136 Review Article

Overgrowth Syndromes
Andrew C. Edmondson1 Jennifer M. Kalish1

1 Division of Human Genetics, Children’s Hospital of Philadelphia and Address for correspondence Jennifer M. Kalish, MD, PhD, Division of
Department of Pediatrics, Perelman School of Medicine at the Human Genetics, Children’s Hospital of Philadelphia and the
University of Pennsylvania, Philadelphia, Pennsylvania, United States Department of Pediatrics, Perelman School of Medicine at the
University of Pennsylvania, ARC 1002, 3615 Civic Center Boulevard,
J Pediatr Genet 2015;4:136–143. Philadelphia, PA 19104, United States
(e-mail: KALISHJ@email.chop.edu).

Abstract Numerous multiple malformation syndromes associated with pathologic overgrowth

have been described and, for many, their molecular bases elucidated. This review

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
describes the characteristic features of these overgrowth syndromes, as well as the
current understanding of their molecular bases, intellectual outcomes, and cancer
predispositions. We review syndromes such as Sotos, Malan, Marshall–Smith, Weaver,
Simpson–Golabi–Behmel, Perlman, Bannayan–Riley–Ruvalcaba, PI3K-related, Proteus,
Keywords Beckwith–Wiedemann, fibrous dysplasia, Klippel–Trenaunay–Weber, and Maffucci.
► overgrowth
syndrome
► Sotos
► Malan
► Marshall–Smith
► Simpson–Golabi–
Behmel
► Perlman
► Bannayan–Riley–
Ruvalcaba
► PI3K-related
► Proteus
► Beckwith–
Wiedemann

Introduction natal onset. It may result from an increased number of cells

(intrinsic cellular hyperplasia), hypertrophy of the normal
About 5% of all newborns have a birth weight greater than number of fetal cells, an increase in interstitial spaces, or a
4,000 g, known as macrosomia.1 Although maternal diabetes combination of all these.1
or neonatal hyperinsulinism may contribute to neonatal Numerous multiple malformation syndromes associated
macrosomia, excessive birth weight frequently represents a with growth excess have been described. These pathologic
normal variation influenced by family history, excessive syndromes share several characteristics: the overgrowth is
maternal weight gain during pregnancy, maternal multipa- present at birth and persists into postnatal life, affects both
rous state, male fetal sex, higher maternal socioeconomic weight and length, and is associated with multiple character-
status,2 familial tall stature, and familial rapid maturation.1 In istic anomalies, sometimes with mental deficiency, and often
contrast, pathologic overgrowth may be of prenatal or post- with a neoplastic predisposition.2,3 This review describes the

received Issue Theme Genetic Advances in Copyright © 2015 by Georg Thieme DOI http://dx.doi.org/
May 15, 2015 Intellectual Disability; Guest Editor: Verlag KG, Stuttgart · New York 10.1055/s-0035-1564440.
accepted after revision Donatella Milani, MD ISSN 2146-4596.
May 20, 2015
published online
September 25, 2015
 Overgrowth Syndromes Edmondson, Kalish 137

characteristic features of the most common overgrowth expected to be at an increased risk for a “second hit” resulting
syndromes, as well as the current understanding of their in increased risk of tumor formation.1 Despite this theoretical
molecular bases, intellectual outcomes, and cancer predis- risk, only approximately 3% of individuals with Sotos syn-
positions. In this review, overgrowth syndromes are grouped drome develop tumors, which include neuroblastoma, sac-
by their underlying genetic mechanisms as constitutional rococcygeal teratoma, presacral ganglioneuroma, acute
syndromes, somatic syndromes, and syndromes for which lymphocytic leukemia, and small-cell lung cancer.9 As the
there is no identified genetic etiology. tumor risk is small, and there are currently no effective
screening modalities for the tumor types observed in Sotos
syndrome, cancer screening is not recommended.5
Sotos-Like Syndromes
The most recently described overgrowth syndrome, Malan
Sotos syndrome has an estimated incidence of 1:14,000 live syndrome, has similar physical characteristics to Sotos syn-
births.4 This syndrome is characterized by increased birth drome but has a different underlying genetic basis. Research-
weight and length, with excessive growth during the first ers searching for molecular causes of unexplained syndromic
4 years and an advanced bone age. Disproportionately long overgrowth screened 18 overgrowth patients with noncon-

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
limbs cause much of the increased length.2 Children with sanguinity, developmental delay, height above the 95th per-
Sotos syndrome have distinctive facial features with macro- centile, and/or macrocephaly and patients with at least two of
dolichocephaly, marked frontal bossing, and a frontoparietal the following: advanced bone age, dysmorphic craniofacial
receding hairline. Bitemporal narrowing gives the appearance features, and congenital malformations with array compara-
of hypertelorism, and the palpebral fissures are typically tive genomic hybridization. Through this analysis, they iden-
down slanting. The face is long and thin with a prominent tified nuclear factor I/X (NFIX) as a candidate gene.
long and narrow inferior mandible.5 Subsequent screening of NFIX in 76 individuals with unex-
Just over 10% of patients with Sotos syndrome have plained syndromic overgrowth identified 3 individuals who
congenital heart defects, usually a patent ductus arteriosus initially had been diagnosed with a Sotos-like phenotype.14
(PDA) or atrial septal defect.6 Renal abnormalities and scolio- Identification of additional cases allowed further characteri-
sis have also been frequently reported.5 Sotos syndrome is zation of the phenotype, which includes neonatal hypotonia
associated with dilatation of the cerebral ventricles and other and feeding difficulties, postnatal overgrowth, macrocephaly,
brain formation abnormalities, including an absent corpus advanced bone age, dysmorphic features (long narrow face
callosum, prominent cortical sulci, trigone, occipital horns, with a high forehead), pectus excavatum, scoliosis, ocular
cavum septum pellucidum, and cavum velum interpositi.6,7 findings (strabismus, nystagmus, optic disc pallor/hypopla-
Approximately 50% of individuals with Sotos syndrome ex- sia), and developmental delay.15
perience seizures.2 Malan syndrome appears to arise from mutations leading
Mutations of the gene encoding nuclear receptor-binding to haploinsufficiency of NFIX.14 NFIX is a transcription factor
SET domain-containing protein 1 (NSD1) are found in ap- in the nuclear factor one (NFI) family, which is important in
proximately 90% of patients.5 Sotos syndrome results from replication, signal transduction, and transcriptional process-
constitutional intragenic loss-of-function mutations,8 pri- es, but the exact genes regulated by NFIX have yet to be
marily truncating mutations,9 and, in the Japanese popula- elucidated. Moderate developmental delay, including autism
tion, whole gene deletions10 of NSD1, which lead to germline (
25% of cases), has been demonstrated in all reported cases
haploinsufficiency. NSD1 is a SET domain-containing histone of Malan syndrome.15 Approximately 25% of patients with
methyltransferase that preferentially methylates lysine resi- Malan syndrome have seizures,15 but there have been no
due 36 of histone 3 (H3K36), which is primarily associated reports of cancer with this syndrome.15
with active transcription.5 Marshall–Smith syndrome is allelic to Malan syndrome. Its
Children with Sotos syndrome can display neonatal hypo- incidence is unknown due to its rarity. Characteristics include
tonia with early feeding difficulties, as well as delays in motor accelerated osseous maturation, dysmorphic features (prom-
development and expressive language, often not walking inent forehead, bushy eyebrows, bulging eyes), and large
until after 15 months or talking until after 2.5 years. Children hands and feet. Individuals with Marshall–Smith syndrome
may show nonprogressive neurologic dysfunction with clum- frequently have failure to thrive, chronic respiratory distress,
siness and poor coordination.11 Most individuals (97%) car- and short lifespan.16 Dominant-negative mutations in NFIX
rying an NSD1 mutation have intellectual disabilities, ranging underlie the syndrome.14,17 Individuals with this syndrome
from mild (
30%) to moderate (
45%) or severe (
20%).9 have moderate to severe mental deficiency and major devel-
Somatic mutations of the protooncogene NSD1 have been opmental delays,14 with many dying as infants. Although the
identified in multiple tumor types. These mutations include a rarity of the disorder precludes identification of an increased
recurrent cryptic t(5;11)(q35.3;p15.5) translocation in ap- cancer risk, one case of Wilms tumor coexisting with Mar-
proximately 5% of childhood acute myeloid leukemia cases,12 shall–Smith syndrome has been reported.14
somatic epigenetic silencing of NSD1 through promoter hy-
permethylation in neuroblastoma and glioma,13 and somatic
Weaver Syndrome
NSD1 mutations in carcinoma of the upper airway and
digestive tract.5 As NSD1 presumably functions as a tumor Owing to the many similar features between the two, Weaver
suppressor gene, individuals with Sotos syndrome are syndrome is often included in the differential diagnosis of

Journal of Pediatric Genetics Vol. 4 No. 3/2015

138 Overgrowth Syndromes Edmondson, Kalish

Sotos syndrome. Weaver syndrome is characterized by pre- brae, sacrococcygeal defects, and scoliosis.2 Malformations of
natal-onset overgrowth with accelerated osseous maturation, the central nervous system are rare, but there have been
widened distal long bones, camptodactyly, and a distinctive reports of partial agenesis of the corpus callosum with
craniofacial appearance. Individuals with Weaver syndrome agenesis of the septum pellucidum and bilateral ventriculo-
have macrocephaly; a broad forehead; a flattened occiput megaly,28 arrhinencephaly, a thin corpus callosum, lipoma of
with large ears that may be mildly dysplastic and low set; true the floor of the third ventricle, and hydrocephalus.26
hypertelorism; a long prominent philtrum; relative micro- Simpson–Golabi–Behmel syndrome is an X-linked disor-
gnathia; soft, loose skin with redundant nuchal skin folds; der caused by constitutional mutations in the glypican 3
umbilical hernia; and thin, deep-set nails.5 Skeletal growth is (GPC3) gene that encodes a heparin sulfate proteoglycan.26
more accelerated than osseous maturation, resulting in ex- One large case series of patients with this disorder found 38%
cessive adult height.2 Individuals may have congenital heart exonic deletions, 24% frameshift mutations, 17% nonsense
defects, such as ventricular septal defect and PDA.18 Brain mutations, 17% missense mutations, and 3% exonic duplica-
anomalies include cysts of the septum pellucidum, cerebral tions in the gene, without an obvious correlation between
atrophy, and pachygyria.2 There is a broad phenotypic spec- genotype/phenotype and the mutation or type of mutation.26

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
trum for Weaver syndrome, making true incidence estimates Despite the multiple congenital anomalies present in
difficult.19 Simpson–Golabi–Behmel syndrome, mental development
Constitutional mutations of enhancer of zeste, drosophila, has been often reported as normal.29 A recent review sug-
homolog 2 (EZH2) have been implicated in Weaver syndrome. gested that individuals have neonatal hypotonia with some
Most of these mutations are missense or unlikely to cause mild delays in milestones, sitting independently at 8.5
simple haploinsufficiency, obscuring the pathogenic mecha- months and walking independently at 16 months.26 They
nism for Weaver syndrome.20 EZH2 is a SET domain-contain- may experience speech difficulties, most frequently caused by
ing histone methyltransferase; however, in contrast to NSD1, macroglossia and/or cleft palate.26 However, less than half of
it shows specificity for lysine residue 27 (H3K27), which is patients had intellectual disabilities and, when present, they
associated with transcriptional repression.5 were typically mild and not associated with developmental
Mild tone abnormalities and motor development delays delays.26 Tumors, usually of renal origin, occur in roughly 8 to
are common in Weaver syndrome. Approximately 18% of 10% of individuals with this syndrome.26,30,31 Hepatoblas-
individuals with mutations of EZH2 have no reported intel- toma32 and one case of leukemia26 have also been reported.
lectual disability; the remainder show intellectual disabilities Tumor screening with abdominal ultrasounds to identify
ranging from mild (
45%) to moderate (26%) or severe (5%).21 renal tumors and α-fetoprotein (AFP) testing to identify
Somatic disruption of EZH2 is important in the development hepatic tumors have been proposed.2
of many tumors, particularly hematopoietic malignancies,22
with both activating and inactivating mutations associated
Perlman Syndrome
with tumorigenesis.5,23,24 Approximately 5% of individuals
with Weaver syndrome develop tumors, such as lymphoma, Perlman syndrome is characterized by neonatal macrosomia,
acute lymphoblastic leukemia, neuroblastoma, and sacrococ- polyhydramnios, a characteristic facial dysmorphology
cygeal teratoma.21,25 However, as with Sotos syndrome, (broad and flat nasal bridge, everted V-shaped upper lip,
routine cancer screening is not recommended.5 low-set ears, deep-set eyes, prominent forehead33), renal
dysplasia, nephroblastomatosis, and multiple congenital
anomalies. Abdominal dystocia due to visceromegaly, typi-
Simpson–Golabi–Behmel Syndrome
cally involving the heart, liver, spleen, pancreas, and kidneys,
Simpson–Golabi–Behmel syndrome is characterized by pre- has been reported.2 Male cryptorchidism is also common.33
natal and postnatal overgrowth. Individuals have coarse facial There is a high neonatal mortality rate (>50%) in the first
features, hypertelorism, down slanting palpebral fissures, month of life,33 and growth parameters of surviving infants
epicanthic folds, a short nose with a broad nasal bridge, are at the lower limits of normal.2 Infants with Perlman
macrostomia, macroglossia, a central groove of the lower syndrome exhibit severe hypotonia.33 Agenesis of the corpus
lip and/or tongue (frequently with eversion of the lower lips), callosum has been reported.34
and, occasionally, cleft lip and palate.2,26 Short and broad Constitutional mutations of DIS3-like exonuclease 2
hands and feet show metatarsus varus, talipes equinovarus, (DIS3L2), a homolog of the Schizosaccharomyces pombe dis3
fingernail hypoplasia of the index finger, cutaneous syndac- gene, have been reported in Perlman syndrome.35 Dis3 is a
tyly, and postaxial polydactyly. Supernumerary nipples are a component of the yeast core RNA exosome complex and is
frequent finding. Organomegaly of the liver, spleen, and responsible for its 3′- to 5′-exoribonuclease activity.36 DIS3L2
kidneys is common, with multicystic dysplasia of the kidneys. regulates mitosis and cell proliferation. Loss of the regulatory
Lung segmentation defects and diaphragmatic defects have mechanisms of DIS3L2 in Perlman syndrome is thought to
been reported. Cardiac abnormalities are found in 36 to 47% of underlie the increased tumor risk through increased cell
patients.27 Gastrointestinal manifestations—including malro- proliferation.35
tation, pyloric ring, and Meckel diverticulum—have been Moderate developmental delay has been reported in pa-
described. Skeletal findings include vertebral segmentation tients with Perlman syndrome.37,38 Furthermore, approxi-
defects, such as C2–C3 fusion, cervical ribs, six lumbar verte- mately 67% of children with Perlman syndrome who survive

Journal of Pediatric Genetics Vol. 4 No. 3/2015

 Overgrowth Syndromes Edmondson, Kalish 139

beyond the neonatal period develop Wilms tumors, which etiology, one extreme of which would be the classically
occur at an earlier age than sporadic cases and are frequently described BWS.
bilateral.39 Approximately 30% of sporadic Wilms tumors are The molecular etiology is complex and involves epige-
expected to harbor mutations or deletions of DIS3L2.35 nomic and genomic alterations in the imprinting clusters on
chromosome 11p15. These changes are detected in up to 80%
of classic BWS patients,46 but less often in isolated hemi-
Bannayan–Riley–Ruvalcaba Syndrome
hyperplasia patients. The 11p15 chromosomal region is
Developmental delay and macrocephaly are hallmark fea- divided into two distinct regulatory domains. The distal
tures of Bannayan–Riley–Ruvalcaba syndrome (BRRS), 40 domain contains the imprinted genes insulin-like growth
which is characterized by cutaneous lesions (pigmented factor 2 (IGF2) and the long noncoding RNA H19 near im-
macules on the penis and cafe-au-lait spots), vascular printing center 1 (IC1), which is a differentially methylated
malformations, lipomas, hamartomatous polyps of the region, methylated on the paternal allele.45 The proximal
distal ileum and colon, and Hashimoto thyroiditis.2,40,41 domain including imprinting center 2 (IC2) spans a 1-Mb
Hemangiomas have traditionally been associated with region containing the imprinted genes, including a paternally

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
BRRS.40 Infants are typically macrosomic, with birth expressed noncoding RNA (KCNQ1OT1) and maternally ex-
lengths above the 97th percentile. Subsequent growth pressed gene encoding a cyclin-dependent kinase inhibitor
deceleration results in normalization of all growth param- (CDKN1C).45 Imprinting defects at IC2 account for 50% of the
eters except macrocephaly.2 molecular defects in BWS patients.46 Approximately 20% of
BRRS is one of several syndromes associated with phos- BWS cases have paternal uniparental disomy (pUPD) involv-
phatase and tensin homolog on chromosome 10 (PTEN), with ing chromosome 11p15, which encompasses both imprinted
high phenotypic overlap among these syndromes. Conse- gene clusters.45 BWS cases with pUPD exhibit somatic
quently, the terms PTEN hamartoma tumor syndrome and mosaicism.45
PTEN-opathies have been used to describe any patient with Individuals with BWS largely have normal intelligence and
germline PTEN mutations, regardless of the phenotype.41 developmental outcomes. Adverse developmental outcomes
Wild-type PTEN regulates the cell cycle, cell migration, and are generally attributable to complications of prematurity or
apoptosis via the canonical PI3K/AKT/mTOR pathway. Lack of extreme hypoglycemia, rather than the syndrome itself.2 The
normal PTEN leads to increased cell migration and cell exception is BWS caused by duplications of paternal chromo-
survival secondary to upregulation of the AKT and MAPK some 11p15, which can be associated with moderate to
pathways.41 PTEN has broad downstream and interacting severe intellectual disability and distinct dysmorphic
networks, and patients with mutations in other genes along features.47
this pathway demonstrate features overlapping with PTEN- Children with BWS have an increased risk (
8.6%) of
opathies.41 developing embryonal tumors.48 The most common tumor
Up to 17% of children with macrocephaly and autism type is Wilms tumor, although hepatoblastoma, neuroblas-
without other BRRS features may have germline PTEN muta- toma, ganglioneuroma, adrenocortical carcinoma, rhabdo-
tions. Thus, it is recommended that all macrocephalic chil- myosarcoma, acute lymphoid leukemia, liver sarcoma,
dren with autism or developmental delay be tested for PTEN thyroid carcinoma, and melanoma have been re-
mutations.42,43 Hypotonia, gross motor delay, mild to severe ported.45,48,49 In BWS, tumor risk appears to be related to
mental deficiency, and speech delay are reported in approxi- the underlying defect.49 Patients with IC1 methylation
mately 70% of BRRS patients. Greater than 25% of BRRS alterations and pUPD11 have the highest risk.46,48,49 Tumor
patients have experienced seizures.2 Lifetime cancer risks screening is recommended in BWS, with serum AFP meas-
for any individual carrying a constitutional PTEN mutation are urements until age 4 years and abdominal ultrasounds until
greater than population norms. Breast, thyroid, renal, and age 8 years.50
endometrial cancers are the predominant cancer types, al-
though colorectal cancer and melanoma are increasingly
PI3K-Related Syndromes
being reported. Patients with constitutional PTEN mutations
are encouraged to undergo frequent cancer screenings for PI3K-related megalencephaly syndromes include megalence-
early tumor detection.44 phaly–polymicrogyria–polydactyly–hydrocephalus (MPPH)
and megalencephaly–capillary malformation (MCAP). These
brain overgrowth disorders are characterized by congenital
Beckwith–Wiedemann Syndrome
or early postnatal megalencephaly, often with progressive
Beckwith-Wiedemann syndrome (BWS) is characterized by ventriculomegaly (leading to hydrocephalus), cerebellar ton-
macrosomia, asymmetric overgrowth (hemihyperplasia), sillar ectopia (leading to Chiari malformation), and cortical
macroglossia, abdominal wall defects (umbilical hernia, om- brain abnormalities (polymicrogyria). MPPH and MCAP can
phalocele, diastasis recti), hypoglycemia, ear creases, viscer- be distinguished by the characteristic features of MCAP,
omegaly, renal malformations, facial nevus flammeus, and which include cutaneous capillary vascular malformations,
embryonal tumors45 (►Fig. 1). Its heterogeneous clinical finger or toe syndactyly, postaxial polydactyly, and mild focal
presentation has led some to suggest renaming BWS as or segmental somatic overgrowth.51 In contrast, there are no
“11p overgrowth spectrum” on the basis of the molecular consistent dysmorphic features in MPPH, and the observed

Journal of Pediatric Genetics Vol. 4 No. 3/2015

140 Overgrowth Syndromes Edmondson, Kalish

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Fig. 1 Clinical features of patients with Beckwith–Wiedemann syndrome (BWS). (A, B) BWS patient with macroglossia at 6 months and 14 months
of age, respectively. (C) BWS patient with omphalocele. (D) BWS patient with severe hemihyperplasia.

abnormal facial features (prominent forehead, low nasal ty.52 CCND2 mutations appear to stabilize cyclin D2, a down-
bridge, apparent hypertelorism) are likely secondary to the stream target of the PI3K-mediated tyrosine kinases. The
megalencephaly. Postaxial polydactyly is reported in less resulting accumulation of cyclin D2 is a unifying mechanism
than half of MPPH individuals.51 Individuals with MPPH in PI3K-AKT-related megalencephaly syndromes.53
and MCAP frequently have seizures with varying degrees of Several other overgrowth syndromes are caused by
controllability by antiepileptics. postzygotic mutations in PIK3CA. These syndromes are
MPPH is believed to be caused by de novo germline characterized by patchy segmental overgrowth and the
mutations in PIK3R2, AKT3, and, potentially, cyclin D2 associated anomalies of the Congenital, Lipomatous, Over-
(CCND2), whereas MCAP is caused by postzygotic, mosaic, growth, Vascular malformations, Epidermal nevi, and Spi-
and rare germline mutations in PIK3CA.51 PIK3R2, AKT3, and nal/skeletal anomalies and/or scoliosis (CLOVES)
PIK3CA are members of the phosphatidylinositol-3-kinase phenotypic spectrum.54 The timing and tissue location of
(PI3K)-v-akt murine thymoma viral oncogene homolog (AKT) the mutation may help explain the phenotypic variability of
pathway, which is critical for proliferation, cell growth, and these overgrowth syndromes, although investigations so
apoptosis. Identified mutations in these three genes typically far have not shown correlation of the mutational load in
lead to activation of the PI3K-AKT pathway.51 PIK3R2 encodes affected tissues with either the quality or overall severity of
the p85b regulatory subunit of class IA PI3K enzymatic the physical manifestations.54
complex and mediates activation of class IA PI3K by receptor Individuals with MPPH and MCAP typically have develop-
tyrosine kinases. All PI3K mutation-positive MPPH individu- mental delays. In one case series of these patients, only one
als carry the same PIK3R2 mutation (p.Gly373Arg), located individual was reported to be developmentally normal. Other
within the Src-homology 2 (SH2) domain of p85b.51 This individuals have delays ranging from mild to severe,55 as well
mutation has been shown to result in increased PI3K activi- as autistic features, unexplained irritability, attention deficit

Journal of Pediatric Genetics Vol. 4 No. 3/2015

 Overgrowth Syndromes Edmondson, Kalish 141

hyperactivity disorder, and obsessive compulsive disorder.55 deformity, beginning with facial asymmetry or a persistent
Almost all individuals on the CLOVES spectrum without brain bump and progressing with expansion of malar prominences
involvement have normal developmental milestones and or frontal bossing into major disfiguration in adulthood.61
cognitive abilities.56 Bony overgrowth in FD can lead to cranial nerve entrapment,
Somatic mutations in P13KCA are seen in many cancers, deafness, vestibular dysfunction, and seizures.62
including glioblastoma and colorectal, ovarian, breast, and FD is caused by activating missense mutations in the guanine
hepatocellular carcinomas.56 MCAP and MPPH may have nucleotide binding protein, α stimulating (GNAS1) gene, which
lower tumor risks than patients with other overgrowth encodes the α subunit of the stimulatory G-protein, Gsα.
syndromes. Nevertheless, Wilms tumor, meningioma, and Mutations occur somatically and result in mosaicism, explaining
leukemia have been reported in MCAP patients,55 and me- the extreme heterogeneity of the condition. The extent and
dulloblastoma was reported in one patient with MPPH.57 severity of disease are related to the timing of the mutational
Wilms tumor was reported in one individual on the CLOVES event during development and the severity of the mutation.61
spectrum.54 Current cancer screening recommendations are Individuals with FD are typically developmentally normal and
based on those for BWS.56 malignancy is rare (
1%), with osteogenic sarcoma being the

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
most common cancer seen in FD.61

Proteus Syndrome
Klippel–Trenaunay–Weber Syndrome
Proteus syndrome is characterized by asymmetric over-
growth with skeletal defects, epidermal nevi, vascular mal- Klippel–Trenaunay–Weber syndrome is characterized by
formations, dysregulated adipose tissue, and pulmonary capillary malformations associated with venous malforma-
abnormalities. While not an obligatory finding, the presence tions consisting of arteriovenous fistulas with bone or tissue
of cerebriform connective tissue nevi is nearly pathognomon- hypertrophy in the affected limb. The most common mani-
ic for Proteus syndrome. Nevi are most frequently identified festation, present in 98% of patients, is capillary malforma-
on the foot plantar surfaces, but have also been observed on tion, represented by cutaneous hemangiomas or port-wine
the hands, abdomen, chest, and nose.58 About 10% of patients stains. Limb hypertrophy is typical when the limb is affected
with Proteus syndrome experience seizures. by capillary malformations; these malformations rarely cross
Proteus syndrome is caused by somatic mutations in AKT1, the midline.63 The lower limbs are much more commonly
explaining the variety of phenotypic features. A single mutation affected than the upper limbs. There is currently no known
in AKT1, c.49G!A, p.Glu17Lys, which causes constitutive acti- genetic cause of Klippel–Trenaunay–Weber syndrome, al-
vation of AKT1 through Ser473 and Thr308 phosphorylation,59 though a somatic mosaic mutation has been postulated.64
has been identified in individuals with Proteus syndrome.60 Developmental outcomes are typically normal, and there is
Most individuals with Proteus syndrome seem to have no known cancer predisposition.
normal intelligence, although approximately 20% of cases
have some degree of mental deficiency. Mental deficiency
Maffucci Syndrome
and seizures are much more likely if there is brain involve-
ment or brain malformations.2 The specific AKT1 mutation Maffucci syndrome is characterized by multiple enchondro-
causative of Proteus syndrome has been reported in some mas and noncancerous cartilaginous growths on the limb
tumors, including breast, thyroid, genitourinary tract, lung, bones. These growths primarily occur on the hands and feet,
and endometrial cancers.60 However, only lipomas are com- but have also been reported on the skull, ribs, and vertebrae.
mon in Proteus syndrome. Other reported neoplasms include Enchondromas occur asymmetrically and result in severe
adenoma of the parotid gland, cystadenoma of the ovary, bone deformities, limb shortening, fractures, and short stat-
testicular tumor, meningioma, and mesothelioma.58 ure.2 Individuals with Maffucci syndrome have venous mal-
formations, capillary hemangiomas, and, occasionally,
lymphangiomas. They are typically born normal and subse-
Fibrous Dysplasia
quently develop enchondromas.
Fibrous dysplasia (FD) is a skeletal overgrowth disorder with a There is currently no known genetic cause of this syndrome.
broad spectrum of clinical expression, ranging from asymp- Individuals with Maffucci syndrome are of normal intelligence
tomatic radiographic findings at a single skeletal site to and achieve normal developmental milestones. Enchondromas
disabling disease. FD may involve one bone (monostotic may undergo malignant transformation and become chondro-
forms), multiple bones (polyostotic FD), or the entire skeleton sarcomas (transformation rate: 17–30%2). Angiosarcoma, fibro-
(panostotic FD). McCune–Albright syndrome is a polyostotic sarcoma, pancreatic carcinoma, hepatic adenocarcinoma,
FD with cutaneous pigmentation and endocrinopathy, includ- ovarian cystadenocarcinoma, teratoma, glioma, astrocytoma,
ing precocious puberty, hyperthyroidism, growth hormone and pituitary adenoma have also been reported.2
excess, and Cushing syndrome.61 Bone pain, fracture, and
deformity are the most common presenting features. Al-
Conclusion
though any bone may be affected, the skull base and proximal
metaphysis of the femora are the most commonly involved The overgrowth syndromes comprise a diverse group of
sites. Overgrowth of the craniofacial bone can result in severe clinically recognizable multiple congenital malformation

Journal of Pediatric Genetics Vol. 4 No. 3/2015

142 Overgrowth Syndromes Edmondson, Kalish

syndromes. Recent elucidation of the genetic bases for many Sotos-like or a Marshall-Smith syndrome. Am J Hum Genet 2010;
of these syndromes provides insight into the normal regula- 87(2):189–198
tion of growth and development. Intellectual outcomes vary 15 Klaassens M, Morrogh D, Rosser EM, et al. Malan syndrome: Sotos-
like overgrowth with de novo NFIX sequence variants and dele-
greatly among the syndromes. Once diagnosed, individuals
tions in six new patients and a review of the literature. Eur J Hum
with overgrowth syndromes should be regularly followed up Genet 2015;23(5):610–615
to ensure optimal developmental outcomes. Some of the 16 Marshall RE, Graham CB, Scott CR, Smith DW. Syndrome of
disorders have elevated risk of neoplasm development, and accelerated skeletal maturation and relative failure to thrive: a
there are recommended clinical cancer screening algorithms newly recognized clinical growth disorder. J Pediatr 1971;78(1):
95–101
in place. We hope this review will provide a context for
17 Schanze D, Neubauer D, Cormier-Daire V, et al. Deletions in the 3′
recognizing overgrowth syndromes such that appropriate
part of the NFIX gene including a recurrent Alu-mediated deletion
developmental follow-up and tumor screening can be insti- of exon 6 and 7 account for previously unexplained cases of
tuted in a timely manner. Marshall-Smith syndrome. Hum Mutat 2014;35(9):1092–1100
18 Huffman C, McCandless D, Jasty R, et al. Weaver syndrome with
neuroblastoma and cardiovascular anomalies. Am J Med Genet

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
2001;99(3):252–255
Acknowledgments
19 Tatton-Brown K, Rahman N. EZH2-Related Overgrowth. In: Pagon
J. M. K. is supported by the National Institutes of Health RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH,
and the Alex’s Lemonade Stand Foundation. The authors et al., eds. GeneReviews(R). Seattle, WA; 1993. Available at: http://
thank Kathryn Kadash-Edmondson for critical reading of www.ncbi.nlm.nih.gov/books/NBK1116/. Accessed May 5, 2015
the manuscript. 20 Tatton-Brown K, Hanks S, Ruark E, et al; Childhood Overgrowth
Collaboration. Germline mutations in the oncogene EZH2 cause
Weaver syndrome and increased human height. Oncotarget 2011;
2(12):1127–1133
21 Tatton-Brown K, Murray A, Hanks S, et al; Childhood Overgrowth
References Consortium. Weaver syndrome and EZH2 mutations: clarifying
1 Stevenson RE, Hall JG. Human Malformations and Related Anom- the clinical phenotype. Am J Med Genet A 2013;161A(12):
alies. Third edition, ed. Oxford; New York: Oxford University Press; 2972–2980
2015 22 Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Res
2 Cohen MM, Neri G, Weksberg R. Overgrowth Syndromes. New 2011;17(9):2613–2618
York: Oxford University Press; 2002 23 Morin RD, Johnson NA, Severson TM, et al. Somatic mutations
3 Cohen MM Jr. Mental deficiency, alterations in performance, and altering EZH2 (Tyr641) in follicular and diffuse large B-cell lym-
CNS abnormalities in overgrowth syndromes. Am J Med Genet C phomas of germinal-center origin. Nat Genet 2010;42(2):181–185
Semin Med Genet 2003;117C(1):49–56 24 Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the
4 Tatton-Brown K, Cole TRP, Rahman N. Sotos syndrome. In: Pagon histone methyltransferase gene EZH2 in myeloid disorders. Nat
RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Genet 2010;42(8):722–726
et al., eds. GeneReviews(R). Seattle, WA; 1993. Available at: http:// 25 Kelly TE, Alford BA, Abel M. Cervical spine anomalies and tumors in
www.ncbi.nlm.nih.gov/books/NBK1116/. Accessed May 5, 2015 Weaver syndrome. Am J Med Genet 2000;95(5):492–495
5 Tatton-Brown K, Rahman N. The NSD1 and EZH2 overgrowth 26 Cottereau E, Mortemousque I, Moizard MP, et al. Phenotypic
genes, similarities and differences. Am J Med Genet C Semin spectrum of Simpson-Golabi-Behmel syndrome in a series of 42
Med Genet 2013;163C(2):86–91 cases with a mutation in GPC3 and review of the literature. Am J
6 Gusmão Melo D, Pina-Neto JM, Acosta AX, Daniel J, de Castro V, Med Genet C Semin Med Genet 2013;163C(2):92–105
Santos AC. Neuroimaging and echocardiographic findings in Sotos 27 Lin AE, Neri G, Hughes-Benzie R, Weksberg R. Cardiac anomalies in
syndrome. Am J Med Genet 2000;90(5):432–434 the Simpson-Golabi-Behmel syndrome. Am J Med Genet 1999;
7 Schaefer GB, Bodensteiner JB, Buehler BA, Lin A, Cole TR. The 83(5):378–381
neuroimaging findings in Sotos syndrome. Am J Med Genet 1997; 28 Pénisson-Besnier I, Lebouvier T, Moizard MP, et al. Carotid artery
68(4):462–465 dissection in an adult with the Simpson-Golabi-Behmel syn-
8 Kurotaki N, Imaizumi K, Harada N, et al. Haploinsufficiency of drome. Am J Med Genet A 2008;146A(4):464–467
NSD1 causes Sotos syndrome. Nat Genet 2002;30(4):365–366 29 Neri G, Gurrieri F, Zanni G, Lin A. Clinical and molecular aspects of
9 Tatton-Brown K, Douglas J, Coleman K, et al; Childhood Over- the Simpson-Golabi-Behmel syndrome. Am J Med Genet 1998;
growth Collaboration. Genotype-phenotype associations in Sotos 79(4):279–283
syndrome: an analysis of 266 individuals with NSD1 aberrations. 30 Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: a
Am J Hum Genet 2005;77(2):193–204 comprehensive review. Am J Med Genet C Semin Med Genet 2005;
10 Kamimura J, Endo Y, Kurotaki N, et al. Identification of eight novel 137C(1):53–71
NSD1 mutations in Sotos syndrome. J Med Genet 2003;40(11): 31 Hughes-Benzie RM, Hunter AG, Allanson JE, Mackenzie AE. Simp-
e126 son-Golabi-Behmel syndrome associated with renal dysplasia and
11 Cohen MM Jr. Overgrowth syndromes: an update. Adv Pediatr embryonal tumor: localization of the gene to Xqcen-q21. Am J
1999;46:441–491 Med Genet 1992;43(1-2):428–435
12 Cerveira N, Correia C, Dória S, et al. Frequency of NUP98-NSD1 32 Lapunzina P, Badia I, Galoppo C, et al. A patient with Simpson-
fusion transcript in childhood acute myeloid leukaemia. Leukemia Golabi-Behmel syndrome and hepatocellular carcinoma. J Med
2003;17(11):2244–2247 Genet 1998;35(2):153–156
13 Berdasco M, Ropero S, Setien F, et al. Epigenetic inactivation of the 33 Morris MR, Astuti D, Maher ER. Perlman syndrome: overgrowth,
Sotos overgrowth syndrome gene histone methyltransferase Wilms tumor predisposition and DIS3L2. Am J Med Genet C Semin
NSD1 in human neuroblastoma and glioma. Proc Natl Acad Sci U Med Genet 2013;163C(2):106–113
S A 2009;106(51):21830–21835 34 Henneveld HT, van Lingen RA, Hamel BC, Stolte-Dijkstra I, van
14 Malan V, Rajan D, Thomas S, et al. Distinct effects of allelic NFIX Essen AJ. Perlman syndrome: four additional cases and review. Am
mutations on nonsense-mediated mRNA decay engender either a J Med Genet 1999;86(5):439–446

Journal of Pediatric Genetics Vol. 4 No. 3/2015

 Overgrowth Syndromes Edmondson, Kalish 143

35 Astuti D, Morris MR, Cooper WN, et al. Germline mutations in and suggested guidelines for local practice. J Paediatr Child Health
DIS3L2 cause the Perlman syndrome of overgrowth and Wilms 2006;42(9):486–490
tumor susceptibility. Nat Genet 2012;44(3):277–284 51 Mirzaa GM, Rivière JB, Dobyns WB. Megalencephaly syndromes
36 Dziembowski A, Lorentzen E, Conti E, Séraphin B. A single subunit, and activating mutations in the PI3K-AKT pathway: MPPH and
Dis3, is essentially responsible for yeast exosome core activity. Nat MCAP. Am J Med Genet C Semin Med Genet 2013;163C(2):
Struct Mol Biol 2007;14(1):15–22 122–130
37 Greenberg F, Stein F, Gresik MV, et al. The Perlman familial 52 Rivière JB, Mirzaa GM, O’Roak BJ, et al; Finding of Rare Disease Genes
nephroblastomatosis syndrome. Am J Med Genet 1986;24(1): (FORGE) Canada Consortium. De novo germline and postzygotic
101–110 mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related
38 Neri G, Martini-Neri ME, Katz BE, Opitz JM. The Perlman syn- megalencephaly syndromes. Nat Genet 2012;44(8):934–940
drome: familial renal dysplasia with Wilms tumor, fetal gigantism 53 Mirzaa GM, Parry DA, Fry AE, et al; FORGE Canada Consortium. De
and multiple congenital anomalies. Am J Med Genet 1984;19(1): novo CCND2 mutations leading to stabilization of cyclin D2 cause
195–207 megalencephaly-polymicrogyria-polydactyly-hydrocephalus
39 Alessandri JL, Cuillier F, Ramful D, et al. Perlman syndrome: report, syndrome. Nat Genet 2014;46(5):510–515
prenatal findings and review. Am J Med Genet A 2008;146A(19): 54 Kurek KC, Luks VL, Ayturk UM, et al. Somatic mosaic activating
2532–2537 mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
40 Gorlin RJ, Cohen MM Jr, Condon LM, Burke BA. Bannayan-Riley- 2012;90(6):1108–1115
Ruvalcaba syndrome. Am J Med Genet 1992;44(3):307–314 55 Mirzaa GM, Conway RL, Gripp KW, et al. Megalencephaly-capillary
41 Mester J, Eng C. When overgrowth bumps into cancer: the PTEN- malformation (MCAP) and megalencephaly-polydactyly-polymi-
opathies. Am J Med Genet C Semin Med Genet 2013;163C(2): crogyria-hydrocephalus (MPPH) syndromes: two closely related
114–121 disorders of brain overgrowth and abnormal brain and body
42 Schaefer GB, Mendelsohn NJ; Professional Practice and Guidelines morphogenesis. Am J Med Genet A 2012;158A(2):269–291
Committee. Clinical genetics evaluation in identifying the etiology 56 Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Clinical delinea-
of autism spectrum disorders: 2013 guideline revisions. Genet tion and natural history of the PIK3CA-related overgrowth spec-
Med 2013;15(5):399–407 trum. Am J Med Genet A 2014;164A(7):1713–1733
43 McBride KL, Varga EA, Pastore MT, et al. Confirmation study of 57 Osterling WL, Boyer RS, Hedlund GL, Bale JF Jr. MPPH syndrome:
PTEN mutations among individuals with autism or developmental two new cases. Pediatr Neurol 2011;44(5):370–373
delays/mental retardation and macrocephaly. Autism Res 2010; 58 Cohen MM Jr. Proteus syndrome review: molecular, clinical, and
3(3):137–141 pathologic features. Clin Genet 2014;85(2):111–119
44 Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime 59 Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the
cancer risks in individuals with germline PTEN mutations. Clin pleckstrin homology domain of AKT1 in cancer. Nature 2007;
Cancer Res 2012;18(2):400–407 448(7152):439–444
45 Choufani S, Shuman C, Weksberg R. Molecular findings in Beck- 60 Lindhurst MJ, Sapp JC, Teer JK, et al. A mosaic activating mutation
with-Wiedemann syndrome. Am J Med Genet C Semin Med Genet in AKT1 associated with the Proteus syndrome. N Engl J Med 2011;
2013;163C(2):131–140 365(7):611–619
46 Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syn- 61 Favus MJ, American Society for Bone and Mineral Research. Primer
drome. Eur J Hum Genet 2010;18(1):8–14 on the metabolic bone diseases and disorders of mineral metabo-
47 Slavotinek A, Gaunt L, Donnai D. Paternally inherited duplications lism. 6th ed. Washington, DC: American Society for Bone and
of 11p15.5 and Beckwith-Wiedemann syndrome. J Med Genet Mineral Research; 2006
1997;34(10):819–826 62 Diaz A, Danon M, Crawford J. McCune-Albright syndrome and
48 Brioude F, Lacoste A, Netchine I, et al. Beckwith-Wiedemann disorders due to activating mutations of GNAS1. J Pediatr Endo-
syndrome: growth pattern and tumor risk according to molecular crinol Metab 2007;20(8):853–880
mechanism, and guidelines for tumor surveillance. Horm Res 63 Lacerda LdaS, Alves UD, Zanier JF, Machado DC, Camilo GB, Lopes
Paediatr 2013;80(6):457–465 AJ. Differential diagnoses of overgrowth syndromes: the most
49 Mussa A, Russo S, De Crescenzo A, et al. (Epi)genotype-phenotype important clinical and radiological disease manifestations. Radiol
correlations in Beckwith-Wiedemann syndrome. Eur J Hum Genet Res Pract 2014;2014:947451
2015; Epub ahead of print. Doi: 10.1038/ejhg.2015.88 64 Oduber CE, van der Horst CM, Hennekam RC. Klippel-Trenaunay
50 Tan TY, Amor DJ. Tumour surveillance in Beckwith-Wiedemann syndrome: diagnostic criteria and hypothesis on etiology. Ann
syndrome and hemihyperplasia: a critical review of the evidence Plast Surg 2008;60(2):217–223

Journal of Pediatric Genetics Vol. 4 No. 3/2015