In this issue


Disproportionate brain growth is the main factor resulting in postnatal cerebellar tonsillar herniation (CBTH) and Chiari 1 malformation in Costello syndrome, write Gripp et al. (p. 1161). Costello syndrome is a rasopathy caused by germline mutations in the proto-oncogene HRAS.

This systematic review of brain and spinal cord images in 28 individuals with Costello syndrome revealed absolute or relative macrocephaly in 100% of patients, ventriculomegaly in 50%, and other abnormalities in 96%. The researchers saw posterior fossa crowding with CBTH in 96% of patients, while in 59%, serial studies revealed that posterior fossa crowding progressed, suggesting an ongoing process rather than a static congenital anomaly.

Comparing images from young infants to subsequent studies demonstrated postnatal development of posterior fossa crowding. The process of evolving megalencephaly and cerebellar enlargement is in keeping with mouse model data and delineates abnormal genesis of neurons and glia, write researchers. The process results in an increased number of astrocytes and enlarged brain volume.

Treatment approaches should be re-evaluated, the researchers suggest. They suspect that cerebellar enlargement showing significant postnatal progression “may be amenable to pharmacotherapy geared towards amelioration of the hyperactivity of the Ras-MAPK pathway.”


A report by Faden et al. (p. 1157) cements the involvement of calcium-activated nucleotidase 1 gene (CANT1) in the pathogenesis of Desbuquois dysplasia with hand involvement and demonstrates the high value of even single cases in the setting of genetically homogeneous disorders when using homozygosity mapping3.

Figure 3.

A) Sequence chromatogram of CANT1 with the 5bp duplication indicated by red upside facing bracket (from top to bottom: control, patient, parent). B) Schematic of CANT1 that shows the location of previously reported mutations including the current study (boxed); black areas represent the UTR.

Desbuquois dysplasia is an autosomal recessive disorder characterized by severe growth restriction, distinct hand and proximal femur appearance, and cognitive impairment.

After identifying 1 newborn with classical features of the disorder and parents who are first cousins, the authors used homozygousity mapping to trace the disorder's origins to 17q25.3. The critical interval was a region that only contained 10 annotated genes, so the authors combined results of their homozygousity mapping with those of others. Serial sequencing of the genes contained within the interval revealed a 5bp duplication within CANT1 that is consistent with what is described in a very recent report by Huber et al.


Dominant mutations in the TRPV4 gene can account for a range of phenotypes of metatropic dysplasia, a clinical heterogeneous skeletal dysplasia, write Camacho et al (p. 1169)6A.

Figure 6A.

The cartilage in the trachea at the level of the thyroid gland is thickened by irregular nodules of cartilage separated by strands of mesenchymal cells. The adjacent tracheal mucosa (arrow) is unremarkable.

Patients with the disorder have short extremities, short trunks with progressive kyphoscoliosis, and craniofacial abnormalities including prominent foreheads, midface hypoplasia, and squared-off jaws.

The researchers identified dominant mutations in the gene encoding TRPV4, a calcium permeable ion channel, in 10 patients with mild to perinatal lethal metatropic dysplasia.

Data demonstrate that the lethal form of the disorder is dominantly inherited and suggest locus homogeneity. Mutations activate the channel, indicating that the mechanism of disease may result from increased calcium in chondrocytes, electrophysiological studies showed.

Histological studies in 2 cases of lethal metatropic dysplasia revealed markedly disrupted endochondral ossification, with reduced numbers of hypertrophic chondrocytes and the presence of islands of cartilage within the zone of primary mineralization.

While the mutation analysis did not reveal a clear relationship between the domain of the protein affected and a particular phenotype, it is likely that the phenotypic consequence of each mutation reflects the extent to which the TRPV4 channel is activated and the downstream consequences of increased calcium in chondrocytes, according to researchers.