Pontine tegmental cap dysplasia: a novel brain malformation with a defect in axonal guidance.

Four unrelated children are described with an identical brainstem and cerebellar malformation on MRI. The key findings are: vermal hypoplasia, subtotal absence of middle cerebellar peduncles, flattened ventral pons, vaulted pontine tegmentum, molar tooth aspect of the pontomesencephalic junction and absent inferior olivary prominence. Peripheral hearing impairment is present in all. Variable findings are: horizontal gaze palsy (1/4), impaired swallowing (2/4), facial palsy (3/4), bilateral sensory trigeminal nerve involvement (1/4), ataxia (2/4). Bony vertebral anomalies are found in 3/4. Additional MR studies in one patient using diffusion tensor imaging (DTI) with colour coding and fibre tracking revealed an ectopic transverse fibre bundle at the site of the pontine tegmentum and complete absence of transverse fibres in the ventral pons. The combined findings indicate an embryonic defect in axonal growth and guidance. Phenotypic analogy to mice with homozygous inactivation of Ntn1 encoding the secreted axonal guidance protein netrin1, or Dcc encoding its receptor Deleted in Colorectal Cancer led us to perform sequence analysis of NTN1 and DCC in all the patients. No pathogenic mutations were found. For the purpose of description the name 'pontine tegmental cap dysplasia' (PTCD) is proposed for the present malformation, referring to its most distinguishing feature on routine MRI.

Cerebral, cerebellar, and colobomatous anomalies in three related males: Sex-linked inheritance in a newly recognized syndrome with features overlapping with Joubert syndrome.

We present a so far unrecognized X-linked mental retardation syndrome with features overlapping with Joubert syndrome (JBS). Two brothers showed hypotonia, mental retardation, ocular abnormalities with impaired vision and colobomas and a breathing pattern compatible with JBS. Neuroimaging revealed cerebellar vermis hypoplasia and ventriculomegaly. A tentative diagnosis of JBS was made, and autosomal recessive inheritance considered most likely. In a subsequent pregnancy that occurred after artificial donor insemination, ultrasound in the 22nd week revealed a Dandy-Walker malformation and hydrocephaly. At autopsy at 34 weeks of gestation, the male infant showed cerebellar vermis aplasia and abnormalities of the brainstem and cerebral cortex. He was considered to have the same disorder as his two half-brothers. This renders the pedigree highly suggestive of X-linked inheritance. The clinical symptoms of this syndrome resemble JBS. However, the absence of the molar tooth sign and the X-linked inheritance do not support JBS. We propose the name X-linked cerebral-cerebellar-coloboma syndrome to distinguish the two disorders. Differentiation of the two disorders is especially important in genetic counseling, where artificial donor insemination may be considered as a means of reducing the recurrence risk, or when female relatives of the patient are concerned.