MPS VII is an ultra-rare genetic disorder, one of the least prevalent MPS types. This case series is the biggest MPS VII data collection of patients alive in Latin America, and as such, contributes to a better understanding of this highly heterogeneous condition. In Brazil, during the last 40 years, 27 MPS VII patients were diagnosed by MGS-HCPA and MPS Brazil Network, representing 1.3 % of the total MPS cases (unpublished data of the MPS Brazil Network). The 13 patients described in this case series include all MPS VII patients known to be alive in the country. This is likely representative of the actual number and geographical distribution of MPS VII patients in Brazil, as MGS-HCPA is the main reference center for the diagnosis of MPS disorders in the country, receiving samples from every Brazilian state since it was established in 1982 [15, 17].
In Brazil, the overall mean rate of consanguineous marriages is about 4.8%, the lowest inbreeding levels were described in the southern states, whereas in some states of the Northeast these rates vary from 6–12% [18, 19]. This could potentially explain why most of the MPS VII patients described here are from this region. Nine out of the 13 patients described here have history of parental consanguinity, seven of which are from the Northeast region.
As previously described in MPS VII [20–22], patients can present a history of NIHF. In our study 58% (7/12) of the patients had a history of NIHF, a proportion higher even than that found in previous case series, with percentages reported as 38.5%, 41.1%, 45.5%  and 48.6% , which reinforces the importance of testing for MPS VII during the etiologic investigation of an hydropic fetus.
As in the cohort described by Montano et al , some phenotypic characteristics are frequently reported in patients with MPS VII and should lead to a suspicion of MPS, highlighting coarse face, thick eyebrows, short trunk and short neck. Montano further described that dysostosis multiplex on X-ray was the most consistent finding in the MPS VII patient survey (90% of the patients), which is in accordance with our findings, as 100% of our patients presented this abnormality.
Cognitive impairment is common in MPS VII patients and has been attributed to the storage of the GAG heparan sulfate (HS). This finding is present in 86 to 94% of patients, according to Montano. Since MPS VII is a progressive disease, due to continuous accumulation of GAGs, patients usually deteriorate cognitively during the course of the disease . All Brazilian patients described here have neuromotor development, cognitive, and/or behavioral disturbances.
The skeletal phenotype of the patients described here is very typical of MPS, with patients presenting a set of abnormalities known as “disostosys multiplex”. However, some characteristics seem to be more prominent in MPS VII patients, such as very short trunk and an apparent proportionally long lower extremities with feet deformities. One of the patients with congenital talipes equinovarus was due to neuro tube defect.
Short stature is one of the most characteristic features observed in patients with MPS VII. However, in this survey, it was not observed in patients under three years of age. Previous cohort studies have also reported normal growth until 18–24 months of age . These findings suggest that short stature not a hallmark for early MSP VIII diagnosis.
Regarding the organomegaly often found in MPS, 50% of the patients from this cohort have hepatomegaly/splenomegaly, compared to 75% from Montano et al , 39.8% from Zielonka et al  and 46.2% from Morrison et al . The fact that 2 out of 13 patients were receiving ERT may have an impact on the proportion of hepatomegaly/splenomegaly observed in our cases. Umbilical and/or inguinal hernia was found in 91% while in other cases ranged from 31,8 to 61% [4, 22, 23].
The cardiorespiratory impairment, which is an important cause of morbidity in patients with MPS, was not so evident in our cohort as from other reports [4, 22]. This may not reflect that the patients in Brazil are less severe, but simply that cardiac and pulmonary assessments were available for one a few patients.
One peculiar characteristic of the Brazilian cohort is that almost all patients are homozygous for the c.526C > T (p.Leu176Phe) mutation. This mutation was first identified in a Mennonite family and was the fourth mutation in GUSB gene reported . This is the most common mutation among MPS VII patients worldwide, with an overall allele frequency of 20.4% . The phenotype-genotype correlation for this mutation is still not clear as some patients were described as moderately severe [8, 25] while others as presenting an attenuated phenotype . We also observed a broad clinical spectrum for this genotype in our study, with a tendency to have patients at the severe end of the spectrum. This level of severity might not be expected based on data from biochemical assays and mouse models, which suggest that the c.526C > T (p.Leu176Phe) GUS allele has 84% of the enzyme activity of wild-type GUS [26, 27].
One patient in this cohort is a compound heterozygote for c.526C > T (p.Leu176Phe) and c.875T > C (p.Leu292Pro), a mutation was not previously reported. This patient has a moderate phenotype despite presenting with very low GUS plasma activity (0.7 nMol/h/mg). In fact, all 13 patients in this study had very low enzyme activity, which does not seem to be predictive of their clinical phenotypes. The heterozygous patient presented initially with persistent jaundice, hepatosplenomegaly and umbilical hernia and by the age of 3, presented coarse facial features, neurodevelopmental delay, and skeletal dysplasia.
Both patients receiving ERT could be considered with a moderate/severe phenotype, they had history of NIHF and all typical MPS VII clinical features, including neurocognitive impairment. Although the objective of this study was not to evaluate the effects of the ERT, it becomes clear that some signs as hepatosplenomegaly were reduced and the progression of the disease was apparently stabilized.