Management of rare diseases of the Head, Neck and Teeth: results of a French population-based prospective 8-year study

To be considered as rare, an individual disease must affect a limited number of people within the population. It is defined, in Europe, by a prevalence lower than 1 per 2000 (European Regulations on Orphan Medicine) [1].

More than 7000 such clinical entities have been described of which between 70 and 80% are genetic [2]. In the Orphanet database [3], rare Head and Neck disorders comprise 2153 diseases [4]. These include rare facial disorders (such as lip and cleft palate, isolated or associated with syndromes like Goldenhar syndrome or van der Woude syndrome), oral and dental disorders (such as isolated oligodontia or associated with syndromes such as ectodermal dysplasia), ORL disorders (such as cervicofacial fistulas associated with BOR syndrome), and cranial disorders (such as craniofaciosynostosis associated for example with Crouzon syndrome).

These rare diseases may be life threatening, cause growth disorders, and impose an economic and social burden because of their repercussions on psychological and physiological growth [5, 6]. Many syndromes present facial anomalies. For some of these anomalies no treatment is required, for example hypertelorism, but for many others surgery is necessary to restore appearance and function [7, 8]. Facial dismorphologies have repercussions for oral functions: breathing, chewing, deglutition, phonation, smiling, mimicking and facial expressions. Sensory deficit can be observed affecting auditory, olfactory and visual capacities. All of these severe health problems generate situations of functional handicap. Moreover, facial appearance negatively impacts the quality of life of patients and their families. Psychological and emotional suffering and social difficulties affecting school life and professional integration are frequently reported [9, 10]. The rarity and the complexity of these diseases also cause some other difficulties, such as access to diagnosis and care [11].

Orofacial functions belong to the first stage of physiological and primary needs. They are essential to daily well-being and are prior to the needs for security, belonging, self-esteem and achievement [12]. For these reasons, it is essential that these diseases are properly and collectively managed throughout the lifetime following the evolving needs of patients. Given the variety of genotypes and treatments, this implies an integrated network of practitioners including geneticists, biologists, surgeons, paediatricians, orthodontists, dental surgeons, speech-language pathologists and psychologists. The care pathway of most of these diseases often begins with surgery. There may be reiterative surgical procedures in the early years of life and even during the teenage and young adult phase [13‐15]. Parents with children suffering from rare diseases regularly express concerns about the long-term health outcomes for children who are born with an oral cleft, for example [16, 17]. Existing studies on Head, Neck and Teeth RD are often case reports and/or gene mutation reports for one disease. Very few studies have been published based on population-level data collection. There are existing epidemiological studies, based on large cohorts in Ethiopia and UK [18, 19], of the most frequent RD (when these are grouped together) such as oral cleft [18, 19]. In France there are regional data but no presently available national-level data on these diseases [20].

The RD Healthcare network in France was first organized in 2005. The Head, Neck and Teeth National Network is one of the 23 French RD healthcare networks created under the national policy on RD (http://​www.​orpha.​net/​actor/​EuropaNews/​2006/​doc/​French_​National_​Plan.​pdf. One hundred and thirty-one expertise centres called reference centres for RD have been established in France, creating highly specialised university and non-university hospital teams for diagnosis and care. A national repository of data on patients with rare diseases, referred to centres involved in one of the rare disease networks, was established during the second French national plan. It is called BNDMR (Banque Nationale de Données Maladies Rares) (http://​enlord.​bndmr.​fr/​#homepage). Each sector includes RD reference centres and RD competence centres. Centres of expertise are called centres of reference in France, and the regional centres are called competence centres. Reference centres are intended to coordinate the definition of referential and therapeutic protocols as well as epidemiological supervision and education and research activities. At regional level, the competence centres identified by the reference centres establish the diagnoses of rare diseases, implement therapies when available, and organise patient care in relation to the designated reference centres and actors, and health and medico-social structures [21]. Reference and competence centres work with many health facilities, through diagnostic laboratories, medico-social professionals, fundamental, clinical and translational research teams, and patient associations.

Data collected from these centres are recorded in The French Rare Diseases Repository (BNDMR) with the following objectives:

The objective of the present study was to describe and analyse the relationship between the supply and the demand for care. The first aim was to describe the healthcare services available at regional and national levels for people suffering from these diseases. A second aim was to assess the level of access to care for these diseases through the national network. Observations at regional and national levels are presented here to better understand the patient care pathway within this specific network.

The epidemiological study reported here provides the first information on rare diseases of the head, neck and teeth in terms of public health in France. This is the first time that data from a national database concerning these diseases have been analysed in France.

This main results show a gap between demand for and supply of care, and reveal how patients travel from their place of residence to the reference centres in Paris with a view to recourse care and management of these very rare diseases.

According to our data, nearly 45% of all patients resided in Paris Region. This disparity between patients From Paris Region and in other French regions is probably to be explained in part by difficulties experienced by the medical teams in completing the database.

Patients were mostly diagnosed very early or at birth. This is encouraging in terms of the network’s ability to meet the patient’s need for early management, which is the best guarantee of success in the treatment of these diseases [26]. Early diagnosis does not depend on the centre (regions versus Paris). The clinical entities represented in the cohort are predominantly early-onset ones (oral clefts are becoming better diagnosed using ultrasound since this became a mandatory part of the checklist [27]).

The five most frequent diseases accounted for nearly half of all patients. These most common diseases (oral clefts and Pierre Robin Syndrome) were those treated by the two Paris centres that completed the database the most.

Our study confirmed that cleft lip and alveolus and cleft palate represented the most frequent disease type, as previously reported [28]. In the literature, some diseases (for instance cleft lip and palate) might appear at first sight not to be rare. For example, what was called an “isolated” cleft lip and or/palate could sometimes not be considered as a rare disease (occurring in one in 750 births) [20]. But the so-called “isolated clefts” in fact group together a great number of different phenotypes and aetiologies due to genetic or environmental factors and teratogenic substances, and must be studied in the same way as the syndromic forms in order to be able to count them according to their aetiology [29].

Their frequent appearance has been explained as a product of patient recruitment and because large numbers of them were coded by centres specialising in these diseases [30]. However, prevalence variations for diseases such as oral cleft may be explained by different factors. The use of the term “clefts” as if all these conditions were one phenotype may be considered a mistake. In global terms, isolated palate cleft falls within the definition of “rare” as the global prevalence is less than 1 per 2000. It also differs chronologically, anatomically, epidemiologically, developmentally, in its genetics and environmental risk factors – and in the approach to its management. Cleft Lip and/or Palate segregate separately in pedigrees and do not cross over, so they are absolutely and fundamentally different [31].

As shown in the previous results about “out-of-Paris-patients” coming to Paris for care, the finding may signify that a large number of patients were diagnosed in their regional competence and reference centres and then referred to Paris for care and/or follow up. It may therefore show that the Paris Region reference centres have a secondary health care role. It is noticeable in the results that the more specialised the centre, the more it detects and quickly diagnoses the clinical entities. Moreover, as the Paris centres also appear as centres of second resort, delays may sometimes be longer before a confirmed diagnosis is made.

In Paris, most of the medical and non-medical staff in reference centres use the database. This is why we decided to use the Paris data as a proxy to discuss the whole-of-France data (in view of the fact that the literature concerned has not shown ecological or environmental variables influencing the diseases studied) [32‐34]. This may explain why the prevalence differed between Paris Region and the rest of France.

Prevalences found in the cohort for Paris Region were consistent with those of Orphanet [3], where the most frequent clinical entities were also cleft lip and alveolus, cleft palate, cleft lip and/or palate, vascular anomaly or angioma, isolated Pierre Robin Syndrome and hard palate cleft.

The ratio between proportion observed and proportion expected showed that patients living in the South of France were more apt to travel to be cared for than those living in Haute-Normandie for example.

In some areas such as South of France or Alsace, therefore, low prevalence is likely to be related to non-fulfilment of the database criteria, and may not just occur because patients are leaving their own region to be treated elsewhere. This was also true for the other regions cited. Figure 1 confirms that these regions have competence and reference centres but do not yet have full compliance with the database requirements.

In Paris, reference centres cover rare ENT malformations, Pierre Robin syndrome and congenital deglutition-suction disorders, dental manifestations of RD, craniosynostosis and craniofacial malformations, and malformations of the face and the oral cavity. Hyper-specialisation of these centres was undoubtedly an attractive feature for patients. This explains how, when diseases are very rare, such as Moebius syndrome, patients make the move to seek an expert opinion in Paris reference centres (Table 5). It was observed that the more rare the disease was, the greater the proportion of patients residing outside Paris (for example, for Treacher Collins where the proportion of patients is P = 0.6%, this proportion was 73.2%.) The same distribution has been described for Moebius syndrome. The proportion of patients suffering from this disease was low as recorded in the reference centre (P = 1.0%), but the proportion of those residing outside Paris Region is close to half of all patients. On the other hand, for oral clefts, which are very well treated in the MAFACE centre, and where the proportion of patients treated there was high, the proportion of patients residing outside Paris Region is lower than for the diseases mentioned above. “Simplicity” of cases does not necessarily imply higher prevalence. Oral clefts, for example, represent the most important pevalences, all anatomical and syndromic forms combined, nationally and regionally. The therapeutic arsenal can be very complex and sometimes needs to repeat surgeries that have failed, or to re-intervene several times before obtaining a satisfactory result.

However, other determinants of recourse or lack of care, such as inequalities faced by patients in their place of residence, should not be forgotten [35]. Measuring the supply of health care requires different indicators of the medical activity in a geographical unit and, in the case of RD, in reference centres: the establishments, their capacity and specialties, the number of doctors, general practitioners and specialists, nurses, and other paramedical professions. It is also necessary to estimate their accessibility and degree of activity. This is what our work did through this particular pathway [36‐38].

Thanks to public policies and local actors, a health network covering the RD problematic from diagnosis through to research has been developed in France in the past ten years. Basic knowledge of a number of clinical entities has increased, but without appreciation of the cumulative weight of these illnesses or of patient care pathways.

At the present time, health care supply and demand are still insufficiently matched. According to the various national plans for rare diseases plans, there are reference and competence centres all over the country. Despite this, some patients are crossing the entire country to seek treatment in Paris. The rarer and more complex the disease, the more expert advice will be solicited. Hyper-specialisation of care, lack of patient information, and a deficit of resources in some centres may be elements contributing to adverse impacts on patients’ quality of life and to the heavy economic and social burdens borne by patients and their families.

Further coordination and improvement of the country-wide care network will be needed to fulfil the objective of impacting positively on the daily lives of patients. This study summarises the present situation, as a first landmark in this national–scale process, with the first confident estimations of frequencies in the French population of cleft palate, the most notable orofacial rare malformation.