Interpeduncular Heterotopia in Joubert Syndrome: A Previously Undescribed MR Finding

Discussion

Nodular interpeduncular tissue with a signal intensity of normal parenchyma and direct contact to the cerebral peduncles was the distinct and previously unreported imaging finding in our patients, who otherwise presented with characteristic imaging and clinical findings of JSRD. We decided to use the term interpeduncular heterotopia to designate the interpeduncular structure based on its isointensity to normal parenchyma, a location not normally occupied by parenchyma, and lack of imaging evidence for a neoplastic or vascular process. We did not use the term hamartoma—though hamartoma and heterotopia may both be isointense to cortex—as a proportion of hamartomas is slightly T2-hyperintense relative to cortex. We nevertheless realize that without histologic confirmation the terminology of this presumedly malformative lesion is somewhat arbitrary.

Imaging findings reported in JSRD encompass the typical molar tooth sign and a range of additional CNS changes. These changes include cystic, Dandy-Walker–like enlargement of fourth ventricle and posterior fossa⁴ (as in patient 3), the rare occipital encephalo- or meningocele,⁵ abnormalities of the corpus callosum,^1,6,7 myelination delay (as in patient 1), and unspecific white matter hyperintensities^7,8 as well as migrational abnormalities.^3,9,10 Absence of the decussation of the superior cerebellar peduncles and of the pyramidal tracts as well as lateralization of deep cerebellar nuclei can be demonstrated by using diffusion tensor imaging³ and is consistent with histopathology reports.^11,12

Imaging findings in our patients were consistent with those reported previously in JSRD with the exception of the interpeduncular heterotopia. This finding has not been described previously, either in JSRD or as a separate entity. Although sagittal and 3D sequences provided greater morphologic detail, the interpeduncular heterotopia was already conspicuous on standard axial images and awareness of its possible occurrence seems the most likely means of increasing its detection. Interestingly, an interpeduncular structure similar to that in our patients is depicted, but not commented on in a paper on brain stem and cerebellar findings in Joubert syndrome (Fig 1c in Alorainy et al¹³). Whether interpeduncular heterotopia identifies a subset of patients with a specific geno- or phenotype cannot be inferred from our 3 patients. As of yet, no correlation between imaging findings and phenotype or genotype has been identified in JSRD, and there is considerable intrafamilial variability.^5,14 In this context, absence of interpeduncular heterotopia in the affected sibling of patient 2 was not surprising.

The main differential diagnosis of the interpeduncular structure is that of hypothalamic hamartoma extending into the interpeduncular fossa. Hypothalamic hamartoma may occur in a specific form of JSRD, namely, in oral-facial-digital syndrome VI. Moreover, hypothalamic hamartoma in combination with the molar tooth sign is specific for oral-facial-digital syndrome VI.¹⁵ In our patients the interpeduncular lesion was clearly not of hypothalamic origin, nor did our patients present with the typical clinical findings of oral-facial-digital syndrome VI, namely, polydactyly, lingual hamartoma, and intraoral frenula.

A reported case of hypothalamic hamartoma without direct connection with the hypothalamus¹⁶ differed from the interpeduncular lesions in our patients by the lack of a broad contact to the mesencephalon, T2-hyperintensity relative to cortex, and a macroscopically cystic area.

The differential diagnosis further includes exophytic diencephalic and mesencephalic neoplasms, oculomotor schwannoma or cavernoma, meningioma, metastasis, pituitary macroadenoma, aneurysm, lipoma, epidermoid, and arachnoid cysts. Most of these entities can be differentiated from the interpeduncular lesions in our patients by their origin and by their signal intensity, if not already by their expansive and/or infiltrative nature. A further potential differential diagnosis is leptomeningial glioneural heterotopia. However, these microscopic pial buds or nests of disorganized glioneuronal tissue within the subarachnoid space¹⁷ are discovered on histopathology, and to our knowledge MR imaging has not been reported.

Pathogenetically, we believe that the interpeduncular heterotopia is part of a spectrum of malformative brain stem changes occurring in JSRD. Postmortem histopathology of 2 patients with Joubert syndrome has shown that there are extensive maldevelopmental changes in the brain stem, eg, hypoplasia of inferior olivary nuclei, disorganized tegmental gray matter, reduction of neurons in brain stem nuclei, and aberrant transverse pontine fibers.^11,12 Together with the absent or partially absent decussation of the superior cerebellar peduncles and the pyramidal tracts,^11,12 these changes indicate aberrant development and more specifically aberrant migration.

The mechanisms resulting in the abnormal brain development of JSRD are still incompletely understood, though identification of currently 10 causative genes has provided some insight: All genes implicated in JSRD encode for proteins involved in the formation or function of the primary cilium.¹⁸ Primary cilia are membrane-bound structures that project from the cell surface. They sense mechanical and chemical signals from the environment and modulate signaling pathways (eg, sonic hedgehog, WNT, platelet-derived growth factor α), which are important for tissue development and homeostasis. Sonic hedgehog signaling and cilium function are required for normal specification of the mid-hindbrain boundary and dorsal-ventral patterning. The malformations in JSRD are thought to result from defective dorsal-ventral patterning and cranio-caudal segment specification in the mid-hindbrain boundary as a consequence of the underlying defects of primary cilia.¹⁹ It is therefore tempting to speculate that the interpeduncular heterotopia in our patients is one manifestation of a spectrum of malformative brain stem changes occurring in JSRD and that it results from misdirected migration due to the underlying ciliopathy.