Microcephalies are classified based upon inheritance, associated clinical features, and causative gene.  There are 41 types of microcephaly:

MIC with severe IUGR deficiency and short stature

• Seckel syndrome with unknown cause (Shanske et al., 1997)

• MOPD syndromes with unknown cause

• Other MIC-IUGR syndromes

• Seckel syndrome with mutations in ATR at 3q22–q24 (O’Driscoll et al., 2003)

• MOPD type 2 with mutations in PCNT at 21q22.3 (Rauch et al., 2008)

• MOPD type 1 with mutations in ORC1 at 1p32 (Bicknell et al., 2011)

• MOPD type 1 with mutations in ORC4 at 2q22-q23 (Guernsey et al., 2011)

• MOPD type 1 with mutations in ORC6 at 16q12 (Bernal and Venkitaraman, 2011)

• MOPD type 1 with mutations in CDT1 at 16q24.3 (Bicknell et al., 2011b)

• MOPD type 1 with mutations in CDC6 at 17q21.2 (Bicknell et al., 2011a)

MIC with variable short stature (severe IUGR to mildly short), moderate to severe DD/ID, normal to thin cortex, SIMP, with/without callosal hypogenesis
Genetically defined with AR inheritance

• Seckel syndrome or AR primary microcephaly (MCPH) with mutations in CENPJ at 13q12.12 (Al-Dosari et al., 2010)

• Seckel syndrome or MCPH with mutations in CEP152 at 15q21.1 (Kalay et al., 2011)

MIC with mildly short stature or normal growth, mild-moderate DD/ID, normal to thin cortex, with/without SIMP, with/without callosal hypogenesis and with/without focal PNH
Clinically defined with AR inheritance

• AR primary microcephaly (MCPH) (Woods et al., 2005) Genetically defined with AR inheritance

• MCPH with mutations in ASPM at 1q31.3 (Bond et al., 2003;Shen et al., 2005; Desir et al., 2008)

• MCPH with mutations in MCPH1 at 8p23.1 (Trimborn et al., 2004; Darvish et al., 2010)

• MCPH with mutations in CDKRAP5 (Bond et al., 2005; W.B.D., in preparation)

• MCPH with mutations in STIL at 1p33 (Kumar et al., 2009)

MIC with mildly short stature or normal growth, severe DD/ID, variable cortical development with SIMP or cortical dysgenesis and with/without ACC (includes genes with spectrum from SIMP to dysgenetic cortex or PMG)
Clinically defined with AR or XL inheritance

• MIC with diffuse PMG

• MIC with asymmetric PMG

• MIC with atypical cortical dysgenesis

  Genetically defined with AR inheritance

• MCPH with mutations in PNKP at 19q13.33 (Shen et al., 2010)

• MCPH, MIC with diffuse PMG (MDP) or MIC with asymmetric PMG (MAP) with mutations in WDR62 at 19q13.12 (Bilgüvar et al., 2010; Yu et al., 2010)

• MCPH, MDP (other cortical malformation) with mutations inNDE1 at 16p13.11 (Alkuraya et al., 2011; Bakircioglu et al., 2011)

• MDP–MAP and ACC with mutations of TBR2 (EOMES) at 3p24.1 (Baala et al., 2007)

MIC with variable anomalies and less well characterized syndromes; with/without SIMP; with/without PNH, with/without CBLH
Clinically defined with probable AR inheritance

• MIC with diffuse periventricular nodular heterotopia

• MIC with disproportionate cerebellar hypoplasia

• MIC (extreme) with jejunal atresia (Stromme et al., 1993)

  Genetically defined with AR inheritance

• MIC–PNH associated with mutations in ARFGEF2 at 20q13.13 (Sheen et al., 2004; de Wit et al., 2009)

MIC with severe DD/ID and evidence of degeneration, with/without mildly short stature, with/without enlarged extra-axial spaces, with/without ACC, with/without atypical cortical dysgenesis
Clinically defined with AR inheritance

• MIC with enlarged extra-axial space

• MIC with enlarged extra-axial spaces and disproportionate cerebellar hypoplasia

• MIC due to foetal brain disruption with unknown cause

  Genetically defined with AR inheritance

• Amish lethal microcephaly associated with mutations inSLC25A19 at 17q25.1 (Rosenberg et al., 2002)

• MIC-capillary malformation syndrome (mutations in pending report)

MIC with LIS (MLIS)—cortex thick or relatively thick, smooth white–grey border

• Barth MLIS syndrome

• Norman–Roberts MLIS syndrome

• MOPD1 variant with three-layer lissencephaly (Juric-Sekharet al., 2011)

• MIC with lissencephaly, CBLH and Hirschsprung disease

MIC with tissue loss and enlarged ventricles (hydrocephalus ex vacuo or hydranencephaly), with/without cortical dysplasia and with/without ACC

• Foetal brain disruption sequence (Corona-Rivera et al., 2001)

• Familial foetal brain disruption-like syndrome with unknown cause

• Familial ‘microhydranencephaly’ with unknown cause (Behunova et al., 2010)

• Familial ‘microhydranencephaly’ associated with mutations of MHAC at 16p13.13–p12.2 (Kavaslar et al., 2000)

Symptoms

Children with microcephaly often have developmental issues.  Individuals with microcephaly have small brains and almost always have intellectual disabilities, although rare individuals with mild microcephaly (-3 SD) and normal intelligence have been reported. Additional clinical features may include short stature or mild seizures.

Diagnosis

Microcephaly is often diagnosed at birth or during routine well-baby examinations when the infant’s height, weight, and head circumference is measured. If you suspect your infant’s head size is too small or not growing normally, consult your health care provider. Head size is measured as the distance around the top of the head.

Causes

Microcephaly can be caused by a variety of genetic and environmentalfactors.

Most genes known to cause primary microcephaly affect pathways involving neurogenesis: transcription regulation (MCPH1, CENPJ, CDK5RAP2); cell cycle progression and checkpoint regulation (MCPH1, CENPJ, CDK5RAP2); centrosome maturation (CDK5RAP2 and CENPJ); dynein binding and centrosome duplication (NDE1); DNA repair (MCPH1); progenitor proliferative capacity (ASPM and STIL); interference with mitotic spindle formation (WDR62 and NDE1); and DNA repair deficit (PNKP and PCNT).

Other factors connected to microcephaly include cytomegalovirus (CMV) and fetal radiation exposure.

Treatment

Generally there’s no treatment for microcephaly, but early intervention may help enhance your child’s development and improve quality of life.

Prognosis

In general, life expectancy for individuals with microcephaly is reduced and the prognosis for normal brain function is poor. The prognosis varies depending on the presence of associated abnormalities.

Prevalence

Microcephaly is common, affecting about 25,000 U.S. infants each year. It can be present at birth and normally develops by age 2.

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Sources

1. Kinsman SL, Johnston MV. Congenital anomalies of the central nervous system.In: Kliegman RM, Stanton BF, St. Geme JW III, Schor NF, Behrman RE, eds.Nelson Textbook of Pediatrics. 19th ed.Philadelphia,Pa: Saunders Elsevier; 2011:chap 585.10.

2. Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. “A developmental and genetic classification for malformations of cortical development:  update 2012. Brain 2012. 10.1093/brain/aws019.

What is Microcephaly?

Microcephaly is a medical condition in which the circumference of the head is smaller than normal because the brain has not developed properly or has stopped growing.  Microcephaly can be present at birth or it may develop in the first few years of life.  It is most often caused by genetic abnormalities that interfere with the growth of the cerebral cortex during the early months of fetal development.  Babies may also be born with microcephaly if, during pregnancy, their mother abused drugs or alcohol; became infected with a cytomegalovirus, rubella (German measles), varicella (chicken pox) virus, or possibly Zika virus; was exposed to certain toxic chemicals; or had untreated phenylketonuria (PKU, a harmful buildup of the amino acid phenylalanine in the blood).  Microcephaly is associated with Down’s syndrome, chromosomal syndromes, and neurometabolic syndromes.

With viral-induced brain injury, such as with the Zika virus, there is often widespread tissue and cell death leading to brain shrinkage rather than simply impaired growth.  The Zika virus is also associated with retinal lesions in about a third of cases, often leading to blindness.

Depending on the severity of the accompanying syndrome, children with microcephaly may have impaired cognitive development, delayed motor functions and speech, facial distortions, dwarfism or short stature, hyperactivity, seizures, difficulties with coordination and balance, and other brain or neurological abnormalities.  

Is there any treatment?

There is no treatment for microcephaly that can return a child’s head to a normal size or shape. Treatment focuses on ways to decrease the impact of the associated deformities and neurological disabilities. Children with microcephaly and developmental delays are usually evaluated by a pediatric neurologist and followed by a medical management team. Early childhood intervention programs that involve physical, speech, and occupational therapists help to maximize abilities and minimize dysfunction. Medications are often used to control seizures, hyperactivity, and neuromuscular symptoms. Genetic counseling may help families understand the risk for microcephaly in subsequent pregnancies.

What is the prognosis?

Some children with microcephaly will have normal intelligence and a head that will grow bigger, but they may track below the normal growth curves for head circumference.  Some children may have only mild disability, while those with more severe cases may face significant learning disabilities, cognitive delays, or develop other neurological disorders.  Many, if not most, cases if Zika microcephaly will be very severe, possibly requiring lifelong intensive care.

What research is being done?

The National Institute of Neurological Disorders and Stroke (NINDS), one of several institutes of the National Institutes of Health (NIH), conducts and funds research aimed at understanding normal brain development, as well as disease-related disorders of the brain and nervous system. Other NIH institutes and centers also support research on disorders that may affect development. Among several projects, scientists are studying genetic mechanisms and identifying novel genes involved with brain development.  Animal models are helping scientists to better understand the pathology of human disease, and to discover how the sizes of tissues and organs are impacted by developmental variability. Other researchers hope to gain a better understanding of normal brain development and the molecular and cellular mechanisms of microcephaly.

NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history.

All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated.

Last Modified March 14, 2016

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