The epidemiology of Moebius syndrome in Italy

Moebius syndrome (MBS) is considered a congenital cranial dysinnervation disorder (CCDD) [1]. Its clinical features are impaired ocular motility, lagophthalmos, and lack of facial expression; these features are related to congenital, nonprogressive nerve palsy of the 6th and 7th cranial nerves that typically affect newborns bilaterally. MBS is diagnosed according to the "Bethesda Diagnostic Criteria", which have been recently updated to include genetic testing to ascertain a diagnosis [2‐5]. The minimum clinical diagnostic criteria for MBS are as follows: “A congenital, uni- or bilateral, nonprogressive facial weakness with limited abduction of the eye(s) and full vertical motility” [2‐4]. Patients who do not meet these criteria are labeled “Moebius-like” and are considered affected by a separate congenital disorder. This is of particular importance since the clinical features of MBS overlap with those of many of other CCDDs with well-described genetic bases, such as congenital fibrosis of the extraocular muscles (CFEOM), Duane’s syndrome, and horizontal gaze palsy with progressive scoliosis (HGPPS) [1]. The differential diagnosis of MBS in the early perinatal period may be complex and should consider different neurological disorders that result in an MBS-like phenotype with myopathic facies, abnormalities of the palate and feeding difficulties. To this end, cerebral MRI is a tool to be considered.

At more than a century after the first description of the disease, the etiology of MBS is still unclear; recent studies have postulated a multifactorial pathogenesis in which fetal toxic exposure acts on a genetic predisposition for vascular terminal instability and focal microcirculatory failure in the lower brainstem [6‐9]. However, it is not clear what causes these changes and why they specifically disrupt the development of the 6th and 7th cranial nerve nuclei; even less is known about the causes of the extraophthalmological signs and symptoms associated with MBS (e.g., lingual and palate dysfunction, hypoplasia of the hand, clubfoot, and thoracic abnormalities). The exact incidence and prevalence of MBS are not clear; the syndrome is considered a "rare disease", as it affects a very small number of people. Clinicians and researchers estimate that this condition affects 1 in 50,000 to 1 in 500,000 newborns, but this estimate is based on only their personal experience with MBS patients, with no epidemiological basis [3, 9‐11]. In a Dutch series, the estimated prevalence of MBS was 0.002% of births (4 per 189,000 newborns); this evidence was obtained in 1996 without the present diagnostic criteria for MBS [12]. The Orphanet Report Series, Rare Disease Collection 2019 reports the estimated prevalence/incidence per 100,000 as "unknown", with only 300 cases described in the literature [13]. Other epidemiological estimates from series reported worldwide are anecdotal, with no statistical basis. It is difficult to plan an epidemiological study of MBS for many reasons: (1) despite the new diagnostic criteria, the disease is often over- and misdiagnosed in newborns; (2) like many other rare diseases, MBS does not have a regional register from which to derive data for epidemiological purposes; (3) there are no referral centers that provide multidisciplinary care with consequent dispersion of cases; (4) few physicians have expertise in MBS, and they may be difficult to reach; and (5) MBS, like other genetic disorders, may carry social stigma, leading affected individuals to self-marginalize. This study reports the epidemiology of MBS in a well-defined population over a very long period; furthermore, we investigated whether there were geographical differences in MBS incidence/prevalence to identify factors that may cause or contribute to its development.

Since 1998, the University Hospital of Parma has been designated by the Italian Association of Moebius Syndrome (AISMO, www.​moebius-italia.​it) and by the Regional Health Department as the only national referral center for the diagnosis and treatment of patients with MBS (e.g., a multidisciplinary facility treating conditions ranging from strabismus correction to smile surgery). This allowed us to contact and virtually follow all of the MBS patients living in Italy. Even MBS patients who currently received medical care elsewhere were evaluated in our hospital at least once during the diagnostic confirmatory phase. All medical data are regularly updated and preserved in the AISMO database, which serves as the electronic medical records of these patients, based on a specific agreement between our university hospital and the association since 1999. Any additional relevant information, such as pregnancy with possible consumption of drugs, type of delivery, and details of the medical history of MBS relatives, is also recorded in the AISMO register. The database is available to only approved researchers and is accessible for medical or scientific purposes regarding MBS only.

As previously reported, the MBS cases included in our analysis satisfied the updated “Bethesda Diagnostic Criteria”. The exclusion criteria included the finding of a genetic profile associated with MBS-like myopathic facies (in particular alterations in the TUBB3, HOXA1, HOXB1, ROBO3 genes) [14] and the possible finding of karyotype macroanomalies producing myopathic facies (e.g., a trisomy of the chromosome 18 or 3). Data on genetic testing or Moebius-like symptoms in relatives and parental consanguinity were obtained from the AISMO database, which acts as a multidisciplinary medical chart and is regularly updated with key information. One patient in our present analysis had already been included in a prior series (patient #11) and carries a pathogenic variant in the REV3L gene [15].

Every MBS patient was periodically evaluated by our multidisciplinary team of physicians, which includes an ophthalmologist (A.C.), a neonatologist or pediatrician, a speech therapist, an orthodontist, an orthopedist (for children with clubfoot or finger anomalies), and a maxillofacial surgeon with expertise in smile surgery; the frequency of visits depended on the severity of the disease, usually ranging from 6 to 24 months. Each visit included a comprehensive ophthalmological evaluation of extraocular motility and refraction under cycloplegia for pediatric patients. A detailed history was obtained from relatives of each patient at the first visit and updated at every visit. All patients (or their relatives if minors) had previously given AISMO consent to use their demographic data for research purposes and statistical analysis. The present series also includes patients who had been included in previous research papers [2, 16]. The study adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee (No. 93/2019/OSS*/UNIPR/June 14, 2019).

This study examined the epidemiology of Moebius syndrome in a well-defined population within a precise geographical area using definite diagnostic criteria for MBS. We found that the overall prevalence of MBS was 0.27/100,000 newborns. This value can be reasonably rounded to 0.3/100,000 (0.0003%) because few patients with MBS may have missed appointments with our medical staff and/or were not enrolled in the AISMO register. This may occur when dealing with patients/families affected by congenital genetic disorders, which may carry social stigma leading to self-marginalization. Regardless, the prevalence observed in our study was different from data reported in different parts of the world. For example, in a Dutch series, Verzijl et al. in 1996 estimated a prevalence of 0.002% (i.e., approximately ten times higher than our results) for MBS, but the details about their sources were poor and different diagnostic criteria were used with respect to those presently adopted [13]. Similar relatively high prevalence rates were reported by physicians with expertise in MBS in the United States, Sweden, and Brazil but without any population-based analysis [9‐11]. Based on our data, we can confirm that MBS is an extremely rare disease. Furthermore, our data may be considered if a dedicated national healthcare program is planned or reorganized. Another important consideration is that we found a uniform distribution of MBS cases among the five areas considered. These five regions were conceived by ISTAT, as people living in them have different social, economic, and working lifestyles, with different climates characterizing each region. As we did not identify a region with a higher prevalence of MBS cases, we can exclude environmental factors such as pollution; weather conditions, such as intense cold or heat; and prolonged sun exposure during pregnancy as causes of MBS. It appears that the environment had little or no influence on disease pathogenesis in our population. The only reported factor that significantly increased the risk of newborns being affected by MBS (by a factor of 30) is the use of misoprostol during the first trimester of pregnancy [19]. Misoprostol (a synthetic prostaglandin E analog) is an illegal abortifacient widely used in Brazil and other countries in South and Central America.

As misoprostol is not administered in Italy, our epidemiological data on MBS lack any pharmacological bias, at least as far as misoprostol is concerned. In addition to misoprostol use, based on the electronic medical chart of each patient made available by the AISMO register, we also excluded the use of vasoconstrictor agents and cocaine and the presence of abdominal trauma during pregnancy for all the considered patients. In our series, the disease affected males and females equally, thus supporting the evidence that MBS is not an inherited X- or Y-related disease. Moreover, all included cases were “sporadic” (i.e., no affected siblings and no family history of MBS). This evidence is in line with the recent hypothesis that MBS has a multifactorial basis with genetic mechanisms having a predisposing role [7‐9, 15, 18]. However, we have strongly supported genetic counseling for every family with an affected member. This with the purpose of investigating the possible transmission of unknown Moebius-like traits. In these families, the risk of recurrence in offspring has been found to reach 50% [20]. Furthermore, genetic testing may be important for a deeper understanding of the pathogenesis of forms presenting with extraocular-associated anomalies.

Another interesting point is that patients who were evaluated by our staff after 2007 received an earlier diagnosis than those born before 2007 (2.2 vs. 3.4 years, respectively), with a significant reduction in the range, which was decreased to between 0 and 5 years of age. This finding likely resulted from efforts made during the last two decades by international associations to increase knowledge of this disease; another explanation may be that our specialized medical staff can be contacted easily by relatives of affected newborns, thereby allowing an earlier diagnosis. An early diagnosis of MBS means that we can initiate care for affected individuals at a young age. This can have extremely positive effects on patients' quality of life by significantly reducing the behavioral and psychological problems related to MBS [21]. For example, with an early diagnosis, we can plan smile surgery at preschool age or we can perform early strabismus surgery when indicated, thereby improving visual performance and reducing the risk of amblyopia.

Our data add to the knowledge of MBS, providing epidemiological information from a highly populated European country, which may be particularly useful when devising medical policies regarding this rare disease. Most rare diseases are considered "orphan diseases" and have no effective treatments; people affected are often psychologically, socially, economically, and culturally vulnerable, as they receive no treatment for their medical condition. These difficulties can be overcome, and the efforts made by the scientific community can increase our knowledge and provide new hope for the future treatment of this disorder.