Holoprosencephaly

• Single ventricle and continuity of the hemisphere across the midline involving the forebrain (prosencephaon) and brain (encephaly)
• lobar, semilobar, and alobar forms, but likely a spectrum of same defect
• associated craniofacial anomalies: midline facial clefts, cyclopia (with proboscis), midline maxillary incisor, nasal anomalies - "holoprosencephaly complex"
• associated microcephaly, mental retardation, hypotonia, seizures, anosmia, pituitary insufficiency (diabetes insipidus, adrenal hypoplasia, hypothyroidism, hypogonadism)
• incidence in 0.48-0.88 per 10,000 live births
• slight female predominance
• alobar form often die by early childhood, lobar or semilobar forms can survive to adulthood
• maternal risk factors include diabetes, ethanol consumption, certain teratogens (alkaloids) affecting the SHH (Sonic hedgehog) signaling pathway
• genetic susceptibility also likely
• syndromes include Smith-Lemli-Opitz, Pallister-Hall, Meckel, velocardiofacial, Genoa, Lambotte, Martin, and Steinfeld syndromes
• trisomy 13 is common association
• many other associated gene mutations involving the Shh pathway and DNA binding
• genes have variable penetrance ranging from holoprosencephaly to normal structure and intelligence

Cyclopia: single orbit with single or partially divided eye
Ethmocephaly: separate but closely spaced orbits with proboscis
Cebocephaly: ocular hypotelorism with single-nostril nose

• Alobar holoprosencephaly:
  • no midline fissure separates the two cerebral hemispheres - fused into a holosphere
  • no Sylvian fissure, no separation between lobes
  • gyri form, but not with normal pattern
  • single large ventricle with posterior cyst-like membrane
  • often normal structure of cerebellum and brainstem (hypoplastic corticospinal tracts)
• Semilobar holoprosencephaly:
  • partial interhemispheric fissure separating the posterior part of the cerebral hemispheres
  • cortex continues through the fissure
  • also disorganized gyral patterns
• Lobar holoprosencephaly:
  • interhemispheric fissure divides entire brain except most rostral and ventral regions of the frontal lobes
  • cerebral cortex still crosses midline
  • posterior aspect may have complete separation and corpus callosum
  • mild cases may have near normal gyral pattern
  • still single ventricle and fused basal ganglia, enlarged thalamus massa intermedia
  • middle hemispheric variant involves malformation of the dorsal thalamus, basal ganglia, and a part of the hemispheres. The remainder of the hemispheres is spared.

Histopathology

• may involve primary neural cell migration defects, but also abnormalities in connections into and out of the cortex
• pia shows extensive glioneuronal rests in midgestation (early)
• hippocampus almost always present, though may be incomplete or abnormal
• basal ganglia and thalamus can have varied changes, can be unrecognizable
• cerebellum can show cortical dysplasia or heterotopia
• hypoplastic corticobulbar and corticospinal tracts
• absent olfactory bulbs
• disorganized vessels from internal carotid to the ventral and frontal regions, or single anterior cerebral artery
• encephaloceles, myelomeningoceles, arachnoid cysts, porencephaly can be associated

Embryology

• Most recent hypothesis is that it is a defect on induction and patterning of the rostral neural tube in the first 4 weeks of gestation.

Atelencephaly/Aprosencephaly

Atelencephaly: absence of the telencephalon with some remaining diencephalic derivatives
Aprosencephaly: loss of the diencephalic and telencephalic structures

These are different from anencephaly due to the presence of a skin-covered skull, although hypoplastic.

Synonyms include Garcia-Lurie syndrome, atelencephalic microcephaly syndrome, XK syndrome, and XK-aprosencephaly syndrome.

Associated with other malformations including congenital heart disease (VSD, ASD, PDA, coarctation of the aorta), limb malformations (thumb hypoplasia/aplasia, oligodactyly, fan-shaped toes, syndactyly, clubfoot, single palmar crease), eye abnormalities (cyclopia, coloboma, hypertelorism, downslanting palpebral fissures, blepharophimosis, microphthalmia, microcornea), vertebral body defects, and genital defects. Usually lethal, or else severe growth and mental retardation.

These are very rare, and chromosomal abnormalities have been associated.

Agenesis of the Corpus Callosum

• can be isolated or part of a syndrome
• over 100 syndromes associated, including many inborn errors of metabolism
• absence of cingulate gyrus, with sulci radiating down to the third ventricle
• slightly dilated ventricles with irregular "bat wing" contour
• bundle of Probst: white matter tract frequently found running in the anterior-posterior direction above the lateral ventricle where the corpus callosum normally sits
• partial agenesis of the corpus callosum also exists, with sparing of the rostrum and genu
• complete absence of corpus callosum also associated with absence of anterior commisure

If found incidentally, can have very subtle deficits on neuropsychological testing, not always disconnection syndromes. Higher incidence of seizures and mental retardation. Believed that the clinical manifestations reflect more associated CNS anomalies than the lack of corpus callosum itself.

Associated metabolic disorders to consider include Smith-Lemli-Optiz syndrome, non-ketotic hyperglycinemia, infantile lactic acidosis associated with pyruvate carboxylase or PDH deficiency, Zellweger syndrome.

Pathogenesis is unclear. Corpus callosum forms from tghe commisural plate of the lamina terminalis between 40-43 days gestation, growing rostral to caudal. Can be caused by axon guidance defects, projection neuron specification defects, and midline glial defects.

Septo-optic Dysplasia

Absence of the septum pellucidum with hypoplastic optic nerves. Constellation known as De Morsier syndrome.

Clinical presentation includes visual impairment, hypothalamic-pituitary insufficency (symptomatic hypoglycemia, diabetes insipidus, growth hormone deficiency), seizures, cognitive retardation (or normal).

Can be associated with porencephaly. Some patients have mutations in HESX1. There can be associated retinal dysplasias or dysplasia of the lateral geniculate nucleus. Heterotopia, polymicrogyria can also be associated.

Other Midline Defects

• Arrhinencephaly: absence of olfactory bulbs, leading to anosmia. Associate with holoprosencephaly, Kallman syndrome (anosmia, hypogonadotropic hypogonadism from GnRH deficiency)
• mildline cysts of the corpus callosum and septum
• midline lipomas
• other tract crossing defects