Joubert syndrome
This six week old boy experienced intermittent severe tachypnea and episodic central apnea since birth. On examination, he exhibited axial hypotonia and intermittently disconjugate eye movements, but no evidence of facial, cranial, or limb dysmorphism. No infectious, metabolic, or cardiopulmonary cause of tachypnea was identified on screening tests. No history of familial consanguinity or congenital abnormalities was elicited. On neuroimaging studies, absence of the cerebellar vermis was evident. The superior cerebellar peduncles were arrayed perpendicular to the brainstem, together with accentuated depth of the interpeduncular fossa, giving a characteristic "molar tooth" sign on axial images. These clinical and radiographic findings are highly suggestive of the syndrome of cerebellar vermian dysgenesis described by Joubert et al. (1969).
Tachypnea in the neonate should be rapidly evaluated to rule out respiratory dysfunction (e.g., hypoxemia, hypercapnia, impaired lung expansion, pulmonary embolus). Metabolic abnormalities such as fever, acidosis (e.g., resulting from ketoacidosis, lactic acidosis, renal failure) and toxin exposure (particularly salicylates) should be screened. Abdominal distension and, less obviously, gastroesophageal reflux, can provoke tachypnea. Ongoing seizure activity can also evoke tachypnea, especially following the apnea induced by individual seizures. Finally, infectious processes such as pneumonia and sepsis should be ruled out. It should be noted that most of these processes can also provoke apnea, particularly in the neonatal period. In this patient, none of these processes were identified by clinical examination or laboratory screening as a likely explanation for the patient's intermittent tachypnea and episodes of apnea. Furthermore, the patient's axial hypotonia and abnormal ocular findings suggested the possibility of a central process, confirmed by neuroimaging (emergent CT to rule out a posterior fossa mass lesion, followed by MRI to better define the anatomic abnormalities detected).
Causes of tachypneic-apneic respiratory patterns in association with cerebellar abnormalities include the Rett, Joubert, Mohr, and Dandy-Walker syndromes. Rett syndrome, an X-linked dominant disorder occurring in females, and associated with mutations in the methyl-CpG-binding protein 2 (MECP2) gene, typically presents after the first year. Rett syndrome patients may exhibit mild and slowly progressive cerebellar atrophy, superimposed on a picture of more diffuse brain atrophy. The rare cases of males with MECP2 mutations have manifested severe neonatal encephalopathy incompatible with extended survival (reviewed in Amir and Zoghbi, 2000). Very recently, cases of MECP2 mutations have been reported in males with mental retardation (e.g., Dotti et al., 2002); these patients do not appear to manifest structural abnormalities beyond mild cerebral atrophy. Variants of the Mohr syndrome (oro-facial-digital syndrome, type II) are associated with abnormal cerebellar development (Anneren et al., 1990), and with tachypnea (OMIM #252100, updated 2001). Patients with Mohr syndrome present with oral (lobate tongue), facial (angular form of the alveolar process of the mandible) and digital abnormalities, and may manifest cleft palate and conductive hearing loss. Recessive inheritance has been suggested in this syndrome. The Dandy-Walker syndrome may present with a bulging occiput and early hydrocephalus, frequently accompanied by cranial nerve palsies, respiratory abnormalities, nystagmus and truncal ataxia suggestive of a progressive posterior fossa process. Anatomically, the complex of findings composing the Dandy-Walker syndrome includes cerebellar vermian dysgenesis, and cystic dilation of the fourth ventricle with upward displacement of the tentorium. A number of monogenic disorders, disorders of undetermined inheritance, and toxin exposures have been associated with malformations of the Dandy-Walker type (reviewed in Chitayat et al., 1994).
Several additional syndromes, such as Arima syndrome (cerebro-oculo-hepato-renal syndrome; Matsuzaka et al., 1986), Senior-Loken syndrome (also known as renal-retinal syndrome), the COACH syndrome of cerebellar dysfunction, congenital hepatic fibrosis and coloboma, as well as familial juvenile nephronophthisis, have been associated with cerebellar dysgenesis. These latter syndromes, while associated with both Joubert-like and Dandy-Walker malformations, are unlikely in this patient in view of the lack of associated multisystem disease documented on examination and screening studies.
The "Joubert syndrome" of episodic hyperpnea, cerebellar vermian dysgenesis with ataxia, and developmental delay was described by Joubert et al. (1969). About 1 in 10 patients with the Joubert syndrome have abnormal CSF collections initially misdiagnosed as Dandy-Walker variants. Dysgenesis of the pontomesencephalic isthmus and widening of the interpeduncular fossa, together with thickening and elevation of the superior cereebellar peduncles, contribute to the characteristic "molar tooth sign" observed on axial MR imaging of the brainstem. The appearance of this radiographic presentation is believed to distinguish cases of the Joubert syndrome from Dandy-Walker variants (e.g., Maria et al., 2001).
Abnormal breathing has been reported in 50-75% of cases of Joubert syndrome. Apnea and periodic hyperpnea may invade both REM and non-REM sleep, as well as the awake state (Schluter et al., 1995). The exact cause of the breathing abnormalities in Joubert syndrome is unknown, although one or more brainstem respiratory centers are hypothesized to be affected in this syndrome.
Oculomotor abnormalities, when assessed, include hypometric saccades with decreased smooth pursuit gain in all directions, suggestive of cerebellar vermian dysfunction. Pendular nystagmus may be observed in some cases. In addition, most patients manifest oculomotor apraxia, with prolonged or impaired saccade initiation, possibly due to disordered projections from the superior colliculus to oculomotor interneurons in the pons and in the rostral interstitial nucleus of the medial longitudinal fasciculus (Tusa and Hove, 1999). A subset of these patients may manifest severe visual loss and retinal dystrophy, possibly overlapping the syndromes with prominent multiorgan involvement (see above).
The facial appearance in patients with Joubert syndrome may be near-normal, or may include high, rounded eyebrows, broadening of the nasal bridge, and mild epicanthus. The nares may be anteverted, and the mouth triangularly shaped. Some patients with Joubert syndrome are severely affected, dying in infancy. The vast majority (> 90%) of surviving patients with Joubert syndrome are below chronological age in cognitive and motor development, although in a few patients, cognition may appear near-normal. About 50% of patients with documented Joubert syndrome learn to walk. Treatment is supportive, with infant stimulation, physical and occupational therapy, and speech therapy recommended as appropriate. There are no published studies on pharmacologic management. The molecular genetic basis for the Joubert phenotype is presently unknown. There is genetic heterogeneity, with some families demonstrating linkage to chromosome 9q (Saar et al., 1999). Furthermore, epigenetic factors may play a large role in phenotypic expression, as highly discordant phenotypes have been reported in monozygotic twins affected with Joubert syndrome (Raynes et al., 1999). To date, there are no well-accepted animal models for the Joubert syndrome, although knockout of the cerebellar development gene WNT, as well as knockdown of a zinc finger protein (Zic1) expressed in the dorsal neural tube, have been reported to cause cerebellar vermian maldevelopment in mice.
We thank the Pediatric Neurology and Neuroradiology services at the Texas Children's Hospital, for their contributions to this case presentation.
-- Dennis R. Mosier, M.D., Ph.D.
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