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Microcephaly (from New Latin ''microcephalia'', from
Ancient Greek Ancient Greek includes the forms of the Greek language used in ancient Greece and the ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following periods: Mycenaean Greek (), Dark Ages (), the Archaic pe ...
μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it may develop in the first few years of life. Since
brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
growth is correlated with head growth, people with this disorder often have an intellectual disability, poor motor function, poor speech, abnormal facial features,
seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...
and dwarfism. The disorder is caused by a disruption to the genetic processes that form the brain early in pregnancy, though the cause is not identified in most cases. Many
genetic syndromes A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek σύνδρομον, meaning "concurrence". When a syndrome is paired ...
can result in microcephaly, including
chromosomal A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...
and single-gene conditions, though almost always in combination with other symptoms. Mutations that result solely in microcephaly (primary microcephaly) exist but are less common. External toxins to the embryo, such as alcohol during pregnancy or vertically transmitted infections, can also result in microcephaly. Microcephaly serves as an important
neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
indication or warning sign, but no uniformity exists in its definition. It is usually defined as a head circumference (HC) more than two standard deviations below the mean for age and sex. Some academics advocate defining it as head circumference more than three standard deviations below the mean for the age and sex. There is no specific treatment that returns the head size to normal. In general, life expectancy for individuals with microcephaly is reduced, and the prognosis for normal brain function is poor. Occasional cases develop normal intelligence and grow normally (apart from persistently small head circumference). It is reported that in the United States, microcephaly occurs in 1 in 800-5,000 births.


Signs and symptoms

There are a variety of symptoms that can occur in children. Infants with microcephaly are born with either a normal or reduced head size. Subsequently, the head fails to grow, while the face continues to develop at a normal rate, producing a child with a small head and a receding forehead, and a loose, often wrinkled scalp. As the child grows older, the smallness of the skull becomes more obvious, although the entire body also is often underweight and dwarfed. Severely impaired intellectual development is common, but disturbances in motor functions may not appear until later in life. Affected newborns generally have striking
neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
defects and seizures. Development of motor functions and speech may be delayed. Hyperactivity and intellectual disability are common occurrences, although the degree of each varies. Convulsions may also occur. Motor ability varies, ranging from
clumsiness Clumsy or clumsiness may refer to: Behaviour *Accident-proneness *Developmental coordination disorder, a motor skills disorder which brings about chronic clumsiness Music * ''Clumsy'' (Our Lady Peace album), a 1997 album by Our Lady Peace ** "Cl ...
in some to
spastic quadriplegia Spastic quadriplegia, also known as spastic tetraplegia, is a subset of spastic cerebral palsy that affects all four limbs (both arms and legs). Compared to quadriplegia, spastic tetraplegia is defined by spasticity of the limbs as opposed to s ...
in others.


Causes

Microcephaly is a type of
cephalic disorder Cephalic disorders () are congenital conditions that stem from damage to, or abnormal development of, the budding nervous system. Cephalic disorders are not necessarily caused by a single factor, but may be influenced by hereditary or genetic c ...
. It has been classified in two types based on the onset:


Congenital

* Isolated *# Familial ( autosomal recessive) microcephaly *# Autosomal dominant microcephaly *# X-linked microcephaly *# Chromosomal (balanced rearrangements and ring chromosome) * Syndromes ** Chromosomal **# Poland syndrome **#
Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual d ...
**# Edward syndrome **# Patau syndrome **# Unbalanced rearrangements ** Contiguous gene deletion **# 4p deletion ( Wolf–Hirschhorn syndrome) **# 5p deletion (
Cri-du-chat Cri du chat syndrome is a rare genetic disorder due to a partial chromosome deletion on chromosome 5. Its name is a French term ("cat-cry" or " call of the cat") referring to the characteristic cat-like cry of affected children. It was first de ...
) **# 7q11.23 deletion ( Williams syndrome) **# 22q11 deletion ( DiGeorge syndrome) * Single gene defects *# Smith–Lemli–Opitz syndrome *# Seckel syndrome *#
Cornelia de Lange syndrome Cornelia de Lange syndrome (CdLS) is a genetic disorder. People with this syndrome experience a range of physical, cognitive, and medical challenges ranging from mild to severe. The syndrome has a widely varied phenotype, meaning people with the sy ...
*#
Holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed ...
*# Primary microcephaly 4 *# Wiedemann-Steiner syndrome * Acquired ** Disruptive injuries **# Ischemic stroke **# Hemorrhagic stroke **# Death of a monozygotic twin ** Vertically transmitted infections **#
Congenital cytomegalovirus infection Congenital cytomegalovirus (CMV) infection refers to a condition where cytomegalovirus is transmitted in the prenatal period. CMV is a member of the virus family herpesviridae and is the most common intrauterine infection. Human cytomegalovirus i ...
**# Toxoplasmosis **# Congenital rubella syndrome **
Congenital Varicella Syndrome
ref name=":2" /> **# Zika virus (see Zika fever#Microcephaly) ** Drugs **#
Fetal hydantoin syndrome Fetal hydantoin syndrome, also called fetal dilantin syndrome, is a group of defects caused to the developing fetus by exposure to teratogenic effects of phenytoin. Dilantin is the brand name of the drug phenytoin sodium in the United States, comm ...
**# Fetal alcohol syndrome * Other *# Radiation exposure to mother *# Maternal malnutrition *# Maternal
phenylketonuria Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may als ...
*# Poorly controlled gestational diabetes *#
Hyperthermia Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extrem ...
*# Maternal hypothyroidism *#
Placental insufficiency Placental insufficiency or utero-placental insufficiency is the failure of the placenta to deliver sufficient nutrients to the fetus during pregnancy, and is often a result of insufficient blood flow to the placenta. The term is also sometimes u ...
*# Craniosynostosis


Postnatal onset

* Genetic ** Inborn errors of metabolism **#
Congenital disorder of glycosylation A congenital disorder of glycosylation (previously called carbohydrate-deficient glycoprotein syndrome) is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defe ...
**# Mitochondrial disorders **#
Peroxisomal disorder Peroxisomal disorders represent a class of medical conditions caused by defects in peroxisome functions. This may be due to defects in single enzymes important for peroxisome function or in peroxins, proteins encoded by ''PEX'' genes that are criti ...
**# Glucose transporter defect **#
Menkes disease Menkes disease (MNK), also known as Menkes syndrome, is an X-linked recessive disorder caused by mutations in genes coding for the copper-transport protein ATP7A, leading to copper deficiency. Characteristic findings include kinky hair, growth ...
**#
Congenital disorders of amino acid metabolism Inborn errors of amino acid metabolism are metabolic disorders which impair the synthesis and degradation of amino acids. Types *Alkaptonuria *Aspartylglucosaminuria *Branched-chain keto acid dehydrogenase kinase deficiency *Methylmalonic acidemi ...
**# Organic acidemia * Syndromes ** Contiguous gene deletion **# 17p13.3 deletion ( Miller–Dieker syndrome) ** Single gene defects **# Rett syndrome (primarily girls) **# Nijmegen breakage syndrome **# X-linked lissencephaly with abnormal genitalia **# Aicardi–Goutières syndrome **#
Ataxia telangiectasia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
**# Cohen syndrome **# Cockayne syndrome * Acquired ** Disruptive injuries **# Traumatic brain injury **#
Hypoxic-ischemic encephalopathy Cerebral hypoxia is a form of hypoxia (reduced supply of oxygen), specifically involving the brain; when the brain is completely deprived of oxygen, it is called ''cerebral anoxia''. There are four categories of cerebral hypoxia; they are, in o ...
**# Ischemic stroke **# Hemorrhagic stroke ** Infections **# Congenital HIV encephalopathy **# Meningitis **# Encephalitis ** Toxins ***
Chronic kidney failure Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, v ...
** Deprivation **# Hypothyroidism **# Anemia **# Congenital heart disease **# Malnutrition Genetic mutations cause most cases of microcephaly. Relationships have been found between autism, duplications of genes and macrocephaly on one side. On the other side, a relationship has been found between
schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...
, deletions of genes and microcephaly. Several genes have been designated "MCPH" genes, after microcephalin (''MCPH1''), based on their role in brain size and primary microcephaly syndromes when mutated. In addition to microcephalin, these include ''
WDR62 WD repeat-containing protein 62 is a protein that in humans is encoded by the ''WDR62'' gene. Function WDR62 is a scaffold protein and interacts with different kinases. WDR62 plays a role in mediating activation of the JNK pathway in response ...
'' (''MCPH2''), ''
CDK5RAP2 CDK5 regulatory subunit-associated protein 2 is a protein that in humans is encoded by the ''CDK5RAP2'' gene. It has necessary roles in the formation and stability of microtubules from the centrosome and has been found to be linked to human bra ...
'' (''MCPH3''), '' KNL1'' (''MCPH4''), ''ASPM'' (''MCPH5''), ''
CENPJ Centromere protein J is a protein that in humans is encoded by the ''CENPJ'' gene. It is also known as centrosomal P4.1-associated protein (CPAP). During cell division, this protein plays a structural role in the maintenance of centrosome integri ...
'' (''MCPH6''), ''
STIL SCL-interrupting locus protein is a protein that in humans is encoded by the ''STIL'' gene. STIL is present in many different cell types and is essential for centriole biogenesis. This gene encodes a cytoplasmic protein implicated in regulation ...
'' (''MCPH7''), '' CEP135'' (''MCPH8''), '' CEP152'' (''MCPH9''), '' ZNF335'' (''MCPH10''), '' PHC1'' (''MCPH11'') and '' CDK6'' (''MCPH12''). Moreover, an association has been established between common genetic variants within known microcephaly genes (such as ''MCPH1'' and ''CDK5RAP2'') and normal variation in brain structure as measured with magnetic resonance imaging (MRI)i.e., primarily brain cortical surface area and total brain volume. The spread of Aedes mosquito-borne Zika virus has been implicated in increasing levels of congenital microcephaly by the
International Society for Infectious Diseases The International Society for Infectious Diseases (ISID), established in 1986, is a nonprofit organization that monitors infectious diseases on a global scale. It also offers grants and fellowships, publishes a journal, and runs online learning p ...
and the US Centers for Disease Control and Prevention. Zika can spread from a pregnant woman to her fetus. This can result in other severe brain malformations and birth defects. A study published in The New England Journal of Medicine has documented a case in which they found evidence of the Zika virus in the brain of a fetus that displayed the morphology of microcephaly.


Microlissencephaly

Microlissencephaly Microlissencephaly (MLIS) is a rare congenital brain disorder that combines severe microcephaly (small head) with lissencephaly (smooth brain surface due to absent sulci and gyri). Microlissencephaly is a heterogeneous disorder, i.e. it has many d ...
is microcephaly combined with lissencephaly (smooth brain surface due to absent sulci and
gyri In neuroanatomy, a gyrus (pl. gyri) is a ridge on the cerebral cortex. It is generally surrounded by one or more sulci (depressions or furrows; sg. ''sulcus''). Gyri and sulci create the folded appearance of the brain in humans and other ...
). Most cases of microlissencephaly are described in consanguineous families, suggesting an
autosomal recessive inheritance In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...
.


Historical causes of microcephaly

After the dropping of atomic bombs "Little Boy" on Hiroshima and "Fat Man" on
Nagasaki is the capital and the largest city of Nagasaki Prefecture on the island of Kyushu in Japan. It became the sole port used for trade with the Portuguese and Dutch during the 16th through 19th centuries. The Hidden Christian Sites in the ...
, several women close to ground zero who had been pregnant at the time gave birth to children with microcephaly. Microcephaly was present in 7 children from a group of 11 pregnant women at 11–17 weeks of gestation who survived the blast at less than from ground zero. Due to their proximity to the bomb, the pregnant women's '' in utero'' children received a biologically significant radiation dose that was relatively high due to the massive
neutron The neutron is a subatomic particle, symbol or , which has a neutral (not positive or negative) charge, and a mass slightly greater than that of a proton. Protons and neutrons constitute the atomic nucleus, nuclei of atoms. Since protons and ...
output of the lower explosive-yielding Little Boy. Researchers studied 286 additional children who were in utero during the atomic bombings, and after a year they found these children had a higher incidence of microcephaly and mental retardation.


Other relations

Intracranial volume also affects this pathology, as it is related with the size of the brain.


Pathophysiology

Microcephaly generally is due to the diminished size of the largest part of the human brain, the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting o ...
, and the condition can arise during embryonic and fetal development due to insufficient neural stem cell proliferation, impaired or premature neurogenesis, the death of neural stem cells or neurons, or a combination of these factors. Research in animal models such as rodents has found many genes that are required for normal brain growth. For example, the Notch pathway genes regulate the balance between stem cell proliferation and neurogenesis in the stem cell layer known as the ventricular zone, and experimental mutations of many genes can cause microcephaly in mice, similar to human microcephaly. Mutations of the abnormal spindle-like microcephaly-associated (ASPM) gene are associated with microcephaly in humans and a knockout model has been developed in ferrets that exhibits severe microcephaly. In addition, viruses such as cytomegalovirus (CMV) or Zika have been shown to infect and kill the primary stem cell of the brain—the radial glial cell, resulting in the loss of future daughter neurons. The severity of the condition may depend on the timing of infection during pregnancy. Microcephaly is a feature common to several different genetic disorders arising from a deficiency in the cellular DNA damage response. Individuals with the following DNA damage response disorders exhibit microcephaly: Nijmegen breakage syndrome, ATR- Seckel syndrome, MCPH1-dependent primary microcephaly disorder, xeroderma pigmentosum complementation group A deficiency,
Fanconi anemia Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of no ...
, ligase 4 deficiency syndrome and Bloom syndrome. These findings suggest that a normal DNA damage response is critical during brain development, perhaps to protect against induction of apoptosis by DNA damage occurring in
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s.


Treatment

There is no known cure for microcephaly. Treatment is symptomatic and supportive. Because some cases of microcephaly and its associated symptoms may be a result of amino acid deficiencies, treatment with amino acids in these cases has been shown to improve symptoms such as seizures and motor function delays.


History

People with small heads were displayed as a public spectacle in
ancient Rome In modern historiography, ancient Rome refers to Roman people, Roman civilisation from the founding of the city of Rome in the 8th century BC to the collapse of the Western Roman Empire in the 5th century AD. It encompasses the Roman Kingdom ...
. People with microcephaly were sometimes sold to
freak shows A freak show, also known as a creep show, is an exhibition of biological rarities, referred to in popular culture as "freaks of nature". Typical features would be physically unusual humans, such as those uncommonly large or small, those with ...
in North America and Europe in the 19th and early 20th centuries, where they were known by the name "pinheads". Many of them were presented as different species (e.g., "monkey man") and described as being the missing link. Famous examples include
Zip the Pinhead William Henry Johnson ( – April 9, 1926), known as Zip the Pinhead, was an American freak show performer known for his tapered head. Early life William Henry Johnson was born one of six children to a very poor African-American family. ...
(although he may not have had microcephaly)," Maximo and Bartola, and Schlitzie the Pinhead,.
Zip the Pinhead William Henry Johnson ( – April 9, 1926), known as Zip the Pinhead, was an American freak show performer known for his tapered head. Early life William Henry Johnson was born one of six children to a very poor African-American family. ...
and Schlitzie the Pinhead, also stars of the 1932 film '' Freaks'', were cited as influences on the development of the long-running comic strip character
Zippy the Pinhead Zippy the Pinhead is a fictional character who is the protagonist of ''Zippy'', an American comic strip created by Bill Griffith. Zippy's most famous quotation, "Are we having fun yet?", appears in ''Bartlett's Familiar Quotations'' and became a ...
, created by
Bill Griffith William Henry Jackson Griffith (born January 20, 1944) is an American cartoonist who signs his work Bill Griffith and Griffy. He is best known for his surreal daily comic strip '' Zippy''. The catchphrase "Are we having fun yet?" is credited to ...
. File:Triboulet.png, Triboulet, 1461 File:Die Gartenlaube (1868) b 204.jpg, Emil R., 1868 File:Idiotie - Microcéphalie.jpg, Elderly female, 1888/89 File:Osseous Deformity Case 6.jpg, 36-year-old male, 1894 (normal intelligence present) File:Microcephalic high-grade idiot.jpg, 52-year-old female, 1900 File:Microcephalus A.jpg, 10-year-old male, 1904 File:Microcephalic idiot.jpg, 20-year-old female, 1906/07 File:Microcephaly sister and brother.jpg, 18-year-old sister and 9-year-old brother, 1917 File:Various types 1 (detail A, microcephaly).jpg, 55-year-old female, 1920 (linear descendant of Pocahontas) File:Microcephalics (2nd image, EFGHIJ).jpg, 6 siblings, 1920


Notable cases

* A 'dwarf' of Punt (ancient Somalia) was given by the Chief clans as partial tribute to the last ruler of Ancient Egypt's Old Kingdom, Pepi II Neferkare (6th Dynasty, circa 2125–2080 BC); it could be inferred that this person was also microcephalic. In a letter preserved at the British Museum, the young king gives instructions by letter, " Harkhuf! The men in your service scorts; soldiers; sailors; guards, etc.ought pay sincere care with the dwarf's head while sleeping during the voyage to the palace" (so that it does not fall off). At the same time, it could be for other reasons unrelated to microcephaly, etc. * ''Triboulet'', a jester of duke René of Anjou (not to be confused with the slightly later Triboulet at the French court). * Jenny Lee Snow and Elvira Snow, whose stage names were Pip and Flip, respectively, were sisters with microcephaly who acted in the 1932 film '' Freaks''. * Schlitze "Schlitzie" Surtees, possibly born Simon Metz, was a widely known sideshow performer and actor, who also appeared in '' Freaks''. * Lester "Beetlejuice" Green, a member of radio host Howard Stern's Wack Pack.


See also

* Anencephaly (Usually rapidly fatal) * Cerebral rubicon * Hydrocephaly * Macrocephaly * Seckel syndrome * Achalasia microcephaly


References


External links

*
NINDS Overview
{{Authority control Congenital disorders of nervous system Disorders causing seizures