Scientific Commentary |
Classifying a novel brain malformation
In this issue of Brain, Barth et al. present four case histories of children with a constellation of symptoms representative of a new brainstem malformation and associated syndrome, calling it ‘pontine tegmental cap dysplasia’ (PTCD: Barth et al., 2007
; p. 2258). This new malformation appears to be part of the ‘molar tooth’ family of brainstem anomalies, although with some unique characteristics that differentiate PTCD from inclusion in the Joubert spectrum of disorders for which the molar tooth sign has been considered a pathognomonic finding. Thus it is worth considering that PTCD may be a novel category within the classification of midbrain and hindbrain malformations, as recently proposed (Parisi and Dobyns, 2003; Table 1).
|
The four children profiled in the paper were unrelated to each other and none were the products of consanguineous unions. Their malformations were all discovered as part of routine referral to paediatric neurology. MRI performed on all four children revealed the molar tooth malformation, vermal hypoplasia, absent inferior olivary prominences, near-absence of the middle cerebral peduncles, flattening of the ventral pons and peaking of the pontine tegmentum (referred to as the ‘cap’ in the name for this malformation).
Despite all four children having these findings, their neurological examination seemed to vary widely. Two were able to ambulate: three used sign language; and one had no purposeful movement and was severely delayed. All four children failed hearing tests, interpreted as indicating cranial nerve VIII involvement. There was variable involvement of the other cranial nerves. For example, three children had VII cranial nerve palsies. The clinical presentations were also disparate in that several of the children had findings indicating supratentorial involvement. One had seizures: two had severe developmental delay; one had episodes of loss of consciousness; and three had ventricular dilatation on MRI. These findings do not typically originate from pathology of the brainstem.
Interestingly, this particular collection of radiographic findings has been noted in the literature twice before. Maeoka et al. (1997) chronicled a 2-year-old girl with sensorineural deafness and a hypoplastic pons with ‘an upward bulge into the fourth ventricle’. They noted that this case did not conform to the degenerative global impairment that typifies the known pontocerebellar atrophies. The second case report (Ouanounou et al., 2005) described a 3-month-old boy originally diagnosed with Mobius syndrome on the basis of his VIth and VIIth cranial nerve palsies. However, he was noted to have hypoplasia of the pons and absence of the middle cerebellar peduncles on MRI. According to Ouanounou and colleagues, this absence of the middle cerebellar peduncles has not previously been noted in the literature. Whether or not this infant had the pontine tegmental ‘cap’ is unclear, as this feature was not mentioned and sagittal views not provided. But the absence of the middle cerebellar peduncles coupled with hypoplasia of the pons (and the rarity of these findings) does suggest that this child also belongs in this select group of children with PTCD. It would be interesting to have follow-up details on this patient and learning whether he now has associated findings such as ataxia. A stable neurological status in this child would serve as further support for re-diagnosis as PTCD; but, if he has deteriorated, a degenerative aetiology such as pontocerebellar atrophy would be more likely.
Given the paucity of such cases in the literature, diffusion tensor imaging on one of the patients here reported was performed in order to evaluate the anatomy of the white matter tracts. As expected, the middle cerebellar peduncles were not observed. Unexpected was the ectopic tract found running transversely (at the level of the pons) that appeared to connect to the cerebellum. What was this ectopic tract and can it tell us anything about the pathogenesis of PTCD? Recent evidence suggests that the condition known as horizontal gaze palsy with progressive scoliosis (HGPPS) has a profound brainstem wiring defect and is due to mutations in the ROBO3 gene (Jen et al., 2004). To determine if PTCD could similarly be due to a defect in a known axon guidance molecule, the authors turned to known murine models with ectopic white matter tracts. They noted that mice deficient in Ntn-1 exhibit loss of pontine neurons and ectopic fiber tracts (Serafini et al., 1996)—findings that are very similar to those observed in this patient. Mice deficient in Dcc also exhibit these characteristics (Fazeli et al., 1997). Ntn-1 codes for netrin-1, which is part of a family of proteins that regulate axonal guidance and neuronal migration (Barallobre, 2005). Dcc encodes a growth cone receptor for Ntn-1. These mice exhibit loss of pontine nuclei and the presence of ectopic fiber tracts (not only in the dorsal pons) due to a defect in axonal guidance. Could PTCD also stem from an error in one of these genes? The authors screened the four patients for mutations in the human homologues of Ntn-1 and Dcc. However, no pathogenic mutations were found. This does not necessarily mean that PTCD does not arise from a defect in axonal guidance. It is entirely possible that signaling molecules downstream of Ntn-1 and Dcc are responsible for the pathogenesis of PTCD. If PTCD does in fact arise from an error in axonal guidance, then it would share a fascinating similarity in pathogenesis with Joubert syndrome, which itself has been hypothesized at least partially to result from a defect in axon guidance (Dixon-Salazar et al., 2004; Ferland et al., 2004).
So if PTCD is accepted as a novel type of brainstem malformation, how does it fit into the present classification of posterior fossa anomalies? For example, molar tooth-associated malformations fall under the category of malformations of both the midbrain and hindbrain. This group also includes Chiari II malformations, cobblestone lissencephaly (LIS) with mid-hindbrain malformation, rhombencephalosynapsis and brainstem-cerebellar hypoplasia-dysplasia. Dandy–Walker malformation is in the category of malformations affecting predominantly the cerebellum and derivatives. The ponto-cerebellar hypoplasias fall under a separate category of malformations associated with prenatal-onset degeneration, which also includes congenital disorders of glycosylation. Why is classifying a novel malformation so important? Not only can taxonomy help with identifying aetiology, it can also serve as a guide for preventative management. For example, if a child is suspected to have Joubert syndrome or related disorder, renal function tests and ophthalmologic screenings should be undertaken, due to the risk of involvement of these organs.
The malformations which are grouped together by the molar tooth sign (Joubert, Dekaban-Arima, Senior-Loken and Oral-facial-digital syndrome type VI syndromes) would be an obvious place at first glance to include PTCD, but these syndromes have more similarities than just the molar tooth sign. In fact, they are similar to the point of being commonly referred to as ‘Joubert syndrome-related disorders’ (Brancati et al., 2007) because they all share the classic findings of hypotonia, developmental delay, oculomotor apraxia, ataxia and polydactyly. The findings that these four children with PTCD had in common were deafness, developmental delay, speech impairment and vertebral anomalies (the latter present in three of four.) Clearly this is a very different clinical picture from that of a patient with a Joubert syndrome-related disorder. So if PTCD is not part of the Joubert spectrum, can it fit into the categories of other malformations? Pontocerebellar hypoplasia seems a possibility, but the lack of clinical degeneration prevents PTCD from being classified amongst this group of conditions (Parisi and Dobyns, 2003). In addition, the suggestion of supratentorial involvement suggests that PTCD may be more than just a malformation of the brainstem and perhaps may actually be a global neurological disorder. Therefore, until more cases of PTCD are profiled, this disorder should be considered as a unique malformation of the brainstem.
Laboratory for Neurogenetics,
Department of Neurosciences,
University of California-San Diego, San Diego,
California, USA
E-mail: jogleeson{at}ucsd.edu
 |
References |
|---|
 Top References |
|---|
Barth PG, Majoie C, Caan M, Weterman M, Kyllerman M, Smit L, et al. Pontine tegmental cap dysplasia: A novel brain malformation with a defect in axonal guidance. Brain (2007) this issue.
Brancati F, Barrano G, Silhavy JL, Marsh SE, Travaglini L, Bielas SL, et al. CEP290 Mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. Am J Hum Genet (2007) 81:104–13.[CrossRef][ISI][Medline]
Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, et al. Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet (2004) 75:979–87.[CrossRef][ISI][Medline]
Fazeli A, Dickinson SL, Hermiston ML, Tighe RV, Steen RG, Small CG, et al. Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature (1997) 386:796–804.[CrossRef][Medline]
Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet (2004) 36:1008–13.[CrossRef][ISI][Medline]
Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rub U, et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science (2004) 304:1509–13.
Maeoka Y, Yamamoto T, Ohtani K, Takeshita K. Pontine hypoplasia in a child with sensorineural deafness. Brain Dev (1997) 19:436–9.[CrossRef][ISI][Medline]
Ouanounou S, Saigal G, Birchansky S. Mobius syndrome. AJNR Am J Neuroradiol (2005) 26:430–2.
Parisi MA, Dobyns WB. Human malformations of the midbrain and hindbrain: review and proposed classification scheme. Mol Genet Metab (2003) 80:36–53.[CrossRef][ISI][Medline]
Serafini T, Colamarino SA, Leonardo ED, Wang H, Beddington R, Skarnes WC, et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell (1996) 87:1001–14.[CrossRef][ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||