.72 cases per 100,000 births.

Causes

Normally, fibroblast growth factor (FGF) has a regulating effect on bone growth. In achondroplasia, the receptor for this factor (FGFR3) is mutated, so it is constitutively active, which leads to shortening of the bones.

People with achondroplasia have one normal copy of the FGFR3 factor gene, but they also have a mutated copy. Two copies of the mutated gene is fatal from before birth. Regarding genetic inheritance, a person with achondroplasia has a 50% chance of inheriting this disease to their children, which means that there is a 50% chance that each child will inherit this disease. On the other hand, if both parents have achondroplasia, their child has a 25% chance of dying shortly after birth, a 50% chance of having achondroplasia, and a 25% chance of the child having the phenotype.

Not all people born with achondroplasia have parents with the same condition, as this can be the result of a new mutation. This condition is not necessarily acquired through genetic inheritance, as there are new gene mutations that can lead to achondroplasia. to achondroplasia. There are some studies that suggest that the advanced age of the parents may be a risk factor

Current studies have shown that new gene mutations for achondroplasia are inherited exclusively from the father and that they occur during spermatogenesis; since during oogenesis there is some kind of regulatory mechanism that prevents gene mutations, however the Women are still capable of presenting the phenotype and genotype, and (thus) of transmitting the mutant allele.

More than 99% of achondroplasia is caused by two different mutations of the FGFR3 factor. In approximately 98% of cases, a mutated G to A point within nucleotide 1138 of the FGFR3 factor gene causes a glycine to arginine substitution (Bellus et al. 1995, Shiang et al. 1994, Rousseau et al. nineteen ninety six). The other (remaining) 1% of cases are caused by a mutated G point to a C point within nucleotide 1138. The mutant gene was discovered by John Wasmuth and his colleagues in 1994.

There are two syndromes that have a genetic basis similar to achondroplasia: hypochondroplasia and thanatophoric dysplasia.

Clinical signs and symptoms

Seneb and his wife. Condroplasia in Ancient Egypt.

People with achondroplasia show a characteristic physical presence as a consequence of the interruption of the development of the cartilage in the epiphyses of the bones, becoming more noticeable in the long bones of the humerus and femur, which are the ones that present the fastest growth. In this way they present a short stature, which does not usually exceed 144 cm (centimeters) in adulthood, with shortening of the extremities and enlargement of the skull, while the trunk retains its normal size. The most important anatomoclinical findings of this disease are shown below:

• Higher extremities: although they are shorter than in a normal individual, the forearms are longer than the arms and are unable to perform a complete extension of the elbow.
• Lower extremities: As in the arms, the lower limbs are also shorter with greater evidence in the femur than in the lukewarm. The axis of the knees takes an abnormal position and originates the Genu varo, a greater separation between both labels that originate a lower arched extremities.
• Sign of the trident: refers to the separation between the third (heart or medium) and fourth (annular) finger of the hand.
• Alterations in the spine: during childhood they can present a dorsal ciphosis due to lack of muscle tone. Sometimes it is combined with a lumbar hyperlordosis that tries to compensate for the deviation.

Diagnosis consists of fetal ultrasound for progressive mismatch between femur length and biparietal diameter by age. A DNA test can be performed before birth to detect the homozygosity of the mutation, a condition that, as already mentioned, is lethal.

Radiological findings

A skeletal radiological study is helpful in confirming the diagnosis of achondroplasia. In this study, a large skull can be observed, with a narrow foramen magnum and a relatively small base; short, flattened vertebral bodies with a relatively large intervertebral space; iliac wings small and square with a narrow sciatic notch and a horizontal acetabular roof; short, thick tubular bones with metaphyseal suckers and irregular growth plates; excessive growth of the fibula; broad hands with short pasterns and phalanges and short cup-shaped ribs at front ends.

If the radiological features are not classic, the search for a differential diagnosis should be considered.

Treatment

Although the gene mutation in the growth factor receptor is known, there is currently no known treatment to treat achondroplasia.

Growth hormone is used by people who do not have achondroplasia to help them grow, however it is not effective in people who do. Despite this, if they wish, they can undergo limb-lengthening surgery, which despite being a controversial issue has been effective in some cases. Generally, the best results appear within the first and second year of hormone therapy. of growth.

After the second year of therapy the beneficial effect of bone growth begins to diminish. This is why growth hormone therapy does not have satisfactory long-term effects.

Gene therapy is still in development. A US company, BioMarin Pharmaceutical Inc., recently announced the initiation of a Phase I study in healthy volunteers for BMN-111, a C-type natriuretic peptide analogue, for the treatment of achondroplasia. The latest research is regulated and controlled by the non-profit organization [Growing Stronger].

In other species

Due to disproportionate dwarfism in some breeds of dogs, they have been classified as achondroplasic. As such, it is the case of the Dachshund, Basset hound and Bulldog breeds, this to mention only a few of them.

Data from the Association for Genomics, studies in short-limbed dogs have shown its close association with a retrogenetic encoding of growth factor 4 (FGF4). Therefore, it seems unlikely that dogs and humans develop achondroplasia for the same reasons. However, histological studies in some achondroplasic dogs have shown altered cell patterns in cartilage, which is very similar to that seen in humans with the disease.

A similar type of achondroplasia was found in a litter of Danish piglets that had an apparent normal phenotype. Dwarfism was dominant in the mother's offspring, and although the piglets were born phenotypically normal, over time the condition became increasingly evident.