In addition to the grossly visible malformations, microscopic sections of normal-appearing brain may show disorganization of the normal laminar neuronal arrangement. Localized deposits of gray matter may be present in regions normally occupied only by white matter (heterotopic gray matter).
Malformations of the cerebral hemispheres may be due to genetic or acquired causes. Acquired causes include infections (eg, cytomegalovirus) and vascular events that interrupt the blood supply to the developing brain.
Microcephaly Microcephaly Microcephaly is a head circumference < 2 standard deviations below the mean for age. (See also Introduction to Congenital Craniofacial and Musculoskeletal Disorders and Overview of Congenital... read more or macrocephaly Macrocephaly Macrocephaly (megacephaly) is a head circumference > 2 standard deviations above the mean for age ( 1, 2). (See also Introduction to Congenital Craniofacial and Musculoskeletal Disorders and... read more , moderate to severe motor and intellectual disability Intellectual Disability Intellectual disability is characterized by significantly subaverage intellectual functioning (often expressed as an intelligence quotient < 70 to 75) combined with limitations of adaptive... read more , and epilepsy Seizure Disorders A seizure is an abnormal, unregulated electrical discharge that occurs within the brain’s cortical gray matter and transiently interrupts normal brain function. A seizure typically causes altered... read more often occur with these defects, with highly variable manifestations.
Treatment is supportive, including antiseizure drugs, if needed.
Holoprosencephaly spectrum occurs when the embryonic prosencephalon does not undergo complete segmentation and cleavage.
The 3 main types of holoprosencephaly, in declining order of severity, are
The alobar variant is the most severe and is usually fatal. It is characterized by complete failure of cleavage and a single ventricular cavity without any septation.
Semilobar holoprosencephaly is characterized by partial cleavage into hemispheres posteriorly but with a communicating unified ventricular cavity anteriorly.
Lobar holoprosencephaly is characterized by absence of the septum pellucidum (the membrane that separates the front of the 2 lateral ventricles), agenesis of the corpus callosum, fusion of the anterior horns of the lateral ventricles, and possibly fusion of the cingulate gyri.
A fourth, rare type, called middle interhemispheric variant, is characterized by fusion of the posterior frontal and parietal lobes as well as possibly the thalamus but with normal hemispheric differentiation elsewhere.
Craniofacial abnormalities Introduction to Congenital Craniofacial and Musculoskeletal Abnormalities Craniofacial and musculoskeletal abnormalities are common among children. They may involve only a single, specific site (eg, cleft lip, cleft palate, clubfoot) or be part of a syndrome of multiple... read more are present in the holoprosencephalies, and their degree of severity usually mirrors the underlying brain abnormality. Included in the spectrum are anophthalmia Anophthalmia Eyes can be absent, deformed, or incompletely developed at birth, often in conjunction with other congenital abnormalities and syndromes. (See also Introduction to Congenital Craniofacial and... read more or cyclopia, malformed or absent nares or nasal cavity, hypotelorism Hypotelorism Eyes can be absent, deformed, or incompletely developed at birth, often in conjunction with other congenital abnormalities and syndromes. (See also Introduction to Congenital Craniofacial and... read more , cleft lip and cleft palate Cleft Lip and Cleft Palate An oral-facial cleft is a birth defect in which the lip, the roof of the mouth, or both do not close in the midline and remain open, creating a cleft lip and/or cleft palate. These defects are... read more , and a central incisor.
Holoprosencephalies may be caused by mutations in a number of genes, of which > 14 are known; among these are the sonic hedgehog signaling pathway genes and their modifiers (1 Holoprosencephaly reference Cerebral hemispheres may be large, small, or asymmetric; the gyri may be absent, unusually large, or multiple and small. In addition to the grossly visible malformations, microscopic sections... read more ). Trisomy 13 Trisomy 13 Trisomy 13 is caused by an extra chromosome 13 and causes abnormal forebrain, midface, and eye development; severe intellectual disability; heart defects; and small birth size. Diagnosis is... read more and trisomy 18 Trisomy 18 Trisomy 18 is caused by an extra chromosome 18 and is usually associated with intellectual disability, small birth size, and various congenital anomalies, including severe microcephaly, heart... read more , as well as other chromosomal deletions Chromosomal Deletion Syndromes Chromosomal deletion syndromes result from loss of parts of chromosomes. They may cause severe congenital anomalies and significant intellectual and physical disability. Specific chromosomal... read more and duplications, have been associated with holoprosencephaly.
Severely affected fetuses may die before birth. Treatment of holoprosencephaly is supportive.
1. Hong M, Srivastava K, Kim S, et al: BOC is a modifier gene in holoprosencephaly. Hum Mutat 38(11):1464–1470, 2017. doi: 10.1002/humu.23286. Epub 2017 Jul 21.
Lissencephaly consists of an abnormally thick cortex, diminished or absent gyral pattern on the surface of the brain, reduced or abnormal lamination of the cerebral cortex, and often diffuse neuronal heterotopias.
This malformation is caused by abnormal neuronal migration, the process by which immature neurons attach to radial glia and move from their points of origin near the ventricle to the cerebral surface. Several single-gene defects Single-Gene Defects Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more may cause this anomaly (eg, LIS1). One X-linked X-Linked Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more gene, DCX, causes familial X-linked lissencephaly in males and another, generally milder, migrational abnormality in females called subcortical band heterotopia. In subcortical band heterotopia, a broad swath of ectopic gray matter in the subcortical white matter resembles a "double cortex" on MRI.
Affected infants almost always have significant intellectual disability Intellectual Disability Intellectual disability is characterized by significantly subaverage intellectual functioning (often expressed as an intelligence quotient < 70 to 75) combined with limitations of adaptive... read more and seizures (often infantile spasms Infantile Spasms Infantile spasms are seizures characterized by sudden flexion of the arms, forward flexion of the trunk, extension of the legs, and hypsarrhythmia on electroencephalography. Treatment is adrenocorticotropic... read more ).
Treatment of lissencephaly is supportive; survival depends on seizure severity and the presence of other complications including swallowing dysfunction, apnea, and difficulty clearing oropharyngeal secretions.
Polymicrogyria, in which the gyri are small and overabundant, also involves abnormal neuronal migration. Other common findings include simplified or absent cortical lamination in affected regions, heterotopic gray matter, a hypoplastic or absent corpus callosum and septum pellucidum, and malformations of the brain stem and/or cerebellum. The structural abnormalities may be diffuse or focal. The most common area of focal involvement is the perisylvian fissure (bilaterally or unilaterally).
Polymicrogyria is highly associated with schizencephaly Schizencephaly Porencephaly is a cavity that may develop prenatally or postnatally in a cerebral hemisphere. Cavities often communicate with a ventricle, but they may also be enclosed (ie, noncommunicating)... read more , in which there are abnormal slits, or clefts, in the cerebral hemispheres. Numerous causes of polymicrogyria have been identified, including a number of single-gene mutations (eg, of SRPX2), and primary maternal infection with cytomegalovirus (ie, in which the mother has no prior immunity— see Congenital and Perinatal Cytomegalovirus Infection (CMV) Congenital and Perinatal Cytomegalovirus Infection (CMV) Cytomegalovirus infection may be acquired prenatally or perinatally and is the most common congenital viral infection. Signs at birth, if present, are intrauterine growth restriction, prematurity... read more ). The most common clinical manifestations are seizures, intellectual disability, and spastic hemiplegia or diplegia.
Treatment of polymicrogyria is supportive.