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Archives de pédiatrie
Volume 24, n° 5S2
pages 596-5101 (mai 2017)
Doi : 10.1016/S0929-693X(18)30024-1
Hypophosphatasia: the patient’s and patient’s family’s point of view
L’hypophosphatasie vue par les malades et leurs familles
 

S. Ursprung
 Président bénévole de l’association Hypophosphatasie Europe, 16, rue Barbanègre, 68330 Huningue, France 

*Corresponding author.
Summary

Today, public opinion and the French authorities are more aware of rare diseases, in particular due to the implementation of national plans for rare diseases (PNMR I: 2005-2008 and PNMR II: 2011-2016), the existence of national networks and the current organization of the reference expert centers for rare diseases. While the management of rare diseases is now better structured, it remains long for the patients to be diagnosed. It is not always easy for physicians to clearly identify one of the 7,000 rare diseases even though they increasingly ask themselves the question: is this a rare disease? A person diagnosed with a rare disease lives in a familial, social and professional environment that has not prepared him or her, suddenly or after years of uncertainty, for such an experience. It may be temptng to take refuge in isolation. The patient’s pathway is a real challenge and include the recognition to his/her ‘difference’ and the right to benefit from the expert medical and social care. Patients affected with hypophosphatasia, a very rare bone and dental disease, are not exceptions to the rule, despite the dynamic support of Hypophosphatasie Europe, the first patient association, created in 2004. In twelve years, the overall understanding of hypophosphatasia has dramatically improved, including through the discovery of novel therapies. Yet, diagnostic errance, transition between childhood and adulthood and management and care of affected adults remain unsolved issues.

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Résumé

Aujourd’hui, l’opinion publique et les instances de l’État sont sensibilisées aux maladies rares notamment grâce à la mise en œuvre des Plans nationaux de maladies rares (PNMR I : 2005-2008 et PNMR II : 2011-2016), à l’existence des filières nationales de santé et au maillage actuel des centres de référence et de compétence. Si la prise en charge de ces maladies s’avère mieux structurée, encore faut-il que les diagnostics soient correctement faits. Il n’est en effet pas toujours simple pour les médecins d’identifier l’une de ces 7 000 maladies, même s’ils ont de plus en plus le réflexe de se poser la question : Et si c’était une maladie rare ? La personne atteinte d’une maladie rare vit dans un environnement familial, social, professionnel qui ne la prédispose pas, du jour au lendemain ou après des années d’errance, à vivre une telle expérience. Sous réserve qu’elle sorte de l’isolement dans lequel elle est parfois tentée de se réfugier, s’engage alors pour elle un vrai parcours du combattant pour être reconnue dans sa « différence » et correctement prise en charge médicalement et socialement. Les malades atteints d’hypophosphatasie (HPP – maladie osseuse et dentaire très rare) ne font pas exception à la règle, même si l’action déterminée d’Hypophosphatasie Europe, première association de patients créée en 2004, a changé la donne. En 12 ans, la connaissance globale de l’HPP a beaucoup évolué. Pourtant, certains aspects comme l’errance diagnostique, la transition entre enfants et adultes et le suivi médical des adultes restent encore problématiques.

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Introduction

In the lottery of life, fortunes vary. We do not all enjoy the same privileges. This applies to one’s place of birth, social environment, family and parents from whom one inherits, one’s ability to learn, etc. This also apples to one’s genetic capital, with the difference that due to heredity or random, there is nothing an individual can do to change his genetic grounds. The risk of being affected by a rare disease is high and everyone is potentially concerned. Thus, when parent or adults begin to think that “something is not right”, and when caregivers are confronted with clinical signs that they are unable to label or identify, they should be able to ask themselves: could this be a rare disease?

HPP: one rare disease among many

A disease is termed rare when it affects less than one person in 2,000, i.e., for France, less than 30,000 persons (definition based on the prevalence defined by the European regulations on orphan drugs). Currently, over 7,000 rare diseases have been identified. Five new rare diseases are reported in the medical literature each month. About 80% of them have a genetic cause. HPP is a very rare bone and dental genetic disease for which the prevalence of the severe forms ranges from 1/100,000 to 1/300,000. In France, for all forms of the disease taken together, we estimate that 80 to 100 persons suffer from the disease. The disease is due to a deficiency in, or inactivity of, the enzyme alkaline phosphatase (ALP). Six clinical presentations of the disease, depending on age at symptom onset, are arbritrarily designed. The disease affects all ages, on all continents worldwide, and affects men and women equally.

In quest of a diagnosis: the need to know

When the patient (or his/her family) realize that something is wrong, he naturally contacts his general practitioner or pediatrician, and then the various specialists to whom he is referred. The patient undergoes numerous tests and examinations, which, in the case of HPP, may not be productive, if one is not aware of what needs to be looked for. Diagnostic errance begins and may last several years. HPP, is still a disease that may be overlooked or confused with other diseases (osteogenesis imperfecta), when not erroneously considered a psychosomatic disease. Undoubtedly, the patient prefers to know, because knowing is understanding that “it’s not all in his head”. Knowing allows the patient to identify the enemy to be fought. Hence the importance of giving a name to his symptoms. Daniel, who was diagnosed very late (although he could have been diagnosed in childhood given the clinical signs he presented) witnesses:

“I have always lived with the disease, without realizing it. I thought I was a fragile person who couldn’t stand pain. […] Is it normal to be in such pain? And then, suddenly, you are told that you have a rare disease which is enormously painful. […] Yes, even though it happened late, being diagnosed was very important to me. It was a satisfaction to know that I did indeed have a disease.” Confirming Daniel’s diagnosis also enabled the disease to be diagnosed in his twin brother and older sister, who were also unaware (or in denial?) of the disease.

Of course, there are also those who suffer without trying to understand. There are those who want to know and there are those who, once they know, have great difficulty accepting their condition although they are the first to express the fact that they had an intuition that something was wrong. Thus, Murielle, alerted by the fact that her baby, aged one year, swallowed a milk tooth while feeding from a bottle, immediately began searching, until the day the diagnosis was announced. She says: “When the disease was announced, I experienced a lot of emotion, a lot of anxiety, but it was over quickly. My husband and I had really had our heads in the sand. […] We were scared, and then our fear turned into denial. We completely refused to accept the diagnosis for several months. Finally, the diagnosis was confirmed after another alkaline phosphatase assay after 2 years of uncertainty. It felt like a cold shower at the time, but I was also very ambivalent: I was reassured. It’s horrible not knowing what to fight against. […] We were offered little psychological support at that time and it’s very regrettable. I felt I had been abandoned to my own resources. My dentist told me that my daughter was the first little patient with the disease that he had seen. That clearly shows how difficult it is to be aware of rare diseases. Because of their very rareness, healthcare professional may not be aware of them.”

After the diagnosis, the need to understand (or not)

Thus, after a period of doubt and uncertainty, of variable duration, HPP is diagnosed and the diagnosis shatters all the patient’s preconceptions. All patients say that there is a “before diagnosis” and an “after diagnosis”. Since the disease is genetic, the first step is to identify the source of transmission, usually in the parents. A veritable tsunami sweeps them into a world of guilt, shame, fear and even resentment. This may weaken couples (or make them stronger) as they are forced to abandon their image of an “ideal, healthy child”.

Similarly, family histories, which were previously taboo, may resurface with serious consequences, as Isabelle explains:

“The problem is that my partner’s family deny that there could be a genetic disease in the family. In my family it is shameful to have a disease, and it must be concealed. So the diagnosis was a triple blow. My husband could not support the idea of having sick children. We separated when the boys were still very small. Before the diagnosis of the disease was announced, I was one of the crowd. I was like everyone else. After the diagnosis was announced, I was no longer one of the crowd. I was isolated.”

After a lag time of variable length (depending on the intensity of the shock, denial and withdrawal experienced by the patient or family) comes the need not to go through the situation alone. Knowing that other people are also affected is reassuring and we are stronger together. Often, the approach is timid: the patient or family has taken the time to search the web and discovered that there is (or is not) an association. For HPP, the association was created in May 2004 by patients and patients’ parents and loved ones, for whom it was essential to combat the disease, share with patients, retrieve the available information, promote research and medicine, and do everything possible to pull HPP out of darkness. As founder, I would like to state that “the association was created after a period of ten years during which I did not want to talk about my disease. Not because I was ashamed, but rather because I wanted to live like everyone else. After a period of professional stability, I felt ready to move forward. I wanted things to change. It was also undoubtedly because I turned 30 that year. The road to creating the association took 2 or 3 years. To begin with, I created a personal website as a forum for HPP, with stories from my life and healthcare experience (anomalies of my growth curve, the various fractures and operations I have experienced) and information gleaned here and there. I discovered the story of a lady in her sixties who had the disease. For ten years she had been living cloistered in her home, confined to bed. Her story made me very scared. I had never thought that in old age I might find myself in such a situation. Having read the lady’s particularly moving story, I needed a breath of fresh air. I told myself I could wait no longer and had to get moving. I threw myself into the battle (this was undoubtedly related to my character, my curiosity and my already long experience of working with associations). I was aware that knocking on the door of an association of patients, for other patients or their families, is not a simple process. It is frequently the fruit of a long process of maturation, which from initial denial slowly leads to acceptance and recognition of one’s status as patient or a patient’s loved one. The initial contacts with the reality of the disease and the associations news are frequently via the website or social networks (since, protected by the screen, one can still remain hidden and anonymous). Then comes the first email in which the patient indicates that he “is concerned by HPP” and asks his question(s). In so doing, the patient has decided to break out of the isolation in which he may find himself and to tell us that he is ready to listen and understand. On the quality of the relationship that we have created (by email or telephone), our attentive receptiveness carefully chosen words, empathy, patience and respect will depend the ability of the person concerned to look into a future made of obstacles, constraints and renunciations. Bringing patients and their families out of their isolation was our first ambition as an association. Then, very quickly, we turned to the fields of research (hitherto almost nonexistent) and medicine (hitherto poorly informed and unable to act), which we considered essential. We thus wished to create a dynamic process, a synergy of information and collaboration between all the players potentially concerned by HPP.”

Finding the right contacts for optimum management

Even though the patient is aware of the diagnosis, he has often not been informed who to turn to in his area for assistance in overcoming the pain, for encouragement with respect to prevention, for treatment of his fractures, for prevention of epileptic seizures, and for support through the course of his disease. This is not due to negligence or ill will but rather to a lack of awareness. Many patients and their loved ones still report difficulty locating physicians, pediatricians, dentists, radiologists, psychologists physiotherapists, prosthetists, etc. aware of the specificities of rare diseases, informed and trained with respect to HPP. As Murielle stated:

“[…] I sometimes had the impression I had been forgotten, that I was not the subject of the conversation. Consultations are frequently more helpful in getting us to understand the origin of the disease than in really providing care. Doctors know little about the disease; no one could tell me what the consequences would be in my everyday life. For them it was, for the time being, ‘only a dental problem’ even though my daughter had lost nearly all her front teeth and I was worried about the effects on her language skills (she already had pronunciation difficulties) or chewing. I contacted the association again several times.” Lucile, a young adult in her twenties, also remembers: “Five years ago I was still able to walk. Then I experienced very acute pain in the knees and ankles. I was prescribed tests and I was told, ‘It’s nothing. It will get better.’ They I tested almost all the pharmacological forms of morphine, anti-inflammatories, nothing worked. Little by little I lost the use of my legs and I had to start using a wheelchair. I knew that I had fragile bones, but I had never imagined being in a wheel chair because of the pain, experiencing the inability to walk and loss of independence.”

Sometimes, it is very difficult for the patient to knock on doors if he has not accepted his new condition: for instance, the door of the office for assistance to handicaped persons (so called Maison Départementale Pour le Handicap in France) in order to obtain financing for technical or human assistance, or request funds for adaptation of housing, or the door of the Commission for the rights and independence of handicapped people to obtain recognition of handicaped worker status. It is true that suffering from a genetic disease does not necessarily mean being handicaped. And yet support exist and could greatly relieve some parents, the natural caregivers for their children, who are overburdened by a difficult daily routine, or patients whose condition is impaired by repeated fractures and who are in need of aid. But, once again, obtaining access to one’s rights presupposes that one’s application file is correctly completed by a physician aware of (and who recognizes) the specific needs of individual patients. Daniel recalls his experience in the matter: “they [the members of the association] helped us to explain what the disease consists in (when we go before the medical commission, it’s up to us to explain the disease because they don’t know). My handicap is not visible. It’s up to you to show, by A + B, that the disease exists, that it needs to be recognized and that it leads to a sometime severe handicap. The association helped us fill out the forms for the Commission. […] I now have a recognized status of about 80% handicap […]. It has been of positive moral benefit for me and my family for me to be recognized as a handicapped person.”

The role of Hypophosphatasie Europe is also to orient patients and their families in the existing healthcare system. Since the institution of the PNMR (national plans for rare diseases), national “rare diseases” healthcare systems are available. Their role is to manage and coordinate the contributions of the various players involved in the management of rare diseases with a common theme (of which, for HPP: the OSCAR and TETECOU networks), and the expert and specially dedicated reference centers (of which, for HPP: The National reference center for constitutional bone diseases at Necker hospital in Paris; the National reference center for the odontological manifestations of rare diseases at the Strasbourg teaching hospital and the Reference center for rare diseases of calcium and phosphate metabolism at Bicêtre Paris Sud hospital in Paris), in the regions, the proximity expert centers responsible for close patient monitoring and the preferred interlocutors of the various local medical and paramedical players. In this new context, it is hoped that patients in search of a diagnosis and those newly diagnosed – not to mention their attending physicians – will more readily find, in their area or region, the right contacts. We also consider it essential that once these contacts have been found a relationship based on trust is established between the patient and healthcare professionals, irrespective of the latter’s field of expertise. The patient knows his body well, is attentive, and tests its physical and psychological limits on a daily basis. The patient is frequently well informed with regard to HPP. He knows and understands that there is no ‘standard’ care for his disease, given that the disease may present very differently even for the same disease form, and patient gender and age. Management must thus be ‘tailored’ to the individual case. A respectful dialogue may thus provide precious information to the practitioner and assist the latter in defining modalities of treatment that are the most appropriate for the circumstances and natural history of the disease. Similarly, when a dialogue and relationship based on trust have been established, they contribute to enhanced acceptance of the disease by the patient and promote the latter’s ability to move forward. On this subject, I would like to say: “I have never had difficulty assuming my disease as such. Even as a child, I was included in the doctors’ decisions regarding my case. They were always very open with me. There were no taboo.”

Living with the disease on a daily basis: patients speak

Living with the disease on a daily basis is not always easy, especially when the consequences of the disease, the handicap it induces, are invisible, but also, on the contrary, when they are too visible, and others’ looks become too painful to withstand. At school, the young child is frequently marginalized. It is not easy for the child to explain to his gym teacher that he cannot take part because it is tiring, because he risks ‘breaking’. And when repeated fractures occur, with the attendant pain, hospitalizations, and long physiotherapy sessions, there is the worry of missing school. In my experience: “From the age of 10, I experienced fractures practically every 3 years. I immediately associate the word ‘hospital’ with long periods alone with myself, my body and my disease.”

Adolescence is in itself a difficult period. For a patient handicaped by his/her disease, the experience is even more challenging and painful. “I would have liked to live my ‘moped’ phase like the other teenagers in my building, but that was impossible. I couldn’t even go to school by myself. My parents had to drive me. The school was too far away. With my crutches, I couldn’t walk home. I couldn’t spend time outside of school with other teenagers, who would often ride around on their mopeds. Being cut off from my peers and left to my own devices helped forge my character.” There is also the difficulty of having relationships, building friendships and having a social life when one’s physical and psychological life is widely fluctuating. “One of the most personal aspects of my disease was that it inevitably cut me off from friendships and relationships. After every fracture, I crossed out names in my address book even though I thought there were plenty of people around me with whom I shared interests. When one has a fracture and crutches and can no longer take part in one’s usual activities, one drops out of sight. This is a situation that I experienced as a child and as an adolescent, and that I continue to experience today.” Losing one’s freedom of movement (temporarily in the event of a fracture, lastingly in the event of confinement to a wheelchair), becoming disoriented, and having to depend on somebody else for everything in adulthood are events that are difficult to live through. In my experience: “When I have lost my independence, in times of great distress, in the absence of contacts and the silence that results, I feel I have ceased to exist. In that difficult context, the presence, looks and words of others are very important and I miss them. I then have the impression that the people I frequent or usually associate with no longer care about me or my life.” But experience has shown me that not everyone reacts to variable-geometry life in the same way. “I have learned to live with my disease since I was very small. If, unfortunately, I am destined to fall and break myself, then it will happen. I think that I have more to gain than to lose by remaining in action. So, I take the risk of exposing myself, of asking a little too much of my body, while remaining extremely reasonable, because I remain aware. My daily life is carefully weighed up. It’s up to me to decide, in full awareness of my condition.”

Similarly, Yann sees his disease as an opportunity to focus on the essential: “In my personal life and in my work, I try to act so that people do not consider me to be an invalid. I try to prove to myself every day that I am a normal person. However, it is difficult to put the disease out of my mind. As soon as I get up and put my feet on the ground, I am in pain. It takes me three attempts to get up in the morning.

But, I take that to be a strength. […]. In my opinion, strength of character helps me look at life differently, view things, perhaps, people, certainly, in a different manner.”

Then there are those who, after months or even years of errance -at last-obtain a diagnosis. And then there are those who, having hitherto lived a symptom-free normal life, are suddenly beset by late-onset symptoms. For the latter the situation is unprecedented and often traumatic. Patricia recounts: “It’s not easy to lay one’s previous life to rest, nor, for that matter, to imagine a future for myself. I try to put the disease out of mind as much as possible. It’s my way of reacting. While sometimes I would like to meet people who have the same concerns as me and who will therefore understand me, what I fear most is to find myself afterward in real life (particularly at work) with people who do not understand anything at all. So, I avoid meeting with people who share my problems.”

Why report that experience? Long ago, Hypophosphatasie Europe acquired the conviction that, with regard to rare diseases, medical management of the patient must be conceived holistically and in light of patient’s daily environment (familial, social, scholastic, professional, associational). Hence the importance of practitioners being able and knowing how to listen to the patient, even if that is not a core professional skill.

Promoting research and medicine so as to no longer remain passive

Understanding the disease, promoting synergies in research and medicine, and discovering treatments constitute the ambitions of Hypophosphatasie Europe in those fields. This commitment has given (and continues to give) to all patients and their families the hope they needed (and still need).

In the field of HPP research, the work done by the association (with the support of the international scientific board that the association founded as of its inception) has been exemplary. In 12 years, the association has organized and financed two symposia attended by the most prominent specialist worldwide. Beginning in 2004 and continuing today, Hypophosphatasie Europe has supported and financed a number of research projects in the fields of genetics, orodental research, and neurology with a view to elucidating phenomena that were imperfectly understood. While those operations have brought HPP into the limelight, numerous mechanisms remain unknown or have not been elucidated such as, for example, the etiology of craniosynostosis or that of pain. Hypophosphatasie Europe will, in consequence, continue to promote research.

Precious links, mainly in the field, have been forged through collaboration with or participation in numerous medical and scientific events, in France and in Europe, in the fields of genetics, bone, teeth, metabolism, general and specialized medicine, (dentists, pediatricians, rheumatologists, radiologists, etc.), and ortho-prosthetists. Participation enables patients to present their views, practitioners to be informed of the specificities of HPP and networking to be promoted. Similarly, Hypophosphatasie Europe has always been, and continues to be, committed to, and an active collaborator with, the reflection and studies conducted by the national networks and reference centers.

Conclusion

A new era is dawning for patients, and, with it, new challenges are arising. In that context, it is therefore crucial that:

those with symptoms for whom no diagnosis has been formulated and those inadequately identified are inventoried and referred to the national expert centers. Practitioners need to work at identifying the premonitory signs of the disease (particularly dental signs) and fitting children (and adults) with dentures;
the transition from childhood to adolescence, and then from adolescence to adulthood be better anticipated, prepared for and organized, in order to promote enhanced medical management and enhanced patient (and family) adaptation to the new environment and new caregivers;
the acquisition of data from registries is organized and rendered systematic in order to further elucidate the natural history of the disease, particularly in adult patients;
the problems encountered and pertinent to patient management are more clearly recognized in order to generate solutions, such as:
-
promoting safe patient handling in emergency situations,
-
assisting radiologists in image interpretation,
-
learning to detect and alleviate stress microfractures,
-
enabling effective relief of everyday pain and enhanced care with respect to psychology, physiotherapy, and orthopedics.

In short, we have new challenges in order to achieve our associational ambitions, of which continuing to inform, support and accompany the healthcare professionals involved, proximately or remotely, in the management of HPP. Hypophosphatasie Europe is committed to interfacing and facilitating with respect to pediatricians who may be contacted by families or patients following a diagnosis of HPP in search of receptiveness, support or guidance on the road to discovery of the disease and its consequences. In that context, a number of communication channels are of value. Similarly, insofar as, in the field, in the regions, in specialized networks, and in meetings, it may be of value or necessary to disseminate current knowledge of HPP (in order to enhance recognition and identify the patients concerned), the association and its partners will always be available.


Statements of interests

S. Ursprung is volunteer president of the association Hyphophosphatasie Europe.

The association Hypophosphatasie Europe has concluded a sponsorship agreement with Alexion Pharma International.

References

Alliance Maladies Rares : www.alliance-maladies-rares.org
Eurordis : fr
Maladies Rares Info Services : www.maladiesraresinfo.org
Orphanet : www.orpha.net
Filière de maladies rares OSCAR (Os, Cartilage, Rein) : blog.filiere-oscar.fr
Filière de maladies rares TETECOU (malformations rares tête, cou, dents) : www.tetecou.fr
Hypophosphatasie Europe : www.hypophosphatasie.eu



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