When, for any reason, an infant lies with the head turned constantly to one side, usually caused by a congenitally shortened sternomastoid muscle (“wry neck”) or hemianopia, for example, the occiput on that side, over time, becomes flattened, as does the opposite frontal bone. The other occipital and frontal bones bulge, so that the maximum length of the skull is not in the sagittal but in the diagonal plane. This condition is called plagiocephaly, or wry head. Craniostenosis of one-half of a coronal suture may also distort the skull in this way.
In acrocephalosyndactyly, craniosynostoses are combined with syndactyly (fused, or webbed, fingers or toes). There are often added complications: cognitive disability, deafness, convulsions, and loss of sight secondary to papilledema. The so-called clover-shaped skull is the most severe and lethal of the craniosynostoses because of the associated developmental anomalies of the brain (see further on).
A variety of mutations in the gene complex FGFR (fibroblast growth factor receptor) have been associated with craniosynostosis syndromes with variable hand and foot malformations. For example, the Apert syndrome, an autosomal dominant disorder, is caused in the majority of cases by a single nucleotide mutation in the FGFR2 gene.
Disturbances of Neuronal Migration and
Neuroembryologic studies have identified several milestones of neuroblast formation, migration, cortical organization, neuron differentiation, and connectivity. Certain developmental anomalies can be traced to one of these stages of cytogenesis and histogenesis in the first trimester of gestation and to the growth and differentiation that take place in the second and third trimesters. During the first trimester, postmitotic neurons that will ultimately reside in the cortex arise in the ventricular zone adjacent to the ventricles. They migrate via microtubules along the scaffold of radial glia to form the multilayered cortex. It is interesting that neurons moving up the scaffold must pass through neurons that are already in position in the cortex, leading to an “inside-out” lamination in which the most recently born and arrived neurons reside on the outermost surface of the forming cortex. The complex genetic and epigenetic regulation of this process is an area of active investigation, as summarized by Shibata and colleagues.
Originally there is an excess of neurons, many of which degenerate during development—a process properly called apoptosis. There are instances in which the full complement of neuroblasts and neurons fails to be generated. In the extreme, the emergence of two separate cerebral hemispheres may not occur (holoprosencephaly), or the bihemispheric brain may remain small (microcephaly). In other instances, a diminished number of neurons are less obvious than their failure to migrate to the cortical surface; they remain scattered through the mantle zone in sheets and heterotopic aggregates. The genetic basis of a variety of malformations of cortical development are reviewed by Desikan and Barkovich; not surprisingly, many of the implicated genes are involved in pathways regulating neurogenesis, cell replication, and microtubule formation.