Primary microcephaly refers to less than normal brain tissue development during pregnancy. Secondary microcephaly refers to the development of normal brain tissue during pregnancy and limited development after birth. Current research suggests that primary microcephaly is due to a decrease in the number of neurons that divide during neuronal production, while secondary microcephaly is due to a decrease in the number of peduncle connections and dendrites during neuronal differentiation. Further studies have found that microcephaly is also related to genetics, and this paper will review the progress of factors affecting microcephaly. 1. Definition Microcephaly is defined by a reduction in head circumference, and is thus thought to be caused by a significant reduction in the volume of brain tissue in the individual. Clinically, microcephaly is diagnosed as a condition in which the occipitofrontal diameter is three standard deviations smaller than that of a person of the same age and sex, while the femur length is within two standard deviations of normal, often accompanied by mental retardation [1]. Because 55% of the human brain is composed of cerebral cortex, individuals with microcephaly have significantly less cerebral cortex and most of the development is delayed, which leads to mental retardation [2]. The incidence of microcephaly is low and has been poorly reported both nationally and internationally. Since Mochida and Walshi first summarized microcephaly, there have been exciting advances in this area of research over time [3, 4]. 2, Classification of microcephaly It is helpful to classify microcephaly into primary and secondary to understand the etiology of microcephaly. Primary microcephaly refers to the development of brain tissue that is significantly smaller than normal at the gestational week during pregnancy; secondary microcephaly refers to the development of brain tissue that is normal during pregnancy and restricted after birth resulting in smaller than normal development. Current research suggests that primary microcephaly is due to a decrease in the number of neurons that divide during neuronal production; secondary microcephaly is due to a decrease in the number of peduncle connections and dendrites during neuronal differentiation. The former occurs before 32 weeks of gestation (neuronogenesis mainly occurs at 21 weeks of gestational age) and manifests as a decrease in neuronal cells, while the latter occurs after birth (synaptic connections and myelin formation occur after birth) and manifests as a decrease in neuronal synaptic connections or a normal number of neurons with reduced activity [5, 6]. 3, causes of microcephaly 3.1 Non-genetic factors The etiology of primary microcephaly is mainly non-genetic, and some scholars have counted the proportion of each influencing factor in 106 patients with microcephaly: early pregnancy infection [7] (especially Toxoplasma gondii infection) 20.75%, neonatal hypoxic-ischemic encephalopathy 16.98%, neonatal intracranial hemorrhage 10.78%, preterm birth 12.26%, chromosomal abnormalities 7.55%, and meningitis encephalopathy 5.66% [8], in addition to accidental traumatic brain injury, infection with syphilis and high intake of alcohol by pregnant women are also influential factors [9, 10]. And the reduction of fetal neuronal cells due to alcohol exposure also involves important genetic factors (such as nitric oxide synthase activity) [11], thus having important social health implications for the identification of high-risk pregnancies that may be at risk for fetal alcohol syndrome (which may lead to mental retardation and microcephaly). 3.2 Genetic factors Further studies have found that microcephaly is also genetically related, and this article will focus on the genetic factors of microcephaly. Neuritogenesis: All fetal CNS cells are derived from pseudocomplex neuroepithelial cells. These newborn nerve cells gradually migrate to a certain location and begin to form functional synapses. The forerunners of these nerve cells undergo two mitotic divisions, the first of which occurs in the neuroepithelium as a balanced division of the neuroepithelial cells, followed by another unbalanced division, resulting in a multiplication of nerve cells. Thus changing the number of divisible neuroepithelial cells is the most effective way to increase the final number of neuronal cells. During neurogenesis, those neurons that fail to establish connections with target cells or target tissues all die at a certain time, and β-catenin was found to have an important role in the establishment of neuronal connections. Its overexpression in rats led to a significant increase in brain volume at birth. These all suggest that β-catenin plays an important role in the control of neuronal division. Transcription factors also play an important role in neuritogenesis. For example, the recently discovered activating transcription factor 5 (ATF5), a basic leucine zipper transcription factor, blocks neuroepithelial cell division [12]. 3.3 Autosomal pathogenic primary microcephaly (MCPH) Individuals with MCPH are born with a marked reduction in head circumference and mental retardation without other neurobiological abnormalities [13]. Brain scans show a reduction in the entire brain, with the major impact being on the cerebral cortex. The two genes responsible for MCPH are microcephalin and abnormal spindle in microcephaly (ASPM) [14], and mutations in these genes lead to the production of truncated proteins that result in microcephaly, but the location of the mutation is not related to the severity of microcephaly [15]. This in turn suggests that the loss of function of the ASPM protein is responsible for MCPH. Both genes are expressed in the neuroepithelial cells of the mammalian embryo and fetal brain. 3.4 Chromosome breakage syndromes Chromosome breakage syndromes are multigroup genetic disorders that manifest as imperfect repair after DNA damage, and this chromosomal damage caused by the accumulation of DNA damage can be detected microscopically. Microcephaly can occur in some chromosomal breakage syndromes such as Bloom syndrome (mainly caused by mutations in recombinant Q protein) and Nijmegen breakage syndrome [16, 17].Seckel syndrome is also an example of 1 disproportionate microcephaly that usually occurs with a body weight <1.5 kg [18]. 3.5 Metabolic disorders Many inborn metabolic disorders are associated with secondary microcephaly, but rarely with primary microcephaly. The autosomal disorder MCPHA is characterized by progressive microcephaly and shortened life expectancy, and its occurrence is associated with the replacement of an amino acid in the SLC25A19 gene, thereby rendering it inactive [19].MCPHA causes abnormal brain development due to the inhibition of mitochondrial DNA synthesis, which leads to energy deficiency. 3.6 Secondary microcephaly syndrome (Rett syndrome) is mainly characterized by secondary microcephaly, which begins at 6 to 18 months of age in such patients, with normal head size and neurological function before the onset of the disease, and as the disease progresses, behavioral decline consistent with impaired brain development manifests and leads to mental retardation and frequent convulsions. This disorder usually occurs in females and is caused by mutations in the X-linked MeCP2 gene [20]. Recent studies have shown that the MeCP2 gene has an important role in establishing and maintaining neuronal function. 3.7 Abnormal neuronal migration lesions These are diseases in which neurons are normal at the time of neuroepitheliogenesis, but an insufficient proportion of neurons are subsequently transferred to the correct location in the central nervous system and function [21]. Microcephaly occurs in the following types of disorders, such as reelin mutations which usually occur in primary microcephaly, and Miller-Dieker syndrome which usually occurs in secondary microcephaly, but the reason for its occurrence of reduced head circumference is not known. These disorders can be diagnosed by MRI. In addition, the hereditary causes of microcephaly can be analyzed in evolutionary terms [22]. In conclusion, neurological lesions associated with the occurrence of microcephaly have been identified one after another, each phenotype being due to a small number of genetic dysfunctions. With the identification of these genes and increased knowledge of neurodevelopmental processes, the understanding of microcephaly will further increase.