Malformations

Incidence 0.5 to 1.3 cases per 1000 live births

Male-to-female ratio—about 1 : 5

Cause of neural tube defects (NTDs): multifactorial (genetic, environmental, and nutritional)

Known environmental factors: folic acid deficiency, maternal diabetes, anticonvulsant medications, hyperthermia

Featured in several genetic syndromes: trisomy 13, trisomy 18, chromosome rearrangements, and deletions of 22q11

Range of symptomatology from in utero demise, coma, severe deficits including paraplegia; can be asymptomatic with spina bifida occulta

Early detection by screening for elevated maternal serum α-fetoprotein

Ultrasound for confirmation

Amniotic fluid α-fetoprotein and amniotic fluid acetylcholinesterase tests used in some cases

Depends on the specific type of defect and extent of nervous system injury

Anencephaly and craniospinal rachischisis are incompatible with life

Spinal defects may be associated with lower-extremity weakness, paralysis, bowel and bladder dysfunction

Meningitis is major complication of open neural tube defects

Folic acid (used in methylation and nucleic acid synthesis, deficiency leads to hyper-homocystinemia) administered during the periconceptional period—significantly reduces but does not eliminate risk

Genetic counseling—risk of recurrence of neural tube defect in those who have a first-degree relative is 5 to 10 times greater than the general population

Classification based on the part of the CNS involved (brain or spinal cord) and whether defect is open or closed (covered by overlying structures—meninges, bone, skin)

Open NTDs:

• Anencephaly: (“without brain”) failure of brain formation with absent calvaria—skull base has formed; froglike facies with bulging eyes (ocular development begins before the critical period of neural tube closure, i.e., during the third to fourth week of gestation)

• Craniospinal rachischisis : failure of closure of most or all of the neuraxis resulting in an absence/exposure of major portions of brain and spinal cord

• Spina bifida cystica with myelomeningocele : herniation of the spinal cord and meninges through spinal defect

• Spina bifida cystica with meningocele : herniation of the meninges, but not the cord

• Encephalocele : usually included with NTDs; brain displaced through occipital or frontal defect

• Iniencephaly : extreme bending of the head to the spine; neck usually absent

Closed NTDs (covered by skin):

• Myelocystocele : terminal cystic dilatation of the cord resulting from hydromyelia

• Lipomyelomeningocele : herniated conus medullaris infiltrated by fat

• Lipomeningocele : meninges surrounded by a lipoma

• Tethered cord : adhesions of spinal cord

• Spina bifida occulta : bony defect in vertebral column; no herniation of CNS elements

Area cerebrovasculosa: poorly formed neurovascular tissue

Meningomyelocele consists of disorganized blood vessels, rudimentary neuroglial tissue, and sometimes peripheral nerves

Amniotic bands with craniocerebral destruction

Hydranencephaly—well-formed skull is usually present in this entity

Incidence: 0.5 to 1 per 10,000 live births

1 per 250 spontaneous abortions

Affects males and females about equally

Chromosomal abnormalities in 25% to 50% of cases (see “Genetics,” discussed later)

Environmental risk factors: maternal diabetes, hypercholesterolemia, Smith-Lemli-Opitz syndrome (defects in cholesterol biosynthesis), various drugs including statins, alcoholism

Highly variable depending on the degree of brain malformation and facial defect

Least severe: arrhinencephaly (discussed later) with anosmia, single central incisor

Cleft lip or palate, hypotelorism, flat single-nostril nose/cebocephaly

Most severe: cyclopia with forehead/proboscis-like structure

Other findings: microcephaly, hydrocephalus

Depends on the type of HPE and associated anomalies

High incidence of fetal demise in most severe cases

Cognitive delay, mental retardation, epilepsy, endocrine abnormalities

Less severe cases have normal or near-normal brain development with mild facial anomalies

Genetic counseling in families with autosomal dominant forms

Alobar holoprosencephaly: complete failure in forebrain separation resulting in a single “holospheric” cerebrum

Semilobar holoprosencephaly: frontal and parietal lobes appear fused with posterior interhemispheric fissure

Lobar holoprosencephaly: only rostralmost areas of cerebral hemispheres show fusion

Syntelencephaly : “middle interhemispheric variant” of holoprosencephaly: the posterior frontal and parietal lobes are not properly separated but rostrobasal forebrain separation normal

Arrhinencephaly : malformation limited to absence of olfactory bulbs and tracts accompanied by absence of the gyri recti

Highly variable; disorganized cortical cytoarchitecture; heterotopias; disorganization of fused midline structures

Brain stem and cerebellum usually spared

Trisomy 13 (most common) and 18

Deletions or duplications in chromosome 13q

Numerous chromosomal regions implicated in holoprosencephaly: HPE 1-7, corresponding to numerous genes including sonic hedgehog ( SHH ), which maps to HPE3 on chromosome 7q36 and ZIC2 on chromosome 13, which corresponds to HPE5

Many other genes implicated or yet to be identified