ß 2008 Wiley-Liss, Inc.

American Journal of Medical Genetics Part A 146A:2023 – 2037 (2008)

Research Review
Genetic Disorders Associated With Macrocephaly
Charles A. Williams,1* Aditi Dagli,1 and Agatino Battaglia2
1
Raymond C. Philips Research and Education Unit, Division of Genetics, Department of Pediatrics, University of Florida,
Gainesville, Florida
2
Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Calambrone, Pisa, Italy
Received 6 February 2008; Accepted 15 May 2008

Macrocephaly is associated with many genetic disorders and organic acidurias are reviewed, but the well known
is a frequent cause of referral to the clinical geneticist. In this conditions involving storage disorders and bone dysplasias
review we classify the commonly encountered macro- are mentioned but not discussed. The genetic macrocephaly
cephaly disorders into useful categories and summarize conditions cover a broad spectrum of gene disorders and
recent genetic advances. Conditions where macrocephaly their related proteins have diverse biological functions. As of
is a predominant aspect of the clinical presentation are yet it is not clear what precise biological pathways lead to
discussed and a diagnostic approach to the common generalized brain overgrowth. ß 2008 Wiley-Liss, Inc.
macrocephaly disorders is provided. Some emphasis is
placed on familial macrocephaly (sometimes referred to as
benign external hydrocephalus) and on the macrocephaly
associated with autism spectrum disorders. The more recent Key words: macrocephaly syndromes; familial macroce-
conditions associated with the leukodystrophies and the phaly; autism; megalencephaly; genetics; macrocephaly

How to cite this article: Williams CA, Dagli A, Battaglia A. 2008. Genetic disorders associated
with macrocephaly. Am J Med Genet Part A 146A:2023–2037.

INTRODUCTION could lead to significantly increased brain size. It is

not surprising then that many conditions with brain
Macrocephaly is a common reason for a medical
overgrowth are not associated with obvious cyto-
genetics referral. As there are many genetic con-
architectual or other histological abnormalities.
ditions associated with macrocephaly, the diagnostic
Macrocephaly refers to an abnormally large head
possibilities are numerous. An OMIM search for
inclusive of the scalp, cranial bone and intracranial
macrocephaly returned 175 entries, and a search
contents. Macrocephaly may be due to megalence-
for megalencephaly returned 21 listings [OMIM,
phaly (true enlargement of the brain parenchyma) or
2008]. Eliminating duplicated entries, there were
due to other conditions such as hydrocephalus or
164 conditions, including 17 metabolic disorders.
cranial hyperostosis. In this review, we will use the
Accordingly, any review of macrocephaly must
term macrocephaly to include conditions of mega-
acknowledge a broad group of genetic conditions.
lencephaly. The head circumference measurement,
The adult brain reaches a total volume of about
herein referred to as the occipital frontal circum-
1,700 ml, composed of 80% parenchyma, 10% blood,
ference (OFC), extends from the most prominent
and 10% cerebrospinal fluid [Blinkov and Glezer,
part of the glabella to the most prominent posterior
1968]. Brain parenchyma is composed mainly of
area of the occiput. The OFC can be affected by thick
neurons and glial cells, the total number of neurons is
hair and cranial bone deformations or hypertrophies.
estimated at 100 billion in the adult. Glial cells
(oligodendrocytes, astrocytes, ependymal cells, and
microglia) may be 10–50 times more numerous than
neurons [Williams and Herrup, 1988]. Additionally,
water constitutes 77–78% of brain weight with most Grant sponsor: Raymond C. Philips Research and Education Contract,
of the remaining due to lipids (10%) and proteins State of Florida, USA.
*Correspondence to: Charles A. Williams, M.D., Division of Genetics,
(8%) [McIlwain and Bachelard, 1985]. Given these Department of Pediatrics, University of Florida, P.O. Box 100296,
aspects, a subtle increase in the number and/or the Gainesville, FL 32610. E-mail: [email protected]
molecular–fluid environment of cells in the CNS DOI 10.1002/ajmg.a.32434
 American Journal of Medical Genetics Part A

2024 WILLIAMS ET AL.

Ethnicity and stature must also be considered TABLE I. Classification of Macrocephaly Conditions
when evaluating the OFC [DiLiberti, 1998]. Relative I. Genetic types
macrocephaly indicates that the OFC plots within Familial macrocephaly
2.0 SD of the mean but plots disproportionately Benign; symptomatic
Autism disorder
above that for stature. The measurement of cranial Multifactorial, non-syndromic type
height in combination with the OFC, or the use of Syndrome associations (many types)
brain imaging, provide a more accurate determina- With cutaneous findings
tion of intracranial volume but these methods have PTEN hamartoma syndromes
mainly been used in the research setting [Gooskens Neurofibromatosis, type 1
Hemimegalencephaly
et al., 1989]. The single OFC measurement however With overgrowth
remains the customary method for identification of Sotos, Weaver
macrocephaly. Macrocephaly cutis marmorata telangiectatica congenita
Non-syndromic macrocephaly refers to conditions Simpson–Golabi–Behmel, Beckwith–Wiedemann syndrome
Neuro-cardio-facial-cutaneous syndromes
in which the enlarged brain is the predominant Noonan, Costello
abnormality, not associated with any other note- Cardiofaciocutaneous (CFC)
worthy physical trait or major malformation. Minor LEOPARD
craniofacial changes can be present but they are due With mental retardation
to the secondary effects of the enlarged cranial vault. Fragile X
Metabolic types
These changes include a prominent or high forehead With leukodystrophy
and a dolichocephalic head shape. Increased width Alexander; Canavan
of the cranial base can at times produce mild Megalencephalic leukodystrophy
hypertelorism and down slanting palpebral fissures. With organic acidurias
Glutaric aciduria, type 1
Also, the facial area may be relatively small giving D-2-hydroxyglutaric aciduria
a triangular craniofacial appearance. Syndromic With storage
macrocephaly means that significant abnormalities Bone dysplasia/hyperplasia
(physical or behavioral) are associated with the Hydrocephalus
generalized brain enlargement. The constellation of Aqueductal stenosis types
Multifactorial, non-obstructive types
these abnormalities creates a recognizable pattern II. Non-genetic types
worthy of a syndromic designation. Syndromic Hydrocephalus
macrocephaly conditions should be distinguished Hemorrhage
from other genetic syndromes in which macro- Infections; other causes
Subdural effusions
cephaly is an occasional but not consistent, or Post-traumatic and infectious
clinically predominant, finding. Finally, the non- Arachnoid cysts
genetic macrocephalies are due to secondary effects
of environmental events such as those related to
neonatal intraventricular hemorrhage or infection.
Familial Macrocephaly
CLASSIFICATION
The typical child with familial macrocephaly (FM)
The genetic and acquired types of macrocephaly has a birth OFC in the higher normal percentiles that
can be categorized based on associated physical, then increases to exceed 2.0 SD by one year of age.
metabolic, or brain imaging findings (Table I). This The growth rate may increase by 0.6–1.0 cm/week in
table resembles those of prior reviews [DeMyer, the first months of life (exceeding the normal rate of
1986; Bodensteiner and Chung, 1993] but is 0.4 cm/week) [Lorber and Priestley, 1981]. During
expanded to include newly recognized syndromic this period, the infant with FM has an enlarged,
conditions. Table I is not a complete listing of the dolichocephalic-appearing cranium. Brain scans
genetic disorders known to be associated with may show only prominent supratentorial CSF spaces,
macrocephaly, but the listings are representative of especially bifrontal widening of the subarachnoid
the more common conditions that the clinician may space and a widened frontal interhemispheric fissure
encounter. Table II indicates the importance of (Fig. 1) [Alvarez et al., 1986]. These findings have also
macrocephaly as a predominant clinical feature of been reported as ‘‘benign external hydrocephalus’’
the given genetic condition; most of these entities are of infancy [Alvarez et al., 1986; Odita, 1992]. More
discussed in this review. This review does not discuss recently, it has been shown that this type of external
metabolic storage diseases or conditions associated hydrocephalus is a normal CSF variant that can be
with the osteochondrodysplasias (e.g., bone dyspla- observed in both normocephalic and macrocephalic
sia and hyperplasia disorders). These general cate- infants [Prassopoulos and Cavouras, 1994; Prasso-
gories are however included in Table I and a few poulos et al., 1995]. In FM, the CSF spaces become
specific conditions are listed in Table II to illustrate normal by 3–4 years of age, but the OFC continues
their importance as a clinical grouping. to develop at or above 2 SD. By adulthood, the
 TABLE II. Table of Macrocephaly Syndromes Summarizing Certain Clinical Aspects of Macrocephaly and Listing Causative Genes, if Known, and Inheritance Patterns
Syndrome/disease "OFC: major "OFC: minor Absolute Relative Identified genes Inheritance
clinical finding clinical finding macrocephaly macrocephaly pattern

Familial macrocephaly
Benign asymptomatic þ þ — ?AD/MF
Autism disorder
Multifactorial, non-syndromic þ þ — MF
Syndrome associations
With cutaneous findings
Bannayan–Riley–Ruvalcaba syndrome (BRRS)/ þ þ PTEN AD
Cowden syndrome/Lhermitte–Duclos syndrome
Neurofibromatosis, type 1 (NF1) þ þ þ NF1 AD
Linear Epidermal Nevus syndrome (LENS) þ þ — ?AD
Klippel–Weber–Trenaunay syndrome (KTW) þ þ VG5Qa ADa
With overgrowth
Sotos syndrome þ þ NSD1 AD
Weaver syndrome þ þ NSD1b AD
Macrocephaly–Cutis–Marmorata telangiectatica þ þ — ?AD
congenita (M-CMCT)
Simpson–Golabi–Behmel syndrome þ þ GPC3c XLD
Beckwith–Wiedemann syndrome þ þ CDKN1Cd AD
With neuro-cardio-facio-cutaneous syndromes
Noonan syndrome þ þ PTPN11, KRAS, SOS1, RAF1 AD
Costello syndrome þ þ HRAS AD
Cardiofaciocutaneous syndrome þ þ KRAS, BRAF, MEK1, MEK2 AD
LEOPARD þ þ PTPN11, RAF1
With mental retardation
Fragile X syndrome þ þ FMR1 XLD
Metabolic types
With organic aciduria
Glutaric aciduria, type 1 (GA-1) þ þ GCDH AR
D-2-hydroxyglutaric aciduria þ þ D2HGD AR
With leukodystrophy
Alexander disease þ þ GFAP AD
Canavan disease þ þ ASPA AR
Megalencephalic leukoencephalopathy with MLC1 AR
subcortical cysts (MLC)
With storage
Hunter syndrome þ þ IDS XLD
Hurler syndrome þ þ IDUA AR
Tay–Sachs disease þ þ HEXA AR
Bone dysplasia/hyperplasia
Achondroplasia þ þ þ FGFR3 AD
Craniometadiaphyseal dysplasia þ þ þ AR, AD
Osteopetrosis þ þ TCIRG1, CLCN7, OSTM1, TNFSF11, PLEKHM1, AR, AD
CA2, LRP5
Hydrocephalus
X-linked aqueductal stenosis/hydrocephalus þ þ L1CAM XLD
Congenital stenosis of aqueduct of Sylvius þ þ — AR
AD, autosomal dominant; AR, autosomal recessive; XLD, X-linked disorder; MF, multifactorial inheritance; OMIM, Online Mendelian Inheritance in Man.
a
Some cases of KTW are caused by mutations in VG5Q [Tian et al., 2004].
b
Some cases have NSD1 mutations.
c
American Journal of Medical Genetics Part A

Not all cases have GPC3 mutations; a second locus is at Xp22.

d
Also caused by abnormal methylation and segmental UPD events in the 11p15.5 region.
 American Journal of Medical Genetics Part A

2026 WILLIAMS ET AL.

measurements in 23 families in which one child

from each family was clinically ascertained to have
macrocephaly [Arbour et al., 1996]. However, the
relatively common observation of macrocephaly in
a sibling or in a parent, and the observation of
extended families in which macrocephaly is appa-
rently segregating as a dominant trait, appears to
distinguish FM from other classical mutifactorial
disorders in which dominant-like, extended pedi-
grees are not often observed. Several authors have
thus proposed an autosomal dominant model of
inheritance [Schreier et al., 1974; Asch and Myers,
1976; Alvarez et al., 1986; DeMyer, 1986]. This type of
dominant inheritance might be due a single gene
exhibiting a major effect as part of a multifactorial
phenomenon in some families.

Autism
FIG. 1. Diagram illustrating the normal brain variants seen in familial Autism spectrum disorders have received increas-
macrocephaly. The subarachnoid compartments and the interhemispheric
fissure width over the frontal regions are relatively enlarged (white arrows) and
ed attention recently because of concerns about its
the frontal lobes appear atrophic. apparent increasing prevalence, estimated as now
occurring in one in 150 children in the United States
craniofacial shape appears normal although the OFC [Anon., 2007]. Mental retardation is as well quite
remains >2 SD (Fig. 2B). prevalent among individuals with autism and is
Criteria for the diagnosis of FM have been set forth estimated to occur in 40–55% [Chakrabarti and
by DeMyer: (1) absence of craniofacial, neurocuta- Fombonne, 2001; Newschaffer et al., 2007]. Autism
neous or somatic anomalies that might identify a is not a homogeneous diagnostic group but has
syndrome; (2) normal radiographic study of the etiologic heterogeneity with 10–15% of this group
brain; and (3) a parent or sibling with macrocephaly having identifiable genetic or metabolic disorders
or macrocephaly that could be traced through [Battaglia and Carey, 2006; Sebat et al., 2007; Schaefer
several generations [DeMyer, 1986]. A small percent- and Mendelsohn, 2008]. However, there remains a
age of children with FM have developmental handi- group in whom extensive genetic testing reveals no
caps, suggesting that FM may be a risk factor for known cause and these children appear to have autism
learning delay [Alvarez et al., 1986; DeMyer, 1986]. consistent with multifactorial model of inheritance.
In addition, 7 of 109 (6.4%) children with apparent Macrocephaly occurs in about 15–35% of autistic
isolated macrocephaly were noted to be ‘‘retarded’’ children and can also be seen in other types of per-
on one study, and another found that, of 75 children vasive developmental disorders [Woodhouse et al.,
in classroom for learning disability, 16% had macro- 1996; Stevenson et al., 1997; Courchesne et al., 2003;
cephaly compared to 4.1% in control children [Lorber Dementieva et al., 2005]. Although minor physical
and Priestley, 1981; Smith et al., 1984]. Accordingly, anomalies have been noted among children with
in a child with macrocephaly and learning disability autism, it is clear that macrocephaly is the most
when other normal family members have macro- prominent correlated physical abnormality. The
cephaly, it can be difficult to know if this familial trait prevalence of macrocephaly among autism cohorts
is truly associated with the child’s developmental is greater than that seen in children with learning
problem. delays, where the prevalence of macrocephaly can
Normally, the OFC measurement shows a con- be up to 15% of children [Smith, 1981; Smith et al.,
tinuous distribution in the population, as is also 1984]. The increased prevalence is present across
observed for stature and body mass. About 50% of all types of autism spectrum children and is even
OFC variance has been shown to be familial [Weaver present in those who have near-normal develop-
and Christian, 1980] and the OFC trait has tradition- mental quotients [Gillberg and de Souza, 2002].
ally been understood as exhibiting multifactorial The macrocephaly observed in autism becomes
inheritance. Studies of affected family members and manifest around 1–3 years of age and is typically
of children with macrocephaly show a 4:1 male to not present at birth (Fig. 2I). There is an apparent
female predominance [Lorber and Priestley, 1981] increased rate of brain growth in the first years of
consistent with ratios often observed in multifacto- life that diminishes and becomes subnormal in later
rially inherited conditions. A multifactorial model of childhood; macrocephaly in adults with autism is less
inheritance of FM has in fact been proposed based on prevalent than in autistic children [Aylward et al.,
a study of the distribution of head circumference 2002]. Brain MRI studies have not found migrational
 American Journal of Medical Genetics Part A

GENETICS OF MACROCEPHALY 2027

FIG. 2. Appearance of macrocephaly in different genetic conditions: (A) PTEN disorder; (B) father and child with benign familial macrocephaly; (C) Achondroplasia;
(D) Sotos syndrome; (E) glutaric aciduria, type 1; (F) fragile X syndrome; (G) Hunter syndrome; (H) craniodiaphyseal-like bone dysplasia; (I) autism of unknown cause.

defects or other structural problems. Quantitative with no other clinical features, have been found to
MRI studies, aimed at determining volume differ- have germline PTEN mutations, and it has been
ences, find that most of the volume change is due suggested that PTEN gene sequencing be included
to differential white matter increase [Courchesne in the diagnostic work-up of these children [Herman
and Pierce, 2005; Herbert, 2005]. Cytoarchitectural et al., 2007]. The relationship between the macro-
studies have found defects ranging from abnormal cephaly and the autism disorder is confounded by
cell distributions in frontal and temporal lobe the observation that first degree relatives of autism
‘‘minicolumns’’ to neuroimmune inflammatory reac- probands have an increased prevalence of macro-
tions [Casanova et al., 2002; Vargas et al., 2005; Pardo cephaly [Fidler et al., 2000]. A recent report also
and Eberhart, 2007]. Overall, no consistent brain showed that both normocephalic and macrocephalic
pathology has been demonstrated [Casanova, 2007]. autistic children were more likely to have parents
It is unclear whether macrocephaly is associated who were macrocephalic [Keegan et al., 2007].
with an autism endophenotype; a recent report on In these studies, the macrocephaly appeared to
quantitative trait locus analysis involving macro- be segregating as an independent trait in the non-
cephaly in sib pairs of autistic children found autistic family members. It is currently not only
evidence of several genomic loci, including one near unclear how macrocephaly is related pathoetiolog-
the PTEN gene region (10q25.2) [Spence et al., 2005]. ically to the autism problem, but it is also unclear how
Several cases have recently been reported where the heritable aspect of autism interplays with that of
children with autism and macrocephaly, and autism macrocephaly.
 American Journal of Medical Genetics Part A

2028 WILLIAMS ET AL.

SYNDROMES WITH CUTANEOUS FINDINGS although learning deficits are common in NF1, they
do not seem to be correlated with the presence of
PTEN Harmartoma-Tumor Syndromes macrocephaly [Hyman et al., 2005].
Bannayan–Riley–Ruvalcaba syndrome (OMIM Neurofibromin, the protein product of the Neuro-
153480) encompasses the association of macro- fibromin or NF1 gene (17q11.2), is a GTP-ase
cephaly with various cutaneous findings (e.g., activating protein that downregulates RAS signaling
lipomas, hemangiomas, and pigmented macules) and this appears to keep in check the mTOR growth
[DiLiberti, 1998, for review]. Macrocephaly has also signaling system [Costa and Silva, 2003]. In the
been noted in Cowden (OMIM 158350) and Lher- mouse, heterozygous NF1 mutations can increase
mitte–Duclos syndromes [Perez-Nunez et al., 2004]. CNS progenitor cell pools, including oligodendro-
These macrocephaly associated conditions are due cytes, and astrogliosis has been observed in some but
to heterozygous mutations in the Phosphatase and not all areas of the mouse brain [Bennett et al., 2003].
tensin homolog deleted on chromosome TEN (PTEN) While astrogliosis has been reported in some parts
gene (10q23.31), hence the term PTEN harmartoma- of the human NF1 brain, only a few individuals
tumor syndromes [Marsh et al., 1999]. They can be have been reported [Nordlund et al., 1995]. Recently
inherited as an autosomal dominant disorder with SPRED 1 gene (15q13.2) mutations have been
extremely variable expression. described in individuals with some clinical features
It appears that most children with PTEN mutations of NF1 including macrocephaly, café au lait spots and
are macrocephalic; in a study of PTEN cases, all 19 axillary freckling. These individuals did not have
individuals, age 15 years or less, who had head neurofibromas. SPRED 1 belongs to the SPROUTY/
circumference measurements, were macrocephalic SPRED family of proteins that act as negative
[Tan et al., 2007]. Prevalence of macrocephaly in regulators of RAS/MAPK pathway [Brems et al.,
adults with Cowden syndrome has been noted as 2007]. Despite these advances, a molecular explan-
80% in a study of 21 patients [Starink et al., 1986]. The ation of the macrocephaly in NF1 remains unknown.
macrocephaly, when present in childhood, can be The MRI has been used to study regional area and
impressive, sometimes >4–8 SD, and developmental volume differences in NF1 and it appears that the
delay and/or autism may be the only apparent macrocephaly is associated mainly with a relative
clinical abnormalities (Fig. 2A) [Butler et al., 2005]. increase in frontal and parietal white matter, but gray
In such cases, closer clinical scrutiny may disclose a matter as well may be affected [Moore et al., 2000;
family history of cerebellar dysplastic gangliocyto- Cutting et al., 2002]. Focal MRI intensity changes are
mas (Lhermitte–Duclos type) or thyroid cancers (as well known in the midbrain, cerebellum or brain-
part of Cowden syndrome). Further physical exami- stem, a finding observed in both macrocephalic and
nation may reveal unique pigmented macules on the normocephalic NF1 individuals [Feldmann et al.,
glans of the penis or small otherwise unrecognized 2003]. Histological study of these areas reveals glial
lipomas on the trunk or arms. Brain MRI has dysplasia and increased intercellular spaces, but
generally been reported as normal although recent these are not sufficient to account alone for the
reports suggest that prominent Virchow–Robin frontal-parietal white matter volume increases
spaces, or vascular flow anomalies may be important [DiPaolo et al., 1995]. More diffuse increases in
indicators of PTEN-associated macrocephaly [Medne presumed white matter water content can be
et al., 2007; Tan et al., 2007]. demonstrated by MRI diffusion brain study and this
The PTEN gene encodes a putative tumor suppres- theoretically could be a major contributor to the
sor protein targeted to phosphoinositidie-3 kinase increased brain volume [Tognini et al., 2005].
(PI3K) which is involved in cell-cycle regulation,
angiogenesis, and cellular growth and proliferation Hemimegalencephaly
[Sansal and Sellers, 2004; Hay, 2005]. As a tumor
suppressor, the dysplastic cerebellar changes (e.g., Hemimegalencephaly implies unilateral increased
gangliocytoma) associated with PTEN mutations size of the entire cerebral hemisphere and should be
could be explained by a 2-hit model but this model distinguished from focal neuronal or glial dysplasias,
seems unlikely to account for generalized macro- although the histological findings may be similar
cephaly. [Mischel et al., 1995; Yasha et al., 1997]. Gross
pathology can show areas of pachygyria and agyria
with enlarged lateral ventricles, easily identified
Neurofibromatosis Type 1 (NF1)
on MRI scans [Barkovich and Chuang, 1990; Brou-
At least 20–30% of older children with NF1 (OMIM mandi et al., 2004]. Hemimegalencephaly has been
162200) have macrocephaly and an even greater observed in tuberous sclerosis (OMIM 191100),
percentage have relative macrocephaly [Clementi Neurofibromatosis-1, linear epidermal nevus syn-
et al., 1999; Szudek et al., 2000]. The macrocephaly drome (LENS), Klippel–Trenaunay–Weber syn-
occurs in otherwise normal NF1 children (i.e., drome (KTW) (OMIM 149000), Proteus syndrome
without intracranial tumor or hydrocephalus) and, (OMIM 176920) and macrocephaly cutis marmorota
 American Journal of Medical Genetics Part A

GENETICS OF MACROCEPHALY 2029

telangiectatica congenita (M-CMCT) (OMIM 602501). pellucidum, cerebral atrophy, localized hypervascu-
LENS is probably the most frequent syndrome larization, and pachygyria [Freeman et al., 1999].
association, hemimegalencephaly was seen in Definite genetic etiology has not been identified but
11/44 cases in one survey [Sasaki et al., 2005]. Most autosomal dominant inheritance is proposed. Some
cases of hemimegalencephaly appear to be sporadic individuals with a clinical phenotype of Weaver
occurrences although one report found mutations syndrome have been found to have mutations in the
in vascular growth factor (VG5Q) gene (5q13.3) in NSD1 gene [Douglas et al., 2003].
some cases of KTW [Tian et al., 2004]. Simpson–Golabi–Behmel syndrome is associated
with macrosomia of prenatal onset, distinctive facial
appearance, developmental delay and other con-
SYNDROMES WITH OVERGROWTH
genital anomalies. The craniofacial appearance is
The overgrowth conditions are well represented in characterized by a large head with coarse features,
any differential listing of conditions associated with thickened lips, wide mouth, large tongue, high-
macrocephaly in combination with generalized arched palate, malposition of the teeth, prominent
somatic overgrowth, and include the syndromes jaw and short neck. Mutations in the glypican-3
of Sotos (OMIM 117550), Weaver (OMIM 277590), (GPC-3) gene, at Xq26, are responsible for most
Simpson–Golabi (OMIM 312870), Beckwith–Wie- cases. GPC-3 controls the growth of mesoderm
demann (OMIM 130650) and others [Cohen, 1999]. tissues in the embryo [Pilia et al., 1996]. A more
Sotos syndrome, initially reported as cerebral severe form of the disorder, Simpson–Golabi–
gigantism in childhood [Sotos et al., 1964], is the Behmel syndrome, type II, maps to Xp22 [Brzusto-
prototypical example of an overgrowth/macroce- wicz et al., 1999]. Macrocephaly is commonly present
phaly syndrome. Individuals with Sotos syndrome at birth and is progressive through childhood. CNS
have a distinctive facial appearance with macro- abnormalities have been reported only in one case
cephaly, a high prominent forehead, downslanting where Chiari malformation and corpus callosum
palpebral fissures, long pointed chin, and high- agenesis were noted [Young et al., 2006].
arched palate. In childhood, the height is above The M-CMTC syndrome consists of congenital
average with an advanced bone-age and large hands telangiectasias (sometimes localized to the face),
and feet. Final adult height may not be increased macrosomia, macrocephaly, developmental delay
[Agwu et al., 1999]. Brain MRI scans in a series of and minor anomalies including syndactyly [Clayton-
Sotos patients typically show no migrational or Smith et al., 1997; Moore et al., 1997]. The syndrome
structural defects but only mild, generalized ventri- has been recently referred to as macrocephaly capil-
culomegaly and enlarged supratentorial extracere- lary malformation syndrome [Toriello and Mulliken,
bral fluid spaces. Thus, it is possible that the 2007]. Often, there is body asymmetry or hemihyper-
macrocephaly observed in childhood is attributable trophy. MRI scans may show generalized parenchy-
mainly to increased CSF spaces [Schaefer et al., 1997]. mal enlargement, white matter irregularities, focal
Aoki et al. [1998] however found macrocephaly due cortical dysplasia, polymicrogyria. Generalized ven-
to parenchymal enlargement in two neonates with triculomegaly, prominent Virchow–Robin spaces
Sotos syndrome who then developed mild ventricu- with dilated dural venous sinuses are seen in many
lomegaly changes as children suggesting that true affected patients [Conway et al., 2007]. Chiari I
megalencephaly is initially present at birth. Sotos anomaly, cerebellar tonsillar herniation and hemi-
syndrome is caused by disruption of the nuclear megalencephaly have been reported [Moore et al.,
receptor SET-domain-containing (NSD1) gene (5q35), 1997; Lapunzina et al., 2004; Garavelli et al., 2005].
which codes for a nuclear steroid receptor co- The genetic cause of M-CMTC has not yet been
regulator protein [Wang et al., 2001]. The clinical determined and neither parents nor siblings have
aspects of Sotos have now been more accurately been affected; sporadic autosomal dominant muta-
delineated in many patients with NSD1 proven tion is thus a possibility [Garavelli et al., 2005].
mutations and/or microdeletions [Cecconi et al.,
2005; Faravelli, 2005]. Nuclear receptor genes control
NEURO-CARDIO-FACIO-CUTANEOUS
diverse roles in cell growth and differentiation via
SYNDROMES
transcriptional modulation [Rayasam et al., 2003].
There does not appear to be any reports yet as to how These conditions include Noonan (OMIM 163950),
NSD1 function relates to brain overgrowth. LEOPARD (OMIM 151100), Costello (OMIM 218040)
Weaver syndrome is characterized by accelerated and cardiofaciocutaneous (CFC) (OMIM 115150)
growth of prenatal onset, advanced osseous matura- syndromes and are associated with mutation the
tion, unusual facial appearance, macrocephaly and RAS/MAP Kinase signaling pathway genes [Denayer
camptodactyly. Loose skin may be observed [Weaver and Legius, 2007]. They are often associated with
et al., 1974; Opitz et al., 1998]. Macrocephaly is relative macrocephaly but in infancy this type of
present in 83% of the individuals [Jones, 2006]. CNS macrocephaly may be a striking component of the
abnormalities reported include cysts of septum craniofacial phenotype. Macrocephaly in Noonan
 American Journal of Medical Genetics Part A

2030 WILLIAMS ET AL.

syndrome may occasionally be associated with young adults may have a long face, large ears and a
hydrocephalus or true megalencephaly. Noonan prominent jaw, but these features may be mild or
syndrome is characterized by short stature, congen- absent in children. Testicular size is increased in the
ital heart defects, webbed neck, abnormal chest, post-pubertal period. Macrocephaly is not a primary
developmental delay, macrocephaly, characteristic identifying characteristic but relative macrocephaly
facial features and varied coagulopathies [Allanson, may be present. In infancy, the OFC tends to be
1987]. Noonan syndrome is caused by mutations in above the mean but occasionally absolute macro-
the PTPN11 gene (12q24.1) in 50% [Tartaglia et al., cephaly is identified (Fig. 2F). Hence, Fragile X
2001, 2002; Jongmans et al., 2004], KRAS gene syndrome should be considered in the differential
(12p12.1) in less than 5% [Schubbert et al., 2006], diagnosis for infants with macrocephaly. Adults with
SOS1 gene (2p22-p21) in 10% [Roberts et al., 2007], Fragile X syndrome continue to have head circum-
and RAF1 gene (3p25) in 3–17% of cases [Pandit ferences above the mean [Partington, 1984; Chiu
et al., 2007; Razzaque et al., 2007]. CFC syndrome is et al., 2007]. It is of interest that infants with Fragile X
characterized by cardiac abnormalities, distinctive syndrome and autism have accelerated OFC growth
craniofacial appearance including relative macro- rates that peak at age 30 months but return to a
cephaly and cutaneous abnormalities. Cognitive normal rate by age 60 months [Chiu et al., 2007]. MRI
delay is seen in all affected individuals [Rauen, of the head demonstrates a diminished white to gray
2-18-2007]. The four genes known to be associated matter ratio and enlarged lateral and fourth ventricles
with CFC syndrome are: BRAF (7q34) in 75–80% [Cohen, 2003]. A recent study of 84 children and
[Niihori et al., 2006; Rodriguez-Viciana et al., 2006], adolescents with full mutation Fragile X syndrome
MAP2K1 (15q21) and MAP2K2 (7q32) in 10–15% showed that a large caudate nucleus, small posterior
[Rodriguez-Viciana et al., 2006], and KRAS in less cerebellar vermis, amygdala and superior temporal
than 5% [Niihori et al., 2006; Schubbert et al., 2006]. gyrus were distinguishing features from normal
Costello syndrome is characterized by failure to controls. The association between macrocephaly
thrive in infancy, short stature, developmental delay, and the above findings was not clarified [Gothelf
coarse facial features, macrocephaly deep palmar et al., 2008]. Routine brain scans however are usually
and plantar creases, papillomata, cardiac abnormal- normal although Moro et al. [2006] reported two
ities, and risk for tumors [Gripp et al., 2006b]. HRAS unrelated cases with periventricular heterotopia.
(11p15.5) missense mutations can be detected in 80–
90% of individuals with this clinical diagnosis [Aoki
METABOLIC, WITH LEUKODYSTROPHY
et al., 2005; Estep et al., 2006; Gripp et al., 2006a,b;
Kerr et al., 2006]. LEOPARD is an acronym for Of all the leukodystrophies, Alexander disease
lentigines, ECG conduction abnormalities, ocular (OMIM 203450), Canavan disease (CD) (OMIM
hypertelorism, pulmonic stenosis, abnormal genita- 271900) and megalencephalic leukoencephalopathy
lia, retardation of growth, and sensorineural deaf- with subcortical cysts (OMIM 604004) are most
ness [Gorlin et al., 1969]. Additionally, LEOPARD clearly associated with macrocephaly. In Alexander
syndrome is associated with learning difficulties, disease, there are widespread astrocytic inclusions
hypertrophic cardiomyopathy and abnormalities of of dense protein aggregates (Rosenthal fibers)
the spine. Mutations in PTPN11 are detected in about composed mainly of abnormal glial fibrillary acidic
90% of affected individuals [Digilio et al., 2002; Legius protein (GFAP) [Towfighi et al., 1983; Lake, 1997].
et al., 2002]. RAF 1 mutations have recently been There is widespread axonal loss and diffuse demye-
reported [Pandit et al., 2007]. lination especially prominent in the frontal lobes,
associated with a distinctive MRI appearance (Fig. 3)
[van der Knaap et al., 2001]. The most common
SYNDROMES WITH MENTAL RETARDATION
presentation involves infants less than 2 years of age
Fragile X Syndrome
who have a severe regressive course associated with
seizures, pyramidal spasticity, and feeding difficul-
Fragile X syndrome (OMIM 300624) occurs when ties. Juvenile and adult forms are also described but
a trinucleotide expansion, usually more than 200 all types are caused by heterozygous (autosomal
repeats, disrupts the function of the promoter region dominant), gain of function mutations in the GFAP
of the FMR1 gene (Xq27.3). The protein product, gene (17q21) [Rodriguez et al., 2001; Li et al., 2005]. In
FMRP, is important for synaptic maturation and a recent report of 26 cases with mutation proven
pruning and might have a regulatory role in activity- infantile presentation, only 62% had macrocephaly
dependant transcription at the synapse [Gatchel and and macrocephaly did not appear to be a feature in
Zoghbi, 2005; Dolen et al., 2007]. the juvenile and adult onset type [Li et al., 2005].
Fragile X syndrome is the most common genetic CD has a higher incidence of associated macro-
cause of mental retardation in males and should be cephaly as by 12 months of age, 54 of 59 affected
considered in the differential diagnosis of males children had head circumferences greater than the
presenting with developmental delay. Affected 90th centile [Traeger and Rapin, 1998]. In the typical
 American Journal of Medical Genetics Part A

GENETICS OF MACROCEPHALY 2031

FIG. 3. Illustration of the pattern of brain abnormalities (black arrows) associated with certain metabolic disorders. The white areas represent the main changes that
can occur in the white matter for the leukodystrophies and in the basal ganglia for glutaric aciduria, type 1.

form, symptoms develop between 2 and 4 months METABOLIC, WITH ORGANIC ACIDURIAS
of life with onset of muscular hypotonia, cognitive
delay, and vision impairment leading to blindness While there are a number of inborn errors of
and optic atrophy but no evidence of retinopathy. metabolism associated with neuronal or glial dys-
Spongiform degeneration of the white matter is the function, few appear to be associated with macro-
classical histological picture. Astrocytes are swollen cephaly. Glutaric aciduria, type 1 (GA-1) (OMIM
and vacuolated with apparent water spaces and 231670), is an exception since macrocephaly is
there is diminished myelin [Lake, 1997]. On MRI these present in the neonate [Hoffmann and Zschocke,
white matter changes are especially evident in the 1999; Horster et al., 2005] (Fig. 2E). Brain scans
arcuate fibers of the frontal and parietal regions demonstrate apparent non-specific frontal and tem-
(Fig. 3) [Sener, 2003]. Deficiency of the enzyme, poral lobe atrophy with prominent overlying sub-
aspartoacylase (ASPA), causes CD [Kaul et al., 1993]. dural spaces. Bridging veins that traverse the subdural
This enzyme is predominantly active in oligodendro- spaces appear at increased risk for subdural hemor-
cytes and hydrolyzes N-acetyl-L-aspartic acid (NAA) rhage, and infants with GA-I have been erroneously
to aspartate and acetate [Kirmani et al., 2002]. diagnosed as abused or neglected children [Hartley
Confirmation of CD can be ascertained by urinary et al., 2001]. In early infancy, there is usually no
determination of NAA, fibroblast enzyme analysis or evidence of metabolic acidosis or episodic illness
by genotyping, demonstrating pathogenic homozy- but, between 6 and 18 months of age, there is usually
gous or compound heterozygous mutations that the onset of a movement disorder with progressive
disrupt function of the ASPA gene (17pter-p13). dystonia and, in some cases, rapid clinical deterio-
Megalencephalic leukoencephalopathy with sub- ration due to acute injury to the basal ganglia area. At
cortical cysts (MLC) is associated often with this time, the MRI scan can show distinctive bilateral
pronounced infantile macrocephaly and leuko- striatal injury, apparently related to the excitatory
dystrophy but lacks the rapid course of neuro- effects of glutaric acid metabolites (Fig. 3) [Kolker
deterioration typically seen in Alexander or CD [van et al., 2004]. The enzyme defect involves a mitochon-
der Knaap et al., 1995; Leegwater et al., 2001]. Over drial flavoprotein, glutaryl-CoA dehydrogenase, with
100 clinical cases have been reported and macro- subsequent increased accumulation of 3-hydoxyglu-
cephaly is uniformly present by early childhood but it taric and glutaconic acids. Diagnosis is usually
is unclear what proportion has congenital macro- confirmed by urine organic acid analysis or plasma
cephaly [Riel-Romero et al., 2005]. The macrocephaly acylcarnitine profiling. Molecular studies reveal
can approach 4–6 SD above the mean. A distinctive mutations consistent with the known autosomal
feature of this entity is relatively large subcortical recessive mechanism of this disorder [Hoffmann and
cysts, especially in the temporal lobes (Fig. 3). This is Zschocke, 1999].
an autosomal recessive disorder that can be con- Macrocephaly has also been noted in some patients
firmed in most cases by genotyping the MLC1 gene with a recently delineated condition characterized
(22q13.33), although there may be some genetic by urine excretion of D-2-hydroxyglutaric aciduria
heterogeneity [Leegwater et al., 2001]. The gene (OMIM 600721). Over 35 cases have been reported
product is a novel transmembrane protein of and the clinical picture demonstrates both severe
unknown function. In the mouse, this protein is and mild types, with cardiomyopathy and severe
extensively expressed in astrocytes [Teijido et al., developmental delay observed in infants with
2004]. the severe type [van der Knaap et al., 1999]. Mutations
 American Journal of Medical Genetics Part A

2032 WILLIAMS ET AL.

in D-2-dehydroxyglutaric dehydrogenase gene cause hemorrhage or infection [Bodensteiner and Chung,

this autosomal recessive condition but it remains 1993]. Prematurity is a well known major risk factor.
unclear what the biochemical neurotoxic mecha- Macrocephaly may be due to subdural hematomas,
nism is [Struys et al., 2005]. most commonly due to child abuse or to birth-related
trauma. Chronic subdural effusions (either sequelae
of trauma or infection) can be associated with
HYDROCEPHALUS
macrocephaly in later infancy. Chronic subdural
Congenital hydrocephalus, both obstructive (e.g., hematoma with macrocephaly can rarely be due to
due to aqueductal stenosis) and non-obstructive bleeding due to a vascular malformation, inherited
type, often have a genetic basis albeit one that is often coagulopathy or metabolic derangement [Powers
difficult to identify [Schrander-Stumpel and Fryns, et al., 2007]. Patients below 2 years with arachnoids
1998; Haverkamp et al., 1999]. Multifactorial inher- cysts can present with macrocephaly. Patients who
itance is presumed for many cases of congenital present with macrocephaly are more likely to require
hydrocephalus and thus confers an increased risk for shunts post-cyst fenestration compared to those
recurrence. Aqueductal stenosis types, especially who present with other features such as seizures or
those occurring in an X-linked pattern of inheritance incidental lesions [Zada et al., 2007].
(OMIM 307000), can be due to mutations in the
L1 cell adhesion molecule gene (L1CAM) (Xq28)
EVALUATION OF MACROCEPHALY
[Weller and Gartner, 2001, for review]. Congenital
aqueductal stenosis can also be caused by autosomal The evaluation approach is relatively straight
recessive mechanisms (OMIM 236635) [Lapunzina forward and is summarized in Figure 4. Physical
et al., 2002]. examination and history alone may identify a
Macrocephaly due to acquired hydrocephalus is syndromic disorder that can then be confirmed by
usually related to the complications of intracranial an appropriate test, for example NSD1 gene analysis

FIG. 4. Algorithm outlining a diagnostic approach to the evaluation of macrocephaly. Megalencephalic leukoencephalopathy with subcortical cysts (MLC);
macrocephaly cutis marmorata telangiectatica congenital (M-CMTC); phosphatase and tensin homolog deleted on chromosome TEN.
 American Journal of Medical Genetics Part A

GENETICS OF MACROCEPHALY 2033

in Sotos syndrome. If there is no neurological dys- Philips Research and Education Contract, State of
function, a brain imaging study may not be needed Florida, USA.
and the possibility of FM should be considered.
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