Disorders of Cerebellar and Brainstem Development

Advances in brain imaging, neuropathology, clinical phenotyping, genetics, and developmental biology have markedly improved the diagnosis of patients with structural disorders of the brainstem and cerebellum, designated as midbrain-hindbrain malformations (MHMs) from their developmental origin. There is considerable diversity of these syndromes, which may be categorized as (1) common or at least relatively common cerebellar malformations, (2) recognizable malformation patterns associated with autosomal-recessive or rarely X-linked inheritance, (3) rare but distinctive brainstem-cerebellar malformations with unclear inheritance, (4) disorders involving only the brainstem, and (5) Chiari malformation and related disorders. The clinical features of most MHM are nonspecific and may include motor delay, intellectual disability, hypotonia, ataxia, and abnormal eye movements. Intellectual disability is common, although the range of cognitive function is broad. Although these features help identify patients with MHM, clinical features alone rarely point to a specific diagnosis, such as Joubert syndrome associated with the pathognomonic molar tooth sign on magnetic resonance imaging or “figure-eight” headshaking and alopecia in rhombencephalosynapsis. In most patients, identifying a unifying diagnosis requires integration of clinical and birth history, examination, neuroimaging, and laboratory, especially genetic, testing. Furthermore, a specific diagnosis can relieve parental guilt and allows families affected by specific rare conditions to connect with each other for support.