P.er most people are dwarfs, a generic term and often used in a broad or derogatory sense (dwarfs to mean children, “dwarfs and dancers”, the “psycho-dwarf”, dwarf as opposed to giant). But that of the “dwarves” is a complex world, and very, very complicated. A world made of so much effort, medical visits and a good dose of the art of getting by. For them, or rather for those (most) whose condition is determined by one rare genetic mutation called achondroplasia (1 out of 25 thousand births), however, in these days there is a great novelty.
A drug against achondroplasia, a revolution
The Italian Medicines Agency (AIFA) has in fact authorized the placing on the market in Italy of the first and currently only medicine that can help them grow in height. «Voxzogo, from BioMarin, can be given as an injection under the skin per day to children of at least 2 years whose “epiphyses”, or the rounded end of the long bones (ie femur, tibia and fibula, humerus, radius and ulna), are not closed. And this usually happens around the age of 12-14, ”he explains Maria Francesca Bedeschi, geneticist at the UOSD of Medical Genetics IRRCS Foundation Ca ‘Granda Ospedale Maggiore Policlinico di Milano and Adjunct Professor of the School of Specialization in Medical Genetics and Orthodontics.
It is a revolution for people with achondroplasia (321 in Italy, between 2 and 18 years of age) and their families. This mutation, in fact, has important consequences and not only, as one might think from the outside, aesthetics. The most visible effect is yes the short stature (a male reaches an average height of about 1.32 meters and a female about 1.24 meters). But bone growth deficiency can get severe repercussions also on his health and psychological well-being.
Maria Francesca Bedeschi, achondroplasia, geneticist at the UOSD of Medical Genetics IRRCS Foundation Ca ‘Granda Ospedale Maggiore Policlinico di Milano and Adjunct Professor of the School of Specialization in Medical Genetics and Orthodontics.
Complications of achondroplasia
“The most important complications», Explains Bedeschi,« They register in the first months and in the first years of life: as the compression of the foramen magnum, that is the opening at the base of the skull which, in case of narrowing, can compress the brain or the spinal cord. But also mediofacial hypoplasia: that is, the uneven growth of the central part of the face compared to the rest of the face. Again, permanent sway of the lower back, spinal stenosis and recurrent ear infections. In the early years, hypotonia of the limbs and defects in the curvature of the spine were frequent ».
People with achondroplasia usually have an average sized trunk, limbs being shorter than typical body proportions. While the head is large and with a prominent forehead. This alone, for example, makes it more difficult for a child to start walking. But also grabbing objects, climbing stairs, washing your head, having a coffee at the counter of a bar to the child who becomes a boy and a man.. The conformation of the face also has its effects: on breathing, with frequent rhinitis, night snoring and the risk of apnea. And on the palate, usually narrow, to be corrected with orthodontic treatments to avoid dental malocclusions.
The social prejudice towards the dwarves
Then there is the social aspect, that of prejudice, as explained in Nanbeing Marco Sessapresident of AISAC. That is the Association for the Information and Study of Achondroplasia, a reference point for families who face this condition every day. As Sessa says, a “dwarf person” has the same aspirations, passions and goals as a so-called able-bodied person. Yet he lives daily with a social stigma that is hard to ignore. There are of course millennia of prejudices behind them: dwarves, in the courts of nobles and kings, even in ancient Egypt of the pharaohs, they were jesters and fools. In the circus, nano is synonymous with clown. And in folk traditions and tales, they are like hobbits, different to whom the main part rarely touches. If an actor with Peter Dinklage has managed to become a star, the Italian actor with achondroplasia Gianluca Cofone instead denounces the effort to break down stereotypes.
The DNA test and achondroplasia
Achondroplasia it can be diagnosed before delivery but usually only in late pregnancy. “A common fetal DNA test (which is performed by taking maternal blood) does not identify it, which is a screening test for the main fetal chromosomal abnormalities and some microdeletions,” explains Bedeschi. Unless there is a suspicion, out of familiarity, that leads to carry out specific genetic investigations, the mutation that leads to achondroplasia is not even looked for. In fact, there would be too many possible mutations to “look for”. “It would be like looking for a needle in a haystack,” says Bedeschi.
It is a mutation in the gene that encodes the FGFR3 receptor and causes cartilage cells, called chondrocytes, to continuously send signals to slow bone growth. Since FGFR3 receptors are always overactive, bone growth slowdown signals override bone growth signals. Therefore, cartilage cells fail to line up to form new bone, impairing bone growth.
The third morphology and the “unexpected diagnosis”
This mutation shows the first effects on the fetus around the third trimester of pregnancy: “Typically, on the occasion of the third morphological ultrasound, a pronounced femoral shortness is noted, accompanied by a macrocephaly”. And what, in jargon, is called an “unexpected diagnosis” takes shape. “Apart from that in the case of a parent with achondroplasia, where the risk of transmission to the child is 50%, in all other cases the condition arises “de novo”“. That is, none of the parents is a carrier of any mutation.
photo by Lorenzo Ceva Valla for Aisac
The only possible intervention: the lengthening of the bones
Until now, there was no drug for achondroplasia. The only possible intervention to increase height was surgical: a long and painful procedure to lengthen the bones. “It usually takes place from the age of 6 and involves the breaking of the bones in the center and their lengthening by means of external fixators”explains Bedeschi. First the two tibiae break and lengthen, then the two femurs, and if you want you can then start over with the shins. A years-long process, during which fatigue can become unbearable.
With the introduction of Voxzogo the lengthening certainly does not end in pulping. Based on the studies done, the growth made possible by this drug is about 1.57 cm tall per yearboth in the spine and in the lower limbs. If it could, this growth could be combined with that derived from elongation, the improvement would be truly exceptional. “There is no indication to the contrary from AIFA,” explains Bedeschi. “But it is worth pointing out that the cases followed were not operated on. The fact that the growth induced by the drug is at the extremities of the long bones, while the growth by elongation in the central part, makes us think.
How the new drug works
What is it about? «Voxzogo is a modified C-type natriuretic peptide (CNP) that regulates the signaling of the fibroblast growth factor receptor 3 (FGFR3) and, consequently, promotes endochondral bone formation»Explains Bedeschi.
BioMarin’s Voxzogo had obtained marketing authorization from the European Medicines Agency (EMA) in August 2021 based on all the data from its clinical development program, including the results of the randomized Phase 3 study. double-blind, placebo-controlled. On 13 September, however, the authorization for the marketing of Aifa.
As with all rare disease drugs, Voxzogo is also very expensive: we are talking about 300 thousand dollars a year (but then obviously it depends on the price that Aifa will negotiate with BioMarin). The reimbursement of Voxzogo in Italy, scheduled today for the age group ranging from 5 to 14 years, it is therefore very important. And the extension of reimbursement is expected shortly also to children from 2 years old, since, obviously, the sooner you start, the better.
One injection every night, and periodic checkups
The administration, as we said, must be done by subcutaneous injection: one every evening, in the buttocks, abdomen or thighs area. «It is important to vary to prevent adverse reactions from occurring, and the area will become inflamed»Says Bedeschi. “But even more important is that the child experiences it peacefully. The parents, who will physically make the injection, must also be prepared in this sense “. The administration must be done in the evening also for the possibility that it leads to a drop in blood pressure, a possible side effect, albeit in low percentages. «The children under treatment will have to carry out periodic checks in the reference centers. Every three months, in the first 6 months, and then every six months for the whole period of the treatment ».
A child with achondroplasia who took the new drug Voxzogo, Photo BioMarin www.biomarin.com/our-treatments/products/voxzogo/
Many will hire him, but not all
From a general point of view of body harmony, “the earlier you start, the more likely it is that your physiognomy will change in a positive way”. Clearly, children entering treatment, if they are enrolled in other drug trials to test other drugs, will have to leave these trials, in order not to compromise the results. “But it’s not so obvious to think that all children with achondroplasia will start taking Voxzogo. The psychological aspect is fundamental, and parents must absolutely take this into account: there are many children who reject the idea of a daily injection, as well as reject stretching“. This option was chosen very frequently in Italy “and less so, for example, in Germany”.
The importance of a serene approach. From the parents
In all cases, psychological support for children but also for families in order to make informed choices is essential. «It is trivial to say it but I notice that the children, and the most serene boys, are those whose parents have developed the sense of guilt that, even unknowingly, they harbor within themselves. If the diagnosis is truly metabolized and the diversity accepted, the complications are managed and the psychological aspects are canceled out ». It is a feat, of course.
But on a positive note, Dr. Bedeschi gives it: «I can tell the parents of the little ones, hang on. The first times are the most difficult: because of the complications, which occur in the first years. Because of the psychological aspect, yours. But also because you don’t know your children yet. That, having a normal cognitive development, they have enormous potential for development“. In short, children will reassure adults as soon as they can. “When boys with achondroplasia enter their early teens we don’t see them anymore. But not only because the age of complications is over. They disappear from our sight because they are happy“.
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