This document defines microcephaly and discusses its classification, etiology, pathogenesis, and diagnosis. Microcephaly is defined as an occipitofrontal circumference more than 3 standard deviations below the mean for age and gender. It can be classified as congenital or postnatal, genetic or environmental, symmetric or asymmetric, and isolated or syndromic. Causes include genetic conditions like primary microcephaly and chromosomal abnormalities, as well as congenital infections, metabolic disorders, and environmental factors. Neuroimaging can aid diagnosis by identifying brain abnormalities and calcifications.

1. MICROCEPHALY
Dr Jo Martin Kuncheria

2. DEFINITION
Defined as a occipitofrontal circumference that measures more than
3 SD below the mean for age, gender and gestation

4. • Birth 34 cm
• 6 months 43 cm
• 1 year 46 cm
• 2 year 48cm “HC usually 1 -2 cm larger than CC”
• 3 year 49cm
• 4 year 50cm
• 12 year 52 cm
Head growth velocity In cm
At birth 34cm
First 0-3 months +2cm/month
Next 3 months (3-6months) +1cm/month
Next 6 months (6-12 months) +0.5cm/month
1-3 year of age +0.25cm/month

5. Standardized charts
•
• FENTON chart for preterm babies from 22 weeks of gestational age
• The Centers for Disease Control and Prevention (CDC) National Center for Health
Statistics head circumference charts for children 0 to 36 months of age
• The World Health Organization (WHO) head circumference charts for children zero
to 60 months of age
• Nellhaus head circumference charts
• Fels head circumference charts

6. PATHOGENESIS
Two major mechanisms involved are:
● Lack of brain development or abnormal brain development during
neurogenesis leading to reduction in the number of neurons
● Injury or insult to a previously normal brain leading to reduction in the
number of dendritic processes and synaptic connections

7. CLASSIFICATION
• Microcephaly can be classified in a number of ways:
• By time of onset: Congenital microcephaly(Congenital microcephaly is present at birth or
by 36 weeks gestation) vs postnatal microcephaly
• By etiology: Genetic vs environmental
• By relation to other growth parameters: Symmetric (proportionate)(OFC is more than 2
to 3 standard deviations (SD) below the mean, but proportionate to weight and length (or height)
which also are below the mean) or asymmetric (disproportionate)
• By association with other anomalies: isolated (or pure) microcephaly(not associated with
any other anomalies) vs syndromal (or complex) microcephaly

8. ETIOLOGY
• Subdivided into 2 main groups:
Primary (genetic/isolated) microcephaly and
Secondary (non-genetic) microcephaly
• A precise diagnosis is important for genetic counseling and for
prediction for future pregnancies

9. Isolated microcephaly
•Also called microcephaly vera, primary microcephaly or true microcephaly. Characteristic clinical
features of this phenotype include:
• Group of conditions which-
Do no usually have associated malformations
Follow mendelian pattern of inheritance or have association with specific genetic syndrome
• Infants are usually identified at birth
•Is present at birth and uncomplicated by anomalies outside the brain
•The brain may have normal architecture but is small (more than 3 standard deviations [SD] below the
mean)
• The more common types include familial and autosomal dominant microcephaly and a series of
chromosomal syndromes .Also have autosomal recessive inheritance

10. Microcephaly primary hereditary, MCPH
• Autosomal recessive microcephaly phenotype
• a rare disorder of neurogenic mitosis
• reduced head circumference at birth with variable degree of
mental retardation.
• brain size reduced to almost one-third of its original volume
due to reduced number of generated cerebral cortical
neurons
• Seven genetic loci (MCPH1-7) with seven corresponding
genes MCPH1, WDR62, ASPM, CDK5RAP2, CEP152, CENPJ,
and STIL identified
• Contribution of ASPM and WDR62 gene mutations is more
than 50%
•

11. AUTOSOMAL DOMINANT
MICROCEPHALY
X LINKED MICROCEPHALY
Microcephaly with normal intelligence,
occasional mild mental retardation
Microcephaly with epilepsy and significant development delay
Short stature with broad thumbs and great
toes
Affected males are thin build with a long and thin face, epicanthic folds,
almond-shaped eyes, upslanting palpebral fissures, micrognathia and
behavioral problems
Philtrum fullness
- Maxillary overbite
Carrier females have normal physical appearance and intelligence
X linked: This means women in this family are likely to be at 50% risk of
having affected sons.
The females who have had affected sons are likely to have a 50% chance of
having a further affected son.
Upslanting palpebral fissures
- Horizontal nystagmus
- Alternating esotropia
- Hypotelorism
Prominent ears

12. Syndromic microcephaly
• Syndromic microcephaly is associated with a large number of conditions:
SYNDROME Clinical features
Trisomy 21 Hypotonia 80%, Poor Moro reflex 85%, Hyperflexibility of joints 80%, Excess skin on back of neck
80%, Flat facial profile 90%, Slanted palpebral fissures 80%, Anomalous auricles 60%, Dysplasia of
pelvis 70%, Dysplasia of midphalanx of fifth finger 60% and Simian crease 45%
Trisomy 18 Prominent occiput, narrow bifrontal diameter, hypoplastic supraorbital ridge, short
palpebral fissures, micrognathia, structural cardiac lesions (ventricular septal defect, atrial
septal defect, patent ductus arteriosus)
Trisomy 13 Holoprosencephaly, wide sagittal suture, cleft lip, cleft palate, loose skin, transverse
palmar crease, polydactyly, posterior prominence of heel; structural cardiac lesions
(ventricular septal defect, patent ductus arteriosus, atrial septal defect, dextrocardia)
Cri-du-chat
(5p15.2 deletion)
Round face, hypertelorism, micrognathia, epicanthal folds, hypotonia, high-pitched cry

13. SYNDROME Clinical features
Fetal alcohol syndrome Pre- and postnatal growth retardation, short palpebral fissures, flat philtrum, thin upper lip
Seckel syndrome Pre- and postnatal growth retardation, proportionate short stature; micrognathia, facial
asymmetry, downslanting palpebral fissures, prominent beaked nose; limb hypoplasia
Smith-Lemli-Opitz Ptosis, broad nasal tip, anteverted nostrils, cleft palate, micrognathia, congenital heart defects,
syndactyly of second and third toes, postaxial polydactyly, hypospadias or cryptorchidism (in boys)
Cornelia de Lange Pre- and postnatal growth retardation, generalized hirsutism, fusion of eyebrows (synophrys),
arched brows, long eyelashes, small upturned nose, thin lips, midline beaking of the upper lip;
limb reduction defects, missing fingers, syndactyly of second and third toes
Miller-Dieker
lissencephaly (17p13.3
deletion)
Bitemporal narrowing, upturned nose, small jaw, vertical furrowing of forehead, micrognathia,
genitourinary anomalies
Wolf-Hirschhorn (4p
deletion)
Congenital heart disease, hearing loss, prominent glabella, hypertelorism, wide nasal bridge,
beaked nose, short philtrum, down-turned upper lip
Rubinstein-Taybi Postnatal short stature, low anterior hairline, hypoplastic maxilla, micrognathia, heavy eyebrows,
long eyelashes, broad thumbs and big toes
Aicardi-Goutières Congenital microcephaly, abnormal eye movements, hepatosplenomegaly, cerebral calcification,
thrombocytopenia, spasticity, seizures

14. Neuroanatomic abnormalities
• These can be-

15. HOLOPROSENCEPHALY SPECTRUM
Incomplete development and septation of the midline
central nervous system structures
Hypotelorism
Facial clefts
Nasal malformations
The clinical manifestations range from an isolated single
maxillary incisor to cebocephaly (eg, small mouth, single
nostril, and close-set eyes or cyclopia.

16. Lissencephaly
• impaired migration of
neurons from the germinal
matrix lining the ventricles
• Smooth brain, loss or
reduction of sulci
• Microcephaly develops in all
patients with lissencephaly
by the first year; a minority
is microcephalic at birth

17. • Atelencephaly (or aprosencephaly) is a rare brain malformation
without any telencephalon derived brain structures (the cerebrum
and related structures)
• It can be differentiated from anencephaly by the presence of a skull
and an intact scalp
FETAL BRAIN DISRUPTION SEQUENCE
• OFC 5.8 SD below the mean, overlapping cranial sutures, prominence of the
occipital bone, and scalp rugae
• It is thought to result from destruction or necrosis of the brain tissue
secondary to prenatal insult(vascular disruption, intrauterine infection,gene
mutations)

18. SCHIZENCEPHALY
• Asymmetric infolding of cortical
gray matter along the primary
brain cleft in the perisylvian
region
POLYMICROGYRIA
Malformation characterized by
excessive gyri on the surface of the
brain

19. PACHYGYRIA
• Developmental malformation
characterized by a reduction in
the number of sulci of the
cerebrum
• Is often seen in lissencephaly
HYDRANENCEPHALY
• Vascular insult to the brain in
which fluid-filled cavities replace
the cerebral hemispheres
• Cerebellum, midbrain, thalami,
and basal ganglia are usually
preserved

20. Metabolic disorders
1. Various metabolic disorders may be associated with
microcephaly
2. Usually causes postnatal or acquired microcephaly

21. Environmental factors

22. CONGENITAL INFECTION FEATURES
CONGENITAL
TOXOPLASMOSIS
Intracranial calcifications (diffuse)
Hydrocephalus
Chorioretinitis
Otherwise unexplained mononuclear CSF pleocytosis or elevated CSF protein
CONGENITAL SYPHILIS
Skeletal abnormalities (osteochondritis and periostitis)
Pseudoparalysis
Persistent rhinitis
Maculopapular rash (particularly on palms and soles or in diaper area)
CONGENITAL RUBELLA
Cataracts, congenital glaucoma, pigmentary retinopathy
Congenital heart disease (most commonly patent ductus arteriosus or
peripheral pulmonary artery stenosis)
Radiolucent bone disease
Sensorineural hearing loss

23. CONGENITAL
CYTOMEGALOVIRUS
Thrombocytopenia
Periventricular intracranial calcifications
Microcephaly
Hepatosplenomegaly
Sensorineural hearing loss
CONGENITAL HERPES
SIMPLEX VIRUS
Mucocutaneous vesicles or scarring
CSF pleocytosis
Thrombocytopenia
Elevated liver transaminases
Conjunctivitis or keratoconjuctivitis
CONGENITAL VARICELLA
Cicatricial or vesicular skin lesions
Microcephaly

24. ACQUIRED MICROCEPHALY
• Results from a large number of noxious agents that can affect a fetus in utero or an infant
during periods of rapid brain growth
• These terms refer to the brain that had normal or near-normal size at birth and grows
abnormally slowly thereafter.
• Particularly the 1st 2 yr of life
• Eg: Rett, Seckel, and Angelman syndromes and in encephalopathy syndromes associated with
severe seizure disorders

25. Diagnosis
Neuroimaging
• Calcifications are better seen in CT than MRI
• primary microcephaly include Simplified gyral pattern(shallow sulci &few
gyri), foreshortened frontal lobe, enlarged ventricles, thin corpus callosum,
delayed myelination & enlarged subarachnoid space
• Metabolic cause produce abnormalities of white matter ,basal ganglia,
corpus callosum & cerebellum
• Acquired perinatal ischemic insult produce white matter loss, thin corpus
callosum,ventricular dilatation , necrosis of basal ganglia

26. Diagnosis
Genetic evaluation (H/o genetic phenotype, family history, consanguinity)
FISH – subtelomeric deletion
Array comparative genome hybridization (array CGH) analysis
Chromosomal breakage analysis
Karyotyping, chromosomal microarray ,clinical exome sequencing – non
syndromic primary microcephaly( if normal do whole exome sequencing)

27. Diagnosis
Metabolic investigations done in case:
Consanguinity, recurrent sibling death, unexplained encephalopathy /seizure
Episodic ataxia/vomiting
Developmental regression
Supportive MRI findings

28. Prognosis & Management
• Lifelong condition with no curative treatment
• Comprehensive management by a team of geneticist, neurologist,
clinical psychologist, physiotherapist, occupational therapist, speech
therapist
• Early intervention will improve final motor , cognitive , behavioural ,
epilepsy, movement disorder, vision & hearing abnormalities
• Life expectancy is reduced & obtaining normal development is meager
• Genetic counseling to prevent future pregnancies being affected.

29. Thank you