Vein of Galen malformations
Nov. 28, 2022
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In this updated article, the author includes an updated clinical vignette including classification of lissencephaly, an important brain malformation related to microcephaly.
• Microcephaly is defined as a head circumference of less than 3 standard deviations from the population mean for age and gender.
• Microcephaly is a clinical finding that can result from a variety of causes. There are both genetic and nongenetic causes of microcephaly.
• Advances in neuroimaging and genetic testing have value for the diagnosis and prognosis of microcephaly.
• The American Academy of Neurology and Child Neurology Society have published an evidence-based review with recommendations for the evaluation of a child with microcephaly.
Microcephaly is a descriptive term that refers to a cranial vault that is significantly smaller than the standard for the person's age and sex. Microcephaly should be considered as a clinical finding rather than a disorder, and it may stem from a variety of causes that lead to the disruption of various stages of brain development. In clinical settings, microcephaly is determined by measuring one's head circumference, which is known to correlate well with cranial volume (11). When the head circumference is smaller than 2 standard deviations below the mean for the age and sex, microcephaly is present. However, most researchers use head circumference of 3 standard deviations below the mean as the definition of microcephaly (07; 88; 51).
Microcephaly has been observed and recognized for a long time, but it was not until the late 19th century that it started to attract scientists' attention. Many theories concerning the pathogenesis of microcephaly have been proposed. Some authors viewed microcephaly as a form of atavism, and others thought that it was due to mechanical compression of the fetal brain by contraction of the uterus. Giacomini, in 1885, proposed a classification of microcephaly, which is of historical significance. He divided microcephaly into 3 categories. The first was named "microcephalia vera," which means "true" microcephaly, in which there is no gross pathological abnormality other than smallness of the brain. Giacomini thought that this condition was due to pure inhibition of brain development. The second category was termed "microcephalia spuria," which refers to "pseudo" microcephaly, in which the pathological process or its residuum is identifiable. The third was "microcephalia combinata," which was thought to be a combination of both inhibitions of developmental and pathological processes. The term "microcephalia vera" is still occasionally used in clinical settings, and refers to patients who have microcephaly with no identifiable gross central nervous system pathology and little or no involvement of the organ systems other than the CNS. Since then, many different classifications and terminologies of microcephaly have emerged. Genetic and nongenetic microcephaly is classification according to etiology. Primary microcephaly is often used synonymously as congenital microcephaly, in which microcephaly is present at the time of birth. In contrast, secondary microcephaly or acquired microcephaly is used when head circumference is normal at birth, and subsequently falls to the microcephalic range (57).
The term micrencephaly refers to "small brain," and this is a pathological term. Although the presence of microcephaly usually implies that the brain is small, normal head circumference does not guarantee a normal-sized brain. Hence, microcephaly and micrencephaly are not interchangeable.
Microcephaly may be evident prenatally, at birth, or may become apparent during the first years of life. Microcephaly may be noticed during routine measurement of the head size or when the presence of neurologic abnormalities or dysmorphic features prompt a measurement of the head size. Determining when microcephaly was noted can help categorize microcephaly into primary or secondary, which directs evaluation of etiology.
When measuring head circumference, one should use a nonstretchable tape measure and place it just above the supraorbital ridge anteriorly. Then, align the tape posteriorly to record the maximal circumference. Normative data for head circumference based on sex and age are available on standardized growth charts from birth to 36 months from the National Center for Health Statistics. Additionally, the World Health Organization has growth charts available for head circumference-for-age from the The World Health Organization. For premature infants or children from other countries being considered for adoption, growth charts are also available through the Center for Adoption Medicine website (06). Different genetic syndromes may also have specific growth charts, such as Down syndrome and Cornelia de Lange syndrome.
Multiple measurements of head circumference over time plotted against a standard growth chart provide important information for diagnosis and prognostication. Therefore, head measurement should first be taken at birth, be part of the routine examination for every well-child visit with the pediatrician, and be part of every neurologic evaluation of a child with a neurologist. In microcephalic patients, the head may appear small compared to the face that is of relatively normal size. This is referred to as craniofacial disproportion, and characterized by a receding, narrow forehead, flat occiput, and prominent ears.
It is also important to note if microcephaly is proportionate with height and weight or disproportionate. If microcephaly is present with the clinical findings of a skull deformity or abnormal cranial sutures, then further urgent evaluation of craniosynostosis is warranted given risk of increased intracranial and intraorbital pressures and restricted brain growth.
Neurologic abnormalities, such as hypotonia, spasticity, seizures, ataxia, tremor, developmental delay, and intellectual disability, may accompany microcephaly. Other associated problems can include vision and hearing deficits and feeding and swallowing issues. The frequency of these associated conditions varies depending on etiology. The prevalence of microcephaly found among children being evaluated in neurodevelopmental clinics ranges from 6% to 40.4%, with an average prevalence of 25% (06). Although significant numbers of children with microcephaly carry a risk for low IQ, the presence of microcephaly itself is not always indicative of intellectual disability. In a large series of children with microcephaly (2 standard deviations below the mean), 10.5% had IQ scores below 70 (meeting the definition of intellectual disability), and 28% had borderline scores between 70 and 80 (22).
Organ systems other than the central nervous system may also be associated with microcephaly caused by intrauterine infections or chromosomal disorders. Facial dysmorphism or other malformations, or both, may be seen with chromosomal disorders or specific genetic syndromes. These additional features are often the clues to the diagnosis of underlying disorders associated with microcephaly.
History is an important aspect in making a diagnosis. A careful history of pregnancy and the perinatal and postnatal period should be obtained. History of travel, maternal illnesses, including acute and chronic infections (Zika, HIV, toxoplasmosis, rubella, etc.), malnutrition, and exposure to teratogenic substances (ie, anticonvulsants, isotretinoin, alcohol, and cocaine) are important clues to the diagnosis. History may reveal hypoxic-ischemic encephalopathy or meningoencephalitis that can predispose to the development of microcephaly after birth. Family history of consanguinity or microcephaly or similar neurologic problems should be obtained because genetic microcephaly and syndromes with a known pattern of inheritance may be evident.
Prognosis of microcephalic patients depends largely on their underlying etiology. If microcephaly is due to a chromosomal disorder with multiple organ system involvement, the overall prognosis is likely to be poor. The prognosis is also likely to be poor if the microcephaly is due to a severe encephaloclastic process such as meningoencephalitis or hypoxic-ischemic injury. Additionally, infection with certain viruses such as rubella and Zika can predict severe outcomes. Comorbidity of epilepsy in infants with microcephaly is associated with worse neurodevelopmental outcome (28).
Cognitive outcome in microcephalic patients is a common question in clinical settings. It is generally true that the smaller the head size, the greater the likelihood of a lower IQ. A study evaluating the phenotype and genetics of microcephaly found a correlation between the severity of developmental delay and intellectual disability and the severity of primary, and not secondary, microcephaly (10). In a retrospective cohort study in Canada, infants less than 29 weeks gestational age with poor head growth followed from birth until 36 months showed an association with significant neurodevelopmental impairment, specifically motor and cognitive delays (64). Another retrospective series of infants from the neonatal intensive care unit showed those with microcephaly are at significant risk for global delays and long-term disability (28). However, it should also be noted that microcephaly does not necessarily lead to intellectual disability. The data from U.S. National Collaborative Perinatal Project showed that 11% of infants with a head circumference between 2 and 3 standard deviations below mean were intellectually disabled (IQ less than 70) at 7 years of age. Among the infants with head circumference smaller than 3 standard deviations below mean, 51% had intellectual disability. Many of the intellectually disabled children in this latter group had identifiable pathology other than a small head, such as congenital infection (22). Clinicians should be aware that certain subsets of children in the microcephalic range are cognitively normal. In 1 study of a normal school population, students with microcephaly had similar mean IQ scores when compared to their normocephalic classmates, but the students with microcephaly did have lower mean achievement scores (57). The autosomal dominant form of microcephaly is often associated with normal intelligence; hence, measuring parents' head size can be useful in assessment. In a study of 6 Italian families with autosomal dominant microcephaly, psychometric testing revealed an IQ of less than 90 in only 1 out of 12 affected individuals. Of the 12, head circumferences ranged from 2.1 to 4.7 standard deviations below the mean (68).
The outcome for intelligence in microcephalic children is generally guarded, and many of them have a significant chance of functioning in the low intelligence range. However, it is important to keep in mind that the prognosis of each individual case should be made through careful evaluation of the history, physical examination, and laboratory studies, and not only on the basis of the head circumference.
A female baby was born to a 34-year-old mother after 35 weeks' gestation via induced vaginal delivery. Labor was induced because of pregnancy-induced hypertension of the mother and intrauterine growth retardation of the fetus. The mother's previous 2 pregnancies had both terminated in spontaneous abortions in the first trimester. The baby's Apgar score was 8 in 1 minute and 8 in 5 minutes. Her birth weight was 1420 g (-2.4 standard deviations). On her third day of life, she developed bloody stool, abdominal distention, and lethargy. Abdominal x-ray showed air in the walls of intestine. She was diagnosed with necrotizing enterocolitis, and on her seventh day of life, laparotomy with partial resection of ileum and cecum was performed. On day 16 she developed myoclonic and multifocal clonic seizures involving all extremities. A physical examination revealed head circumference of 27 cm (-3.7 standard deviations). She was a nondysmorphic infant with normal muscle tone and normal head control for age. Deep tendon reflexes were 3+ and symmetrical. No ankle clonus was noted. Toes were upgoing bilaterally. Both CT scan and MRI of the brain revealed absence of gyri, consistent with a diagnosis of lissencephaly.
Cytogenetic analysis using the fluorescent in situ hybridization method detected a deletion on the short arm of chromosome 17. Seizures were controlled with phenobarbital.
The diagnosis was Miller-Dieker syndrome (MDS).
This child was born with significant microcephaly, an important clue to the diagnosis of intracranial pathology. Lissencephaly (LIS) literally describes a “smooth brain” and is a spectrum of rare brain cortical malformations that includes agyria, pachygyria, and subcortical band heterotopia (double cortex). Agyria is defined as sulci greater than 3 cm apart, and pachygyria is defined as wide gyri with sulci 1.5 to 3 cm apart. Further division of agyria and pachygyria is based on cortical thickness and includes classical lissencephaly with 10 to 15 mm thickness and severe variant lissencephaly subtypes with 5 to 10 mm thickness (44). Lissencephaly can be further differentiated based on additional MRI findings of other congenital malformations, the anterior-posterior or temporal gradients of the lissencephaly, mode of inheritance, and identified pathologic gene mutations. MRI morphological classifications includes 21 lissencephaly patterns (18).
Miller-Dieker syndrome is a genetic syndrome of lissencephaly with dysmorphic features including narrow bitemporal diameter, high forehead, and an anteverted nostril. Additionally, severe intellectual disability is virtually universal, and almost all of the patients have epilepsy, often in the form of infantile spasm or Lennox-Gastaut syndrome. Miller-Dieker syndrome is caused by deletion 17p13.3 involving the gene LIS -1 now known as PAFAH1B1. Severity of lissencephaly can be increased by loss of another gene, YWHAE, in the same region (14). There are 31 identified genes associated with lissencephaly, and this list notably includes LIS-1(PAFAH1B1)- YWHAE, DCX, TUBA1A, TUBA3, TUBB2B, ARX, RELN, VLDLR, NDE1, KATNB1, and CDK5 (59; 91; 01).
Previous classification of type I and type II lissencephaly is no longer used as research shows distinct pathological mechanisms relegating cobblestone malformation and polymicrogyria into their own division termed “malformation of cortical division” (MCD).
Microcephaly is a neurologic sign and clinical finding, not a diagnosis by itself, and it can be caused by many different underlying etiologies. In general, etiology is divided into genetic and nongenetic causes. In "genetic" microcephaly, failure of brain growth is determined by intrinsic genetic information. Hereditary forms of microcephaly, chromosomal disorders, and many syndromes are included in this category. In "nongenetic" microcephaly, a normally developing brain fails to grow after a certain point because of external insults (46). Infections, intrauterine drug or toxin exposure, and hypoxic-ischemic injury are major conditions that belong to this category. A further distinction of microcephaly onset, congenital or postnatal, can be used with both genetic and nongenetic causes to help delineate an etiology. In 2009, the American Academy of Neurology and Child Neurology Society published an evidence-based review with recommendations for the evaluation of a child with microcephaly. A complimentary algorithm for the medical evaluation of microcephaly has been proposed (85).
The growth of the brain is primarily responsible for the growth of skull and head. Hence, interference in brain growth is usually responsible for development of microcephaly.
The first major event of human brain development occurs as the neural plate forms the neural tube, which gives rise to the central nervous system. This stage, called primary neurulation, takes place during 3 to 4 weeks' gestation. The closure of the neural tube proceeds rostrally and caudally. Failure in closure of the rostral part and the caudal part leads to anencephaly and myelomeningocele, respectively. Subsequently, during 2 to 3 months' gestation, prosencephalic development takes place. This is a complex process leading to the formation of much of the face and forebrain. Disturbance of this process may lead to conditions such as holoprosencephaly and agenesis of corpus callosum. Along with prosencephalic development, neuronal proliferation begins.
Quantitative measurements of the human brain during various stages of development have shown that there are 2 phases of cell proliferation (20). The first phase is from 2 to 4 months' gestation, which corresponds to the phase of neuronal proliferation. The second phase is from 5 months' gestation and lasts into the first year of life. This phase mainly corresponds to glial proliferation. It is conceivable that environmental insults during this rapid neuronal proliferation phase can lead to subsequent microcephaly. For example, in most instances of microcephaly due to in utero irradiation, exposure occurred before 15 weeks' gestation (87). Although the most susceptible period of brain development appears to be between 2 and 4 months' gestation, microcephaly may develop from later environmental insults because rapid physical growth of the brain continues throughout gestation and into the first years of life.
Pathology of microcephaly is diverse, reflecting its etiology. The updated classification of malformations of cortical development divides microcephaly into separate categories based on the underlying mechanism, reduced neuronal and glial proliferation, or accelerated apoptosis and abnormal postmigrational development, and details the known gene mutations and mode of inheritance (08). The identification of genetic causes of congenital microcephaly has rapidly grown due to the use of new genetic technology. This expanse has revealed underlying pathomechanisms. For example, genetic congenital microcephaly is understood by pathomechanisms that include abnormalities of centrosome number and structure, cilia function, mitotic microtubule spindle structure, and DNA repair, DNA damage response signaling, and replication (03). In addition, innovations in technology have advanced our knowledge of the underlying molecular pathology of primary microcephaly (78). Specifically, research uses human organoids, which are stem cell-derived cell culture systems, to model brain development and investigate the mechanism of microcephaly (26; 43).
The genetics of microcephaly is also complex. Hereditary microcephaly can be seen in autosomal recessive, autosomal dominant, and X-linked recessive inheritance. Also, it can occur as a sporadic case. When a genetic form of microcephaly is suspected, it is often difficult to determine the pattern of inheritance after the first affected child is born to unrelated parents. It is difficult to distinguish different modes of inheritance based on clinical phenotype, unless there are features of a certain syndrome associated with microcephaly. Therefore, a full family pedigree, if available, becomes very important to determine inheritance.
Genetic loci and genes in autosomal recessive primary microcephaly have been identified using linkage analysis. This is a group of nonsyndromic disorders not associated with other organ malformations. Currently, the Online Mendelian Inheritance in Man (OMIM) lists these loci, termed MCPH1 through MCPH28 to date, which map to different chromosome locations involving different proteins and can be accessed at the following website: OMOM.org. MCPH5 caused by ASPM gene and MCPH2 caused by WDR62 gene are the most common forms, 50% and 10%, respectively (82). Initially identified as a cancer associated gene, CASC5 is a cause of MCPH4 as it is important in mitotic cell division as a kinetochore protein (82). Research continues to uncover new DNA variants of these genes (67). The loss of function of the genes associated with each autosomal recessive primary microcephaly leads to cell-cycle dysregulation and a decrease in the number of neurons in the fetal brain (37). These genes have numerous roles including cell division, cell cycle regulation, and neuronal precursor cell division (51; 54). However, through the use of functional studies and the identification of new genes, knowledge of their roles have expanded even more to include DNA replication and repair, autophagy, cytokinesis, transmembrane and intracellular transport, Wnt signaling, and centromere and kinetochore function (36).
A form of autosomal recessive microcephaly has been described among the Amish of Pennsylvania and is known as MCPHA or Amish lethal microcephaly. The common gene missense mutation (p.Gly177Ala) is in SLC25A19 on chromosome 17q25.3 (41). Affected infants have metabolic acidosis, increased levels of alpha- ketoglutarate in the urine, severe microcephaly, and associated malformations, including cerebellar vermis hypoplasia, lissencephaly and corpus callous agenesis, and seizures (commonly myoclonic). Death usually occurs in infancy. Head circumference is usually more than 2 standard deviations below the mean and can be greater than 6 standard deviations.
Incidence varies among populations, but in searching birth defect registries throughout the world, it has been described as between 1.3 to 150 per 100,000 live births (39). The wide range of prevalence estimates in surveillance programs may be partially due to differences in the definition of microcephaly, either 2 or 3 standard deviations below the mean. Prevalence of microcephaly in Europe in a population-based study was 1.53 per 10,000 live births (52). An Australian population-based birth defects registry showed a prevalence of microcephaly of 5.5 per 10,000 live births (30). A study by the Australian Paediatric Surveillance Unit revealed an annual birth prevalence of 1.12 per 10,000 live births, and no congenital or probable Zika cases were reported (56). A United States population-based microcephaly surveillance revealed a prevalence of 8.7 per 10,000 live births (16). Before evidence of Zika virus infections, birth defects surveillance programs in New York State reported a prevalence of microcephaly of 7.5 per 10,000 live births and prevalence of severe congenital microcephaly of 4.2 per 10,000 live births (29). If head circumference had a normal distribution within the population, 2.3% of children would meet the criteria for microcephaly using the definition of 2 standard deviations below the mean (06).
Exposure to teratogenic agents in utero is the most preventable cause of microcephaly. Alcohol and illicit drug use by pregnant women should be strongly discouraged. Ionizing radiation generally should be avoided during pregnancy; even low doses may convey risk (76). Maternal phenylketonuria is another preventable cause of microcephaly. It has been demonstrated that maternal blood phenylalanine levels correlate well with the risk of microcephaly and neurologic abnormalities in offspring. A low-phenylalanine diet during pregnancy is likely to reduce this risk (70). A thorough evaluation of maternal medications is important to help modify risk.
Some congenital infections are also preventable. Immunization for rubella has been effective in preventing cases of congenital rubella syndrome, and antiretroviral treatment of pregnant women can diminish the transmission of HIV to the offspring. Currently, there is no available vaccine for Zika, but numerous formulations are being studied in preclinical trials (63). However, as the Zika epidemic has waned, there are many challenges for vaccine candidates (60). This epidemic has resulted in numerous prevention strategies outlined by the CDC, including avoiding mosquito bites (barrier skin protection, insect repellant, controlling access to living quarters, and eliminating standing water), sexual transmission (condoms and abstinence), travel to endemic and epidemic areas, and exposure to an infected person’s blood and bodily fluids. There has been a marked decline in Zika infections since the outbreak 6 years ago, and the CDC recommends pregnant woman and those planning a pregnancy to consult with their health care provider before traveling to at-risk locations. Please refer to www.cdc.gov/zika for the most up-to-date Zika information and recommendations, including testing for pregnant women, suspected exposed newborns, and infants at risk.
Accuracy of neurosonography in diagnosis of fetal brain anomalies prior to 24 weeks can be high, as shown by a retrospective cohort study (75). Therefore, there is a high diagnostic value to prenatal genetic testing, which highlights the role of genetic counseling as an important part of a multidisciplinary team approach. A discrepancy in some aspects of fetal head measurements between ultrasound and MRI has been raised, and it has been proposed to validate ultrasound diagnosis of microcephaly with MRI (89). Prenatal MRI may also detect small head size and provide more detail of brain anatomy (33). However, there are limitations to identifying genetic microcephaly as it may not be evident at birth, such as in Rett syndrome. Prenatal MRI may also detect small head size and provide more detail of brain anatomy (33). Early stage research is working toward potential treatments for microcephaly using gene therapy in an animal model.
For most genetic causes of microcephaly, there are no effective means of prevention. Early stage research is working toward potential treatments for microcephaly using gene therapy in an animal model. In addition, the development of microcephaly models using human organoids offers a promising approach for rapid testing of potential treatments and a greater understanding of the pathology of microcephaly (26; 43).
Table 1 lists the major causes of microcephaly that a neurologist may encounter. Each entity will then be discussed briefly.
Genetic causes of microcephaly
• Hereditary microcephaly
- Autosomal dominant microcephaly
• Chromosomal disorders
- Down syndrome (trisomy 21) and other trisomies (13, 18)
• Microcephaly associated with miscellaneous syndromes (only major ones listed here)
- Smith-Lemli-Opitz syndrome
• Inborn errors of metabolism
- Amino acidopathies and organic acidurias
• Cerebral malformations and migration disorders*
• Idiopathic microcephaly
* In some of the conditions listed, such as schizencephaly, both genetic and nongenetic etiology may exist.
Nongenetic causes of microcephaly
• Infectious diseases
- Congenital rubella syndrome
• Intrauterine exposure to teratogenic agents
- Ionizing radiation
• Hypoxic-ischemic injury
Autosomal recessive primary microcephaly (MCPH) is the prototype of genetic causes. Classically, this form is characterized by microcephaly without other organ involvement and mild to moderate intellectual disability. Other associated features may sometimes occur, including mild seizures, hyperactivity, and short stature. However, there is a broad clinical phenotype that depends on the affected gene, resulting in further classification, MCPH1-MCPH25. Autosomal dominant forms of microcephaly can be variably associated with lymphedema and/or chorioretinopathy (38). An autosomal dominant form can be associated with normal intellect or mild intellectual disability (65; 68). Autosomal dominant forms of microcephaly can be variably associated with lymphedema and/or chorioretinopathy (38). The X-linked recessive forms of microcephaly commonly occur with other neurologic symptoms, including intellectual disability, brain malformations, and dysmorphic features. Mutations in the SLC9A6 gene cause X-linked mental retardation syndrome, which is characterized by microcephaly, ataxia, epilepsy, and lack of speech, and it phenotypically resembles Angelman syndrome (27). There are numerous identified genetic syndromes in this category, including lethal forms.
Chromosomal abnormalities are causes of microcephaly. Among patients with Trisomy 21, up to one third have a head circumference below the third percentile (45). Other trisomies and deletion and duplication syndromes also commonly cause microcephaly, usually in association with other dysmorphic features. Cri-du-chat syndrome (deletion 5p) and trisomy 18 are among the relatively common chromosomal abnormalities associated with microcephaly.
Microcephaly is seen as a part of many syndromes. These are too numerous to discuss here, but some are important to recognize either because they are likely to be brought to the neurologist's attention due to their high frequency, or because they are relatively common syndromes that have microcephaly as a common feature. Smith-Lemli-Opitz syndrome is an autosomal recessive disorder of cholesterol biosynthesis. Anteverted nostril, syndactyly of second and third toes, and genital abnormalities in males are characteristic. Microcephaly is a frequent finding and is often severe (55). Developmental delay, broad thumbs and toes, slanted palpebral fissures, and hypoplastic maxilla characterize Rubinstein-Taybi syndrome. Microcephaly has been seen in a majority of patients documented in the literature (72; 73). However, the average head circumference of a small number of adult patients was at the 25th percentile in males and at the 5th percentile in females, suggestive of catch-up head growth before adulthood (81). Major abnormalities of the Cornelia de Lange (Brachmann-de Lange) syndrome are synophrys, thin down-turning upper lip, micromelia, and microbrachycephaly. Microcephaly is seen in a majority of patients with the "classical" phenotype, but appears to be less common in patients with the "mild" phenotype (32). Aicardi syndrome is thought to be of X-linked dominant inheritance and its cardinal features include agenesis of corpus callosum, infantile spasm, chorioretinal lacunae, and microcephaly. Rett syndrome is also considered X-linked dominant. Autistic regression with loss of purposeful hand movement starts usually between 6 to 18 months of age. Clinical deterioration is accompanied by the development of acquired microcephaly in the typical form. Severe intellectual disability and speech impairment, "puppet-like" gait, and a happy demeanor characterize Angelman syndrome. Head circumference measurements at birth are usually within normal range, but more than two thirds of the patients develop microcephaly, mainly during the first year of life (12). Epilepsy is common, usually starting before the age of 3 years. Data suggest that patients with Angelman syndrome due to an imprinting mutation have microcephaly less frequently (13). Other syndromes that are often associated with microcephaly include Cockayne syndrome and bird-headed dwarfism (Seckel syndrome).
Many inborn errors of metabolism, such as amino acid disorders and urea cycle disorders, eventually lead to microcephaly if not well controlled in the early postnatal period. Glut-1 deficiency syndrome is classically characterized by developmental delay, early-onset epilepsy, movement disorder of ataxia, dystonia and spasticity, and acquired microcephaly. An expanded phenotype is evolving (62). Inherited mitochondrial disorders can present in syndromic, as well as non-syndromic forms, and can be associated with neurologic manifestations such as microcephaly (24). One example of mitochondrial-related microcephaly is pontocerebellar hypoplasia (PCH). PCH type 1 and type 6, characterized by progressive microcephaly, have associated mutations in a gene encoding mitochondrial tRNA synthetase (53). Congenital disorders of glycosylation, which currently comprises more than 45 subtypes, have varied phenotypes, but some may include dysmorphic features and neurologic symptoms such as developmental delay, hypotonia, epilepsy, and microcephaly (34). X-linked creatine deficiency may be associated with microcephaly, and commonly affected individuals have mild to severe intellectual disability, epilepsy, and behavioral disorders (15).
Cerebral malformations and migration disorders may manifest themselves with microcephaly. If there is significant disturbance in cerebral structure or cortical architecture, they are also likely to be accompanied by other neurologic manifestations such as seizure and developmental delay. This is a heterogeneous group of disorders, which shares microcephaly and simplified gyral pattern as common features. Clinical manifestations vary significantly among patients belonging to this group. A small cranial vault often accompanies cephalocele. Although the abnormality is visible, MRI helps delineating anatomical details.
Sporadic (idiopathic) cases of microcephaly are difficult to distinguish from hereditary forms of microcephaly based on clinical phenotype. The genetic basis of microcephaly appears complex, and there are no clear data about what proportion of microcephaly is sporadic.
Microcephaly can also be caused by a variety of environmental insults, a major category of which is congenital infection. The importance of Zika virus as a cause of congenital microcephaly has been identified. In April 2016, scientists at the CDC announced the conclusion that Zika virus is a cause of microcephaly and other severe fetal brain defects, based on a comprehensive analysis of multiple sources of data (66). According to the CDC, congenital Zika syndrome includes 5 features: (1) severe microcephaly where the skull has partially collapsed, (2) decreased brain tissue with a specific pattern of brain damage, (3) damage to the back of the eye, (4) joints with limited range of motion, such as clubfoot, and (5) too much muscle tone restricting body movement soon after birth (https://www.cdc.gov/zika/healtheffects/birth_defects.html). Information on Zika is growing, and some infants with congenital Zika virus infection without perinatal microcephaly may later show decelerated head growth and develop postnatal microcephaly. Case series of congenital Zika syndrome will continue to add to our knowledge of this new diagnosis (25).
Toxoplasma gondii, rubella, cytomegalovirus, and herpes simplex virus infection are important causes of long-term neurologic morbidity. In congenital rubella syndrome, maternal infection before 13 weeks' gestation was associated with a head circumference below the 10th percentile in approximately 60% of cases (50). Ultrasound features can help identify congenital rubella syndrome (90). A population-based cohort study reported an increase of at least a 7-fold in microcephaly prevalence at birth with congenital cytomegalovirus infection (48). In another study of congenital cytomegalovirus infection, microcephaly and intracranial calcification were seen in 27% and 43% of cases respectively (21). Cytomegalovirus has an affinity for the germinal matrix and causes periventricular tissue necrosis with subsequent calcification in this area (40). Congenital toxoplasmosis more commonly causes hydrocephalus, but microcephaly can also be seen. In a study of 108 patients with congenital toxoplasmosis affecting the central nervous system, hydrocephalus and microcephaly were observed in 28% and 13% respectively (23). Intracranial calcification often takes a form of multifocal, scattered lesions, with predilection to the basal ganglia and cortex. Although the majority of Herpes simplex infection occurs perinatally or postnatally, intrauterine infection does occur, and may cause microcephaly. Intrauterine infection with varicella zoster virus is rare, and usually associated with maternal varicella infection between 8 to 20 weeks' gestation. Microcephaly was seen in 12% of cases (04).
Perinatal and early postnatal central nervous system infection can lead to microcephaly through the destruction of cerebral tissue. HIV infection is important to recognize. Microcephaly usually develops postnatally along with developmental delay. Imaging studies show universal cerebral atrophy and often involve basal ganglia calcification (71). Meningoencephalitis due to Herpes simplex virus or numerous bacterial pathogens in the perinatal period may lead to marked loss of brain parenchyma and poor brain growth leading to microcephaly.
Intrauterine exposure to teratogenic agents may cause microcephaly. Ionizing radiation as a cause of microcephaly has long been recognized, but it was the studies of offspring whose mothers were exposed to atomic bomb radiation while pregnant that provided a significant amount of data about the relationship between radiation and microcephaly. In a study of cohort that was exposed to the Hiroshima atomic bomb in utero, most of the subjects who had a head circumference smaller than 3 standard deviations below mean were within 1500 meters from hypocenter and were less than 15 weeks' gestation (87). Animal models are helping establish risk of even low doses of radiation on microcephaly (76).
Abuse of certain substances is known to be related to microcephaly. Microcephaly is a manifestation of fetal alcohol syndrome. In a study, 12% of infants born to mothers who were heavy drinkers were microcephalic at birth, as opposed to 0.4% in infants born to abstinent mothers or moderate drinkers (58). The effect of cocaine to the fetal central nervous system is not yet completely elucidated, but there are data suggestive of a relationship between cocaine exposure and microcephaly. Among children referred to a pediatric neurology clinic with a history of cocaine exposure in utero, 8% were microcephalic in contrast to 3% in the control group (84). Toluene embryopathy has dysmorphic features similar to fetal alcohol syndrome. Microcephaly has been reported in approximately two thirds of the cases. Interestingly, in about half of these cases, microcephaly developed postnatally (05; 61).
In utero exposure to hydantoin anticonvulsants is associated with microcephaly. Twenty-nine percent of 35 children prospectively followed for in utero hydantoin exposure had microcephaly (31). Warfarin, isotretinoin, and folic acid antagonists (aminopterin and methotrexate) are other drugs that are associated with microcephaly when taken by pregnant women.
Maternal phenylketonuria is associated with microcephaly, prenatal and postnatal growth retardation, congenital heart diseases, and developmental delay. There is a significant correlation between maternal blood phenylalanine level and the frequency of these abnormalities (70). Even with diet control, long-term outcomes in these children continue to reveal a risk of microcephaly (86).
Hypoxic-ischemic events that occur while the brain is developing may also lead to microcephaly. Severe perinatal hypoxic-ischemic encephalopathy is a major cause of postnatal microcephaly, but mild hypoxic-ischemic encephalopathy is highly unlikely to lead to microcephaly. Head circumference may not fall into the microcephalic range until after 12 months of age, but slowing of head growth is significantly associated with patterns of brain lesions, specifically severe white matter, basal ganglia, and thalamic lesions (47). A majority of these children are severely handicapped due to spasticity and seizure disorder, and severe multicystic encephalomalacia is present on CT and MRI.
Published data suggest that the degree of derangement in cerebral oxidative metabolism measured by magnetic resonance spectroscopy in neonates with hypoxic-ischemic event correlates well with later development of microcephaly and neurodevelopmental morbidity (69). Severe placental insufficiency may lead to microcephaly through chronic prenatal hypoxia. These children may also manifest features of intrauterine growth retardation.
Severe head trauma and intracranial hemorrhage associated with significant tissue loss in the brain during the first years of life may lead to microcephaly. It should also be noted that child abuse is 1 of the major causes of head trauma in young infants.
Metabolic derangements, such as severe acidosis or recurrent episodes of hypoglycemia in the early postnatal period, can lead to microcephaly by hindering normal development of the brain.
Malnutrition usually affects weight and height before it affects head circumference. It is the body's natural response to preserve brain growth even at the expense of body growth. However, severe malnutrition can lead to microcephaly, as demonstrated in a study of Australian Aboriginal children (74). Microcephaly due to malnutrition may be reversible if treated early (42).
Craniosynostosis is a condition characterized by premature closure of cranial sutures. If severe and untreated, this might lead to restriction of brain growth due to a small cranium. Diagnosis is usually suspected from the misshapen skull and confirmed by CT scan, 3-D reconstruction CT scan, or plain x-ray of skull.
A diagnostic workup should be planned after detailed evaluation of the history and physical findings. Imaging studies of the brain are usually indicated unless clinical features are strongly suggestive of an obvious syndrome, such as Down syndrome, or in cases of autosomal dominant microcephaly with normal cognitive function, where imaging studies are unlikely to add much information in patient management. MRI is usually the modality of choice because of better anatomic delineation as well as evaluation of myelination and gray or white differentiation (80; 17). Midline structures such as the corpus callosum and septum pellucidum are also better visualized using MRI compared to CT. When there is clinical suspicion of diseases that cause cerebral calcification, such as congenital cytomegalovirus infection and congenital toxoplasmosis, CT scan may be indicated. CT scan, especially using bone windows and 3-dimensional reconstruction techniques, is helpful in diagnosing craniosynostosis. The overall diagnostic yield of imaging studies to explain the cause of microcephaly ranges from 43% to 80% in the literature (06). If a cerebral malformation is identified through imaging studies, a published updated classification system may be helpful in describing comorbidities of microcephaly (08). The pattern of brain imaging seen in severe microcephaly can assist somewhat with counseling families about prognosis, based on the identification of 4 distinct patterns in a small cohort of children (09).
Genetic evaluations are evolving. Previously, chromosomal testing was strongly indicated when multiple major or minor anomalies were observed. However, there are some cases of chromosomal abnormality that are "non-dysmorphic" (17). Chromosomal abnormalities often have implications for genetic counseling; therefore, in cases of undiagnosed microcephaly, chromosomal study is usually indicated even without obvious dysmorphic features. Genetic testing may yield a diagnosis in cases of microcephaly, and rates have been reported from 15.5% to 53.3% (06). Specific DNA tests, such as deletion analysis using the fluorescent in situ hybridization method, can be indicated in cases of recognizable syndromes that need further confirmation. Angelman syndrome and Miller-Dieker syndrome are examples. Chromosome microarray has become a preferred testing modality. The American Academy of Neurology recommends it in the evaluation of children with unexplained global developmental delay and intellectual disability as the genetic test with the highest diagnostic yield (49). It is reasonable to consider its use in the evaluation of microcephaly, in concert with evaluation of family history and microcephaly-associated symptoms. The next generation of genetic testing includes whole-exome sequencing and whole-genome sequencing. They have the potential to offer a cost-effective and efficient genetic evaluation that affects patient management (19). Identification of genes related to microcephaly is rapidly increasing each year with the widespread use of these techniques. For example, whole-exome sequencing identified an atypical presentation of ACAD9 deficiency, which helped alter and optimize treatment and expand its phenotype (02). The use of whole-exome sequencing by pediatric neurology practices as a high-yield test for patients with various neurodevelopmental disabilities was demonstrated (77). A prospective study showed the cost-effectiveness of whole-exome sequencing used early in the diagnostic pathway (79).
Tests for congenital infections should be considered when the history, clinical features, or both are suggestive of the diagnosis. The CDC provided up-to-date Zika testing information for pregnant mothers, newborns and infants.
Metabolic screening tests, such as amino acid and organic acid analysis, are usually reserved for the cases in which the clinical picture leads to a suspicion of inborn errors of metabolism. In metabolic disorders, microcephaly is usually the result of continuous or repetitive metabolic insults to the postnatal brain. Hence, it generally holds true that metabolic disorders do not manifest themselves as microcephaly at birth. However, there are exceptions to this rule as illustrated by documented cases of an inborn error of serine biosynthesis (3-phosphoglycerate dehydrogenase deficiency). In original cases of this disorder, microcephaly at birth, profound psychomotor retardation, hypertonia, and seizures were seen (35).
Management of microcephaly is usually supportive. Long-term involvement of therapies can include physical, occupational, developmental, speech, hearing, vision, and nutrition. Treatment for associated neurologic conditions, such as epilepsy, movement disorders, and spasticity, should be provided. Genetic counseling is important when dealing with a family with an affected child because of increased risk of recurrence in siblings (83). Children with microcephaly have a higher prevalence of ophthalmologic and audiologic abnormalities and require screening for disorders of these systems (06). If an underlying genetic syndrome is suspected or confirmed, further evaluation of other associated body systems may be warranted.
Avoidance of teratogenic medications, including hydantoin; exposure to radiation, including x-rays and CT scans; alcohol; cocaine; and exposure to viruses known to be associated with fetal microcephaly are recommended for women who are or are trying to become pregnant.
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Robyn Filipink MD
Dr. Filipink of Children's Hospital of Pittsburgh of UPMC has no relevant financial relationships to disclose.See Profile
Nina Schor MD PhD
Dr. Schor of the National Institutes of Health has no relevant financial relationships to disclose.See Profile
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