Microcephaly

File:Hold Me Mother, 2018 - Wellcome Photography Prize 2019.jpg

A mother holding her son who was born with microcephaly due to vertically transmitted infection with Zika virus

Microcephaly (from Neo-Latin microcephalia, from Ancient Greek μικρός mikrós "small" and κεφαλή kephalé "head"<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>) is a medical condition involving a smaller-than-normal head.<ref name=NIH2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Microcephaly may be present at birth or it may develop in the first few years of life.<ref name=NIH2015/> Brain development is often affected; people with this disorder often have an intellectual disability, poor motor function, poor speech, abnormal facial features, seizures and dwarfism.<ref name=NIH2015/>

The disorder is caused by a disruption to the genetic processes that form the brain early in pregnancy,<ref name="NIH2015" /> though the cause is not identified in most cases.<ref name="CDC" /> Many genetic syndromes can result in microcephaly, including chromosomal 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.<ref name="BMC">Template:Cite journal</ref> External toxins to the embryo, such as alcohol during pregnancy or vertically transmitted infections, can also result in microcephaly.<ref name="NIH2015" /> Microcephaly serves as an important neurological 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Some academics advocate defining it as head circumference more than three standard deviations below the mean for the age and sex.<ref>Template:Cite book</ref>

There is no specific treatment that returns the head size to normal.<ref name=NIH2015/> 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).<ref name=NIH2015/><ref name="Stoler-Poria Lev Schweiger Lerman-Sagie pp. 154–158">Template:Cite journal</ref> It is reported that in the United States, microcephaly occurs in 1 in 800-5,000 births.<ref name="CDC">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Signs and symptoms

File:Peterson 291-292.jpg

Microcephaly (left) vs. normocephaly (right)

File:Microcephaly.png

Neural scans of a normal-sized skull (left) and a case of microcephaly (right)

There are a variety of symptoms that can occur in children. Infants with microcephaly are born with either a normal or reduced head size.<ref name="Stanford">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> As the child grows older, the smallness of the skull becomes more obvious, although the entire body also is often underweight and dwarfed.<ref name="Stanford" />

Severely impaired intellectual development is common, but disturbances in motor functions may not appear until later in life.<ref name="Stanford" /> Affected newborns generally have striking neurological defects and seizures.<ref name="Stanford" /> 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 in some to spastic quadriplegia in others.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Causes

Microcephaly is a type of cephalic disorder. It has been classified in two types based on the onset:<ref>Template:Cite journal</ref>

Congenital

• Isolated
  1. Familial (autosomal recessive) microcephaly<ref name="Health Encyclopedia">Template:Cite encyclopedia</ref>
  2. Autosomal dominant microcephaly<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref><ref>{{#ifeq:|none||{{#switch: | short = OMIM: | shortlink = OMIM: | plain = Online Mendelian Inheritance in Man: | full | #default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if:Microcephaly 18, Primary, Autosomal Dominant; MCPH18 |Microcephaly 18, Primary, Autosomal Dominant; MCPH18 - }} 617520</ref>

• 1. X-linked microcephaly<ref name="Health Encyclopedia" />
  2. Chromosomal (balanced rearrangements and ring chromosome)
• Syndromes
  • Chromosomal
    1. Poland syndrome<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Down syndrome<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Edward syndrome<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Patau syndrome<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Unbalanced rearrangements
  • Contiguous gene deletion
    1. 4p deletion (Wolf–Hirschhorn syndrome)
    2. 5p deletion (Cri-du-chat)
    3. 7q11.23 deletion (Williams syndrome)
    4. 22q11 deletion (DiGeorge syndrome)
• Single gene defects
  1. Smith–Lemli–Opitz syndrome
  2. Seckel syndrome
  3. Cornelia de Lange syndrome
  4. Dihydropteridine reductase deficiency - in up to 25% of patients<ref name="pmid32456656">Template:Cite journal</ref>
  5. 5,10-methenyltetrahydrofolate synthetase deficiency
  6. Holoprosencephaly
  7. Primary microcephaly<ref>Template:Cite journal</ref>
  8. Wiedemann-Steiner syndrome
• Acquired
  • Disruptive injuries
    1. Ischemic stroke<ref name="UpToDate">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Hemorrhagic stroke<ref name="UpToDate" />
    2. Death of a monozygotic twin
  • Vertically transmitted infections
    1. Congenital cytomegalovirus infection<ref name="Mayo Clinic">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Toxoplasmosis<ref name="Mayo Clinic" />
    2. Congenital rubella syndrome<ref name="Mayo Clinic" />
    3. Congenital varicella syndrome<ref name="Mayo Clinic" />
    4. Zika virus (see Zika fever#Microcephaly)<ref>Template:Cite journal</ref>
  • Drugs
    1. Fetal hydantoin syndrome<ref name="Mayo Clinic" />
    2. Fetal alcohol syndrome<ref name="Mayo Clinic" />
• Other
  1. Radiation exposure to mother
  2. Maternal malnutrition<ref name="Mayo Clinic" />
  3. Maternal phenylketonuria<ref name="Mayo Clinic" />
  4. Poorly controlled gestational diabetes
  5. Hyperthermia
  6. Maternal hypothyroidism
  7. Placental insufficiency
  8. Craniosynostosis<ref name="Mayo Clinic" />

Postnatal onset

• Genetic
  • Inborn errors of metabolism
    1. Congenital disorder of glycosylation<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Mitochondrial disorders<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Peroxisomal disorder<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Glucose transporter defect<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Menkes disease
    2. Congenital disorders of amino acid metabolism<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Organic acidemia<ref>Template:Cite journal</ref>
• Syndromes
  • Contiguous gene deletion
    1. 17p13.3 deletion (Miller–Dieker syndrome)<ref>{{#ifeq:|none||{{#switch:

| short = OMIM: | shortlink = OMIM: | plain = Online Mendelian Inheritance in Man: | full | #default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if:Miller-Dieker Lissencephaly Syndrome; MDLS |Miller-Dieker Lissencephaly Syndrome; MDLS - }} 247200</ref>

• • Single gene defects
    1. Rett syndrome (primarily girls)
    2. Nijmegen breakage syndrome
    3. X-linked lissencephaly with abnormal genitalia
    4. Aicardi–Goutières syndrome
    5. Ataxia telangiectasia
    6. Cohen syndrome
    7. Cockayne syndrome
• Acquired
  • Disruptive injuries
    1. Traumatic brain injury<ref>Template:Citation</ref>
    2. Hypoxic-ischemic encephalopathy<ref name="Mayo Clinic" />
    3. Ischemic stroke<ref name="UpToDate" />
    4. Hemorrhagic stroke<ref name="UpToDate" />
  • Infections
    1. Congenital HIV encephalopathy<ref>Template:Cite journal</ref>
    2. Meningitis<ref>Template:Cite journal</ref>
    3. Encephalitis<ref>Template:Cite journal</ref>
  • Toxins
    • Chronic kidney failure<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • Deprivation
    1. Hypothyroidism<ref>Template:Cite journal</ref>
    2. Anemia<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • 1. Congenital heart disease<ref>Template:Cite journal</ref>
    2. Malnutrition<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

Genetic mutations cause most cases of microcephaly.<ref name="NIH2015" /> 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, deletions of genes and microcephaly.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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 (MCPH2), CDK5RAP2 (MCPH3), KNL1 (MCPH4), ASPM (MCPH5), CENPJ (MCPH6), STIL (MCPH7), CEP135 (MCPH8), CEP152 (MCPH9), ZNF335 (MCPH10), PHC1 (MCPH11) and CDK6 (MCPH12).<ref name="BMC" /> 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)Template:Nsmdnsi.e., primarily brain cortical surface area and total brain volume.<ref name="Rimol_2010">Template:Cite journal</ref>

Arbovirus

Bites and stings from Arthropods can often be a cause of vector-borne diseases. These include mosquitoes, fleas, sand flies, lice, ticks, and mites that are hematophagous vectors. The Centers for Disease Control (CDC) stated that "mosquitoes kill more people than any other creature and considers that mosquitoes are "the most dangerous animals on earth".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The spread of Aedes mosquito-borne Zika virus has been implicated in increasing levels of congenital microcephaly by the International Society for Infectious Diseases and the US Centers for Disease Control and Prevention.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Zika can spread from a pregnant woman to her fetus. This can result in other severe brain malformations and birth defects.<ref name="NEJM201604">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref>

Microlissencephaly

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Microlissencephaly is microcephaly combined with lissencephaly (smooth brain surface due to absent sulci and gyri). Most cases of microlissencephaly are described in consanguineous families, suggesting an autosomal recessive inheritance.<ref name="Cavallin">Template:Cite journal</ref><ref>Template:Cite book</ref><ref>Template:Cite book</ref>

Historical causes of microcephaly

After the dropping of atomic bombs "Little Boy" on Hiroshima and "Fat Man" on Nagasaki, several women close to ground zero who had been pregnant at the time gave birth to children with microcephaly.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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 Template:Convert from ground zero.<ref name=Kalter10>Template:Cite book</ref> 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 output of the lower explosive-yielding Little Boy.<ref name=Kalter10/> 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.<ref>Template:Cite journal</ref><ref name=Kalter10/>

Other relations

Intracranial volume also affects this pathology, as it is related with the size of the brain.<ref>Template:Cite journal</ref>

Pathophysiology

Microcephaly generally is due to the diminished size of the largest part of the human brain, the cerebral cortex, 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.<ref>Template:Cite journal</ref> 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,<ref>Template:Cite journal</ref> similar to human microcephaly.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name="JohnsonSun2018">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The severity of the condition may depend on the timing of infection during pregnancy.Template:Citation needed

Microcephaly is a feature common to several different genetic disorders arising from a deficiency in the cellular DNA damage response.<ref>Template:Cite journal</ref> 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, 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 neurons.<ref>Template:Cite journal</ref>

Treatment

File:Bebê com microcefalia 01.jpg

Baby with microcephaly during a physical therapy session

There is no known cure for microcephaly.<ref name=NIH2015/> Treatment is symptomatic and supportive.<ref name=NIH2015/> 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.<ref>Template:Cite journal</ref>

History

People with small heads were displayed as a public spectacle in ancient Rome.<ref>Template:Cite book</ref>

People with microcephaly were sometimes sold to freak shows 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.<ref>Template:Cite journal</ref> Famous examples include Zip the Pinhead (although he may not have had microcephaly), Maximo and Bartola and Schlitzie the Pinhead.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Stars of the 1932 film Freaks were cited as influences on the development of the long-running comic strip character Zippy the Pinhead, created by Bill Griffith.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

• Triboulet.png

  Triboulet, a French court jester, 1461

• Die Gartenlaube (1868) b 204.jpg

  18-year-old Emil R., 1868

• Idiotie - Microcéphalie.jpg

  Elderly female, 1888/89

• Microcephalic high-grade idiot.jpg

  52-year-old female, 1900

• Microcephalus A.jpg

  10-year-old male, 1904

• Microcephalic idiot.jpg

  20-year-old female, 1906/07

• Microcephalic idiots.jpg

  3 relatives, 1913

• Microcephaly sister and brother.jpg

  18-year-old sister and 9-year-old brother, 1917

• Various types 1 (detail A, microcephaly).jpg

  55-year-old female, 1920 (linear descendant of Pocahontas)

• 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 [escorts; 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.<ref>Template:Cite journal</ref>
• 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
• Oropouche orthobunyavirus

External links

• Template:NINDS
• NINDS Overview