Septo-optic dysplasia plus: A spectrum of malformations of cortical development

Case reports.

A 10.5-year-old right-handed girl was seen for evaluation of deafness and left hemiparesis, noted initially at 2 years on admission to an orphanage. There was no history of seizures. Examination revealed short stature (< third percentile for height and weight), microcephaly (45.5 cm, 4 cm < second percentile for age), a left spastic hemiparesis involving the face and upper and lower extremities equally, and global developmental delay. She was able to vocalize but used signing to communicate language content. She was able to ride a tricycle, as well as feed and dress herself. Growth hormone deficiency was documented. EEG demonstrated an inactive generalized epileptic discharge recorded bilaterally with right-sided predominance. Cranial MRI demonstrated an absent septum pellucidum, absent left cochlea, hypoplasia of the optic chiasm, and polymicrogyria of the right perisylvian region (figure 1A).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1. (A) Axial T1-weighted scan (spin echo 400/14) shows an absence of the septum pellucidum with dysmorphism of right perisylvian area with polymicrogyria. (B) Axial T1-weighted scan (spin echo 400/14) shows absence of the septum pellucidum with focal polymicrogyria in the left parietal region. (C) Axial T1-weighted scan (spin echo 500/10) shows absence of the septum pellucidum and an open-lipped schizencephaly involving the right cerebral hemisphere associated with polymicrogyria.

A 4-year-old ambidextrous boy had absent visual fixation and “drifting eye movements” from age 3 months. The mother smoked one-half pack of cigarettes per day during an otherwise uncomplicated pregnancy. Labor was spontaneous at 38 weeks’ gestation, and delivery was vaginal vertex. The birth weight was 5 pounds 2 ounces. The neonatal period was complicated by mild jaundice requiring phototherapy. At age 7 months, an ophthalmologist detected optic nerve hypoplasia, and a CT scan revealed an absent septum pellucidum. On examination, there were wide-set eyes, bilateral optic nerve hypoplasia, and global developmental delay. Gross and fine motor skills were performed at the 5- to 8-month level, and activities of daily living at the 6- to 9-month level. Cranial MRI done at age 1 year demonstrated an absent septum pellucidum, hypoplasia of the optic chiasm, and focal polymicrogyria of the left parietal lobe (figure 1B).

A 4-year-old right-handed girl was seen for evaluation for selective dorsal rhizotomy. The pregnancy was uncomplicated. Labor was spontaneous at term, and delivery was vaginal vertex and uncomplicated. Birth weight was 8 pounds 8 ounces. She was seen initially at age 3 years with global developmental delay, drooling, with an asymmetric spastic quadriparesis more severe on the left side. On evaluation at age 4 years, she was able to walk with a quadripod cane and was starting to make phrases, but continued to have substantial articulation difficulty and drooling. On examination the head circumference was 49.5 cm (10th percentile). Speech was dysarthric, but she was able to say simple phrases. There was a facial diplegia and drooling. Motor examination revealed spastic quadriparesis with left-sided predominance. MRI revealed absence of the septum pellucidum, hypoplasia of the optic chiasm, and unilateral right open-lipped schizencephaly (figure 1C).

Discussion.

SOD is considered a disorder of midline prosencephalic development occurring in the latter half of the second month through the third month of gestation.3 This likely accounts for the variable co-occurrence of dysplasia of the septum pellucidum, optic nerve, and hypothalamus in SOD. Consistent with the heterogeneous ocular and endocrine manifestations of SOD, only one of our children had visual impairment secondary to optic nerve hypoplasia, and another child had short stature secondary to documented growth hormone deficiency. Of note is that all three children had global developmental delay, and two of the three children also had spastic motor deficits. In a previous series of seven patients with SOD, six of the seven had normal cognitive and language development and an “intact neurologic status.”4 The only abnormal neuromotor finding was early poor motor coordination, which was thought to be related to decreased visual acuity.4 Given these results, and Barkovich’s observations of SOD “without schizencephaly,” significant intellectual, behavioral, or neurologic deficits cannot be attributed solely to congenital absence of the septum pellucidum.1,4

As the septum pellucidum, optic nerves, and hypophysis are collectively vulnerable to vascular insufficiency, it has been maintained that SOD is most likely a vascular disruption sequence.5 The association of SOD with schizencephaly,1,2 classically considered a vascular condition, has been used to support the vascular hypothesis of SOD. However, the focal malformations of cortical organization seen in two ofour patients implicate pathogenic mechanisms in the postmigratory phase beyond 5 months’ gestation,3,6 well after midline prosencephalic development hascompleted.

Mutations in HESX1, a human homeobox gene for which the mouse homologue HesX1 has an important role in forebrain, midline, and pituitary development,7 have recently been demonstrated as the cause of SOD in two siblings. This supports the hypothesis that given the disparate timing of midline prosencephalic development and subsequent cortical organization, the association of SOD with malformations of cortical organization is unlikely secondary to a single vascular disruption, and is more likely secondary to genetic abnormalities with effects at multiple developmental stages in cerebral development. HesX1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke’s pouch, the primordium of the anterior pituitary gland. These observations demonstrate that gene expression is developmentally regulated both temporally and anatomically. Both siblings, in addition to SOD, also had agenesis of the corpus callosum, a previously reported association,8 further implicating a single gene in multiple, apparently separate, developmental processes.

There is increasing evidence that many malformations of cortical organization are the result of genetic mutations. Mutations in the gene EMX2, a human homologue of the drosophila gene empty spiracles, which encodes for a homeodomain-containing protein that is preferentially expressed in the developing cerebral cortex, have been associated with some cases of severe schizencephaly.9 Even though specific genetic defects have not yet been discovered, familial forms of symmetric bilateral polymicrogyria have been described.9 Of interest in this context is the report of a 3-year-old girl with bilateral rolandic cortical “dysplasia” (polymicrogyria) and SOD,10 raising the possibility of common genetic pathways of polymicrogyria and SOD. However, as EMX2 mutations and HESX1 mutations are not seen in most cases of schizencephaly and SOD, respectively, it remains to be determined which other genetic defects cause the remainder of these disorders.7,9

The clinical features of our patients with SOD-plus are distinguished from isolated SOD by the presence of significant global developmental delay and motor deficits. Given the occurrence of these neurologic deficits in previous reports of SOD, associated malformations of cortical development other than schizencephaly may be under-recognized. The occurrence of SOD with global developmental delay or spastic motor deficits should prompt detailed neuroimaging with MRI to seek an associated cortical malformation diagnostic of the SOD-plus spectrum. Advances in MRI have yielded increasing recognition of malformations of cortical development as causes of developmental deficits.6 MRI could be used to provide specific prognostic information regarding the risk of subsequent neurodevelopmental deficits in the presence of a cortical malformation. Distinguishing the syndrome of SOD-plus from isolated SOD highlights that SOD is not a single distinct entity. It is hoped that this distinction will aid in eventually clarifying the etiology of these heterogeneous syndromes.