Hold Me Mother, 2018 - Wellcome Photography Prize 2019

Microcephaly (from

New Latin New Latin (also called Neo-Latin or Modern Latin) is the revival of Literary Latin used in original, scholarly, and scientific works since about 1500. Modern scholarly and technical nomenclature, such as in zoological and botanical taxonomy ...

''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 peri ...

μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal

head A head is the part of an organism which usually includes the ears, brain, forehead, cheeks, chin, eyes, nose, and mouth, each of which aid in various sensory functions such as sight, hearing, smell, and taste. Some very simple animals may ...

. Microcephaly may be present at birth or it may develop in the first few years of life. Since

brain A brain is an 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 vision. It is the most complex organ in a v ...

growth is correlated with head growth, people with this disorder often have an

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

, 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 neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...

and

dwarfism Dwarfism is a condition wherein an organism is exceptionally small, and mostly occurs in the animal kingdom. In humans, it is sometimes defined as an adult height of less than , regardless of sex; the average adult height among people with dw ...

. 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 are ...

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 Alcohol use in pregnancy includes use of alcohol at any time during gestation, including the time before a mother-to-be is aware that she is pregnant. Alcohol use at some point during pregnancy is common and appears to be rising in prevalence. Al ...

vertically transmitted infections A vertically transmitted infection is an infection caused by pathogenic bacteria or viruses that use mother-to-child transmission, that is, transmission directly from the mother to an embryo, fetus, or baby during pregnancy or childbirth. It can ...

, 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 ...

indication or warning sign, but no uniformity exists in its definition. It is usually defined as a head circumference (HC) more than two

standard deviation In statistics, the standard deviation is a measure of the amount of variation or dispersion of a set of values. A low standard deviation indicates that the values tend to be close to the mean (also called the expected value) of the set, while ...

s 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 Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stabl ...

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.

Infant An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...

s 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 The scalp is the anatomical area bordered by the human face at the front, and by the neck at the sides and back. Structure The scalp is usually described as having five layers, which can conveniently be remembered as a mnemonic: * S: The ski ...

. As the child grows older, the smallness of the

skull The skull is a bone protective cavity for the brain. The skull is composed of four types of bone i.e., cranial bones, facial bones, ear ossicles and hyoid bone. However two parts are more prominent: the cranium and the mandible. In humans, the ...

becomes more obvious, although the entire body also is often underweight and dwarfed. Severely impaired

intellectual An intellectual is a person who engages in critical thinking, research, and reflection about the reality of society, and who proposes solutions for the normative problems of society. Coming from the world of culture, either as a creator or a ...

development is common, but disturbances in

motor function Motor control is the regulation of movement in organisms that possess a nervous system. Motor control includes reflexes as well as directed movement. To control movement, the nervous system must integrate multimodal sensory information (both f ...

s may not appear until later in life. Affected newborns generally have striking

defects and

seizure 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 los ...

s. Development of motor functions and

speech Speech is a human vocal communication using language. Each language uses Phonetics, phonetic combinations of vowel and consonant sounds that form the sound of its words (that is, all English words sound different from all French words, even if ...

may be delayed.

Hyperactivity Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...

and intellectual disability are common occurrences, although the degree of each varies.

Convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a s ...

s 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 ...

. It has been classified in two types based on the onset:

Congenital

* Isolated *# Familial (

autosomal recessive 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 and t ...

) microcephaly *#

Autosomal dominant 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 and t ...

microcephaly *#

X-linked Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...

microcephaly *# Chromosomal (balanced rearrangements and ring chromosome) * Syndromes ** Chromosomal **#

Poland syndrome Poland syndrome is a birth defect characterized by an underdeveloped chest muscle and short webbed fingers on one side of the body. There may also be short ribs, less fat, and breast and nipple abnormalities on the same side of the body. Typical ...

**#

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 dis ...

**# Edward syndrome **#

Patau syndrome Patau syndrome is a syndrome caused by a chromosome, chromosomal abnormality, in which some or all of the Cell (biology), cells of the body contain Trisomy, extra genetic material from chromosome 13 (human), chromosome 13. The extra genetic mater ...

**# Unbalanced rearrangements ** Contiguous gene deletion **# 4p deletion (

Wolf–Hirschhorn syndrome Wolf–Hirschhorn syndrome (WHS) is a chromosomal deletion syndrome resulting from a partial deletion on the short arm of chromosome 4 (del(4p16.3)). Features include a distinct craniofacial phenotype and intellectual disability. Signs and sympto ...

) **# 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 Williams syndrome (WS) is a genetic disorder that affects many parts of the body. Facial features frequently include a broad forehead, underdeveloped chin, short nose, and full cheeks. Mild to moderate intellectual disability is observed in people ...

) **# 22q11 deletion (

DiGeorge syndrome DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent in ...

) * Single gene defects *#

Smith–Lemli–Opitz syndrome Smith–Lemli–Opitz syndrome is an inborn error of cholesterol synthesis. It is an autosomal recessive, multiple malformation syndrome caused by a mutation in the enzyme 7-Dehydrocholesterol reductase encoded by the DHCR7 gene. It causes a bro ...

Seckel syndrome Seckel syndrome, or microcephalic primordial dwarfism (also known as bird-headed dwarfism, Harper's syndrome, Virchow–Seckel dwarfism and bird-headed dwarf of Seckel) is an extremely rare congenital nanosomic disorder. Inheritance is autosomal r ...

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 and t ...

*# Primary microcephaly 4 *# Wiedemann-Steiner syndrome * Acquired ** Disruptive injuries **#

Ischemic stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

**#

Hemorrhagic stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...

**# Death of a monozygotic twin **

Vertically transmitted infection A vertically transmitted infection is an infection caused by pathogenic bacteria or Pathogenic virus, viruses that use mother-to-child transmission, that is, Transmission (medicine), transmission directly from the mother to an embryo, fetus, or ...

s **#

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 is ...

**#

Toxoplasmosis Toxoplasmosis is a parasitic disease caused by ''Toxoplasma gondii'', an apicomplexan. Infections with toxoplasmosis are associated with a variety of neuropsychiatric and behavioral conditions. Occasionally, people may have a few weeks or months ...

**#

Congenital rubella syndrome Congenital rubella syndrome (CRS) can occur in a developing fetus of a pregnant woman who has contracted rubella, usually in the first trimester. If infection occurs 0–28 days before conception, the infant has a 43% risk of being affected. If ...

**
Congenital Varicella Syndrome
ref name=":2" /> **#

Zika virus ''Zika virus'' (ZIKV; pronounced or ) is a member of the virus family ''Flaviviridae''. It is spread by daytime-active ''Aedes'' mosquitoes, such as '' A. aegypti'' and '' A. albopictus''. Its name comes from the Ziika Forest of Uganda, whe ...

(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, com ...

**# Fetal alcohol syndrome * Other *#

Radiation In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or through a material medium. This includes: * ''electromagnetic radiation'', such as radio waves, microwaves, infrared, visi ...

exposure to mother *# Maternal

malnutrition Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues a ...

*# 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 also resu ...

*# Poorly controlled

gestational diabetes Gestational diabetes is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy. Gestational diabetes generally results in few symptoms; however, it increases the risk of pre-eclampsia, depression, and of ...

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 extreme ...

*# Maternal

hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...

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 use ...

Craniosynostosis Craniosynostosis is a condition in which one or more of the fibrous sutures in a young infant's skull prematurely fuses by turning into bone (ossification), thereby changing the growth pattern of the skull. Because the skull cannot expand perpe ...

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 defecti ...

**#

Mitochondrial disorders Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of ...

**#

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 Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Because glucose is a vital source of energy for all life, these 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 **#

Organic acidemia Organic acidemia, is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present. The branched-chain amino ac ...

* Syndromes ** Contiguous gene deletion **# 17p13.3 deletion (

Miller–Dieker syndrome Miller–Dieker syndrome, Miller–Dieker lissencephaly syndrome (MDLS), and chromosome 17p13.3 deletion syndrome is a micro deletion syndrome characterized by congenital malformations. Congenital malformations are physical defects detectable in a ...

) ** Single gene defects **#

Rett syndrome Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...

(primarily girls) **# Nijmegen breakage syndrome **# X-linked

lissencephaly Lissencephaly (, meaning "smooth brain") is a set of rare brain disorders whereby the whole or parts of the surface of the brain appear smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation resulting in ...

with abnormal genitalia **#

Aicardi–Goutières syndrome Aicardi–Goutières syndrome (AGS), which is completely distinct from the similarly named Aicardi syndrome, is a rare, usually early onset childhood, inflammatory disorder most typically affecting the brain and the skin (neurodevelopmental disord ...

**#

Ataxia telangiectasia Ataxia is a neurological sign consisting of lack of voluntary Motor coordination, coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicati ...

**#

Cohen syndrome Cohen syndrome (also known as Pepper syndrome or Cervenka syndrome) is a very rare autosomal recessive genetic disorder with varied expression, characterised by obesity, intellectual disability, distinct craniofacial abnormalities and potential ocu ...

**#

Cockayne syndrome Cockayne syndrome (CS), also called Neill-Dingwall syndrome, is a rare and fatal autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosen ...

* Acquired ** Disruptive injuries **#

Traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic b ...

**#

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 ...

**#

** Infections **# Congenital HIV encephalopathy **#

Meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...

**#

Encephalitis Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations, ...

** 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, vom ...

** Deprivation **#

Hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...

**#

Anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...

**#

Congenital heart disease A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...

**#

Malnutrition Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues a ...

Genetic mutations cause most cases of microcephaly. Relationships have been found between

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

, duplications of genes and

macrocephaly Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...

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 withdra ...

, deletions of genes and microcephaly. Several genes have been designated "MCPH" genes, after

microcephalin Microcephalin (MCPH1) is a gene that is expressed during fetal brain development. Certain mutations in ''MCPH1'', when homozygous, cause primary microcephaly—a severely diminished brain. Hence, it has been assumed that variants have a role in ...

(''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 t ...

'' (''MCPH2''), '' CDK5RAP2'' (''MCPH3''), ''

KNL1 KNL1 (kinetochore scaffold 1, aka CASC5) is a protein that is encoded by the ''KNL1'' gene in humans. Function KNL1 is part of the outer kinetochore. It is a part of KMN network of proteins together with MIS12, and NDC80. KNL1 is involved in m ...

'' (''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 integrit ...

'' (''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 Centrosomal protein of 135 kDa is a protein that in humans is encoded by the ''CEP135'' gene. It is part of the centrosome throughout the cell cycle, being distributed in the pericentriolar material Pericentriolar material (PCM, sometimes also cal ...

'' (''MCPH8''), ''

CEP152 Centrosomal protein of 152 kDa, also known as Cep152, is a protein that in humans is encoded by the ''CEP152'' gene. It is the ortholog of the ''Drosophila melanogaster'' gene asterless (asl) and both are required for centriole In cell biology ...

'' (''MCPH9''), '' ZNF335'' (''MCPH10''), ''

PHC1 Polyhomeotic-like protein 1 is a protein that in humans is encoded by the ''PHC1'' gene. Function This gene is a homolog of the ''Drosophila'' polyhomeotic gene, which is a member of the Polycomb group of genes. The gene product is a component ...

'' (''MCPH11'') and ''

CDK6 Cell division protein kinase 6 (CDK6) is an enzyme encoded by the ''CDK6'' gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of th ...

'' (''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 Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

(MRI)i.e., primarily brain cortical surface area and total brain volume. The spread of

Aedes ''Aedes'' is a genus of mosquitoes originally found in tropical and subtropical zones, but now found on all continents except perhaps Antarctica. Some species have been spread by human activity: ''Aedes albopictus'', a particularly invasive spe ...

mosquito Mosquitoes (or mosquitos) are members of a group of almost 3,600 species of small flies within the family Culicidae (from the Latin ''culex'' meaning " gnat"). The word "mosquito" (formed by ''mosca'' and diminutive ''-ito'') is Spanish for "li ...

-borne

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 pl ...

and the US

Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...

. 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

(smooth brain surface due to absent

sulci Sulci or Sulki (in Greek , Steph. B., Ptol.; , Strabo; , Paus.), was one of the most considerable cities of ancient Sardinia, situated in the southwest corner of the island, on a small island, now called Isola di Sant'Antioco, which is, howev ...

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 ma ...

). 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 and t ...

Historical causes of microcephaly

After the dropping of

atomic bombs A nuclear weapon is an explosive device that derives its destructive force from nuclear reactions, either fission (fission bomb) or a combination of fission and fusion reactions ( thermonuclear bomb), producing a nuclear explosion. Both bomb ...

"Little Boy" on

Hiroshima is the capital of Hiroshima Prefecture in Japan. , the city had an estimated population of 1,199,391. The gross domestic product (GDP) in Greater Hiroshima, Hiroshima Urban Employment Area, was US$61.3 billion as of 2010. Kazumi Matsui h ...

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 In relation to nuclear explosions and other large bombs, ground zero (also called surface zero) is the point on the Earth's surface closest to a detonation. In the case of an explosion above the ground, ''ground zero'' is the point on the ground ...

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 Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregna ...

who survived the blast at less than from ground zero. Due to their proximity to the bomb, the pregnant women's ''

in utero ''In Utero'' is the third and final studio album by American rock band Nirvana. It was released on September 21, 1993, by DGC Records. After breaking into the mainstream with their second album, ''Nevermind'' (1991), Nirvana hired Steve Albini t ...

'' 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 nuclei of atoms. Since protons and neutrons beh ...

output of the lower explosive-yielding

Little Boy "Little Boy" was the type of atomic bomb dropped on the Japanese city of Hiroshima on 6 August 1945 during World War II, making it the first nuclear weapon used in warfare. The bomb was dropped by the Boeing B-29 Superfortress ''Enola Gay'' p ...

. 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 of ...

, and the condition can arise during embryonic and fetal development due to insufficient

neural stem cell Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor ste ...

proliferation, impaired or premature

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...

, the death of neural

stem cells In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

neurons 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. N ...

, 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 The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembr ...

genes regulate the balance between stem cell proliferation and

in the stem cell layer known as the

ventricular zone In vertebrates, the ventricular zone (VZ) is a transient embryonic layer of tissue containing neural stem cells, principally radial glial cells, of the central nervous system (CNS). The VZ is so named because it lines the ventricular system, whic ...

, 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

ferret The ferret (''Mustela furo'') is a small, Domestication, domesticated species belonging to the family Mustelidae. The ferret is most likely a domesticated form of the wild European polecat (''Mustela putorius''), evidenced by their Hybrid (biol ...

s that exhibits severe microcephaly. In addition, viruses such as

cytomegalovirus ''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Betaherpe ...

(CMV) or

Zika Zika fever, also known as Zika virus disease or simply Zika, is an infectious disease caused by the Zika virus. Most cases have no symptoms, but when present they are usually mild and can resemble dengue fever. Symptoms may include fever, red ...

have been shown to infect and kill the primary stem cell of the brain—the

radial glial cell Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and ol ...

, 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 DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

response. Individuals with the following DNA damage response disorders exhibit microcephaly: Nijmegen breakage syndrome, ATR-

MCPH1 Microcephalin (MCPH1) is a gene that is expressed during fetal brain development. Certain mutations in ''MCPH1'', when homozygous, cause primary microcephaly—a severely diminished brain. Hence, it has been assumed that variants have a role in ...

-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 nor ...

, ligase 4 deficiency syndrome and

Bloom syndrome Bloom syndrome (often abbreviated as BS in literature) is a rare autosomal recessive genetic disorder characterized by short stature, predisposition to the development of cancer, and genomic instability. BS is caused by mutations in the ''BLM'' gen ...

. These findings suggest that a normal DNA damage response is critical during

brain development The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The fiel ...

, perhaps to protect against induction of

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

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. N ...

Treatment

There is no known cure for microcephaly. Treatment is

symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...

atic 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 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 (753–509 B ...

. 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 i ...

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 Máximo and Bartola (also known as Maximo Valdez Nunez and Bartola Velasquez respectively) were the stage names of two Salvadoran siblings both with microcephaly and cognitive developmental disability who were exhibited in human zoos in the 19th ...

, and

Schlitzie Schlitzie (alternatively spelled Schlitze or Shlitze; September 10, 1901 – September 24, 1971), possibly born Simon Metz and legally Schlitze Surtees, was an American sideshow performer. He also appeared in a few films, and is best known for his ...

the Pinhead,.

and Schlitzie the Pinhead, also stars of the 1932 film ''

Freaks Freak has several meanings: a person who is physically deformed or suffers from an extraordinary disease and condition, a genetic mutation in a plant or animal, etc. Freak, freaks or The Freak may also refer to: Fictional characters * Freak (Ima ...

'', were cited as influences on the development of the long-running

comic strip A comic strip is a sequence of drawings, often cartoons, arranged in interrelated panels to display brief humor or form a narrative, often serialized, with text in balloons and captions. Traditionally, throughout the 20th and into the 21st ...

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 Pocahontas (, ; born Amonute, known as Matoaka, 1596 – March 1617) was a Native American woman, belonging to the Powhatan people, notable for her association with the colonial settlement at Jamestown, Virginia. She was the daughter of ...

) 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 Pepi II Neferkare (2284 BC – after 2247 BC, probably either 2216 or 2184 BC) was a pharaoh of the Sixth Dynasty in Egypt's Old Kingdom who reigned from 2278 BC. His second name, Neferkare (''Nefer-ka-Re''), means "Beautiful is ...

(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 A jester, court jester, fool or joker was a member of the household of a nobleman or a monarch employed to entertain guests during the medieval and Renaissance eras. Jesters were also itinerant performers who entertained common folk at fairs and ...

of duke

René of Anjou René of Anjou ( it, Renato; oc, Rainièr; ca, Renat; 1409–1480) was Duke of Anjou and Count of Provence from 1434 to 1480, who also reigned as King of Naples as René I from 1435 to 1442 (then deposed as the preceding dynasty was restored to ...

(not to be confused with the slightly later

Triboulet Nicolas Ferrial (1479–1536), also known as Le Févrial or Triboulet, was a jester for kings Louis XII and Francis I of France. He appears in Book 3 of François Rabelais' Pantagrueline chronicles. He also appears in Victor Hugo's ''Le Roi s ...

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 ''

''. * Schlitze "Schlitzie" Surtees, possibly born Simon Metz, was a widely known sideshow performer and actor, who also appeared in ''

''. * Lester "Beetlejuice" Green, a member of radio host Howard Stern's Wack Pack.

References

External links

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