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

Abstract

A new patient with severe mucopolysaccharidosis (MPS) type VII is reported. Non-immune hydrops fetalis (NIHF) was diagnosed during pregnancy. At birth, he showed generalized hydrops and dysmorphic features typical of MPS. Many diagnoses were excluded before reaching the diagnosis of MPS VII at 8 months of life. During the first year of life he had frequent respiratory infections associated with restrictive and obstructive bronchopneumopathy and underwent three surgical interventions: decompression of the spinal cord at the craniocervical junction, bilateral inguinal hernia, and bilateral clubfoot. At 14 months of life he underwent successful haematopoietic cell transplantation (HCT). During the following 10 months, his bronchopneumopathy progressively worsened, needing chronic pharmacological treatment and O₂ administration. The patient died of respiratory insufficiency during a respiratory syncytial virus infection at 25 months of age. Molecular analysis showed the homozygous variant c.1617C > T, leading to the synonymous mutation p.Ser539=. This caused aberrant splicing with partial skipping of exon 10 (r.1616_1653del38) and complete skipping of exon 9 (r.1392_1476del85; r.1616_1653del38). No transcript of normal size was evident. The parents were both confirmed to be carriers. In a subsequent pregnancy, a prenatal diagnosis showed an affected fetus. Ultrasound examination before abortion showed NIHF. The skin and placenta examination by electron microscopy showed foamy intracytoplasmic vacuoles with a weakly electron-dense substrate. MPS VII is a very rare disease but it is possible that some cases go undiagnosed for several reasons, including that MPS VII, and other lysosomal storage diseases, are not included in the work-up for NIHF in many institutions, and the presence of anasarca at birth may be confounding for the recognition of the typical facial characteristics of the disease. This is the eighth patient affected by MPS VII who has undergone HCT. It is not possible to draw conclusions about the efficacy of HCT in MPS VII. Treatment with enzyme replacement is now available and will probably be beneficial for the patients who have a milder form with no or little cognitive involvement. Increased awareness among clinicians is needed for prompt diagnosis and to offer the correct treatment as early as possible.

Keywords: Beta-glucuronidase; GUSB gene; HCT; Haematopoietic cell transplantation; LSDs; MPS VII; Mucopolysaccharidosis; NIHF; Non-immune hydrops fetalis.

Fig. 1

The MPS VII patient at 20 days of age (a, b), 3 months (c) and 8 months (d). Note ascites, hydrocele, and feet and face oedema (a, b), and typical dysmorphic appearance of the facies at 3 and 8 months of age

Fig. 2

X-rays of an MPS VII infant at the age of 3 months (a–d) and 12 months (e, f) showing generalized skeletal dysplasia (dysostosis multiplex). The pelvis (a) shows typical imaging features characterized by rounded iliac wings and inferior tapering of the ilia with an undeveloped acetabulum; proximal epiphysis of the femurs are not ossified. The femurs (c) are short with hypoplastic epiphyses, similarly to the upper left limb (b) in which cortical thinning, flared metaphysis, and metacarpal widening are also identifiable. The hand (b) and foot (d) are typically dysmorphic: broad and short metacarpals and bullet-shaped phalanges. In the antero-posterior projection of the thorax (e), a marked thickening of the ribs is evident (oar shaped ribs). In the latero-lateral projection of the dorsal and lumbar spine (f), the lumbar vertebral bodies from L2 to L5 are markedly wedge deformed with anterior beaking aspect (arrows), and with angulation of the dorsal-lumbar tract

Fig. 3

Brain MRI of an MPS VII patient at 12 months acquired post-surgery. On MR T2-weighted images acquired on the axial plane (a, b) through lateral ventricles and basal ganglia, enlargement of subarachnoid spaces and dilatation of the ventricular system are visible. On the sagittal plane (c) the corpus callosum is thinned and dysmorphic (arrowheads), and at the C1–C2 level, a cervical canal stenosis is still detectable (arrow)

Fig. 4

Growth centiles of the MPS VII patient showing a progressive decrease in height and weight and mild increase in head circumference

Fig. 5

Electron microscopy of the skin (left) and placenta (right) of an 18-week MPS VII fetus, showing the presence of many foamy intracytoplasmatic vacuoles with a weakly electron-dense substrate