American Journal of Medical Genetics Part C (Seminars in Medical Genetics)

A R T I C L E

Genetic Disorders Associated With Postnatal

Microcephaly
LAURIE E. SELTZER

AND

ALEX R. PACIORKOWSKI

Several genetic disorders are characterized by normal head size at birth, followed by deceleration in head growth
resulting in postnatal microcephaly. Among these are classic disorders such as Angelman syndrome and MECP2related disorder (formerly Rett syndrome), as well as more recently described clinical entities associated with
mutations in CASK, CDKL5, CREBBP, and EP300 (RubinsteinTaybi syndrome), FOXG1, SLC9A6 (Christianson
syndrome), and TCF4 (PittHopkins syndrome). These disorders can be identied clinically by phenotyping across
multiple neurodevelopmental and neurobehavioral realms, and enough data are available to recognize these
postnatal microcephaly disorders as separate diagnostic entities in their own right. A second diagnostic grouping,
comprised of Warburg MICRO syndrome, Cockayne syndrome, and Cerebral-oculo-facial skeletal syndrome,
share similar features of somatic growth failure, ophthalmologic, and dysmorphologic features. Many postnatal
microcephaly syndromes are caused by mutations in genes important in the regulation of gene expression in the
developing forebrain and hindbrain, although important synaptic structural genes also play a role. This is an
emerging group of disorders with a fascinating combination of brain malformations, specic epilepsies,
movement disorders, and other complex neurobehavioral abnormalities. 2014 Wiley Periodicals, Inc.
KEY WORDS: postnatal microcephaly; Angelman syndrome; MECP2-related disorder; Christianson syndrome; CASK; CDKL5; FOXG1; Pitt
Hopkins syndrome; RubinsteinTaybi syndrome; Warburg MICRO syndrome, Cockayne syndrome, Cerebral-oculo-facial skeletal
syndrome

How to cite this article: Seltzer LE, Paciorkowski AR. 2014. Genetic disorders associated with postnatal
microcephaly. Am J Med Genet Part C 9999:116.

INTRODUCTION
Several genetic disorders are characterized by normal head size at birth,
followed by postnatal deceleration of
head growth such that the occipital

Several genetic disorders are

characterized by normal head
size at birth, followed by
postnatal deceleration of head
growth such that the occipital
frontal circumference (OFC)
falls greater than 3 SD below

the mean. These disorders

have been referred to
collectively as postnatal
microcephalies to distinguish
them from conditions with
abnormally small head size
congenitally.
frontal circumference (OFC) falls greater
than 3 standard deviations (SD) below
the mean. These disorders have been
referred to collectively as postnatal
microcephalies to distinguish them

from conditions with abnormally small

head size congenitally. This distinction
of postnatal versus congenital onset
of microcephaly has proven useful not
only for our ability to provide families
with meaningful prognosis but also for
our understanding of genetic etiology.
An early observation among the
postnatal microcephalies was the frequency of complex neurobehavioral
disabilities in affected children. The
first of these patterns to be well described
was Angelman syndrome, and these
disorders were often included in discussions of syndromic autism, contributing to the controversy regarding the
phenotypic boundaries of autism

Grant sponsor: The National Institutes of Health (NIH), National Institute of Neurologic Disorders and Stroke (NINDS).
Dr. Seltzer is a child neurologist and pediatric epilepsy fellow at the University of Rochester Medical Center, with a research interest in early life
epilepsies.
Dr. Paciorkowski is a clinical neurogeneticist at the University of Rochester Medical Center, and principal investigator at the Center for Neural
Development and Disease with a NINDS-supported research program in the genetic causes of developmental brain disorders.
*Correspondence to: Alex R. Paciorkowski, M.D., Child Neurology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester NY 14642.
E-mail: alex_paciorkowski@urmc.rochester.edu
DOI 10.1002/ajmg.c.31400
Article rst published online in Wiley Online Library (wileyonlinelibrary.com).

2014 Wiley Periodicals, Inc.

AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

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cy of this genetic mechanism is 23% of

cases but increases with parental age
[Clayton-Smith and Laan, 2003]. Class
III genetic mechanism in Angelman
syndrome occurs in patients without
deletions or uniparental disomy, but
with abnormal methylation patterns
resulting from imprinting center defects.
These defects are found in 35% of
individuals with Angelman syndrome
[Clayton-Smith and Laan, 2003]. Finally, Class IV consists of mutations in
UBE3A [Kishino et al., 1997] and is
found in 510% of those with Angelman
syndrome. Individuals with deletions
have a more severe neurodevelopmental
phenotype than the other genetic
mechanisms [Gentile et al., 2010; Mertz
et al., 2014].
The expression of UBE3A is directed by parent-of-origin allele-specific
methylation, and in the brain the gene is
expressed from the maternal allele, but
from both alleles in most other tissues
[Landers et al., 2005]. In the mouse, the
expression of paternal-derived Ube3a in
neurons is downregulated after the first
postnatal week while maternal-derived
allele expression occurs throughout
postnatal life, with an increasingly
nuclear localization of Ube3a protein
[Judson et al., 2014]. Non-neuronal glia
and oligodendrocytes in the cortex and
white matter tracks have biallelic expression of Ube3a [Judson et al., 2014].
This pattern of neuronal repression of
paternally derived UBE3A appears to
be preserved in induced pluripotent
stem cells derived from Angelman
syndrome patients [Chamberlain et al.,
2010]. Although much is understood
about tissue expression patterns, and
methylation of 15q11q13 in general, the
biological role of UBE3A in the pathogenesis of Angelman syndrome remains
unclear.
Individuals with Angelman syndrome have a severe and specific pattern
of physical and behavioral features that
includes intellectual impairment and
absent language. Distinctive facial features associated include a thin vermilion
of the upper lip and course facial features
in adults with mid-face retrusion and
prognathism (Fig. 1A). Hypopigmentation is often associated with deletions of

15q11q13 that also cause hemizygosity

of OCA2, although UBE3A itself also
may regulate other factors involved
in melanocortin function [Low and
Chen, 2011]. The behavioral phenotype
of Angelman syndrome typically includes a happy demeanor with frequent
laughing, and a relative strength in social
skills. Despite their social strengths, there
are problem behaviors prevalent in
Angelman syndrome including hyperactivity and aggression [Gentile et al.,
2010]. Abnormal movement patterns
seen in the disorder include ataxic gait
and jerk-like limb movements [Smith
et al., 1996; Tan, 2013]. Sleep abnormalities are frequent in Angelman
syndrome including difficulty with falling and staying asleep.
Medically refractory epilepsy is
common in Angelman syndrome with
8090% of individuals affected. The
average age of seizure onset was 1 year
old with a range of 4 months to 2
years 11 months [Valente et al., 2006].
Multiple seizure types are observed
including atypical absence, myoclonic,
partial, complex partial, generalized
tonic-clonic, as well as status epilepticus
[Valente et al., 2006]. Of note, the
behavior of paroxysmal laughing is not
an ictal phenomenon of Angelman
syndrome. Seizure activity typically
persists into adulthood [Thibert et al.,
2013].

spectrum disorders. Expressive language

is usually severely restricted or even
absent in children with postnatal microcephaly syndromes, but they often have
other characteristics beyond the classical
autism triad of abnormal language, social
impairment, and repetitive thought and
behavior patterns. These can include
specific epilepsy syndromes, clinically
definable movement disorders, as well as
abnormalities in GI motility, breathing
rhythms, functional hand use, food
behavior, mood, pain tolerance, and
sleep patterns. Many disorders presenting with postnatal microcephaly can be
helpfully identified with the assistance of
phenotyping across these multiple neurodevelopmental and neurobehavioral
realms (Table I). Postnatal microcephalies have frequently been termed
Angelman-like or Rett-like disorders, but through close attention to
phenotyping it is possible to discriminate
among them, allowing more accurate
diagnosis and prognosis.
In this review, we survey the
historical identification of postnatal
microcephaly disorders and the most
recent data on their phenotypes, genetic
causes, and classifications.

ANGELMAN SYNDROME
Angelman syndrome is one of the classic
postnatal microcephaly disorders, first
described in 1965 in three patients with
similar facial features and a behavioral
phenotype that included fits of laughter,
developmental disability, as well as ataxic
movements [Angelman, 1965]. The
genetic etiology of Angelman syndrome
is the loss of expression of the maternally
inherited copy of the imprinted gene
UBE3A on chromosome 15q11q13
[Magenis et al., 1987; Rougeulle et al.,
1997]. Four different mechanisms cause
Angelman syndrome and these are
differentiated into four different classes.
In Class I, there is a de novo deletion in
chromosome 15q11q13, which occurs
in approximately 7075% of individuals
with Angelman syndrome [Knoll et al.,
1989]. Class II mechanisms consist of
uniparental disomy for chromosome 15,
where there is failure to inherit the
maternal copy of UBE3A. The frequen-

MECP2-RELATED
DISORDER (FORMERLY
RETT SYNDROME)
MECP2-related disorder is an X-linked
syndrome that typically affects females.
Andreas Rett, a developmental pediatrician whose early career was marked by
enthusiastic participation in the Nazi
Party [Ronen et al., 2009], described the
disorder in 1966 [Rett, 1966]. His first
observations were not widely publicized
until 1983 when other patient reports
emerged from around the world [Hagberg et al., 1983; Percy, 2002]. In 1999,
loss-of-function mutations in MECP2
were identified in association with the
phenotype [Amir et al., 1999; Percy,
2011]. Methyl-CpG-binding protein 2
is highly expressed in the brain and

impairment

hand use

Fine motor/

syndrome

Epilepsy

impairment

rhythm

Breathing

Brain

impairment

morphology

atrophy, basal

types

Multiple seizure

cerebellar

atrophy

hand use

Loss of

epilepsy

Childhood onset

calcifications

ganglia

brainstem, and

subcortical

Cerebral

cortical/

polymicrogyria,

dysfunction

myocardial

impairment

dysautonomia,

system

Awareness

disturbances,

nervous

MECP2

Cardiac rhythm

Ataxic gait

Angelman

Autonomic

impairment

Ambulation

feature

Phenotypic

motor skills

Loss of fine

epilepsy

onset

mutations
childhood

with CREBBP
females:

infantile-onset
syndrome,

types, can be

types, can be

Type II:

eventual loss,

motor with

Type I: Delayed fine

infantile-onset

Multiple seizure

Multiple seizure
epilepsy, and

Occasional

seizures

epilepsy, variable

Childhood onset

myoclonic

spasms,

Males: infantile

more common

epilepsy

Childhood onset

Ohtahara

epilepsy

Childhood onset

onset

infantile-

Infantile spasms,

bulging

cortical

caudate nuclei

hypoplasia,

cerebellar

hyperintensity

cerebellar

hypoplasia

white matter

T2 FLAIR

volume

Brainstem and

Corpus callosum

syrinx

Chiari

Type II:

Type I: Progressive,

reflux

Gastroesophageal

ambulatory

Type II: Non-

of ambulation

walking and loss

Type I: Delayed

cerebellar

reflux

Gastroesophageal

Cockayne

atrophy,

matter volume,

Global atrophy

Warburg
MICRO

malformation,

hyperintensity

Hypohidrosis

RubinsteinTaybi

hypoplasia,

disease

hirschsprung

Constipation,

PittHopkins

Corpus callosum

Hypohidrosis

Girls:

Boys: ;

CASK

hypoplasia

ambulation

; Loss of

Christianson

Pontocerebellar

Decreased white

reflux

Gastroesophageal

mutations)

matter

Decreased white

CDKL5

(deletions/

FOXG1
COFS

(Continued)

epilepsy

Infantile-onset

hypoplasia,

Corpus callosum

reflux

Gastroesophageal

TABLE I. Detailed Neurodevelopmental and Neurobehavioral Features Helpful in the Identification and Diagnosis of Postnatal Microcephaly Syndromes

Reduced interest

mutations)

Christianson

CASK

PittHopkins

Increased interest

RubinsteinTaybi

Warburg

MICRO

Type I: Delayed

Cockayne

Chorea

cataracts

congenital

Microphthalmia,

Parkinsonism

stereotypies

abnormalities

Oculomotor

Stereotypies

Stereotypies

Oculomotor

Type II:
congenital
cataracts

hearing loss

Progressive

Type I:

arthrogryposis

Increased tone,

megacornea),

microcornea

Congenital cataracts,

Type II:

followed by loss,

development

early social

Type I: Normal

Hyperkinesis

hearing loss,

Hearing loss

Hyperkinesis

(glaucoma,

Stereotypies

Easily upset

COFS

abnormalities

other eye

abnormalities,

Stereotypies

laughter

Hand

laughter

laughter

Hand stereotypies,

inappropriate

inappropriate

inappropriate

Ataxic gait

Happy demeanor,

Happy demeanor,

Happy demeanor,

, greater disability.

impairment

Sleep

impairment

Sensory

impairment

Reciprocity

disorder

Movement

Mood

CDKL5

impairment

Reduced interest

MECP2

speech, Type II:

Angelman

FOXG1
(deletions/

(expressive)

Language

Food behavior

feature

Phenotypic

Table 1. (Continued)

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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

Figure 1. Twin brothers aged 25 years (A1a and A1b) and individuals aged 14 years (A2a) and 18 years (A2b) with Angelman
syndrome [reproduced from Laan et al., 1998]. Facial appearance of 12 subjects with MECP2-related disorder (B) [reproduced from Smeets
et al., 2003]. Five-year-old girl (C) and 8-year-old boy (D) with FOXG1 mutation [images shown with parental consent]. MRI of subject
with p.Glu144 FOXG1 mutation showing foreshortened frontal lobes, mild dilation of lateral ventricles (E) and hypogenesis of the genu of
the corpus callosum (F). MRI of a subject with 6.3 Mb deletion of 14q12 including FOXG1, with small frontal lobe volume, parallel lateral
ventricles (G) and complete agenesis of the corpus callosum (H).

regulates transcription of thousands of

genes by binding to their promoter
regions and primarily activating expression [Chahrour et al., 2008]. This
activation of expression occurs in the
forebrain as well as the hindbrain [BenShachar et al., 2009]. Loss of MECP2
from forebrain excitatory neurons results
in decreased GABAergic transmission
and increased excitation [Zhang et al.,
2014a].
Girls with MECP2-related disorder
typically have profound intellectual
impairment, stereotypic hand move-

ments, and growth failure including

deceleration of head growth, following

Girls with MECP2-related

disorder typically have
profound intellectual
impairment, stereotypic hand
movements, and growth
failure including deceleration
of head growth, following a

period of normal development

early in life. As with
Angelman syndrome, the
disorder has been characterized
as a syndromic form
of autism.
a period of normal development early in
life (Fig. 1B).
As with Angelman syndrome, the
disorder has been characterized as a

AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

syndromic form of autism [Young

et al., 2008]. The major diagnostic
criteria include a period of regression
of development that includes loss of
purposeful hand skills and language, gait
abnormalities, and stereotypic hand
movements, but postnatal deceleration
of head growth is not found in all
individuals [Neul et al., 2010]. These
symptoms may occur as early as 6 months
of age or as late as 2.5 years old.
However, not all girls follow a course
of regression, with some displaying early
developmental delay. Affected individuals also have other distinguishing features
categorized as minor criteria including
breathing abnormalities, bruxism, abnormal sleep patterns [Young et al.,
2007], abnormal muscle tone (especially
spasticity), and scoliosis (80% of girls over
16 years of age) [Riise et al., 2011].
Movement disorders may be prominent,
with hyperkinesis more common in
younger patients with a pattern of
bradykinesia and Parkinsonian features
emerging in older girls [FitzGerald
et al., 1990]. Breathing irregularities
are a hallmark of the disorder, including
hyperventilation and breath holding,
usually during wakefulness but also
during sleep [Ramirez et al., 2013].
Mecp2-deficient mice display abnormalities in the development of noradrenergic and serotonergic neurons in
medullary breathing centers [Viemari
et al., 2005]. Girls with MECP2related disorder have a 300-fold increased risk of sudden cardiac death,
attributed to rhythm disturbances, cardiac dysautonomia, as well as biventricular myocardial dysfunction [De Felice
et al., 2012].
Epilepsy occurs frequently in individuals with MECP2-related disorder as
seen in a patient series that found that
60% of individuals had seizures [Glaze
et al., 2010]. Affected children may have
multiple seizure types including complex partial, generalized tonic-clonic,
atypical absence, atonic, tonic, and
myoclonic seizures. Individuals with
MECP2-related disorder typically develop epilepsy in childhood with a mean
of 4.7 years in one series [Pintaudi
et al., 2010]. The characteristic EEG
progression in MECP2-related disorder

follows four stages that mirror the

progression of epilepsy and encephalopathy [Dolce et al., 2013]. Nonepileptic
behavioral vacant spells are also common occurrences in affected girls [Cooper et al., 1998].
Males with MECP2 mutations are
rare, and typically do not have the same
clinical features as females. Males with an
XY karyotype may not manifest all of
the diagnostic criteria, especially regression in development, but they share
absence of language and often have a
much more severe phenotype that is fatal
early in life [Percy, 2002].

CDKL5-RELATED
DISORDER
During the characterization of MECP2related disorder, a subgroup of girls were
identified with early onset

In 2004, mutations in
CDKL5 were discovered in
these patients, and since then
much has been learned about
the natural history, including
the characteristics of epilepsy
that depart from the clinical
course of MECP2-related
disorder. Despite clearly being
a different disorder, the
concept of CDKL5-related
disorder as a Rett variant
has persisted in
the literature.
epilepsy (usually infantile spasms) who
went on to have some characteristics
reminiscent of girls with MECP2 mutations [Hanefeld, 1985]. In 2004, mutations in CDKL5 were discovered in
these patients [Weaving et al., 2004],
and since then much has been learned
about the natural history, including the
characteristics of epilepsy that depart
from the clinical course of MECP2-

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related disorder [Bahi-Buisson et al.,

2008]. Despite clearly being a different
disorder, the concept of CDKL5related disorder as a Rett variant has
persisted in the literature [Pini et al.,
2012].
The key difference between mutations in CDKL5 and MECP2 is the early
onset of epilepsy during infancy in
CDKL5 disorders. Unlike MECP2related disorder, infantile spasms and
infantile-onset myoclonic seizures are
common in CDKL5. Children with
mutations in CDKL5 lack the later onset
of regression and instead show evidence
of developmental abnormality starting
in infancy associated with epileptic
encephalopathy [Guerrini and Parrini,
2012]. Deceleration of head growth is
common, with 11 out of 20 subjects
(55%) in one series demonstrating
postnatal microcephaly [Bahi-Buisson
et al., 2008]. Similar to MECP2-related
disorder, those with CDKL5 mutations
also have delayed motor development
and motor dyspraxia as well as poor
functional hand use, and some have
disordered breathing and sleep [Hagebeuk et al., 2013]. Most individuals with
mutations of CDKL5 are nonambulatory and have poor fine motor skills
[Bahi-Buisson et al., 2008]. Mutations of
CDKL5 do occur in males, and in a
cohort of 205 boys with developmental
epilepsy, 3% had mutations in CDKL5
[Mirzaa et al., 2013]. Brain imaging in
those affected with CDKL5 mutations
demonstrated cortical atrophy and white
matter hyperintensities [Bahi-Buisson
et al., 2008].
CDKL5 is a serinethreonine kinase whose biological role was not clear
until its interaction with NGL-1 and
PSD95 in glutamatergic post-synapses
was discovered [Ricciardi et al., 2012].
CDKL5 protein is now known to be
important during dendritic spine development [Zhu et al., 2013] and by
stabilizing the post-synaptic membrane
[Zhang et al., 2014b].

FOXG1-RELATED
DISORDERS
FOXG1 was first described in 2005 in a
female patient with severe cognitive

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FOXG1 was first described in

2005 in a female patient with
severe cognitive disability,
agenesis of the corpus
callosum, microcephaly, and a
chromosome 14 translocation.
Further patients were
then identified, and FOXG1related disorders were labeled a
Rett variant, which has
sown confusion for families
regarding counseling, natural
history, and prognosis.

disability, agenesis of the corpus callosum, microcephaly, and a chromosome 14 translocation [Shoichet et al.,
2005]. Further patients were then
identified, and FOXG1-related disorders were labeled a Rett variant
[Ariani et al., 2008; Papa et al., 2008],
which has sown confusion for families
regarding counseling, natural history,
and prognosis [unpublished observations]. FOXG1-related disorders are
also one of the few conditions where
deletion of long-range non-coding
regions regulating gene expression has
been documented to be pathogenic
[Allou et al., 2012]. As more knowledge
has been attained regarding FOXG1related disorders, two clinical syndromes
can be recognized, deletions/mutations
of FOXG1 and duplications.
Deletions and intragenic loss-offunction mutations in FOXG1 typically
result in severe global developmental
delay and cognitive impairment beginning early in infancy [Kortum
et al., 2011]. These children generally
do not attain ambulation and have a
movement disorder characterized by
chorea, features distinct from MECP2related disorder (Fig. 1C and D) [Kortum et al., 2011]. Head circumference
has been noted to be low normal to
borderline small at birth and clear
postnatal microcephaly is seen in most

AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

patients by 2 years of age [Kortum

et al., 2011]. Individuals with FOXG1
deletions and mutations have sleep
dysfunction (frequent awakening) and
gastroesophageal reflux severe enough to
warrant surgical fundoplication and
feeding tube placement. Brain imaging
in FOXG1 mutations and deletions
shows a spectrum of morphologic
abnormalities of the corpus callosum,
including hypoplasia of the genu in
children with intragenic FOXG1 mutations to full agenesis in children with
larger 14q12 deletions. Foreshortened
frontal lobes and reduced white matter
volume are also seen (Fig. 1EH) [BahiBuisson et al., 2010; Kortum et al.,
2011]. These imaging findings are
characteristic of FOXG1 and are not
seen in patients with MECP2-related
disorder.
Epilepsy is a common comorbidity
in children with deletions and intragenic
mutations of FOXG1, and typically
develops after 1 year of age. Multiple
seizure types are seen in FOXG1
mutations and deletions including complex partial seizures, myoclonic seizures,
and generalized tonic seizures. Intractable seizures persist into childhood and
typically multiple antiseizure medications are required [Seltzer et al., 2014].
Individuals with duplications of
FOXG1 have a similar developmental
encephalopathy yet with distinct features
that allow them to be distinguished both
from deletions/intragenic FOXG1 mutations and from MECP2-related disorder. Unlike deletions of FOXG1,
children with duplications are usually
normochephalic with normal MRI
scans [Brunetti-Pierri et al., 2011].
Chorea is also not seen in children
with duplications. These patients also
have a different specific epilepsy phenotype of infantile spasms that are responsive to adrenocorticotropic hormone
(ACTH), and very infrequent occurrence of epilepsy later in life [Seltzer
et al., 2014].
FOXG1 is a transcription factor
that regulates dorsal-ventral brain patterning [Hebert and Fishell, 2008], is
important in development of CajalRetzius cells, and is known to inhibit
gliogenesis and promote neurogenesis

[Brancaccio et al., 2010]. Although

FOXG1 controls neuronal differentiation through transcriptional repression
[Kumamoto et al., 2013], the detailed
mechanism of how copy number abnormalities of this gene lead to two
constellations of neurodevelopmental
symptoms remains unclear.

CHRISTIANSON
SYNDROME
In 1999, an X-linked disorder characterized by intellectual disability,
craniofacial dysmorphology, epilepsy,
ophthalmoplegia, and cerebellar and
brainstem atrophy was described

In 1999, an X-linked disorder

characterized by intellectual
disability, craniofacial
dysmorphology, epilepsy,
ophthalmoplegia, and
cerebellar and brainstem
atrophy was described.
Similarities with Angelman
syndrome were noted and
included postnatal
microcephaly, absent verbal
language, and happy mood
with easily provoked
laughter.
[Christianson et al., 1999]. Similarities
with Angelman syndrome were noted
and included postnatal microcephaly,
absent verbal language, and happy
mood with easily provoked laughter
(Fig. 2A) [Gilfillan et al., 2008]. Progressive neurologic dysfunction, including loss of ambulation was common
[Schroer et al., 2010]. In 2008, mutations in the sodiumhydrogen solute
carrier SLC9A6 were subsequently
identified in patients with Christianson
syndrome [Gilfillan et al., 2008].
Affected boys with Christianson syndrome make early motor developmental

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gains in infancy, but these skills plateau

with little functional hand use, poor
oromotor abilities, and an ataxic gait
[Schroer et al., 2010]. Motor skills are
often lost by the end of the first decade of
life. Female carriers have been reported
with learning disabilities [Christianson
et al., 1999], but it is not clear from the
literature how consistent this finding is
[Schroer et al., 2010]. Ophthalmologic
abnormalities have been described, including those of extraocular motility
[Christianson et al., 1999] and one
patient had retinitis pigmentosa [Mignot
et al., 2013].
Intractable epilepsy is common in
affected individuals, with onset of mixed
generalized seizure types occurring by
2 years of age [Schroer et al., 2010].
Other epileptic encephalopathies such
as electrical status epilepticus during
slow-wave sleep (ESES) have been
reported [Zanni et al., 2014]. Brain
MRI findings have included brainstem
and cerebellar atrophy, commonly evident after 12 months of age [Christianson et al., 1999; Bosemani et al., 2013].
An unusual pattern of cerebellar cortex
hyperintensity has also been reported
[Schroer et al., 2010; Bosemani
et al., 2013] (Fig. 2BE).
Neuropathologic studies of a family
with SLC9A6 mutation found widespread neuronal loss with tau deposition
in neurons and glia in both cortical and
subcortical regions [Garbern et al.,
2010]. In the mouse, Slc9a6 depletion
leads to accumulation of GM2 ganglioside and unesterified cholesterol in late

Figure 2. Individuals at 28 years

(left) and 15 years (right) with Christianson syndrome (A). Brain MRI in Christianson syndrome showing cerebellar
vermis volume loss (B), cerebellar atrophy
(D), and cerebellar cortical hyperintensities (C, E) [reproduced from Schroer
et al., 2010]. Characteristic facial features
of female (F) and male individuals (G)
with CASK mutations, demonstrating
oval shaped face, large eyes and ears, broad
nasal bridge, and epicanthal folds. MRI
findings (H, I) in CASK-related postnatal
microcephaly include mild-moderate
pontine hypoplasia and cerebellar vermis
and hemispheric hypoplasia. The corpus
callosum may appear relatively large
compared to the rest of the forebrain
[reproduced from Takanashi et al., 2012].

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endosomes and lysosomes of neurons in

the amygdala, hippocampi, and cerebral
cortex, undetectable b-hexosaminidase
activity, and neuroaxonal dystrophy in
the cerebellum with loss of Purkinje cells
[Stromme et al., 2011].

include pontine and cerebellar hypoplasia of varying degree, and often

simplified cerebral gyral pattern in the
frontal region (Fig. 2H and I) [Moog
et al., 2011]. The corpus callosum
may appear relatively thick compared
to the small forebrain [Takanashi
et al., 2012].

CASK-RELATED
DISORDERS
In 2008, heterozygous deletions and
mutations in CASK were identified in a
series of girls and one boy with severe
microcephaly with pontocerebellar hypoplasia [Najm et al., 2008]. CASK
encodes a calcium/calmodulin-dependent serine protein kinase which effects
synapse formation as well as cortical
development through interactions in
the nucleus with RELN and TBR1
[Hsueh, 2006]. Subsequently, further
affected males with intellectual disability
and oculomotor abnormalities were
identified [Hackett et al., 2010]. Microcephaly with pontocerebellar hypoplasia
in females is caused by null mutations
while hypomorphic missense mutations
in males cause the phenotype of intellectual disability with or without nystagmus [Hayashi et al., 2008; Moog
et al., 2011].
Clinical findings include OFC
initially in the normal to mildly microcephalic range (around 2 SD) with
mild to severe progressive postnatal
microcephaly that is usually apparent
by 4 months of age (OFC less than 10
SD) [Takanashi et al., 2012]. Affected
individuals may have optic nerve abnormalities, glaucoma, megalocornea,
and sensorineural hearing loss [Burglen
et al., 2012]. Absent language and
autistic features may accompany intellectual disability. The facial appearance
seen in CASK mutations includes broad
nasal bridge and tip, small nose, protruding maxilla or long philtrum, short
chin, large ears, and arched eyebrows
(Fig. 2F and G) [Moog et al., 2011].
Epilepsy was seen in more than half of
female subjects [Takanashi et al., 2012].
Affected males had infantile-onset epilepsy with more severe phenotypes
including Ohtahara syndrome and infantile spasms [Saitsu et al., 2012]. The
MRI findings in CASK mutations

PITTHOPKINS SYNDROME
This intellectual disability syndrome
with associated coarse facial features
and overbreathing was first described
in 1978 [Pitt and Hopkins, 1978].
Further patients were reported [Van
Balkom et al., 1998], with emphasis on
the particular respiratory dysrhythmia
manifested in the majority of affected
individuals [Whalen et al., 2012]. This
combination of hyperventilation punctuated with breath-holding behavior
that can worsen with excitement [Giurgea et al., 2008] may not occur until the
second half of the first decade [Peippo
et al., 2006; Marangi et al., 2011]. A
specific dysmorphic facial phenotype has
also been described, with deep-set eyes,
high cheekbones, an overhanging nasal
tip with flared nares, protruding philtrum, wide mouth, and floppy cupshaped ears [Peippo et al., 2006; Zweier
et al., 2008] (Fig. 3A and B). Persistent
fetal fingertip pads have also been noted
in some affected individuals [Lehalle
et al., 2011].
De novo loss-of-function mutations in the helix-loop-helix transcription factor TCF4 have been associated
with PittHopkins syndrome [Amiel
et al., 2007]. TCF4 is highly expressed
in the embryonic human brain throughout development, and on into the
postnatal period as well [de Pontual
et al., 2009]. TCF4 forms heterodimers
with HASH1 [Persson et al., 2000],
a helix-loop-helix transcription factor
involved in the development of
PHOX2B-positive noradrenergic neurons that control respiratory drive in
the brainstem [de Pontual et al.,
2003], and this association may
explain the characteristic respiratory
dysrhythmia.
Epilepsy is common in individuals
with PittHopkins syndrome with onset

Epilepsy is common in
individuals with PittHopkins
syndrome with onset later in
childhood, usually after
2 years of age, although
seizures in infancy have been
occasionally reported.

later in childhood, usually after 2 years of

age [Amiel et al., 2007; de Pontual
et al., 2009], although seizures in infancy
have been occasionally reported [Zweier
et al., 2008]. In one series, seizures were
more commonly found in individuals
with missense mutations in TCF4 than
deletions, nonsense, or splicing mutations [Rosenfeld et al., 2009]. Brain
MRI findings have been variable
and include hypoplasia of the corpus
callosum, mild-moderate dilation of
the lateral ventricles, cerebellar hypoplasia, and an unusual bulging of the
caudate nuclei into the lateral ventricles
[Peippo et al., 2006; Zweier et al.,
2008].

CNTNAP2 AND NRXN1RELATED DISORDERS

Autosomal recessive mutations in
CNTNAP2 and NRXN1 have been
described in individuals with a phenotype similar to PittHopkins syndrome
[Zweier et al., 2009]. These patients
had intellectual disability, including
severely limited verbal language, variable age of epilepsy onset, and respiratory dysrhythmia [Zweier et al., 2009].
A further study identified heterozygous
mutations in both CNTNAP2 and
NRXN1, however, in all cases except
two the mutations were parentally
inherited and no second mutation was
identified [Gregor et al., 2011]. The
full spectrum of CNTNAP2- and
NRXN1-related disorders, and whether
there are phenotypic findings distinct
from PittHopkins syndrome, remains
unclear.

10

AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

ARTICLE

Figure 3. Characteristic facial features of a child with PittHopkins syndrome (A, B) [reproduced from de Pontual et al., 2009].
Characteristic facial features of eight individuals with RubinsteinTaybi syndrome (CJ) [reproduced from Stevens et al., 2011].

RUBINSTEINTAYBI
SYNDROME
First described in 1963 by Rubinstein
and Taybi, the syndrome is characterized
by a characteristic facial appearance with
highly arched eyebrows, long eyelashes,
downslanting palpebral fissures, an
overhanging nasal tip with columella
extending below the nasal alae, and
mild micrognathia [Hennekam, 2006]
(Fig. 3CJ). Growth restriction, intellectual disability, and broad thumbs and
great toes are also commonly observed.
A classic dental finding called talon
cusps can also be found [Bloch-Zupan

et al., 2007]. Head growth matches

somatic growth in a pattern of deceleration after birth, with postnatal microcephaly a frequent feature. A variety of
additional malformations have been less
commonly described, including ophthalmologic findings, congenital heart
disease, and renal abnormalities. Additional brain malformations have been
reported, including Chiari malformation and pituitary hypoplasia [Parsley
et al., 2011; Marzuillo et al., 2013].
De novo mutations in CREBBP
were first associated with Rubinstein
Taybi syndrome in 1995 [Petrij et al.,
1995], followed in 2005 by identifica-

tion of mutations in EP300 in individuals with the same phenotype [Roelfsema

et al., 2005]. Both CREBBP and EP300
are histone acetyltransferases and transcriptional co-activators [Roelfsema and
Peters, 2007], and therefore mediate a
variety of downstream controls on gene
expression during development. Mutations in CREBBP in lymphoblastoid cell
lines from RubinsteinTaybi syndrome
patients showed abnormalities in histone
acetylation, in particular histone H2B
and histone H2A, a deficit that could be
reversed by histone deacetylase inhibitors [Lopez-Atalaya et al., 2012]. By
inducing deficits in the histone

ARTICLE

AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

11

Figure 4. Three-year-old child with Warburg MICRO syndrome, with microcephaly, micrognathia, tented mouth, flat nasal bridge,
and microcornea (A, B). Brain MRI scans of children with Warburg MICRO syndrome, showing thinning of the corpus callosum,
abnormal cortex, and perisylvian regions consistent with polymicrogyria (CH). [reproduced from Graham et al., 2004]. Five-year 11month-old girl with Cockayne syndrome, showing facial features, microcephaly, and somatic growth failure (I) [reproduced from
Natale, 2011]. Head CT of a child with Cockayne syndrome, showing cortical atrophy, enlargement of the lateral ventricles, and basal
ganglia calcifications (J) [reproduced from Tan et al., 2005].

modification of chromatin structure,

mutations in the RubinsteinTaybi
syndrome genes therefore share epigenetic similarities with the molecular
pathogenesis of MECP2-related disorder [Urdinguio et al., 2009].

WARBURG MICRO
SYNDROME
MICRO syndrome was first described as
an autosomal recessive disorder among

MICRO syndrome was first

described as an autosomal
recessive disorder among
children with microcephaly,
microcornea, and cataracts, a
clinical presentation that can
overlap some prenatal
infections. Further delineation
of the syndrome led to the
understanding that the
microcephaly was generally
postnatal in onset.
children with microcephaly, microcornea, and cataracts, a clinical presentation
that can overlap some prenatal infections
[Warburg et al., 1993]. Further delineation of the syndrome led to the
understanding that the microcephaly
was generally postnatal in onset [Graham

et al., 2004]. Recognizable facial features

include deeply set eyes, wide nasal
bridge, and narrow mouth (Fig. 4A
and B) [Morris-Rosendahl et al., 2010].
Hypogonadism is also common [Warburg et al., 1993]. Brain malformations
can be seen, such as callosal hypoplasia,
cortical and subcortical atrophy, and
polymicrogyria (Fig. 4CH) [Graham
et al., 2004; Morris-Rosendahl et al.,
2010]. Loss-of-function mutations in
RAB3GAP1 were subsequently found
in individuals with Warburg MICRO
syndrome [Aligianis et al., 2005]. Rab
proteins have several roles regulating
both exocytic and endocytic vesicle
membrane transport, including of neurotransmitters and hormones [Takai
et al., 2001]. Further studies have
identified mutations in other Rab family
genes, including RAB3GAP2 [Borck
et al., 2011], RAB18 [Bem et al., 2011],
and most recently loss-of-function mutations in TBC1D20 [Liegel et al.,
2013]. Martsolf syndrome is now
recognized as a similar constellation of
intellectual disability and cataracts,
caused by milder mutations in the Rab
family genes [Aligianis et al., 2006;
Handley et al., 2013].

COCKAYNE SYNDROME
Cockayne syndrome comprises a phenotypic spectrum ranging from classical Type I, more severe Type II
overlapping with cerebral-oculo-facial
skeletal syndrome (COFS), and a milder
Type III [Laugel et al., 2008; Natale,

2011]. Xeroderma pigmentosumCockayne syndrome is also recognized.

The classical Type I Cockayne syndrome
presents with postnatal growth failure,
including postnatal microcephaly, and
progressive neurodevelopmental disability [Rapin et al., 2006] (Fig. 4I). In Type
II Cockayne syndrome, these symptoms
of growth failure and severe neurologic
dysfunction are present at birth, with
little postnatal development occurring.
Congenital cataracts and other structural
eye malformations are often found. The
mildest form, Type III Cockayne syndrome, may have normal growth and
intellectual development, or the symptoms have onset later in childhood.
Characteristic oro-dental features have
also been described, including microretrognathia, hypodontia, microdontia,
and enamel hypoplasia [Bloch-Zupan
et al., 2013]. Hearing loss is usually
progressive and parallels loss of cognitive
function [Morris et al., 2007]. A hyperkinetic movement disorder is often
present [Hebb et al., 2006]. Less common medical complications include
dilated cardiomyopathy and aortic dilatation [Ovaert et al., 2007]. A variety of
dermatologic abnormalities are seen
[Frouin et al., 2013].
Autosomal recessive mutations in
ERCC6 (CSB) cause most (65%) cases of
Cockayne syndrome [Troelstra et al.,
1992, 1993], with mutations in ERCC8
(CSA) accounting for the remainder
[Henning et al., 1995; Laugel et al.,
2010]. Both proteins are involved in
DNA repair after ultraviolet damage,

12

AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

and abnormalities may be detected in

patient skin fibroblasts [van Gool
et al., 1997; van den Boom et al., 2004].
Brain imaging in Cockayne syndrome include cerebral, cerebellar, and
brainstem atrophy, mild to moderate
dilation of the lateral ventricles, and basal
ganglia calcifications [Koob et al., 2010;
Mundaganur, 2012] (Fig. 4J). MR
spectroscopy can show the presence of
a lactate peak and decreased choline and
N-acetylaspartic acid [Koob et al.,
2010]. Brain neuropathology has found
subcortical demyelination, calcium deposits, and relative preservation of
neurons [Itoh et al., 1999].
COFS syndrome is a severe phenotype that overlaps with Cockayne syndrome and is also caused by autosomal
recessive mutations in ERCC6 [Meira
et al., 2000]. Individuals with COFS
syndrome have arthrogryposis, dysmorphic facial features (including micrognathia and prominent nasal root),
congenital cataracts, borderline micro-

cephalic head size at birth followed by

severe deceleration of both head and
somatic growth [Laugel et al., 2008].
Brain MRI is notable for global cerebral
atrophy. As most COFS syndrome cases
reported in the literature have not been
genotyped, it is possible some cases
reported had Warburg MICRO syndrome [Graham et al., 2004].

CONCLUSIONS
Syndromes featuring postnatal microcephaly present a fascinating combination of brain malformations, specific
epilepsies, movement disorders, and
other complex neurobehavioral abnormalities. Here, we strongly emphasize
that enough phenotype and natural
history data are available to recognize
Angelman syndrome, Christianson
syndrome, MECP2-, CDKL5-, and
FOXG1-related disorders as separate
diagnostic entities in their own right,
and encourage clinicians to dispense

ARTICLE

with the unhelpful terms Angelmanlike and Rett-like disorders. This

diagnostic clarity will aid counseling,
provision of more accurate prognostic
information, and will help guide future
natural history studies and treatment
trials.
Specific biological pathways can be
identified for many of the postnatal
microcephalies (Table II), with genes
important in the regulation of gene
expression, histone modification, as well
as transcription-related DNA repair
playing prominent roles. CASK appears
to have a dual function in both RELNTBR1 directed neuronal migration, and
also in supporting synaptic structure.
GTPase signal transduction is important
as well. Presumably, all of these pathways
converge on common features of neuronal differentiation, cell survival, and
dendrite and synapse development and
function, accounting for the array of
neurobehavioral symptoms seen in these
disorders. The next research horizon

TABLE II. Genes, Syndromes, and Pathways Associated With Postnatal Microcephaly
Gene

Protein function

Transcriptional regulators
MECP2
Methyl-CpG-binding domain protein
FOXG1
Transcription factor
TCF4
Transcription factor
CREBBP
Histone acetyltransferase
EP300
Histone acetyltransferase
Neuronal migration
CASK
Serine protein kinase
Synaptic structural support
CASK
Serine protein kinase
CDKL5
Serinethreonine protein kinase
Endosome regulation
SLC9A6
Sodiumhydrogen exchange protein
Vesicle membrane transport
RAB3GAP1
GTPase-activating protein
RAB3GAP2
GTPase-activating protein
RAB18
Ras-related GTPase
TBC1D20
GTPase activator protein
DNA repair
ERCC6
Transcription-coupled excision repair protein
ERCC8
Transcription-coupled excision repair protein
Unknown pathway
UBE3A
Ubiquitinprotein ligase

Syndrome

Inheritance

MECP2-related disorder
(formerly Rett syndrome)
FOXG1-related disorders
PittHopkins syndrome
RubinsteinTaybi syndrome
RubinsteinTaybi syndrome

De
De
De
De

CASK-related disorder

X-linked

CASK-related disorder
CDKL5-related disorder

X-linked
X-linked

Christianson syndrome

X-linked

Warburg
Warburg
Warburg
Warburg

AR
AR
AR
AR

MICRO
MICRO
MICRO
MICRO

X-linked
novo
novo
novo
novo

Cockayne syndrome
Cockayne syndrome

AR
AR

Angelman syndrome

Imprinting

ARTICLE

will likely be the detailed study of how

these pathways may be affected pharmacologically, and lead to improvement of
target behavioral symptoms.

ACKNOWLEDGMENTS
We wish to thank our research families
for their participation and support of our
work. Dr. Seltzer is supported by the
National Institute of Neurological Disorders and Stroke (NINDS) of the
National Institutes of Health (NIH)
award number K12NS066098 and
Dr. Paciorkowski by award number
K08NS078054. The authors have no
financial disclosures.

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