Since 1998, the University Hospital of Parma has been identified by the Italian Association of Moebius Syndrome (AISMO, www.moebius-italia.it) and by the Regional Health Department as the only national referral centre for the diagnosis and treatment of patients with MBS (e.g., a multidisciplinary approach treating conditions ranging from strabismus correction to smile surgery). This allowed us to contact and follow virtually 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 in the diagnostic confirmatory phase. All medical data are regularly updated and preserved in the AISMO database, which acts as electronic medical record of these patients, basing on a specific agreement between our University Hospital and the Association operating since 1999. Any additional information regarding pregnancy with possible assumption of drugs, type of delivery, details regarding the medical history of MBS relatives, are also recorded in the AISMO register. The database is available only for allowed researchers and it is accessible for medical or scientific purposes on MBS only.
As previously reported, MBS cases included in our analysis must satisfy the updated “Bethesda Diagnostic Criteria”. The finding of a genetic profile associated with MBS-like myopathic facies (in particular alterations of the TUBB3, HOXA1, HOXB1, ROBO3 genes) was a criterion of exclusion from the study cohort.14 The same goes for the possible finding of karyotype macro-anomalies 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 works as our multi-disciplinary medical chart and regularly updated with key information.
One case of the present analysis (patient #11) had already been included in a prior series as a carrier for the mutation of the gene REV3L.15
Every MBS case was periodically evaluated by our multidisciplinary team of physicians, which includes an ophthalmologist (A.C.), a neonatologist or paediatrician, a speech therapist, an orthodontist, an orthopaedist (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 includes a comprehensive ophthalmological evaluation of extraocular motility and refraction under cycloplegia in paediatric cases. A detailed history was obtained at the first visit from relatives of each patient and updated at every visit. All patients (or relatives if minors) have previously given the AISMO consent to use their demographic data for research purposes and statistical analysis. The present series takes into account also patients who had been encompassed 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).
The authors used data made available by AISMO to obtain the following information for each registered member: date of birth, date and age of diagnosis, gender, and place of provenance/residence. The subjects were assigned to the five geographical regions (i.e., Northeast, Northwest, Central, South, and Islands) conventionally used for surveys and epidemiological investigations in Italy. Every study parameter was then calculated by reference to the entire country and each region. The rates and prevalence (number of cases per 100000 people) of MBS were calculated referring to the 2018 Italian census performed by the National Institute of Statistics.16 The rate and corresponding prevalence were calculated for the entire population and each gender (i.e., affected males/Italian males; affected females/Italian females). Concerning the birth prevalence, it was calculated by referring to the year of birth of each patient. Chi-square (c2) analysis was used to investigate possible differences among geographic regions and gender. For gender tests, unweighted (i.e., each rate was weighted equally across regions, independently of the actual gender population in the corresponding region) and weighted (i.e., each rate was scaled to the corresponding gender weight, according to the population density in each region) data were analyzed. A p-value <0.05 was considered statistically significant.
Data Availability Statement: data used for the study can be checked at the following links: www.moebius-italia.it and www.istat.it.