Imaging findings of mucopolysaccharidoses: a pictorial review

The most important radiological findings in the axial skeleton regard the skull, thorax, spine and pelvis.

The skull is often characterised by an abnormal “J-shaped” conformation of the sella turcica, seen on the lateral view of the cranium (Fig. 1). The sella turcica is normally a saddle-shaped depression in the sphenoid bone, while in MPS patients it is usually wide with long clinoid apophyses and horizontal orientation: the tuberculum sellae is flattened and the dorsum sellae is rounded, respectively, forming the straight edge and the loop of the “J”. This configuration may represent a normal anatomic variant and may be associated with neurofibromatosis or with a slow-growing tumour adjacent to the sella, such as an optic chiasm glioma, so the “J-shaped” sella turcica is characteristic, but not diagnostic of mucopolysaccharidosis.

The cortical bone of the skull is thickened. The premature closure of the sagittal suture is responsible for the development of macrocephaly with dolicocephaly, plus the metopic perisutural hyperostosis causes a vertical frontal crest. The most important facial anomalies are represented by the lack of pneumatization of mastoid cells and paranasal cavities; the mandible is short and broad, mandibular condyles are undeveloped and the temporomandibolar joint may exhibit limited motion; unerupted and widely spaced teeth can also be found (Fig. 1).

Concerning the thorax, the main abnormality concerns the ribs, which can be “paddle-shaped” or “oar-shaped” because of the widening of the anterior archs and of the tapering of the posterior ones. Other common modifications are small scapulae, usually with flattening of the glenoid cavities, a short sternum and short and thickened aspect of the clavicles (Fig. 2) [17].

Issues affecting the spine are extremely common (Figs. 3 and 4), and MPS patients may risk important complications due to compression on the spinal cord and emerging nerve roots.

At the craniovertebral junction level, the most important abnormalities are:

These features represent a critical aspect in MPS (particularly in MPS IV), because if the spinal cord is compressed, cervical myelopathy may result. MRI is more appropriate for the evaluation of spinal cord alterations.

Modifications of the shape of vertebral bodies are very common, resulting in flattened and rounded vertebrae (Fig. 5). At the thoraco-lumbar level the vertebral body can show a deficiency in its anterosuperior corner and, as a consequence, an apparent prolongation of the anteroinferior one, resulting on the lateral X-ray in an “anterior beaking” aspect. When hypoplasia of both anterior corners occurs, the vertebral body is wedge-shaped.

These vertebral morphologic changes may progressively evolve to gibbus deformity (Fig. 6), particularly in MPS I. Scoliosis is usually not bad enough to require surgery; however, myelopathy can represent an indication of the need for surgical treatment [12].

The most common radiological features in the pelvis are rounded iliac wings and inferior tapering of the ileum (Fig. 7) [18]. The alterations of the hip joint can lead to hip dysplasia because of the poor development of the acetabulum and the underdevelopment of the medial portion of the proximal femoral epiphysis. This alteration has not been shown to respond to medical therapy, so for these children surgical reconstruction is often required; the target of this treatment is the optimisation of hip mechanics [12].

In MPS patients, the long bones are often characterised by several alterations. Diaphyses are shortened and curved in the distal part; the epiphyses are slightly hypoplastic and thinned cortically with osteoporosis [15]. Other features that can be found are the notching of the proximal part of the humerus, the long and narrow aspect of the femoral neck (Fig. 8), and the hypoplasia of the lateral tibial hemiplate, resulting in genu valgum.

Knees can also be involved, particularly in children with MPS IV and MPS I, developing genu valgum (Fig. 9). This condition is sometimes severe enough to require surgery. In adulthood an advanced state of arthrosis can be recognised because of the considerable delamination of articular cartilage. These patients are potential surgical candidates for total knee arthroplasty [12].

On MRI images, the growth plate is irregularly enlarged, with multiple defects and erosions well depicted on coronal fast spin-echo proton-density-weighted images (Fig. 10).

Almost all forms of MPS show distortion of the hand (Fig. 11) and foot structure. Carpal and tarsal bones are hypoplastic and irregularly shaped; the metacarpal bones are proximally pointed, shortened and thickened. The functionality of the fingers is compromised because of the bone alterations and the thickening of the subcutaneous tissues, resulting in a failure of a complete extension of the fingers with a “claw hand” deformity [19, 20].

Distal ulna and radius can be hypoplastic and have a “V-shaped” appearance; this oblique deformity of the terminal part of both bones results in the alteration of the carpal angle. The alterations in the skeletal anatomy, combined with an excessive GAG deposition in the connective tissue, cause the constriction of the median nerve resulting in carpal tunnel syndrome [21].

One of the typical neuroradiological imaging findings is represented by focal or diffuse white matter lesions, detected as areas of high signal intensity on T2-weighted sequences. These alterations show an increase with aging, becoming more extensive with time.

Diffuse white matter lesions usually show a symmetrical periventricular distribution, although they can also be found as patchy lesions in the subcortical region (Fig. 13). They derive from the delay of myelination in young children and progressive demyelination in the course of the disease; these lesions can also reflect gliosis [32, 33]. Focal white matter lesions consist of multiple small spot-like areas isointense to the cerebrospinal fluid (CSF) on fluid attenuated inversion recovery (FLAIR), T2-weighted and T1-weighted sequences (Fig. 14) because of periventricular space enlargement.

The corpus callosum, best depicted on sagittal images, is sometimes the only location of these lesions, although they can also be encountered in the parietal and occipital lobe, in the basal ganglia, in the thalamus and at the grey-white matter junction level [32‐34]. A typical imaging feature in the brain of patients with MPS is the “honeycomb-like” appearance in the basal ganglia and thalami (Fig. 15); this imaging finding has been observed in patients with MPS I, II and IIIB [35, 36]. Two theories have been proposed to explain the pathogenesis of basal ganglia involvement; the first concerns the accumulation of GAGs in neurons and astrocytes, leading to neuronal loss and demyelination; another theory maintains that the basal ganglia appearance could be related to an increase of fluid content in the periventricular spaces.

The pathogenesis of enlargement of perivascular spaces is not entirely clear [34]. Two main hypotheses have been formulated: accumulation of GAG around vessels [37] and impairment of cerebrospinal fluid reabsorption (caused by the deposit of mucopolysaccharides in the leptomeninges) [32].

In addition, in the white matter of parietal and occipital lobes, multifocal variable-sized areas of high signal intensity—which doesn’t match that of cerebrospinal fluid—may be detected on FLAIR and T2-weighted sequences; these lesions, probably due to gliosis, tend to become extensive and confluent.

Ventricular enlargement, with or without involvement of the subarachnoid spaces, is a common finding in patients with MPS (Figs. 13, 14, 15, 16 and 17). Communicating hydrocephalus may be the consequence of either diffuse brain atrophy or reabsorption failure of cerebrospinal fluid due to dysfunction of the arachnoid granulations. A cystic-appearing enlargement of the cerebellomedullary and/or suprasellar cisterna has been described [34].

The atrophy of the brain, probably due to neuronal death and myelin loss, is a common feature in MPS and is seen as widened subarachnoid spaces and enlargement of the cortical sulci. The neuronal death could be explained by ischaemic damages due to the progressive accumulation of GAG in blood vessels [38]; on the other hand, the neuronal death could be caused by direct intracellular storage of GAG.

The MRI evaluation of these findings is a useful marker of axonal loss [16]. Brain atrophy usually develops earlier in MPS I, II, III and VII, becoming visible during the first few years of life; on the contrary, patients with MPS IV and VI typically have normal intelligence and don’t show signs of atrophy until the second decade of life.

The different degree of brain atrophy has been recently evaluated for monitoring disease progression and response to therapy [15, 33]; these authors reported a classification using the method introduced by Lee et al. [38]. Brain atrophy could be:

A strong correlation was found between severity of brain atrophy and cognitive impairment in MPS [33, 39], whereas other authors did not find the same correlation [40].

Compression of the spinal cord most frequently occurs at the atlanto-axial (C1-C2) joint (Figs. 18 and 19), especially affecting patients with MPS IV and VI. Many of these patients suffer from several craniocervical junction abnormalities due to structural defects involving the spine. The most important one is atlanto-axial subluxation, which is the result of several causes: laxity of the transverse ligament, dural thickening resulting from deposition of collagen and GAGs, hypoplasia or absence of the odontoid, anterior soft tissue mass of the odontoid (representing a combination of unossified fibrocartilage and reactive changes) and indentation of the posterior arch of C1 [33]. The anomaly of the odontoid process ranges in severity from total aplasia to a triangular-shaped configuration with a loss in vertical height and a broad-based tip [41]. Chronic subluxation of the C1-C2 level may lead to a ligamentous hypertrophy and to further narrowing in the region of the craniocervical junction with the consequence of additional cord compression. Another cause of cord compression in these patients is gibbous formation in the thoracic spine, resulting from the malformations of vertebral bodies (most common in Morquio disease). Compressive cervical myelopathy is a critical problem since the involvement of the bulbar-spine junction may lead to central respiratory failure [33].

MRS (Fig. 20) is a non-invasive imaging technique able to provide information about tissue molecular structures. Brain application leads to revealing the concentration of brain metabolites and can be used to monitor biochemical changes in brain diseases.

Numerous studies have suggested a contribution of MRS to mucopolysaccharidoses assessment [42, 43].

Davison et al. [42, 43] found a reduction of the white matter N-acetylaspartate/creatine (NAA/Cr) ratio in MPS IVa and II proportional to cognitive indices and to disease progression [42, 43], while Vedolin did not find a significant difference in the NAA/Cr ratio between patients with and without cognitive impairment; Vedolin found instead an elevated myo-inositol/creatine (mIns/Cr) ratio in patients with cognitive impairment [39]. The increase in the mIns/Cr ratio is interpreted as a possible marker of glial activity (Fig. 20).

Takahashi et al. [44] measured presumptive mucopolysaccharides in white matter lesions and in white matter without lesions and compared the presumptive MPS/Cr ratios before and after bone marrow transplantation (BMT) [44]. They found a reduction in mucopolysaccharides in white matter without lesions after the BMT; they also found a correlation between mucopolysaccharide accumulation and neuronal damage resulting in a decreased NAA/Cr ratio [44].

In summary, new evidence is needed in order to understand the real value of MRS in the evaluation of neurological involvement.

Another commonly found sign in MPS patients is macrocephaly, resulting from hydrocephalus combined with abnormal accumulation of incompletely broken down GAGs within the brain, meninges and skull. Macrocephaly is diagnosed when the circumference of the head exceeds normal values by more than two standard deviations. Other dysmorphic features, such as frontal prominence, scaphocephaly, a short neck and enlarged tongue, can be observed.

Several orbital abnormalities can be found: thickening of the sclera and of the optic nerve sheath, optic canal narrowing and optic nerve atrophy (Fig. 21).

Finally, another imaging features reported in literature [31] is the closed encephalocele (Figs. 22 and 23); regarding this point, the presence of parenchymal/meningeal herniation at the level of the anterior or middle cranial fossa has been described as a characteristic neuroradiological feature of patients affected by MPS II. Instead of the term “meningoencephalocele,” which indicates the herniation of brain and/or meningeal tissue through a bone defect, the term “closed cephalocele” has been proposed to describe this skull abnormality because the protrusion of intracranial structures occurs without a detectable bone defect. The etiopathogenesis of this further manifestation seems to be related to an increased intracranial pressure and/or an altered bone maturation process. CT and MRI reveal a variable-sized pouch filled with brain parenchyma and cerebrospinal fluid, delimited by a bone wall and usually located in the anterior cranial fossa at the level of the lamina cribrosa as a weak area of the skull. The radiologist should look out for the presence of a closed cephalocele because it may interfere with rhinosurgery and cause epilepsy [31].