Developmental Malformations
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May. 08, 2026
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Microcephaly …
- Updated 07.08.2025
- Released 07.29.1998
- Expires For CME 07.08.2028
Microcephaly
Introduction
Overview
In this updated article, the author highlights a suggested algorithm for the medical evaluation of suspected fetal microcephaly. Additionally, the updated 2026 CDC Yellow Book: Health Information for International Travel is referenced to provide travel guidance for women who are presently or who are trying to become pregnant. Current information on Zika vaccines and monoclonal antibodies is also presented.
Key points
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• Microcephaly is defined as a head circumference of less than three standard deviations from the population mean for age and gender. | |
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• Microcephaly is a clinical finding that can result from various causes. There are both genetic and nongenetic causes of microcephaly. | |
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• Advances in neuroimaging and genetic testing have value for the diagnosis and prognosis of microcephaly. | |
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• The American Academy of Neurology and Child Neurology Society have published an evidence-based review with recommendations for evaluating a child with microcephaly. |
Historical note and terminology
Microcephaly is a descriptive term referring to a cranial vault that is significantly smaller than the standard for the person's age and sex. Microcephaly should be considered a clinical finding rather than a disorder, and it may result from various causes that lead to the disruption of different 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 (12). When the head circumference is smaller than two standard deviations below the mean for the age and sex, microcephaly is present. However, most researchers use head circumference of three standard deviations below the mean as the definition of microcephaly (08; 95; 55). More specifically, the severity of microcephaly is classified as mild when head circumference is less than two standard deviations and severe when head circumference is less than three standard deviations.
Microcephaly has been observed and recognized for a long time, but it was not until the late 19th century that it started to draw 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. In 1885, Giacomini proposed a classification of microcephaly, which is of historical significance. He divided microcephaly into three 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 are classified 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 decreases to the microcephalic range (62).
The term micrencephaly refers to "small brain," 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.
Clinical manifestations
Presentation and course
Microcephaly may be evident prenatally or at birth; however, it may become apparent during the first years of life. Microcephaly may be noticed during conventional prenatal ultrasound screening, routine measurement of the head size at birth, during subsequent well-child exams, or when the presence of neurologic abnormalities or dysmorphic features prompts a measurement of the head size. Determining when microcephaly was noted can help categorize microcephaly into primary or secondary, which then 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, Fragile X syndrome, and Cornelia de Lange syndrome.
Multiple head circumference measurements over time plotted against a standard growth chart provide important information for diagnosis and prognostication. Therefore, head measurements 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. An observed dysmorphic feature in some microcephalic patients is craniofacial disproportion whereby the head may appear small compared to the face, which is of relatively normal size. This is referred to as craniofacial disproportion and is 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 (23).
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 diagnostic clues of underlying disorders associated with microcephaly.
History is an essential part of making a diagnosis of microcephaly. A detailed history of pregnancy and the perinatal and postnatal period should be obtained. History of travel, maternal illnesses, including acute and chronic infections (Zika, HIV, CMV, toxoplasmosis, rubella, etc.), malnutrition, and exposure to teratogenic substances (ie, radiation, 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, microcephaly, developmental regression, global delays, intellectual disabilities, or other neurologic disorders should be obtained because genetic microcephaly and syndromes with a known inheritance pattern may be evident.
Prognosis and complications
The 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 outcomes (30). An algorithm has been presented that suggests medical evaluation for suspected fetal microcephaly along with predicted prognosis (33). These authors discuss the inherent challenges in making a prenatal diagnosis given the differences in definition and measurement of head circumference in fetuses and newborns. They also highlight the need for improved diagnostic accuracy through the use of prenatal genetic testing, advanced prenatal imaging, and updated head circumference charts.
Cognitive outcome in microcephalic patients is a common question in the clinical setting. 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 (11). In a retrospective cohort study in Canada, infants younger 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 (68). 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 (30). However, it should also be noted that microcephaly does not necessarily lead to intellectual disability. The data from the U.S. National Collaborative Perinatal Project showed that 11% of infants with a head circumference between 2 and 3 standard deviations below the mean were intellectually disabled (IQ less than 70) at seven years of age. Among the infants with head circumference smaller than three 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 (23). Clinicians should be aware that certain subsets of children in the microcephalic range are cognitively normal. In one 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 (62). 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 six Italian families with autosomal dominant microcephaly, psychometric testing revealed an IQ of less than 90 in only 1 of 12 affected individuals. Of the 12, head circumferences ranged from 2.1 to 4.7 standard deviations below the mean (73).
The outcome for intelligence in microcephalic children is generally guarded, and many will have a significant risk 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 not on the basis of the head circumference alone but through careful evaluation of the history, physical examination, brain imaging, and laboratory studies, including genetic testing.
Clinical vignette
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 two 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 the intestine. She was diagnosed with necrotizing enterocolitis, and on her seventh day of life, laparotomy with partial resection of the ileum and cecum was performed. On day 16, she developed myoclonic and multifocal clonic seizures involving all extremities. A physical examination revealed a 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 an 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, which was 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 (47). 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 (19).
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 will 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. The severity of lissencephaly can be increased by the loss of another gene, YWHAE, in the same region (15). 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 (65; 98; 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).
Biological basis
Etiology and pathogenesis
Microcephaly is a neurologic sign and clinical finding, not a diagnosis by itself, and it can be caused by many different etiologies.
The growth of the brain is primarily responsible for the growth of skull and head. Hence, interference with brain growth is usually responsible for the 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 occurs. This complex process leads to the formation of much of the face and forebrain. Disturbance of this process may lead to conditions such as holoprosencephaly and agenesis of the 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 two phases of cell proliferation (21). 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 (94). 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.
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 (49). Infections, intrauterine drug or toxin exposure, and hypoxic-ischemic injury are major conditions that are in 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 (92).
The pathology of microcephaly is diverse, reflecting its varied etiology. The commonly used 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 (09). The identification of genetic causes of congenital microcephaly, also known as primary 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, technological innovations have advanced our knowledge of the underlying molecular pathology of primary microcephaly (85). Specifically, research uses human organoids, which are stem cell-derived cell culture systems, to model brain development and investigate the mechanism of microcephaly (27; 46). A review of human cerebral organoids includes a discussion of different methodologies of producing organoids, their use to model different neurologic disorders, including microcephaly and Zika virus infection, limitations of use, and future research directions (25). The additional role of transcriptional factors in the pathology of microcephaly has been highlighted and five critical gene subsets (homeobox-, basic helix-loop-helix-, forkhead box-, high mobility group box-, and zinc finger domain-containing transcription factors) are described (50). It must be acknowledged that as gene discoveries occur at a rapid pace, the classification of microcephaly will also evolve and require a more comprehensive view. A review article discussed the current inherent difficulties in classifying subtypes of congenital microcephaly given the variable clinical and genetic heterogeneity in the spectrum of shifting from nonsyndromic to syndromic congenital microcephaly as gene discovery continues (07). The authors specifically posit that classification should consider genetic modifiers, de novo gene variants, and brain-specific splicing events as related to the phenotype spectrum associated with specific genes.
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, de novo 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 in determining 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. The Online Mendelian Inheritance in Man (OMIM) lists these loci, termed MCPH1 through MCPH30 to date, which map to different chromosome locations involving different proteins and can be accessed at the following website: OMIM.org. MCPH5, caused by the ASPM gene, and MCPH2, caused by the WDR62 gene, are the most common forms, 50% and 10%, respectively (89). 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 (89). Research continues to uncover new DNA variants of these genes (71). 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 (40). These genes have numerous roles, including cell division, cell cycle regulation, and neuronal precursor cell division (55; 59). However, through the use of functional studies and the identification of new genes, knowledge of their roles has expanded even more to include DNA replication and repair, autophagy, cytokinesis, transmembrane and intracellular transport, Wnt signaling, and centromere and kinetochore function (39).
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 is SLC25A19 on chromosome 17q25.3 (44). 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 ranges from greater than two to more than six standard deviations below the mean.
Epidemiology
When searching birth defect registries throughout the world, incidence varies among populations, but it has been described as between 1.3 to 150 per 100,000 live births (42). The wide range of prevalence estimates in surveillance programs may be partially due to differences in the definition of microcephaly with head circumference criteria, either 2 or 3 standard deviations below the mean. The prevalence of microcephaly in Europe in a population-based study was 1.53 per 10,000 live births (56). An Australian population-based birth defects registry showed a prevalence of microcephaly of 5.5 per 10,000 live births (34). 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 (61). A United States population-based microcephaly surveillance revealed a prevalence of 8.7 per 10,000 live births (17). 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 the prevalence of severe congenital microcephaly of 4.2 per 10,000 live births (31). If head circumference had a normal distribution within the population, 2.3% of children would meet the criteria for microcephaly using the definition of two standard deviations below the mean (06).
Prevention
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 (83). 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 likely reduces this risk (75). A thorough evaluation of maternal medications is important to help modify risk prenatally.
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 or stop the transmission of HIV to the offspring. No licensed vaccines or monoclonal antibodies (mAbs) are available for Zika. As the Zika epidemic has waned and future outbreaks are unpredictable, there is a great challenge for their continued development and commercial availability. A meeting of global Zika experts identified that there are 16 vaccines in phase 1 or phase 2 trials and three mAbs in phase 1 trials and formulated an agenda to advance the worldwide licensure of these preventions and treatments (63). Other research is ongoing for Zika infection treatment but is at the cell culture and animal model stages (100; 101).
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 2015 outbreak, and the CDC recommends pregnant women and those planning a pregnancy to consult with their healthcare 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.
The accuracy of neurosonography in the diagnosis of fetal brain anomalies before 24 weeks can be high, as shown by a retrospective cohort study (82). 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 (96). Prenatal MRI may also detect small head size and provide more detail of brain anatomy (37). 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 (37). 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 (27; 46).
Differential diagnosis
Table 1 lists the major causes of microcephaly that a neurologist may encounter. Each entity will then be discussed briefly.
Table 1. Differential Diagnosis of Microcephaly
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Genetic causes of microcephaly | ||
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• Hereditary microcephaly | ||
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- Autosomal dominant microcephaly | ||
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• Chromosomal disorders | ||
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- Down syndrome (trisomy 21) and other trisomies (13, 18) | ||
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• Microcephaly associated with miscellaneous syndromes (only major ones listed here) | ||
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- Smith-Lemli-Opitz syndrome | ||
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• Inborn errors of metabolism | ||
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- Amino acidopathies and organic acidurias | ||
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• Cerebral malformations and migration disorders* | ||
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- Lissencephaly | ||
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• Idiopathic microcephaly | ||
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* In some of the conditions listed, such as schizencephaly, both genetic and nongenetic etiology may exist. | ||
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Nongenetic causes of microcephaly | ||
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• Infectious diseases | ||
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- Congenital rubella syndrome | ||
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• Intrauterine exposure to teratogenic agents | ||
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- Ionizing radiation | ||
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• 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-MCPH30. Autosomal dominant forms of microcephaly can be variably associated with lymphedema and/or chorioretinopathy (41). An autosomal dominant form can be associated with normal intellect or mild intellectual disability (69; 73). Autosomal dominant forms of microcephaly can be variably associated with lymphedema and/or chorioretinopathy (41). 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 (29). 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 (48). 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 (60). 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 (78; 80). 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 (88). 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 (36). 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 (13). Epilepsy is common, usually starting before the age of three years. Data suggest that patients with Angelman syndrome due to an imprinting mutation have microcephaly less frequently (14). Other syndromes that are often associated with microcephaly include Cockayne syndrome and bird-headed dwarfism (Seckel syndrome). CASK (calcium/calmodulin-dependent serine protein kinase) gene disorders first reported in 2008 are associated with intellectual disability, microcephaly, and pontine and cerebellar hypoplasia (57). However, the phenotype can vary. It is an example of a genetic syndrome with growing identification through evolving genetic testing and understanding through elucidating gene mutation effects and interactions with other genes (32; 72). Progressive deceleration of fetal head circumference growth prenatally has been observed (28).
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 (67). Inherited mitochondrial disorders can present in syndromic, as well as non-syndromic forms, and can be associated with neurologic manifestations such as microcephaly (26). 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 (58). Congenital disorders of glycosylation have varied phenotypes with multiorgan involvement, and our understanding of clinical characteristics is expanding (99). There are now more than 160 identified subtypes of congenital disorders of glycosylation.
X-linked creatine deficiency may be associated with microcephaly, and commonly affected individuals have mild to severe intellectual disability, epilepsy, and behavioral disorders (16).
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, which includes 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 (70). According to the CDC, congenital Zika syndrome includes five 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/mmwr/volumes/71/wr/mm7103a1.htm). Information on Zika continues to grow, and there is the suggestion that increased risk of occurrence and severity is associated with polymorphisms of genes involved in innate immune responses (79).
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 (54). Ultrasound features can help identify congenital rubella syndrome (97). A population-based cohort study reported an increase of at least a 7-fold in microcephaly prevalence at birth with congenital cytomegalovirus infection (52). In another study of congenital cytomegalovirus infection, microcephaly and intracranial calcification were seen in 27% and 43% of cases respectively (22). Cytomegalovirus has an affinity for the germinal matrix and causes periventricular tissue necrosis with subsequent calcification in this area (43). 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 (24). 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 is 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 (77). 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 three standard deviations below mean were within 1500 meters from hypocenter and were less than 15 weeks' gestation (94). Animal models are helping establish risk of even low doses of radiation on microcephaly (83).
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 (64). 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 (91). 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; 66).
In utero exposure to hydantoin anticonvulsants (such as phenytoin) is associated with microcephaly. Twenty-nine percent of 35 children prospectively followed for in utero hydantoin exposure had microcephaly (35). 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 (75). Even with diet control, long-term outcomes in these children continue to reveal a risk of microcephaly (93). An updated review of phenylketonuria presents information on the effects of high phenylalanine levels on brain development (76).
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 (51). 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 (74). 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 one 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 (81). Microcephaly due to malnutrition may be reversible if treated early (45).
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 is usually confirmed by 3D reconstruction CT scan of the head.
Diagnostic workup
A diagnostic workup should be planned after a detailed history and physical and neurologic exams. 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 (87; 18). 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 (09). The pattern of brain imaging seen in severe microcephaly can assist somewhat with counseling families about prognosis, based on the identification of four distinct patterns in a small cohort of children (10).
Genetic evaluations are evolving. Previously, chromosomal testing was strongly indicated when multiple major or minor anomalies were observed. However, some cases of chromosomal abnormality are "non-dysmorphic" (18). 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 (53). It is reasonable to consider its use in evaluating 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 (20). 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 (84). A prospective study showed the cost-effectiveness of whole-exome sequencing used early in the diagnostic pathway (86).
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 (38).
Management
Management of microcephaly is usually supportive. Evaluation by a developmental pediatrician, pediatric neurologist, or neurodevelopmental disability physician is recommended to ensure referral to appropriate interventions and supportive services and consideration of classroom placement and educational accommodations. Long-term involvement of therapies can include physical, occupational, developmental, speech, behavioral, hearing, vision, and nutritional.
The following are specific recommendations for children with microcephaly and associated developmental delays or intellectual disability. They may also have associated hearing or vision impairments, sensory issues, behavioral problems, and feeding or nutritional issues. These recommendations are for persons in the United States, and standard recommendations may vary in different countries.
For children 0 to 3 years of age, a referral to early Intervention is highly recommended for a comprehensive developmental assessment and access to home-based therapies. If qualifying delays or needs continue at 3 years of age, the child should be referred to a supportive preschool program, which they may attend until starting elementary school. This preschool may be available through the local public school district or county-based. This process involves an evaluation to determine qualifying services and therapies and the creation of an individualized education plan (IEP). An IEP provides specially designed instruction and related services, including therapies and accommodations.
For school-aged children, the preschool IEP will transition with the child or be created when school begins if not previously completed. IEP services are reviewed annually to determine whether any changes are needed and reassess goals and supports. Special education law requires that children with an IEP be in the least restrictive environment feasible at school and be included in general education as much as possible. Speech, occupational, and physical services can be provided in the IEP to the extent that the need affects the child's access to academic material. Additional therapies can include vision, hearing, and behavioral when warranted. Often, additional private therapies may be needed to supplement needs that are beyond the scope of school-based therapies. Starting at 14 years of age, a transition plan for post-graduation is discussed and added to the IEP.
Treatment for associated neurologic conditions, such as epilepsy, movement disorders, and spasticity, should be provided. Referral should be provided to the appropriate specialists, which may include Child Neurology or Physical Medicine and Rehabilitation. Genetic counseling is important for a family with an affected child, given the possible increased risk of recurrence in siblings (90). Children with microcephaly have a higher prevalence of ophthalmologic and audiologic abnormalities and require screenings (06). Therefore, referrals should be given for audiology and ophthalmology evaluations. If an underlying genetic syndrome is suspected or confirmed, further evaluation of other associated body systems may be warranted, including additional referrals to other medical specialists.
Special considerations
Pregnancy
It is important to avoid teratogenic medications, including hydantoin (phenytoin); exposure to radiation, including x-rays and CT scans; alcohol; and cocaine and other drugs of abuse. Women who are presently or who are trying to become pregnant should plan travel carefully, and the CDC has updated detailed information in the 2026 CDC Yellow Book: Health Information for International Travel.
Pregnant women specifically should consider the risk of exposure to viruses known to be associated with fetal microcephaly, including the Zika virus. The CDC provides a current list of countries and territories where Zika virus is a risk: https://wwwnc.cdc.gov/travel/page/zika-information and also provides targeted guidance for pregnant women through their Zika website: https://www.cdc.gov/zika/hcp/clinical-pregnant/index.html.
Media
References
- 01
- Abdel-Hamid MS, El-Dessouky SH, Ateya MI, Gaafar HM, Abdel-Salam GM. Phenotypic spectrum of NDE1-related disorders: from microlissencephaly to microhydranencephaly. Am J Med Genet 2019;179(3):494-7. PMID 30637988
- 02
- Aintablian HK, Narayanan V, Belnap N, Ramsey K, Grebe TA. An atypical presentation of ACAD9 deficiency: diagnosis by whole exome sequencing broadens the pnenotypic spectrum and alters treatment approach. Mol Genet Metab Rep 2016;10:38-44. PMID 28070495
- 03
- Alcantara D, O’Driscoll M. Congenital microcephaly. Am J Med Genet Part C Semin Med Genet 2014;166C(2):124-39. PMID 24816482
- 04
- Alkalay AL, Pomerance JJ, Rimoin DL. Fetal varicella syndrome. J Pediatr 1987;111:320-3. PMID 3625399
- 05
- Arnold GL, Kirby RS, Langendoerfer S, Wilkins-Haug L. Toluene embryopathy: clinical delineation and developmental follow-up. Pediatrics 1994;93:216-20. PMID 7510062
- 06
- Ashwal S, Michelson D, Plawner L, Dobyns WB; Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2009;73(11):887-97. PMID 19752457
- 07
- Asif M, Abdullah U, Nürnberg P, Tinschert S, Hussain MS. Congenital microcephaly: a debate on diagnostic challenges and etiological paradigm of the shift from isolated/non-syndromic to syndromic microcephaly. Cells 2023;12(4):642. PMID 36831309
- 08
- Barkovich AJ, Ferriero DM, Barr RM, et al. Microlissencephaly: a heterogeneous malformation of cortical development. Neuropediatrics 1998;29(3):113-9. PMID 9706619
- 09
- Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. A developmental and genetic classification for malformations of cortical development: update 2012. Brain 2012;135(Pt 5):1348-69. PMID 22427329
- 10
- Basel-Vanagaite L, Dobyns WB. Clinical and brain imaging heterogeneity of severe microcephaly. Pediatr Neurol 2010;43(1):7-16. PMID 20682196
- 11
- Boonsawat P, Joset P, Steindl K, et al. Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly. Genet Med 2019;21(9):2043-58. PMID 30842647
- 12
- Bray PF, Shields WD, Wolcott GJ, Madsen JA. Occipitofrontal head circumference--an accurate measure of intracranial volume. J Pediatr 1969;75:303-5. PMID 5795351
- 13
- Buntinx IM, Hennekam RCM, Brouwer OF, et al. Clinical profile of Angelman syndrome at different ages. Am J Med Genet 1995;56:176-83. PMID 7625442
- 14
- Burger J, Kunze J, Sperling K, Reis A. Phenotypic differences in Angelman syndrome patients: imprinting mutations show less frequently microcephaly and hypopigmentation than deletions. Am J Med Genet 1996;66:221-6. PMID 8958335
- 15
- Cardoso C, Leventer RJ, Ward HL, et al. Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003;72(4):918-30. PMID 12621583
- 16
- Clark AJ, Rosenberg EH, Almeida LS, et al. X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Hum Genet 2006;119(6):604-10. PMID 16738945
- 17
- Cragan JD, Isenburg JL, Parker SE, et al. Population-based microcephaly surveillance in the United States, 2009 to 2013: An analysis of potential sources of variation. Birth Defects Res A Clin Mol Teratol 2016;106(11):972-82. PMID 27891783
- 18
- Curry CJ, Stevenson RE, Aughton D, et al. Evaluation of mental retardation: recommendations of a consensus conference. Am J Med Genet 1997;72:468-77. PMID 9375733
- 19
- Di Donato N, Chiari S, Mirzaa GM, et al. Lissencephaly: Expanded imaging and clinical classification. Am J Med Genet A 2017;173(6):1473-88. PMID 28440899
- 20
- Dixon-Salazar TJ, Silhavy JL, Udpa N, et al. Exome sequencing can improve diagnosis and alter patient management. Sci Transl Med 2012;138:138ra78. PMID 22700954
- 21
- Dobbing J, Sands J. Quantitative growth and development of human brain. Arch Dis Child 1973;48:757-67. PMID 4796010
- 22
- Dobbins JG, Stewart JA, Demmler GJ. Surveillance of congenital cytomegalovirus disease, 1990-1991. Collaborating Registry Group. MMWR CDC Surveill Summ 1992;41(2):35-9. PMID 1317505
- 23
- Dolk H. The predictive value of microcephaly during the first year of life for mental retardation at seven years. Dev Med Child Neurol 1991;33:974-83. PMID 1743426
- 24
- Eichenwald HF. A study of congenital toxoplasmosis. In: Siim JC, editor. Human toxoplasmosis. Copenhagen: Munksgaard, 1960:41-9.
- 25
- Eichmuller OL, Knoblich JA. Human cerebral organoids—a new tool for clinical neurology research. Nat Rev Neurol 2022;18(11):661-80. PMID 36253568
- 26
- Finsterer J. Inherited mitochondrial disorders. Adv Exp Med Biol 2012;942;187-213. PMID 22399423
- 27
- Gabriel E, Ramani A, Altinisik N, Gopalakrishnan J. Human brain organoids to decode mechanisms of microcephaly. Front Cell Neurosci 2020;14:115. PMID 32457578
- 28
- Gafner M, Boltshauser E, D’Abrusco F, et al. Expanding the natural history of CASK‐related disorders to the prenatal period. Dev Med Child Neurol 2023;65(4):544-50. PMID 36175354
- 29
- Gilfillan GD, Selmer KK, Roxrud I, et al. SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. AM J Hum Genet 2008;82(4):1003-10. PMID 18342287
- 30
- Gordon-Lipkin E, Gentner MB, German R, Leppert ML. Neurodevelopmental outcomes in 22 children with microcephaly of different etiologies. J Child Neurol 2017;32(9):804-9. PMID 28482742
- 31
- Graham KA, Fox DJ, Talati A, et al. Prevalence and clinical attributes of congenital microcephaly – New York, 2013-2015. MMWR Morb Mortal Wkly Rep 2017;66(5):125-9. PMID 28182608
- 32
- Guo Q, Kouyama-Suzuki E, Shirai Y, Cao X, Yanagawa T, Mori T, Tabuchi K. Structural analysis implicates CASK-Liprin-α2 interaction in cerebellar granular cell death in MICPCH syndrome. Cells 2023;12(8):1177. PMID 37190086
- 33
- Haddad L, Hadi E, Leibovitz Z, et al. Small size, big problems: insights and difficulties in prenatal diagnosis of fetal microcephaly. Front Neurosci 2024;18:1347506. PMID 38533444
- 34
- Hansen M, Armstrong PK, Bower C, Baynam GS. Prevalence of microcephaly in an Australian population-based birth defects register, 1980-2015. Med J Aust 2017;206(8):351-6. PMID 28446117
- 35
- Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975;87:285-90. PMID 50428
- 36
- Ireland M, Donnai D, Burn J. Brachmann-de Lange syndrome. Delineation of the clinical phenotype. Am J Med Genet 1993;47:959-64. PMID 8291539
- 37
- Ito H, Shiwaku H, Yoshida C, et al. In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells. Mol Psychiatry 2015;20(4):459-71. PMID 25070536
- 38
- Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E. 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis. Arch Dis Child 1996;74;542-5. PMID 8758134
- 39
- Jayaraman D, Bae B, Walsh CA. The genetics of primary microcephaly. Annu Rev Genom Hum G 2018;19(1):177-200. PMID 29799801
- 40
- Jean F, Stuart A, Tarailo-Graovac M. Dissecting the genetic and etiological causes of primary microcephaly. Front Neurol 2020;11:570830. PMID 33178111
- 41
- Jones GE, Ostergaard P, Moore AT, et al. Microcephaly with and without chorioretinopathy, lymphedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations. Eur J Hum Genet 2014;22(7):881-7. PMID 24281367
- 42
- Kaindl AM, Passemard S, Kumar P, et al. Many roads lead to primary autosomal recessive microcephaly. Prog Neurobiol 2010;90(3):363-83. PMID 19931588
- 43
- Kawasaki H, Kosugi I, Meguro S, Iwashita T. Pathogenesis of developmental anomalies of the central nervouse system induced by congenital cytomegalovirus infection. Pathol Int 2017;67(2):72-82. PMID 28074532
- 44
- Kelley RI, Robinson D, Puffenberger EG, Strauss KA, Morton DH. Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria. Am J Med Genet 2002;112(4):318-26. PMID 12376931
- 45
- Kessel A, Tal Y, Jaffe M, Even L. Reversible brain atrophy and reversible developmental retardation in a malnourished infant. Isr J Med Sci 1996;32:306-8. PMID 8641869
- 46
- Kim J, Koo BK, Knoblich JA. Human organoids: model systems for human biology and medicine. Nat Rev Mol Cell Biol 2020;21(10):571-84. PMID 32636524
- 47
- Koenig M, Dobyns WB, Di Donato N. Lissencephaly: update on diagnostics and clinical management. Eur J Paediatr Neurol 2021;35:147-52. PMID 34731701
- 48
- Kwong KL, Wong V. Neurodevelopmental profile of Down syndrome in Chinese children. J Paediatr Child Health 1996;32:153-7. PMID 9156526
- 49
- Leroy JG, Frias JL. Nonsyndromic microcephaly: an overview. Adv Pediatr 2005;52:261-93. PMID 16124344
- 50
- Lim Y. Transcription factors in microcephaly. Front Neurosci 2023;17:1302033. PMID 38094004
- 51
- Mercuri E, Ricci D, Cowan FM, et al. Head growth in infants with hypoxic-ischemic encephalopathy: correlation with neonatal magnetic resonance imaging. Pediatrics 2000;106(2):235-43. PMID 10920145
- 52
- Messinger CJ, Lipsitch M, Bateman BT, et al. Association between congenital cytomegalovirus and the prevalence at birth of microcephaly in the United States. JAMA Pediatr 2020. PMID 32926077
- 53
- Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2011;77(17):1629-35. PMID 21956720
- 54
- Miller E, Cradock-Watson JE, Pollock TM. Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet 1982;2:781-4. PMID 6126663
- 55
- Mochida GH. Genetics and biology of microcephaly and lissencephaly. Semin Pediatr Neurol 2009;16(3):120-6. PMID 19778709
- 56
- Morris JK, Rankin J, Garne E, et al. Prevalence of microcephaly in Europe: population based study. BMJ 2016;354:i4721. PMID 27623840
- 57
- Najm J, Horn D, Wimplinger I, et al. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Gen 2008;40(9):1065-7. PMID 19165920
- 58
- Namavar Y, Barth PG, Poll-The BT, Baas F. Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia. Orphanet J Rare Dis 2011;6:50. PMID 21749694
- 59
- Nicholas AK, Khurshid M, Desir J, et al. WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 2010;42(11):1010-4. PMID 20890279
- 60
- Nowaczyk MJ, Irons MB. Smith-Lemli-Optiz syndrome: phenotype, natural history, and epidemiology. Am J Med Genet C Semin Med Genet 2012;160C(4):250-62. PMID 23059950
- 61
- Nunez C, Morris A, Jones CA, et al. Microcephaly in Australian children, 2016–2018: national surveillance study. Arch Dis Child 2021;106(9):849-54. PMID 33229416
- 62
- Opitz JM, Holt MC. Microcephaly: general considerations and aids to nosology. J Craniofac Genet Dev Biol 1990;10:175-204. PMID 2211965
- 63
- Ostrowsky JT, Katzelnick LC, Bourne N, et al. Zika virus vaccines and monoclonal antibodies: a priority agenda for research and development. Lancet Infect Dis 2025;25(7):e402-15. PMID 40024262
- 64
- Ouellette EM, Rosett HL, Rosman NP, Weiner L. Adverse effects on offspring of maternal alcohol abuse during pregnancy. N Engl J Med 1977;297:528-30. PMID 887104
- 65
- Parrini E, Conti V, Dobyns WB, Guerrini R. Genetic basis of brain malformations. Mol Syndromol 2016;7(4):220-33. PMID 27781032
- 66
- Pearson MA, Hoyme HE, Seaver LH, Rimsza ME. Toluene embryopathy: delineation of the phenotype and comparison with fetal alcohol syndrome. Pediatrics 1994;93:211-5. PMID 7510061
- 67
- Pearson TS, Akman C, Hinton VJ, Engelstad K, De Vivo DC. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep 2013;13(4):342. PMID 23443458
- 68
- Raghuram K, Yang J, Church PT, et al. Head growth trajectory and neurodevelopmental outcomes in preterm neonates. Pediatrics 2017;140(1):e20170216. PMID 28759409
- 69
- Ramirez ML, Rivas F, Cantu JM. Silent microcephaly: a distinct autosomal dominant trait. Clin Genet 1983;23:281-6. PMID 6851218
- 70
- Rasmussen SA, Janieson DJ, Honein MA, Petersen LR. Zika virus and birth defects- reviewing the evidence for causality. NEJM 2016;374:1981-87. PMID 27074377
- 71
- Rasool S, Baig JM, Moawia A, et al. An update of pathogenic variants in ASPM, WDR62, CDK5RAP2, STIL, CENPJ, and CEP135 underlying autosomal recessive primary microcephaly in 32 consanguineous families from Pakistan. Mol Genet Genomic Med 2020;8(9):e1408. PMID 32677750
- 72
- Rodriguez-Garcia ME, Cotrina-Vinagre FJ, Sánchez-Calvin MT, et al. A novel de novo variant in CASK causes a severe neurodevelopmental disorder that masks the phenotype of a novel de novo variant in EEF2. J Hum Genet 2023;68(8):543-50. PMID 37072624
- 73
- Rossi LN, Candini G, Scarlatti G, Rossi G, Prina E, Alberti S. Autosomal dominant microcephaly without mental retardation. Am J Dis Child 1987;141:655-9. PMID 3578190
- 74
- Roth SC, Baudin J, Cady E, et al. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol 1997;39:718-25. PMID 9393884
- 75
- Rouse B, Azen C, Koch R, et al. Maternal Phenylketonuria Collaborative Study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae. Am J Med Genet 1997;69:89-95. PMID 9066890
- 76
- Rovelli V, Longo N. Phenylketonuria and the brain. Mol Genet Metab 2023;139(1):107583. PMID 37105048
- 77
- Roy S, Geoffroy G, Lapointe N, Michaud J. Neurologic findings in HIV-infected children: a review of 49 cases. Can J Neurol Sci 1992;19(4):453-7. PMID 1384947
- 78
- Rubinstein JH. Broad thumb-hallux (Rubinstein-Taybi) syndrome 1957-1988. Am J Med Genet Suppl 1990;6:3-16. PMID 2118774
- 79
- Santos CN, Magalhães LS, Fonseca AB, et al. Association between genetic variants in TREM1, CXCL10, IL4, CXCL8 and TLR7 genes with the occurrence of congenital Zika syndrome and severe microcephaly. Sci Rep 2023;13(1):3466. PMID 36859461
- 80
- Schorry EK, Keddache M, Lanphear N, et al. Genotype-phenotype correlations in Rubinstein-Taybi syndrome. Am J Med Genet 2008;146A(19):2512-9. PMID 18792986
- 81
- Skull SA, Ruben AR, Walker AC. Malnutrition and microcephaly in Australian Aboriginal children. Med J Aust 1997;166:412-4. PMID 9140346
- 82
- Snoek R, Albers MEWA, Mulder EJH, et al. Accuracy of diagnosis and counseling of fetal brain anomalies prior to 24 weeks of gestational ago. J Matern Fetal Neonatal Med 2017:1-7. PMID 28585870
- 83
- Sreetharan S, Thome C, Tharmalingam S, et al. Ionizing radiation exposure during pregnancy: effects on postnatal development and life. Radiat Res 2017;187(6):647-58. PMID 28418814
- 84
- Srivastava S, Cohen JS, Vernon H, et al. Clinical whole exome sequencing in child neurology practice. Ann Neurol 2014;76(4):473-83. PMID 25131622
- 85
- Stracker TH, Morrison CG, Gergely F. Molecular causes of primary microcephaly and related diseases: a report from the UNIA Workshop. Chromosoma 2020;129(2):115-20. PMID 32424716
- 86
- Stark Z, Schofield D, Alam K, et al. Prospective comparison of the cost-effectiveness of clinical whole-exome sequencing with that of usual care overwhelmingly supports early use and reimbursement. Genet Med 2017;19(8):867-74. PMID 28125081
- 87
- Steinlin M, Zurrer M, Martin E, Boesch C, Largo RH, Boltshauser E. Contribution of magnetic resonance imaging in the evaluation of microcephaly. Neuropediatrics 1991;22:184-9. PMID 1775213
- 88
- Stevens CA, Hennekam RCM, Blackburn BL. Growth in the Rubinstein-Taybi syndrome. Am J Med Genet Suppl 1990;6:51-5. PMID 2118779
- 89
- Takimoto M. D40/KNL1/CASC5 and autosomal recessive primary microcephaly. Congenit Anom (Kyoto) 2017;57(6):191-6. PMID 28901661
- 90
- Tolmie JL, McNay M, Stephenson J, Doyle D, Connor JM. Microcephaly: genetic counseling and antenatal diagnosis after the birth of an affected child. Am J Med Genet 1987;27:583-94. PMID 3307411
- 91
- Tsay CH, Partridge JC, Villarreal SF, Good WV, Ferriero DM. Neurologic and ophthalmologic findings in children exposed to cocaine in utero. J Child Neurol 1996;11:25-30. PMID 8745381
- 92
- von der Hagen M, Pivarcsi M, Liebe J, et al. Diagnostic approach to microcephaly in childhood: a two center study and review of literature. Dev Med Child Neurol 2014;56(8):732-41. PMID 24617602
- 93
- Waisbren SE, Rohr F, Anastasoaie V, et al. Maternal phenylketonuria: long-term outcomes in offspring and post-pregnancy maternal characteristics. JIMD Rep 2015;21:23-33. PMID 25712380
- 94
- Wood JW, Johnson KG, Omori Y. In utero exposure to the Hiroshima atomic bomb. An evaluation of head size and mental retardation: twenty years later. Pediatrics 1967;39:385-92. PMID 6066886
- 95
- Woods CG. Human microcephaly. Curr Opin Neurobiol 2004;14(1):112-7. PMID 15018946
- 96
- Yaniv G, Katorza E, Tsehmaister Abitbol V, et al. Discrepancy in fetal head biometry between ultrasound and MRI in suspected microcephalic fetuses. Acta Radiol 2017;58(12):1519-27. PMID 28304179
- 97
- Yazigi A, De Pecoulas AE, Vauloup-Fellous C, Grangeot-Keros L, Ayoubi JM, Picone O. Fetal and neonatal abnormalities due to congenital rubella syndrome: a review of literature. J Matern Fetal Neonatal Med 2017;30(3):274-27. PMID 27002428
- 98
- Yigit G, Wieczorek D, Bögershausen N, et al. A syndrome of microcephaly short stature, polysyndactyly, and dental anomalies caused by a homozygous KATNB1 mutation. Am J Med Genet 2016;170(3):728-33. PMID 26640080
- 99
- Yoldas Celik M, Yazici H, Erdem F, et al. Unique clinical presentations and follow-up outcomes from experience with congenital disorders of glycosylation: PMM2-PGM1-DPAGT1-MPI-POMT2-B3GALNT2-DPM1-SRD5A3-CDG. J Pediatr Endocrinol Metab 2023;36(6):530-8. PMID 37042760
- 100
- Zhou GF, Qian W, Li F, et al. Discovery of ZFD-10 of a pyridazino [4, 5-b] indol-4 (5H)-one derivative as an anti-ZIKV agent and a ZIKV NS5 RdRp inhibitor. Antiviral Res 2023;214:105607. PMID 37088168
- 101
- Zhu Y, Liang M, Yu J, et al. Repurposing of doramectin as a new anti-Zika virus agent. Viruses 2023;15(5):1068. PMID 37243154
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Robyn Filipink MD
Dr. Filipink of Children's Hospital of Pittsburgh of UPMC has no relevant financial relationships to disclose.
See Profile
Editor
-
Nina F Schor MD PhD
Dr. Schor of the University of Rochester School of Medicine and Dentistry has no relevant financial relationships to disclose.
See Profile
Former Authors
- Ganeshwaran H Mochida MD PhD
- Kalpathy S Krishnamoorthy MD
- Deirdre O'Reilly MD MPH
Patient Profile
- Age range of presentation
-
- 0 month to 18 years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity typical
- heredity may be a factor
- autosomal dominant
- autosomal recessive
- sex-linked recessive
- Population groups selectively affected
-
- None selectively affected
- Occupation groups selectively affected
-
- None selectively affected
ICD & OMIM codes
- ICD-10
-
- Microcephaly: Q02
- ICD-11
-
- Microcephaly: LA05.0
- OMIM
-
- Microcephaly, primary autosomal recessive, 1: #251200
- Microcephaly with spastic quadriplegia: 251280
- Microcephaly, autosomal dominant: %156580
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