A new case report of severe mucopolysaccharidosis type VII: diagnosis, treatment with haematopoietic cell transplantation and prenatal diagnosis in a second pregnancy

Mucopolysaccharidosis (MPS) type VII, or Sly syndrome (MIM 253220), is a very rare, autosomal recessive, inherited lysosomal storage disorder with an estimated overall frequency between 1/300,000 and 1/2,000,000 [1]. It is caused by deficiency of the lysosomal enzyme β-glucuronidase (EC 3.2.1.31), which leads to the storage of glycosaminoglycans (GAGs) dermatan sulfate, heparan sulfate, chondroitin sulfate in many tissues [2]. The gene encoding β-glucuronidase (GUSB; MIM# 611499) is 21 kb long and contains 12 exons. The presence of unprocessed multiple pseudogenes requires particular attention in diagnostic mutation analysis. To date, 64 different mutations have been reported in the GUSB gene at the Human Gene Mutation Database Professional (http://www.hgmd.org).

The phenotypic characteristics of MPS VII are reported to be similar to those of MPS I and MPS II, although non-immune hydrops fetalis (NIHF) is much more frequent in MPS VII [3]. As of June 2016, according to Montano et al. [1], there were 143 MPS VII patients described in the literature with a wide spectrum of severity, from milder, late-onset forms with coarse facial features, corneal clouding and frequent upper respiratory infections but mild skeletal abnormalities and normal intellectual performances, to the more severe forms characterized by hydrops fetalis, short stature and severe skeletal dysplasia, macrocephaly, ear infections, hepatosplenomegaly, hernias, and cognitive impairment.

Few single cases or small series were reported in the literature until 2016 when Montano et al. reviewed the clinical history of 56 patients collected all over the world through a survey among medical specialists who had or had previously had MPS VII patients under their charge [1]. Among these patients, 23 (41%) had NIHF; 10 of these showed a severe fetal-neonatal presentation with early death while 13 survived longer, despite NIHF. Little is known about the clinical history of the 10 patients with early death who died prenatally or shortly after birth. Of the 13 patients with history of hydrops and longer survival, five patients received haematopoietic cell transplantation (HCT) at an age between 7 months and 7 years and three of them have survived. Two other patients are reported who received HCT at the age of 11 months and 12 years and showed apparent benefit 2 years and 31 months after HCT, respectively [4, 5].

Here, we describe the clinical history of a new severe case, from consanguineous healthy parents, who was treated with HCT. The results of the prenatal diagnosis of a second pregnancy of this couple are also shown.

To our knowledge, this is the first report of an MPS VII patient ever diagnosed in Italy. However, the ethnic background of the patient was not European but Southern Asian. Until now, only a subject with a pseudodeficiency of the gene (Asp152Asn) is described with Italian origin in the literature [9]. This variant, Asp152Asn, shows a European allele frequency of 0.00172 versus that found in the Asian (0.00006224), Latino (0.0003956), and African (0.000206) populations, respectively (data from ExAC Browser Beta http://exac.broadinstitute.org/). We suppose that MPS VII is very rare in Italy, as in other countries in western Europe, but attenuated cases might have been overlooked. MPS VII is an ultra-rare disease and is probably less known and diagnosed than the other MPS types. [1]. Our patient was tested for many other metabolic disorders before being tested for MPS VII. It is possible that the presence of anasarca in many MPS VII newborns may prevent recognition based on the coarse facies and contributes to delayed diagnosis. As recently reported in a systematic review aiming to evaluate the incidence of lysosomal storage disorders (LSDs) in 54 case series of NIHF published from 1979 through January 2014 [10], LSDs were not tested in 72% of the papers reporting work-up for NIHF. Nonetheless, there are at least fourteen LSDs that are a possible cause of NIHF [11] and among them MPS VII is the most frequent accounting alone for 20% [10]. It is therefore evident that MPS VII should be tested in all cases of NIHF, even though it is an ultra-rare disease. The availability of new techniques such as next-generation sequencing (NGS) might help to improve the number of diagnoses in this field; a specific NGS panel for NIHF, testing not only LSDs but also the other metabolic disturbances known to be a cause of NIHF, such as CDG syndromes, peroxisomal disorders, disturbances of cholesterol metabolism, and others, could be used as a first-line investigation technique as recently proposed by Sudrié-Arnaud et al. [12].

According to the classification of Montano et al. [1], the proband had the severe infantile form. He was able to recover from NIHF and also survived the three surgical interventions performed in his first year of life. His pulmonary involvement was severe and it was the cause of his death. Reasonably, rather than a consequence of his HCT, his bronchopneumopathy can be interpreted as an expression of a chronic bronchopulmonary disease, favoured by prematurity, NIHF with pleural effusion, mechanical ventilation, and chest wall deformities which prevented a normal chest expansion. Interestingly, 71% of the patients in the study of Montano et al. [1] had decreased pulmonary function (both restrictive and obstructive); they had thoracic deformities contributing to restrictive airway disease, leading to chronic hypoventilation with low forced vital capacity, but also individual patients were reported with severe pulmonary disease (bronchopulmonary dysplasia with fibrosis), recurrent pneumothoraces, interstitial lung disease, and prolonged oxygen dependency [1]. It appears that severe bronchopulmonary involvement in MPS VII is similar to that found in MPS II [13] but is probably more frequent than in MPS I [14].

The major limitation of ERT for MPS is that it does not cross the blood–brain barrier preventing any effect on the central nervous system (CNS) in severely affected patients who show cognitive involvement (see Concolino et al. in this Supplement for details [18]).

The synonymous mutation (c.1617C > T; p.Ser539=), previously reported in a compound heterozygous patient [7], is first described in the homozygous state in the present report.

In addition, the RT-PCR analysis on the proband’s samples provided new insights on the effect of the substitution c.1617C > T, creating a non-canonical intra-exonic 5′ splice site (GT) on GUSB mRNA processing. Indeed, the results revealed not only the presence of the previously described shorter transcript with partial skipping of exon 10 [7], but also an additional shorter GUSB transcript in which complete skipping of exon 9 occurred upstream of the partial skipping of exon 10.

The ultrastructural appearance of the fetal tissues (Fig. 5) with numerous cytoplasmic vacuoles was consistent with previous findings in the literature [7, 8].

Over the last few years, the use of multiple diagnostic NGS-based panels has become available for genetic disorders. Therefore, in the near future, it is possible that NGS techniques could help clinicians in performing earlier diagnoses of ultra-rare diseases, a fundamental condition for timely access of patients with a progressive disease to therapies that offer hope for a better prognosis.