Lissencephaly Type Iii And Bone Dysplasia

Clinical Features

Encha Razavi et al. (1996) reported a distinct pattern of primary central nervous system degeneration affecting neuronal survival in the brain and spinal cord in 5 fetuses with fetal akinesia sequence (FAS). This neuropathologic pattern was characteristic of a lethal entity that they proposed calling type III lissencephaly syndrome. They presented observations on 2 affected female sibs and stated that this, as well as parental consanguinity, supported autosomal recessive inheritance. Abnormal apoptosis and/or deficiency in neurotrophic factors were mentioned as possible causal mechanisms. In the affected sibs reported by Encha Razavi et al. (1996), fetal ultrasound screening at 23 weeks had shown polyhydramnios and severe arthrogryposis with cerebral malformations (agenesis of the corpus callosum and vermis). Autopsy demonstrated pulmonary hypoplasia and a smooth brain with a hypoplastic brainstem and cystic cerebellum. Coronal sections confirmed the absence of corpus callosum and the presence of large ventricles, and disclosed severe bilateral multicystic periventricular lesions extending to the basal ganglia. Histologic study showed severe neuronal loss. Type I lissencephaly is a major manifestation of Miller-Dieker syndrome (247200) and Norman-Roberts syndrome (257320). Type II lissencephaly, also called cortical dysplasia, is a distinct cytoarchitectonic disorder mainly characterized by the obliteration of the subarachnoid space with neuroglial ectopic tissue, responsible for thick opaque meninges and hydrocephalus. Type II lissencephaly is a specific component of Walker-Warburg syndrome (236670), Fukuyama congenital muscular dystrophy (253800), and some other familial syndromes.

Attia-Sobol et al. (2001) described lissencephaly type III in association with stippled epiphyses and loose, thick skin in 2 male sibs born to young, healthy, second-cousin parents. In the first sib, fetal ultrasound screening at 32 weeks' gestation showed microcephaly, skin infiltration, and equinovarus feet. MRI disclosed cerebral agyria, hypoplastic cerebral mantle, and posterior agenesis of the corpus callosum. The infant died soon after birth at term. His brother was found to have skin infiltration by ultrasound study performed at 16 weeks' gestation. Pregnancy was terminated at 22 weeks' gestation after an MRI showed microcephaly with agenesis of the corpus callosum and cerebellar hypoplasia. The fetus had a normal XY karyotype. Like the index case, he had craniofacial edema and arthrogryposis, as well as epiphyseal stippling of cervical vertebrae, feet, and sacrum. Metacarpal bones were shortened with hypoplastic distal phalanges. Neuropathologic findings showed an agyric brain with hypoplastic brain stem and cerebellum, as well as severe neuronal loss of the cortical plate, matrix zone, basal ganglia, brainstem nuclei, and spinal cord with axonal swelling and microcalcification. Attia-Sobol et al. (2001) suggested that the disorder in this family is a new type III lissencephaly syndrome because of epiphyseal calcifications and metacarpal phalangeal bone dysplasia. The possibility of close linkage of 2 recessive disorders and pleiotropism involving a single mutant gene is not resolvable in this family.