Descriptive statistics
The AISMO register contained 231 subjects. Of these, 59 subjects did not fully satisfy the “Bethesda Criteria or they had genetic profile not compatible with MBS (i.e. karyotype anomalies, TUBB3, HOXA family or ROBO3 mutations); 4 subjects were not Italian citizens (4 subjects) and 4 subjects had incomplete data. In total 67 subjects (29%) were excluded from our cohort. The remaining 164 MBS patients (73 men, 44.5%) were considered for the study and analyzed for epidemiological purposes (Table 1).
Table 1. Relative rate (%) of MBS in the five Italian regions.
|
No. of cases (N)
|
Age range at diagnosis
(years)
|
No. of males (M)
|
%
Males
|
No. of
females (F)
|
%
Females
|
Northeast
|
35
|
0*–38
|
16
|
45.7
|
19
|
54.3
|
Northwest
|
51
|
0*–55
|
19
|
37.3
|
32
|
62.7
|
Central
|
34
|
0*–49
|
16
|
47.1
|
18
|
52.9
|
South
|
29
|
0*–34
|
15
|
51.7
|
14
|
48.3
|
Islands
|
15
|
0*–18
|
7
|
46.7
|
8
|
53.3
|
Total
|
164
|
0*–55
|
73
|
44.5
|
91
|
55.5
|
0* means that diagnosis was achieved before the first year of life of the newborn.
All patients were Caucasian and all cases were sporadic. The median age at diagnosis was 3.6 years, ranging from 0-55 (a value of 0 means that the diagnosis was achieved within the first 12 months of life); this range was significantly reduced to 0-5 years (median age at diagnosis: 2.2 years) for patients included after 2007.
The Figure 1 shows the newly recorded cases in the AISMO register based on the year of birth; a progressive increase in recorded cases is evident from 1998, when the AISMO register was established, with the new diagnoses peaking (16 cases) in 2005–2006 (coincidentally after the Consensus Conference on Moebius Syndrome, which produced the “Bethesda Criteria”). The birth prevalence calculated referring to the most recent available national data (2016) was 0.06 cases per 10000 live births. The mortality rate in our cohort is 0 (zero) as there was no case of known death. In our series we recorded two cases of homozygous twins both affected by the disease even if with different clinical expression; we have no case of affected siblings and almost all cases were bilateral (8 cases were bilateral but asymmetric and 4 were monolateral). Extra-ocular associated features of our cases are summarized in Table 2.
Table 2. Percentage (%) of extra-ocular anomalies in our MBS patients (possible more than one in a single patient).
EXTRA-OCULAR anomalies
|
%
|
Club foot
|
32%
|
Speech problems
|
22%
|
Hypoplastic hand
|
20%
|
Dental anomalies
|
18%
|
Suction defects
|
14%
|
Palate malformations
|
7%
|
Hearing deficiency
|
7%
|
Tongue disfunctions
|
6%
|
Scoliosis
|
5%
|
Dysphagia
|
4%
|
Poland's syndrome
|
2%
|
Statistical analysis
The relative rate of MBS in the Italian population was calculated for males and females in terms of the total number of patients diagnosed and separately for each region (Table 1). The rates were evenly distributed across the different regions, with the exception of the Northwest, where more cases were located (Figure 2). Moreover, in this region, the gender rate differed since there were 1.5-times more females than males (62.7% vs. 37.3%). The difference in the rate in the Northwest was confirmed with reference to both the total population (P-MT: 0.12 vs. P-FT: 0.20) and the gender-based subdivisions (P- MM: 0.24 vs. P-FF: 0.39), see Table 3.
Table 3. Prevalence (including gender-specific) of MBS in each region.
|
P-TT
Tot cases/Popa (per 100000)
|
P-MT
M cases/Popa (per 100000)
|
P-FT
F cases/Popa
(per 100000)
|
P-MM
M cases/M-Popb (per 100000)
|
P-FF
F cases/F-Popc (per 100000)
|
Northeast
|
0.30
|
0.14
|
0.16
|
0.28
|
0.32
|
Northwest
|
0.32
|
0.12
|
0.20
|
0.24
|
0.39
|
Central
|
0.28
|
0.13
|
0.15
|
0.27
|
0.29
|
South
|
0.21
|
0.11
|
0.10
|
0.22
|
0.19
|
Islands
|
0.22
|
0.10
|
0.12
|
0.22
|
0.23
|
Total
|
0.27
|
0.12
|
0.15
|
0.25
|
0.29
|
a Pop: overall Italian Population size; b M-Pop: Italian Male population size; c F-Pop: Italian Female population size.
The MBS rate of the total population (i.e., both males and females) subdivided into the five regions differed significantly (p < 0.001; c2-test). To verify whether this result was due to the larger population in the Northwest, the data were weighted to account for the different populations in the five regions. This analysis involved weighted rate data (i.e., data rescaled to the actual population in each region). After this adjustment, no statistical significance was observed. Finally, c2-test for the separate sex rates was performed. The analysis of males confirmed that the distribution across different regions was similar (no statistical differences for both "unweighted" and "weighted" data over the male population in the different regions). The analysis of females showed a significant (p < 0.001) difference for "unweighted" data. However, this difference lost significance when "weighted" data over the female population in different regions were considered. An analysis of the total weighted population dataset showed no significant differences comparing the five regions.