Characterization of the Beckwith‐Wiedemann spectrum: Diagnosis and management

Abstract

Beckwith‐Wiedemann syndrome (BWS) is the most common epigenetic overgrowth and cancer predisposition disorder. Due to both varying molecular defects involving chromosome 11p15 and tissue mosaicism, patients can present with a variety of clinical features, leading to the newly defined Beckwith‐Wiedemann spectrum (BWSp). The BWSp can be further divided into three subsets of patients: those presenting with classic features, those presenting with isolated lateralized overgrowth (ILO) and those not fitting into the previous two categories, termed atypical BWSp. Previous reports of patients with BWS have focused on those with the more recognizable, classic features, and limited information is available on those who fit into the atypical and ILO categories. Here, we present the first cohort of patients recruited across the entire BWSp, describe clinical features and molecular diagnostic characteristics, and provide insight into practical diagnosis and management recommendations that we have gained from this cohort.

Full text

RESEARCH ARTICLE
Characterization of the Beckwith-Wiedemann spectrum:
Diagnosis and management
Kelly A. Duffy
1
| Christopher M. Cielo
2,3
| Jennifer L. Cohen
1,3
|
Christina X. Gonzalez-Gandolfi
1
| Jessica R. Griff
1
| Evan R. Hathaway
1
|
Jonida Kupa
1
| Jesse A. Taylor
4,5
| Kathleen H. Wang
1
| Arupa Ganguly
6
|
Matthew A. Deardorff
1,3
| Jennifer M. Kalish
1,3,6,7
1
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
2
Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
3
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
4
Division of Plastic and Reconstructive Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
5
Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
6
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
7
Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
Correspondence
Jennifer M. Kalish, Division of Human
Genetics, Center for Childhood Cancer
Research, The Children's Hospital of
Philadelphia, 3501 Civic Center Blvd, CTRB
Rm 3028, Philadelphia, PA 19104.
Email: kalishj@email.chop.edu
Funding information
Alex's Lemonade Stand Foundation for
Childhood Cancer; National Cancer Institute,
Grant/Award Number: K08 CA193915; St.
Baldrick's Foundation, Grant/Award Number:
Scholar Award
Abstract
Beckwith-Wiedemann syndrome (BWS) is the most common epigenetic overgrowth
and cancer predisposition disorder. Due to both varying molecular defects involving
chromosome 11p15 and tissue mosaicism, patients can present with a variety of clinical
features, leading to the newly defined Beckwith-Wiedemann spectrum (BWSp). The
BWSp can be further divided into three subsets of patients: those presenting with clas-
sic features, those presenting with isolated lateralized overgrowth (ILO) and those not
fitting into the previous two categories, termed atypical BWSp. Previous reports of
patients with BWS have focused on those with the more recognizable, classic features,
and limited information is available on those who fit into the atypical and ILO categories.
Here, we present the first cohort of patients recruited across the entire BWSp, describe
clinical features and molecular diagnostic characteristics, and provide insight into practi-
cal diagnosis and management recommendations that we have gained from this cohort.
KEYWORDS
Beckwith-Wiedemann spectrum, Beckwith-Wiedemann syndrome, cancer predisposition,
lateralized overgrowth, macroglossia
1|INTRODUCTION
1.1 |Overview
Beckwith-Wiedemann Syndrome (BWS, OMIM 130650) is the most
common overgrowth and cancer predisposition disorder, affecting
1 in 10,340 patients (Mussa et al., 2013). First described in 1963 and
1964 by Drs. J. Bruce Beckwith (Beckwith, 1963) and Hans-Rudolf
Wiedemann (Wiedemann, 1964), the disorder was initially character-
ized by macroglossia, omphalocele, and macrosomia. Since BWS was
first described, it has been recognized that patients could be
affected by a variety of clinical features, leading to designation of
Received: 7 May 2019 Revised: 9 August 2019 Accepted: 12 August 2019
DOI: 10.1002/ajmg.c.31740
Am J Med Genet. 2019;1–16. wileyonlinelibrary.com/journal/ajmgc © 2019 Wiley Periodicals, Inc. 1

“complete”and “incomplete”forms of the syndrome (Gaston et al.,
2001; Sotelo-Avila, Gonzalez-Crussi, & Fowler, 1980). In recognition
of the variety of clinical features that can occur in patients with
BWS, the syndrome was recently redefined as the Beckwith-
Wiedemann Spectrum (BWSp) during an international BWS consen-
sus meeting (Brioude et al., 2018).
1.2 |Clinical features
The most common features of BWSp, designated as “cardinal fea-
tures”(Figure 1a) by the BWS consensus, include macroglossia,
omphalocele, lateralized overgrowth, multifocal, and/or bilateral
Wilms tumor or nephroblastomatosis, and hyperinsulinism (Brioude
et al., 2018). Additional “suggestive features”that can occur in BWSp
include being large for gestational age (birth weight > 2 SDS above
mean), facial nevus simplex, polyhydramnios, placentomegaly, ear
creases/pits, transient hypoglycemia, nephromegaly, hepatomegaly,
umbilical hernia, diastasis recti, and tumors including neuroblastoma,
rhabdomyosarcoma, unilateral Wilms tumor, hepatoblastoma, adreno-
cortical carcinoma, and pheochromocytoma (Brioude et al., 2018). The
suggestive features can also occur in the general population and
therefore have less weight in calculating the BWS clinical score (see
below) (Figure 1b). Pathology findings that are considered cardinal
features of BWSp include adrenal cortex cytomegaly, placental mes-
enchymal dysplasia, and pancreatic adenomatosis (Figure 1c).
1.3 |Lateralized overgrowth
Lateralized overgrowth (LO; OMIM 235000), formerly referred to as
hemihypertrophy or hemihyperplasia, is defined as asymmetric over-
growth of one or more regions of the body (Kalish et al., 2017a). The
feature can be isolated (ILO) or accompany other major/minor find-
ings suggestive of a syndrome. In patients with BWSp, the LO is char-
acterized by increased muscle bulk. Skeletal asymmetry can also
occur; however, skeletal asymmetry without associated muscle bulk
differences is not typically seen in BWSp. Additional growth disorders
that can cause asymmetry include neurofibromatosis (NF1; OMIM
162200), Proteus syndrome (OMIM 176920), PIK3CA-related seg-
mental overgrowth (OMIM 612918), and Klippel-Trenaunay-Weber
syndrome (OMIM 149000). These disorders are most often catego-
rized by other abnormalities not typically seen in BWSp, such as skin
pigmentation differences or asymmetry in adipose tissue rather than
muscle (Hoyme et al., 1998; Mirzaa, Conway, Graham Jr., &
Dobyns, 1993).
Asymmetry in muscle bulk differences can also occur in the under-
growth disorder, Russell-Silver syndrome (RSS, OMIM 180860). Some
molecular defects causing RSS occur in the same region of chromo-
some 11p15 as BWS; however, with the opposite methylation and
gene dysregulation changes to those seen in BWS. A recent case
series highlights patients referred for BWS/asymmetry and subse-
quently found to have RSS instead (Mackay et al., 2019).
(a)
(c)
(b)
FIGURE 1 BWS diagnostic features. (a) Cardinal and (b) suggestive clinical features (not pictured: Hypoglycemia, ear pits, diastasis recti,
polyhydramnios, and other embryonal tumors are also suggestive features of BWS). (c) Pathologic and placenta findings in patients with BWS.
Pathologic findings including adrenal cytomegaly, pancreatic adenomatosis, and mesenchymal dysplasia are cardinal features and placentomegaly
is a suggestive feature
2DUFFY ET AL.

1.4 |Clinical diagnosis
The BWS consensus developed a clinical scoring system to aid in the
categorization of BWSp (Brioude et al., 2018). Cardinal features were
assigned two points each and suggestive features were assigned one
point each. For a clinical diagnosis of BWSp, patients require a clinical
score greater than or equal to four points. Patients with a clinical
score greater than or equal to two points were recommended to war-
rant molecular analysis. The consensus also introduced three subtypes
of BWS: patients presenting with “classic”features (i.e., macroglossia,
omphalocele, overgrowth, etc.); patients presenting with isolated
lateralized overgrowth (ILO); and patients with a BWS molecular
defect that do not fit into the previous groups, termed “atypical”
(Brioude et al., 2018). Patients with BWSp can fall anywhere on the
“spectrum,”ranging from ILO to atypical to classic.
1.5 |Mosaicism
The clinical spectrum in BWSp is likely due to the postzygotic nature
of the epigenetic changes in most cases of BWSp. The earlier the epi-
genetic change occurs, the more cells with the change and the more
parts of the body that demonstrate clinical features. The later the
change, the fewer physical features observed. Mosaicism here is
defined as a mixture of normal cells and cells with the genetic or epi-
genetic change causing BWS. This also occurs within multiple tissues
in which normal and BWS cells can occur in differing ratios depending
on the tissue tested in a given patient. We and others have demon-
strated this mosaicism (Alders et al., 2014; Brioude et al., 2018;
Eggermann et al., 2016; Kalish et al., 2016; Russo et al., 2016).
1.6 |Molecular diagnosis and frequencies
Molecular testing in BWS includes methylation analysis at imprinting
control regions 1 and 2 (IC1 and IC2) on chromosome 11p15, chromo-
some microarray analysis, and CDKN1C analysis (Brioude et al., 2018).
In the case of negative blood analysis, testing of multiple affected tis-
sues may increase the diagnostic yield due to mosaicism (Alders et al.,
2014; Brioude et al., 2018; Eggermann et al., 2016; Kalish et al., 2016;
MacFarland et al., 2018; Russo et al., 2016).
BWSp is caused by epigenetic or genetic defects on chromosome
11p15 (Figure 2). The most common cause is loss of methylation at
KCNQ1OT1:TSS DMR (IC2 LOM), occurring in 50% of all patients
(Brioude et al., 2018). Other causes include paternal uniparental iso-
disomy of chromosome 11 (pUPD11) (20% of patients), gain of
(a) (c)
(d)
(e)
(b)
FIGURE 2 Schematic representations of the differential genetic and epigenetic causes of BWS on chromosome 11p15. (a) Normal
methylation patterns demonstrate methylation at imprinting control region 1 (IC1) on the paternally inherited allele and methylation at imprinting
control region 2 (IC2) on the maternally inherited allele. (b) Hypermethylation at IC1 results in the overexpression of IGF2. (c) Hypomethylation at
IC2 results in the reduced expression of CDKN1C. (d) Paternal uniparental isodisomy results in the overexpression of IGF2 and the reduced
expression of CDKN1C. (e) CDKN1C mutations of the maternal allele
DUFFY ET AL.3

methylation at H19/IGF2:IG DMR (IC1 GOM) (5% of patients), and
mutations in the CDKN1C gene (5% of patients) (Brioude et al., 2018).
More rarely, duplications, deletions, or chromosome trans-
locations/inversions can occur which affect the 11p15 region (11p15
anomalies), affecting approximately 3–6% of patients (Brioude et al.,
2018). Defects involving pUPD11 can occur beyond the 11p15 region
and affect all chromosomes (genome-wide paternal uniparental iso-
disomy, GWpUPD) and it is estimated that up to 10% of patients with
pUPD11 have GWpUPD (Brioude et al., 2018).
1.7 |Epigenotype-phenotype correlations
Patients with IC2 LOM have been reported to have higher frequen-
cies of omphalocele, macroglossia, ear creases/pits, facial nevus sim-
plex, and prematurity and lower frequencies of
organomegaly/nephromegaly, large for gestational age, lateralized
overgrowth, and tumors compared with patients with IC1 GOM and
pUPD11 (Bliek et al., 2004; Brioude et al., 2013; Cooper et al., 2005;
DeBaun et al., 2002; Engel et al., 2000; Gaston et al., 2001; Ibrahim
et al., 2014; Maas et al., 2016; Mussa et al., 2016; Weksberg et al.,
2001). Lateralized overgrowth appears most commonly in patients
with pUPD11 (Brioude et al., 2013; Cooper et al., 2005; DeBaun
et al., 2002; Ibrahim et al., 2014; Maas et al., 2016; Mussa et al.,
2016). Other less frequent associations reported include diastasis recti
and polyhydramnios in IC1 GOM patients (Mussa et al., 2016).
Although some previous reports have indicated that hypoglycemia is
more common in patients with pUPD11 (Brioude et al., 2013; DeBaun
et al., 2002), others have not found an association with a specific
molecular subtype (Cooper et al., 2005; Ibrahim et al., 2014; Maas
et al., 2016; Mussa et al., 2016). In a previous case series of patients
with severe hypoglycemia (hyperinsulinism) and Beckwith-
Wiedemann syndrome, pUPD11 was the molecular defect identified
in 26/28 of patients (Kalish et al., 2016). Patients with mutations in
CDKN1C are less well characterized, but appear to be more affected
by omphalocele and preterm birth (Mussa et al., 2016).
Here, we present a previously unreported cohort that represents
the full BWSp and evaluate the BWS consensus guidelines in regards
to clinical and molecular diagnosis of this cohort and provide some
amendments to the consensus to aid in the practical application of
those guidelines.
2|METHODS
A growth and genetic/epigenetic disorder registry was created at Chil-
dren's Hospital of Philadelphia (CHOP) in 2014 to systematically col-
lect clinical information and samples from patients with a goal to
understand more about these rare disorders. Consent was obtained
from all participants/guardians and the study is approved by CHOP's
Institutional Review Board (IRB 13–010658). At time of enrollment in
the study, patients are assigned a unique identification number and
their associated diagnosis/diagnoses are recorded. Medical records
are reviewed by the study team and information about prenatal, birth,
and surgical histories in addition to hospital discharge summaries, spe-
cialist notes, and genetic testing results are collected and entered into
the database by their unique ID numbers. Efforts are made to collect
medical records from all institutions related to the patient. In the case
of incomplete data, interviews with the patient, family members, and
other physicians involved in their care are conducted as available.
Records are reviewed at regular intervals and any updates are entered
into the system.
2.1 |Patient selection
The registry was queried to identify patients that fit criteria for the
Beckwith-Wiedemann spectrum (BWSp). Patients enrolled and processed
prior to March 2019 were eligible for the search. Search terms included
cardinal features of BWSp: macroglossia, omphalocele, lateralized over-
growth/asymmetry/hemihypertrophy, hyperinsulinism, and Wilms tumor.
Additional search terms included Beckwith-Wiedemann syndrome and
overgrowth disorder.
The initial search yielded 462 potentially eligible patients. Due to
insufficient data, 30 patients were initially excluded. The remaining
432 patients were then screened in a two-step process. Genetic
testing results were reviewed and 25 patients were excluded due to
a molecularly confirmed alternative diagnosis. The remaining 407
patients were then assessed for eligibility for a BWSp diagnosis:
33 were excluded due to the presence of clinical features suggestive
of an alternative diagnosis and 17 were excluded due to the presence
of an isolated feature (i.e., isolated omphalocele or hyperinsulinism
without other features to meet criteria for BWSp). The less affected
among monozygotic twins with concordant BWS molecular testing
and discordant features were also excluded (n= 13), as the less
affected twin of monozygotic pairs often presents with little to no
BWS features (Cohen et al., 2019).
2.2 |Data collection
Medical records were reviewed and data regarding demographic infor-
mation, prenatal and birth history, BWS clinical features, and molecu-
lar testing results were abstracted. In some cases, interviews with
patients and/or family members or outside hospital physicians were
conducted to gather additional data. The BWSp clinical score was cal-
culated according to the consensus criteria (Brioude et al., 2018):
2 points were assigned for the presence of each cardinal feature and
1 point was assigned for the presence of each suggestive feature. As
pathology testing may not be routinely performed in patients, we
excluded pathology findings from the clinical score calculations.
2.3 |Clinical feature definitions
Lateralized overgrowth was defined as visible/palpable and/or
measureable 5% difference in asymmetry in one or more limbs pre-
sumed to be related to muscle bulk differences. The presence of
hypoglycemia overall was recorded and separated into two forms:
transient hypoglycemia defined as low blood glucose levels lasting
4DUFFY ET AL.

<1 week, and hyperinsulinism defined as prolonged hypoglycemia
(lasting >1 week) requiring escalated treatment. The presence of
tumor(s) overall was recorded and separated into two groups based
on the consensus criteria: multifocal and/or bilateral Wilms tumor
(WT) or nephroblastomatosis (NB), and typical BWSp tumor (unilateral
WT, hepatoblastoma, neuroblastoma, pheochromocytoma, etc).
Pathology results on the tumors were reviewed for classification
when available.
2.4 |Diagnostic indication definitions
Patients were assigned to five groups based on the feature(s) that led
to the clinical/molecular diagnosis of BWSp: Patients presenting with
a constellation of BWS features (BWS features group); those pre-
senting with asymmetry as their main indication (asymmetry group);
those first presenting with hyperinsulinism (hyperinsulinism group) or
tumor (tumor group) before BWSp was suspected; and those who
were not suspected to have BWS but had genetic testing for another
reason and had results consistent with BWS (incidental group).
Patients were also grouped according to the age at diagnosis: prena-
tally confirmed; neonatal (<30 days); and postneonatal, which was
assigned when the patient was diagnosed past 30 days old. The age in
months at diagnosis in the postneonatal group was recorded when
available.
2.5 |BWSp group definitions
The BWS consensus established three groups of patients within the
spectrum: classic, atypical, and isolated lateralized overgrowth (ILO).
Although these groups were established, no set criteria for designa-
tion to these groups were defined. For the purposes of this study, we
arbitrarily defined these groups for analysis. In an effort to properly
categorize patients in their respective groups prior to presenting with
a tumor (as ideally patients would be recognized clinically prior to the
development of a tumor), tumors were excluded from the clinical
score when classifying. Patients presenting with hyperinsulinism or
tumors automatically were grouped into atypical, as many of these
patients had subtle lateralized overgrowth and the combination of
these features may artificially inflate a score and cause a patient to fit
“classic”criteria when they are not initially presenting as “classic.”
Group definitions were as follows:
2.5.1 |Classic BWSp
Patients with a clinical score ≥6 with two or more cardinal features
(except if hyperinsulinism and lateralized overgrowth were the two
features).
2.5.2 |Atypical BWSp
Patients with a clinical score < 6 with at least one cardinal feature; or
Patients with a clinical score ≥6 with hyperinsulinism and lateralized
overgrowth as the two cardinal features; or
Patients diagnosed with BWS after presenting with hyperinsulin-
ism; or
Patients diagnosed with BWS after presenting with tumor (except
if LO was the only cardinal feature).
2.5.3 |Isolated lateralized overgrowth
Patients with a clinical score < 4 with LO as the only cardinal feature.
2.6 |Statistical analysis
Data were analyzed using SPSS Statistics (version 25.0). Continuous
variables were summarized by means/SDs and nominal/categorical
variables were summarized by frequencies. Differences between the
groups were evaluated by independent ttests or one-way ANOVA for
continuous variables and Fisher's Exact and Pearson chi square ana-
lyses for nominal/categorical variables as applicable. For groups with
significant differences overall, Tukey post hoc analysis was performed
for continuous variables and column proportion testing (ztest) with
adjusted pvalues using the Bonferroni method was used to evaluate
for differences within groups that were found to be overall signifi-
cantly different by Pearson chi square. Significance was set at p< .05.
3|RESULTS
A total of 344 patients were included in the final cohort. Characteris-
tics of the cohort are summarized in Table 1. There were slightly more
females than males, more than half were Caucasian, and the majority
lived in the United States. Patients were followed from birth for an
average of 70.0 ± 111.22 months.
3.1 |Clinical features
The most common clinical feature present in the group was lateralized
overgrowth (Table 2). Differences in degree of severity of LO were
observed between patients (Figure 3), as well as differences in degree
over time were observed for some (Figure 4). Macroglossia was also
common with approximately 2/3 of the cohort having some degree of
the feature. Among those with macroglossia, about half required a
tongue reduction. Slightly more than half of patients had some degree of
hypoglycemia and ear creases/pits. Slightly less than half of patients
were large for gestational age at birth and had facial nevus simplex.
Overall tumor incidence was 14.5%.
3.2 |Molecular testing
The recommended molecular testing for BWS includes methylation test-
ing at IC1 and IC2 followed by copy number testing using a variety of
techniques (Brioude et al., 2018). Single nucleotide polymorphism (SNP)
array analysis is also recommended to distinguish pUPD11 from
GWpUPD. The molecular breakdown of this BWSp cohort is demon-
strated through the molecular diagnostic algorithm proposed in the
DUFFY ET AL.5

consensus (Figure 5). The most common molecular subtype in the cohort
was IC2 LOM. The majority of patients were molecularly confirmed
through blood analysis (n= 224) and an additional 38 patients were
molecularly confirmed through tissue testing (Figure 6). Among patients
molecularly tested, tissue analysis increased the diagnostic yield from
70.2% (224/319) to 82.1% (262/319). The most common molecular sub-
type among those confirmed through tissue testing was pUPD11.
Among patients with pUPD11, 9.3% were found to have GWpUPD.
3.3 |Diagnostic characteristics of group
Among the 321 patients with information regarding reason for refer-
ral, the majority were referred due to the presence of BWS features
(64.2%) or asymmetry (17.8%). Other indications for diagnosis
included presenting with hyperinsulinism (10.3%) or tumor (5.9%) and
a few patients were incidentally diagnosed with BWS by genome-
wide microarray analysis performed for another reason (1.9%). Age at
diagnosis was available for 308 patients and were divided into three
groups: prenatally confirmed (7.5%), neonatal (<30 days; 47.4%), and
postneonatal (45.1%). The average age at diagnosis for the post-
neonatal group was 14.06 ± 23.51 months.
3.4 |BWSp clinical score
The average clinical score of the group was 6.72 ± 2.58 points. The
average number of cardinal features was 1.85 ± 0.81 points and the
average number of suggestive features was 3.04 ± 1.70 points. A wide
TABLE 1 Characteristics of the Beckwith-Wiedemann spectrum
(BWSp) cohort
Characteristic Total, N(%)
Sex, male: female 154:190/344 (44.8%:55.2%)
From the United States 302/344 (87.8%)
Race/ethnicity group
Caucasian only 227/344 (66.0%)
Mixed race/ethnicity 49/344 (14.2%)
Non-Caucasian or Hispanic only 49/344 (14.2%)
Unknown/not reported 19/344 (5.5%)
BWSp subgroup
Classic 207/322 (64.3%)
Atypical 55/322 (17.1%)
ILO
a
60/322 (18.6%)
Diagnosis group
IC1 GOM
b
32/344 (9.3%)
IC2 LOM
c
118/344 (34.3%)
pUPD11
d
78/344 (22.7%)
CDKN1C mutation 7/344 (2.0%)
GWpUPD
e
8/344 (2.3%)
11p15 anomaly 19/344 (5.5%)
Negative testing 57/344 (16.6%)
No testing 19/344 (5.5%)
Unknown 6/344 (1.7%)
a
ILO: isolated lateralized overgrowth.
b
IC1 GOM: gain of methylation at H19/IGF2:IG DMR.
c
IC2 LOM: loss of methylation at KCNQ1OT1:TSS DMR.
d
pUPD11: paternal uniparental isodisomy of chromosome 11p15.
e
GWpUPD: genome wide paternal uniparental isodisomy.
TABLE 2 Clinical features of the Beckwith-Wiedemann spectrum
(BWSp) cohort
Feature Total n(%) or mean (SD)
Pregnancy/birth
Assisted reproductive technology
a
None 257/309 (83.2%)
IUI
b
and/or hormone stimulation 6/309 (1.9%)
IVF
c
and/or ICSI
d
46/309 (14.9%)
Multiple gestation 44/315 (14.0%)
Polyhydramnios 79/301 (26.2%)
Placentomegaly 36/299 (12.0%)
Gestational age 35.81 wks (3.96)
Premature (<37 weeks) 139/319 (43.6%)
LGA
e
200/320 (62.5%)
Typical features
Macroglossia 226/340 (66.5%)
Tongue reduction 96/205 (46.8%)
Facial nevus simplex 138/313 (44.1%)
Ear creases/pits 180/309 (58.3%)
Abdominal wall defect 211/320 (65.9%)
Omphalocele 65/332 (19.6%)
Umbilical hernia 108/318 (34.0%)
Diastasis recti 53/312 (17.0%)
Lateralized overgrowth 244/329 (74.2%)
Hypoglycemia 171/321 (53.3%)
Transient 99/321 (30.8%)
Hyperinsulinism 72/329 (21.9%)
Pancreatectomy 26/67 (38.8%)
Organomegaly 118/316 (37.3%)
Hepatomegaly 64/302 (21.2%)
Nephromegaly 63/305 (20.7%)
Splenomegaly 37/294 (12.6%)
Tumor 48/332 (14.5%)
Bilateral/multifocal WT/NB
f
16/331 (4.8%)
Typical BWSp tumor 32/344 (9.6%)
Other features
Cleft palate 7/304 (2.3%)
Undescended testes 37/123 (30.1%)
Family history of BWS 8/344 (2.3%)
a
ART: assisted reproductive technology.
b
IUI: intrauterine insemination.
c
IVF: in vitro fertilization.
d
ICSI: intracytoplasmic sperm injection.
e
LGA: large for gestational age (>2 SDs above the mean).
f
WT/NB: Wilms tumor or nephroblastomatosis.
6DUFFY ET AL.

variation in BWSp clinical scores among the molecular subgroups was
observed.
3.5 |EpiGenotype/phenotype correlations
3.5.1 |Clinical features
Clinical data was available for 228 patients with IC2 LOM, IC1 GOM,
and pUPD11 molecular defects (Table 3). Patients with IC2 LOM were
found to have significantly increased incidence of macroglossia,
abdominal wall defects overall, omphalocele, facial nevus simplex, and
ear creases/pits compared with patients with IC1 GOM and pUPD11
subtypes. Polyhydramnios, prematurity (<37 weeks gestation), and
undescended testes were also more common in patients with IC2
LOM compared with patients with pUPD11, but no significant differ-
ence was observed between IC2 LOM and IC1 GOM for these charac-
teristics. Patients with pUPD11 were found to have a significantly
increased incidence of lateralized overgrowth, hyperinsulinism, and
pancreatectomy and patients with IC1 GOM were found to have a
significantly increased incidence of diastasis recti compared with the
other subtypes. Tumor incidence was significantly increased in
patients with IC1 GOM and pUPD11 compared with patients with
IC2 LOM. A significant increase in multifocal/bilateral Wilms tumor
was observed in patients with IC1 GOM compared with pUPD11
patients; however, no difference was observed for incidence of other
typical BWSp tumors.
3.5.2 |Diagnostic characteristics
Patients with IC2 LOM were more likely to be diagnosed prenatally or
in the neonatal period while patients with IC1 GOM and pUPD11
were more likely to be diagnosed in the neonatal period or post-
neonatally. Indications for diagnosis varied between the groups, with
the majority of IC2 LOM patients diagnosed based on presenting with
FIGURE 3 Spectrum of lateralized overgrowth in patients with BWS or isolated lateralized overgrowth. Abbreviations: IC1 GOM = imprinting
center 1 gain of methylation; pUPD11 = paternal uniparental isodisomy of chromosome 11; and ILO = isolated lateralized overgrowth. (a) Clinical
BWS (no molecular diagnosis), 11 months old; (b) IC1, 8 years old (c) pUPD11, 32 months old (d) ILO, 32 months old (e) pUPD11, 4 years old; (f)
pUPD11, 22 months old; and (g) ILO, 14 months old
FIGURE 4 Isolated lateralized
overgrowth in one patient overtime.
(a) 14 months old, (b) 32 months old,
and (c) 45 months old
DUFFY ET AL.7

FIGURE 5 Testing algorithm and
the molecular breakdown of the BWSp
cohort based on testing. Testing at
H19/IGF2:IG DMR and KCNQ1OT1:
TSS DMR by methylation, copy
number variant (CNV), and single
nucleotide polymorphism (SNP) array
analysis
FIGURE 6 Patients with BWS with (1) IC1 gain of methylation, (2) IC2 loss of methylation, (3) paternal uniparental isodisomy (pUPD11),
(4) genome-wide paternal uniparental isodisomy (GWpUPD), (5) CDKN1C mutations, (6) an 11p15 anomaly (deletions or duplications), (7) an
unknown subtype, (8) no genetic testing, and (9) no defect identified. (a) Patients with BWS reported by Brioude et al., 2018. (b) Patients with
BWS in the BWSp cohort at the Children's Hospital of Philadelphia. (c) Patients in the cohort with a molecularly confirmed diagnosis. (d) Patients
in the cohort with positive testing in blood. (e) Patients in the cohort with positive testing in tissue
8DUFFY ET AL.

TABLE 3 EpiGenotype/phenotype correlations
Feature Total
a
n(%) or mean (SD) IC1 GOM
b
IC2 LOM
c
pUPD11
d
pvalue
e
Sex, male 99/228 (43.4%) 12/32 (37.5%) 54/118 (45.8%) 33/78 (42.3%) .684
Diagnosis source, blood 192/228 (84.2%) 25/32 (78.1%) 116/118 (98.3%) 51/78 (65.4%) <.001***
Clinical score 7.14 (2.53) 6.09 (2.60) 7.74 (2.22) 6.71 (2.71) .001**
Suggestive features 3.25 (1.65) 2.78 (1.70) 3.59 (1.42) 2.93 (1.84) .006**
Cardinal features 1.95 (0.82) 1.66 (0.83) 2.07 (0.81) 1.89 (0.81) .031*
Diagnosis indication <.001***
BWS features 151/213 (70.9%) 15/29 (51.7%) 106/113 (93.8%) 30/71 (42.3%)
Asymmetry 21/213 (9.9%) 4/29 (13.8%) 3/113 (2.7%) 14/71 (19.7%)
Hyperinsulinism 19/213 (8.9%) 0/29 (0%) 2/113 (1.8%) 17/71 (23.9%)
Tumor 19/213 (8.9%) 10/29 (34.5%) 2/113 (1.8%) 7/71 (9.9%)
Incidental 3/213 (1.4%) 0/29 (0%) 0/113 (0%) 3/71 (4.2%)
Diagnosis age group .003**
Prenatal (confirmed) 15/209 (7.2%) 0/29 (0%) 14/109 (12.8%) 1/71 (1.4%)
Neonatal (<30 days) 108/209 (51.7%) 12/29 (41.1%) 60/109 (55.0%) 36/71 (50.7%)
Postneonatal 86/209 (41.1%) 17/29 (58.6%) 35/109 (32.1%) 34/71 (47.9%)
Postneonatal age at diagnosis (m) 16.36 (27.60) 27.80 (28.92) 12.78 (24.60) 14.81 (29.39) .198
Race/ethnicity group .125
Caucasian 149/221 (67.4%) 22/31 (71.0%) 80/112 (71.4%) 47/78 (60.3%)
Mixed 39/221 (17.6%) 7/31 (22.6%) 19/112 (17.0%) 13/78 (16.7%)
Non-Caucasian 33/221 (14.9%) 2/31 (6.5%) 13/112 (11.6%) 18/78 (23.1%)
Pregnancy/birth
ART
f
use <.001***
Natural 168/208 (80.8%) 27/30 (90.9%) 75/109 (68.8%) 66/69 (95.7%)
IUI
g
and/or hormone stim 2/208 (1.0%) 2/30 (6.7%) 0/109 (0%) 0/69 (0%)
IVF
h
and/or ICSI
i
38/208 (18.3%) 1/30 (3.3%) 34/109 (31.2%) 3/69 (4.3%)
Multiple gestation 31/213 (14.6%) 3/30 (10.0%) 22/111 (19.8%) 6/72 (8.3%) .074
Polyhydramnios 52/196 (26.5%) 6/29 (20.7%) 34/98 (34.7%) 12/69 (17.4%) .033*
Placentomegaly 27/194 (13.9%) 3/29 (10.3%) 19/97 (19.6%) 5/68 (7.4%) .069
Gestational age 36.01 (3.74) 35.92 (3.73) 35.50 (3.76) 36.81 (3.63) .079
Premature (<37 weeks) 88/213 (41.3%) 12/30 (40.0%) 55/111 (49.5%) 21/72 (29.2%) .023*
LGA
j
135/212 (63.7%) 18/28 (64.3%) 70/112 (62.5%) 47/72 (65.3%) .927
Typical features
Macroglossia 162/226 (71.7%) 17/32 (53.1%) 112/118 (94.9%) 33/76 (43.4%) <.001***
Tongue reduction 78/145 (53.8%) 8/16 (50.0%) 57/101 (56.4%) 13/28 (46.4%) .610
Facial nevus simplex 103/205 (50.0%) 6/27 (22.2%) 77/108 (71.3%) 20/71 (28.2%) <.001***
Ear creases/pits 125/201 (62.2%) 9/27 (33.3%) 81/104 (77.9%) 35/70 (50.0%) <.001***
Abdominal Wall defect 149/213 (70.0%) 17/30 (56.7%) 92/110 (83.6%) 40/73 (54.8%) <.001***
Omphalocele 52/220 (23.6%) 0/32 (0%) 47/115 (40.9%) 5/73 (6.8%) <.001***
Umbilical hernia 73/211 (34.6%) 8/30 (26.7%) 40/109 (36.7%) 25/72 (34.7%) .593
Diastasis recti 35/205 (17.1%) 12/27 (44.4%) 9/107 (8.4%) 14/71 (19.7%) <.001***
Lateralized overgrowth 158/215 (73.5%) 23/30 (76.7%) 64/110 (58.2%) 71/75 (94.7%) <.001***
Hypoglycemia 129/212 (60.8%) 14/31 (45.2%) 63/109 (57.8%) 52/72 (72.2%) .023*
Transient 81/212 (38.2%) 11/31 (35.5%) 49/109 (45.0%) 21/72 (29.2%) .096
Hyperinsulinism 48/218 (22.0%) 3/32 (9.4%) 14/112 (12.5%) 31/74 (41.9%) <.001***
Pancreatectomy 22/47 (46.8%) 0/3 (0%) 2/14 (14.3%) 20/30 (66.7%) .001**
(Continues)
DUFFY ET AL.9

BWS features, while HI indication was significantly increased in
patients with pUPD11 and tumor indication was significantly
increased in patients with IC1 GOM. Asymmetry indication was signif-
icantly greater in patients with IC1 GOM and pUPD11 compared with
patients with IC2 LOM. A significant difference in source of positive
molecular testing was found with positive blood analysis increased in
patients with IC2 LOM, while approximately three-quarters of
patients with IC1 GOM and pUPD11 were diagnosed through positive
tissue analysis after negative blood analysis. The BWSp groups were
also found to significantly differ between the molecular subtypes.
Patients with IC2 LOM were more likely to be “classic”and less likely
to be “ILO.”
3.5.3 |BWSp clinical score
Patients with IC2 LOM were found to have increased clinical scores
compared with IC1 GOM (p= .001) and patients with pUPD11
(p= .008). In comparison with patients with IC1 GOM, patients with
IC2 LOM had an increased number of cardinal features (p= .012) and
suggestive features (p= .008). An increased number of suggestive fea-
tures was found in patients with IC2 LOM compared with pUPD11
(p= .011); however, no significant difference was found in the number
of cardinal features (p= .137). No significant differences between
patients with IC1 GOM and pUPD11 were found for BWSp clinical
score or the number of cardinal or suggestive features.
3.6 |BWSp group correlations
The most common BWSp group among the cohort was classic
(Table 4). A variation of facial features was observed among the
molecular subtypes and BWSp groups (Figure 7). A significant
decrease in molecular confirmation was found in the ILO group com-
pared with the classic and atypical groups. Patients in the classic
group were significantly more often diagnosed through blood while
patients in the atypical and ILO groups were more often diagnosed
through tissue. Molecular subtype was found to differ significantly
between the three groups. A significant difference in IC2 LOM diag-
nosis was observed across all three groups with IC2 LOM most com-
mon in the classic group and least common in the ILO group. The
incidence of pUPD11 was greater in the atypical group compared with
the classic group.
The indication for diagnosis significantly differed between groups.
The presenting feature of typical BWS features was most common in
the classic group, hyperinsulinism as the presenting feature was most
common in the atypical group, and asymmetry was most common in
the ILO group. Tumor as the presenting feature was more common in
the atypical and ILO group compared with the classic group.
A significant difference in age at diagnosis was also observed
between the groups. Patients in the classic group were more often
prenatally confirmed compared with patients in the atypical and ILO
groups. All groups were different for neonatal diagnosis, with the
highest incidence in the classic group and lowest incidence in the ILO
TABLE 3 (Continued)
Feature Total
a
n(%) or mean (SD) IC1 GOM
b
IC2 LOM
c
pUPD11
d
pvalue
e
Organomegaly 80/206 (38.8%) 13/29 (44.8%) 37/106 (34.9%) 30/71 (42.3%) .478
Hepatomegaly 42/197 (21.3%) 9/28 (32.1%) 15/100 (15.0%) 18/69 (26.1%) .072
Nephromegaly 42/198 (21.2%) 8/28 (28.6%) 17/100 (17.0%) 17/70 (24.3%) .307
Splenomegaly 29/193 (15.0%) 5/28 (17.9%) 12/97 (12.4%) 12/68 (17.6%) .584
Tumor 43/219 (19.6%) 16/31 (51.6%) 5/114 (4.4%) 22/74 (29.7%) <.001***
Bilateral/multifocal WT/NB
k
14/219 (6.4%) 10/31 (32.3%) 1/114 (0.9%) 3/74 (4.1%) <.001***
Typical BWSp 29/220 (13.2%) 6/31 (19.4%) 4/115 (3.5%) 19/74 (25.7%) <.001***
Other features
Cleft palate 3/202 (1.5%) 0/28 (0%) 2/104 (1.9%) 1/70 (1.4%) .756
Undescended testes 29/81 (35.8%) 3/9 (33.3%) 24/46 (52.2%) 2/26 (7.7%) .001**
a
Total refers to totals of the three subgroups compared (IC1 GOM, IC2 LOM, pUPD11).
b
IC1 GOM: gain of methylation at H19/IGF2:IG DMR.
c
IC2 LOM: loss of methylation at KCNQ1OT1:TSS DMR.
d
pUPD11: paternal uniparental isodisomy of chromosome 11p15.
e
pvalues refer to the frequency of each feature between the three subgroups (IC1 GOM, IC2 LOM, pUPD11), so all subgroups are compared at the
same time.
f
ART: assisted reproductive technology.
g
IUI: intrauterine insemination.
h
IVF: in vitro fertilization.
i
ICSI: intracytoplasmic sperm injection.
j
LGA: large for gestational age (>2 SDs above the mean).
k
WT/NB: Wilms tumor or nephroblastomatosis.
*Significant at p< .05; **Significant at p< .01; ***Significant at p< .001.
10 DUFFY ET AL.

groups. Postneonatal diagnosis was most common in the ILO group
and least common in the classic group. The age at diagnosis in the ILO
group significantly differed from the classic group by one-way
ANOVA testing with Tukey post hoc testing (mean difference 13.58
± 4.19 months, p= .004).
4|DISCUSSION
In evaluating a cohort of patients with BWSp that represent the com-
plete spectrum, we observed that IC2 LOM patients were most com-
monly recognized as indicated by prenatal and early postnatal
diagnoses and their composition of features had the highest clinical
score. These patients looked most like the classic textbook cases of
BWS. Patients with IC1 GOM and pUPD11 demonstrated much more
variability in diagnostic features. Based on our further designation of
classic, atypical, and ILO versions of BWS in the methods, we have
made distinct recommended updates to the current BWS consensus
guidelines to aid in diagnosis of patients in the atypical category as
described below.
4.1 |Epigenotype–phenotype correlations
Our results are consistent with previous epigenotype–phenotype cor-
relations (Bliek et al., 2004; Brioude et al., 2013; Cooper et al., 2005;
DeBaun et al., 2002; Engel et al., 2000; Gaston et al., 2001; Ibrahim
TABLE 4 BWSp group correlations
Feature Total
a
n(%) or mean (SD) Classic Atypical ILO
b
pvalue
c
Molecular confirmation, yes 248/305 (81.3%) 178/195 (91.3%) 45/53 (84.9%) 25/57 (43.9%) <.001***
Molecular subtype <.001***
IC1 GOM
d
32/322 (9.9%) 15/207 (7.2%) 7/55 (12.7%) 10/60 (16.7%)
IC2 LOM
e
110/322 (34.2%) 97/207 (46.9%) 12/55 (21.8%) 1/60 (1.7%)
pUPD11
f
73/322 (22.7%) 38/207 (18.4%) 21/55 (38.2%) 14/60 (23.3%)
CDKN1C mutation 7/322 (2.2%) 5/207 (2.4%) 2/55 (3.6%) 0/60 (0%)
GWpUPD
g
7/322 (2.2%) 4/207 (1.9%) 3/55 (5.5%) 0/60 (0%)
11p15 anomaly 19/322 (5.9%) 19/207 (9.2%) 0/55 (0%) 0/60 (0%)
Negative testing 57/322 (17.7%) 17/207 (8.2%) 8/55 (14.5%) 32/55 (53.3%)
No testing 15/322 (4.7%) 10/207 (4.8%) 2/55 (3.6%) 3/55 (5.0%)
Unknown 2/322 (0.6%) 2/207 (1.0%) 0/55 (0%) 0/60 (0%)
Diagnosis source, blood 210/248 (84.7%) 174/178 (97.8%) 26/45 (57.8%) 10/25 (40.0%) <.001***
Diagnosis indication <.001***
BWS features 195/308 (63.3%) 179/199 (89.9%) 15/53 (28.3%) 1/56 (1.8%)
Asymmetry 56/308 (18.2%) 8/199 (4.0%) 5/53 (9.4%) 43/56 (76.8%)
Hyperinsulinism 32/308 (10.4%) 7/199 (3.5%) 25/53 (47.2%) 0/56 (0%)
Tumor 19/308 (6.2%) 2/199 (1.0%) 6/53 (11.3%) 11/56 (19.6%)
Incidental 6/308 (1.9%) 3/199 (1.5%) 2/53 (3.8%) 1/56 (1.8%)
Diagnosis age group <.001***
Prenatal (confirmed) 22/295 (7.5%) 22/190 (11.6%) 0/53 (0%) 0/52 (0%)
Neonatal (<30 days) 140/295 (47.5%) 115/190 (60.5%) 21/53 (39.6%) 4/52 (7.7%)
Postneonatal 133/295 (45.1%) 53/190 (27.9%) 32/53 (60.4%) 48/52 (92.3%)
Postneonatal age at diagnosis (m) 12.3 (1.9) 6.3 (8.2) 14.6 (22.7) 19.9 (28.1) .006**
Race/ethnicity group .098
Caucasian 216/307 (70.4%) 136/194 (70.1%) 33/54 (61.1%) 47/59 (79.7%)
Mixed 48/307 (15.6%) 32/194 (16.5%) 8/54 (14.8%) 8/59 (13.6%)
Non-Caucasian 43/307 (14.0%) 26/194 (13.4%) 13/54 (24.1%) 4/59 (6.8%)
a
Total refers to totals of the three subgroups compared (Classic, Atypical, ILO).
b
ILO: isolated lateralized overgrowth.
c
pvalues refer to the frequency of each feature between the three subgroups (Classic, Atypical, ILO), so all subgroups are compared at the same time.
d
IC1 GOM: gain of methylation at H19/IGF2:IG DMR.
e
IC2 LOM: loss of methylation at KCNQ1OT1:TSS DMR.
f
pUPD11: paternal uniparental isodisomy of chromosome 11p15.
g
GWpUPD: genome wide paternal uniparental isodisomy.
*Significant at p< .05; **Significant at p< .01; ***Significant at p< .001.
DUFFY ET AL.11

et al., 2014; Maas et al., 2016; Mussa et al., 2016; Weksberg et al.,
2001). An unreported phenotype we found was the increased inci-
dence of undescended testes in patients with IC1 GOM and IC2 LOM
compared with patients with pUPD11. This finding is most likely cau-
sed by the increased incidence of prematurity observed in these
groups, as in the general population undescended testes are more
common in premature patients (Niedzielski, Oszukowska, &
Slowikowska-Hilczer, 2016). We also found an increased incidence of
hyperinsulinism in the pUPD11 group, consistent with some previous
reports (Brioude et al., 2013; DeBaun et al., 2002). As these reports
evaluated hypoglycemia overall, further characterization of hyperinsu-
linism is necessary as we previously described (Kalish et al., 2016).
Sex distribution is variably reported in the large case series of patients
with BWS. Some series have reported higher frequencies of female
patients (Brioude et al., 2013; Maas et al., 2016), while others have shown
slightly higher frequencies of males (DeBaun et al., 2002; Ibrahim et al.,
2014; Zarate et al., 2009). To our knowledge, only one series has reported
the frequency of sexes among the most common molecular subtypes
(Maas et al., 2016). In this series, males represented 45.9% of the cohort,
with similar frequencies observed within the subtypes evaluated. We
observed similar frequencies to Maas et al. (2016) in our cohort, with the
exception of IC1 GOM, in which females were overrepresented (62.5%).
In the general pediatric population, patients with bilateral WT are more
often female and the reasoning for this is unknown (Charlton, Irtan,
Bergeron, & Pritchard-Jones, 2017). In our analysis, we demonstrated that
IC1 GOM patients have bilateral/multifocal WT significantly more often
than patients with IC2 LOM or pUPD11. The increased prevalence of IC1
GOM in female patients may be explained by the established connection
between females and bilateral WT.
4.2 |Cardinal features and limitations
In looking at the cardinal features present in patients with a confirmed
molecular diagnosis, the most useful features were macroglossia,
omphalocele, LO, and hyperinsulinism.
Patients with IC2 LOM most often fit into the classic group while
an increased incidence of pUPD11 and IC1 GOM was observed in the
atypical and ILO groups. These results indicate that the current BWS
criteria are focused on diagnosing IC2 LOM patients and may not be
useful in diagnosing patients with other molecular defects and those
at the highest risk for tumors.
In the consensus, multifocal/bilateral WT/NB is considered a cardi-
nal feature while unifocal/unilateral WT and other embryonal tumors
are considered a suggestive feature. In our cohort, multifocal/bilateral
WT/NB were not common however unifocal/unilateral WT or other
embryonal tumors were, suggesting that perhaps identification of one of
these other tumor types and/or not limiting WT to bilateral or multifocal
should be considered in this analysis. In our cohort, 6% of patients were
diagnosed with BWSp after presenting with a tumor and more than half
(55.6%) had a unilateral/unifocal WT or other typical BWSp tumor.
Interestingly, one patient was molecularly diagnosed with BWS in blood
after presenting with a presumed WT but final pathology revealed uni-
lateral nephroblastomatosis, which would not have warranted BWS
molecular testing at all.
FIGURE 7 Facial photographs of patients with BWS demonstrating the variation of facial gestalt within each molecular subtype.
Abbreviations: IC2 = imprinting center 2 loss of methylation; IC1 = imprinting center 1 gain of methylation; pUPD11 = paternal uniparental
isodisomy of chromosome 11; CDKN1C =CDKN1C mutation; ILO = isolated lateralized overgrowth. Top row, classic BWS patients: (a) IC2,
1 month old (b) IC1, 12 months old (c) pUPD11, 13 months old (d) CDKN1C, 12 months old; middle row, atypical BWS patients: (e) IC2,
24 months old (f) IC1, 12 months old (g) pUPD11, 12 months old (h) CDKN1C, 8 months old; bottom row, ILO patients: (i) IC2, 7 years old (j) IC1,
26 months old (k) pUPD11, 30 months old (l) there are no patients with CDKN1C and ILO in our cohort
12 DUFFY ET AL.

4.3 |Clinical diagnosis
The consensus developed the clinical scoring system to recognize
BWS as a spectrum and acknowledge that not all patients with BWSp
will look like the textbook cases (classic patients) with BWS. The scor-
ing system was developed to aid in diagnosis and to prevent a poten-
tial diagnosis being dismissed due to the absence of classic BWS
features. In this study, we have also noted that requiring 4 points on
the clinical scoring scale for a clinical diagnosis may not be sufficient
without further caveats. In practical application of this system in a
cohort that spans the BWSp, we recommend several modifications:
4.3.1 |Isolated lateralized overgrowth
Patients with ILO and no other cardinal or suggestive features warrant
consideration for inclusion in the spectrum, assuming the asymmetry
is caused by proportionate growth and muscle bulk differences. Tissue
analysis through skin biopsies of the larger limb is likely to aid in
molecular characterization.
4.3.2 |Hyperinsulinism and tumor as presenting
features
Patients presenting with hyperinsulinism or a tumor typically occurring
in patients with BWS may present with ILO as their only cardinal fea-
ture, or may be affected by a constellation of suggestive features that
would not provide a high suspicion for BWS diagnosis without the
occurrence of the tumor or hyperinsulinism. Despite this, approximately
16% of our cohort was diagnosed with BWS after presenting with
hyperinsulinism or a tumor. Patients referred for hyperinsulinism were
most often grouped in the atypical group and patients referred for
tumors were most often characterized in the atypical and ILO groups.
These results support the notion that these patients most often do not
fit into the classic BWS presentation, however can still be affected by
the disorder thus representing the spectrum. As a result, we suggest
that all patients presenting with hyperinsulinism and typical BWSp
tumors be evaluated for subtle asymmetry and other BWSp suggestive
features. These patients also warrant molecular testing in available tis-
sues in addition to molecular blood analysis.
In the consensus scoring system, the presence of multifocal
and/or bilateral Wilms tumor/nephroblastomatosis receives two
points to warrant genetic testing, while unilateral Wilms tumor and
hepatoblastoma receive one point. We suggest that all patients pre-
senting with Wilms tumor and hepatoblastoma receive genetic testing
on both blood and affected tissue.
4.3.3 |Assisted reproductive technology
The increased risk of BWS and use of assisted reproductive technol-
ogy (ART) (~four–sixfold) is well documented (DeBaun, Niemitz, &
Feinberg, 2003; Gicquel et al., 2003; Maher et al., 2003), with an
increased risk as high as 1 in 1,126 reported (Mussa et al., 2017). In
industrialized countries, ART accounts for 1–3% of all live births
(Brioude et al., 2018). In this study, ART was used for conception for
14.9% of patients. Furthermore, approximately a quarter of patients
conceived via IVF and/or ICSI were characterized in the atypical or
ILO groups (data not shown). This observation clearly shows that
patients conceived by IVF or ICSI may not have classic BWS features
and supports a proposal that conception by IVF or ICSI could be
viewed as one of the diagnostic criteria for BWSp.
The majority of patients with BWS born after ART (BWS-ART) are
affected by IC2 LOM (Brioude et al., 2018). To this date, three BWS-
ART patients with pUPD11 have been reported (Johnson et al., 2018;
Mussa et al., 2017). Additionally, a BWS-ART patient was found to
have isolated IC2 LOM and IC1 GOM after pUPD11 was excluded
(DeBaun et al., 2003). To our knowledge no patient with isolated IC1
GOM after ART has been previously reported. In this study, three
patients had pUPD11 and one patient had IC1 GOM. These patients
displayed classic features, besides one pUPD11 patient who was diag-
nosed after presenting with hyperinsulinism and the pUPD11 was
identified in pancreatic tissue. These findings support the previous
suggestion that ART may be implicated in genomic events beyond
methylation defects (Mussa et al., 2017).
4.4 |Molecular diagnosis
Based on the analysis of this cohort, the consensus recommendations
to test multiple tissues are quite useful in expanding the molecular
diagnosis in these patients. Among our cohort, we found that testing
multiple tissues increased the diagnostic yield from 70% to 82%
(Figure 5). As a result, we recommend molecular testing on affected
tissue whenever possible, especially in atypical and ILO presentations
of BWSp.
Almost all patients in the classic group with molecular confirma-
tion were diagnosed by blood, compared with approximately half of
the patients in the atypical and ILO groups. The patients in these
groups were significantly more often diagnosed through tissue com-
pared with the classic group and the most common molecular subtype
among those diagnosed through tissue was pUPD11. Patients in the
atypical or ILO groups also had fewer BWS features, indicating the
(epi)genetic changes occurred later in development and are more
mosaic compared with patients with classic BWS. As a result, testing
additional tissues in these groups increases the diagnostic yield of
detecting mosaicism and is important to help characterize patients in
the BWS spectrum. This is especially important in patients presenting
with hyperinsulinism or a tumor.
4.5 |Tumor risk
Although all patients with BWS have an increased tumor risk,
epigenotype–phenotype correlations have identified tumor risk differs
in regard to molecular subtypes. Patients with IC1 GOM and pUPD11
defects are at the greatest risk, while tumor risk is lower in patients
with IC2 LOM and mutations in CDKN1C (Brioude et al., 2018). Tumor
incidence in our group overall (14.5%) was higher than previously pub-
lished (8%; Maas et al., 2016). Similarly, we observed higher tumor
DUFFY ET AL.13

incidences within the three most common molecular subtypes com-
pared with the previously published data (Maas et al., 2016): IC1
GOM with 51.6% compared with 28%; pUPD11 with 29.7% com-
pared with 16%; and IC2 LOM with 4.4% compared with 2.6%. Tumor
incidence observed in our population may be higher compared with
previous published groups due to increased recognition of subtle fea-
tures, as well as molecular diagnosis through tissue testing. As a num-
ber of patients in our cohort were diagnosed with BWS due to
presenting with a tumor or hyperinsulinism, it is likely these patients
would not have been included in previous reports. Patients at the
highest risk for tumors (IC1 GOM and pUPD11) were also observed
more often to be diagnosed through tissue testing. This observation
highlights the importance of recognizing patients along the spectrum,
as all are at an increased risk of developing tumors. In this analysis, we
did not explore specific tumor types or clinical features that may
increase the risk of tumors, and additional analysis is warranted in
order to better characterize BWSp patients at the greatest risk.
4.6 |Management recommendations
For the most part, management recommendations are inline with the
consensus recommendations (Brioude et al., 2018). There are two
areas in which these differ based on our experience with this BWSp
cohort. These include hyperinsulinism and tumor screening.
4.6.1 |Hyperinsulinism
Hypoglycemia occurred in half of the patients in our cohort with 20%
of patients having hyperinsulinism. Among those with hyperinsulinism,
more than a third required a pancreatectomy. Patients with pUPD11
molecular defects were most often affected by hyperinsulinism; how-
ever, hyperinsulinism occurs in other BWSp molecular defects as well.
Management of hyperinsulinism is further discussed in the hyperinsu-
linism article in this issue.
4.6.2 |Tumor screening
Until recently, there were uniform recommendations that all patients
with BWS undergo routine tumor surveillance for detection of the two
most common tumors (Wilms tumor and hepatoblastoma), with serial
alpha-fetoprotein measurements and abdominal/renal ultrasounds.
Based on differing approaches to acceptable risk in different regional
and practice environments in combination with epigenotype–phenotype
correlations, some groups have used a 5% tumor risk cutoff and have
begun stratifying tumor surveillance to those subtypes at the greatest
risk (Brioude et al., 2018), while others maintain a more conservative
approach using a 1% tumor risk cutoff, similar to that used by the Amer-
ican Association for Cancer Research (AACR) and continue to screen all
patients (Kalish et al., 2017b). The largely European BWS consensus
advocated for tumor screening in just those patients with the highest
risk: IC1 GOM, pUPD11, and those without a molecular defect identi-
fied,aswellaspatientswithCDKN1C mutations and did not advocate
surveillance in patients with IC2 LOM (Brioude et al., 2018). Tumor
surveillance strategy recommended by the consensus includes screening
by abdominal ultrasound every 3 months from time of diagnosis until
age 7 years for detection of embryonal tumors (Brioude et al., 2018).
The consensus did not recommend using serial alpha-fetoprotein (AFP)
measurements for detection of hepatoblastoma due to low risk and dif-
ficultly in interpretation.
Based on an acceptable risk threshold of >1%, our tumor screen-
ing recommendations are in line with recommendations from the
AACR (Kalish, Doros, et al., 2017b) for all patients with BWSp:
•abdominal ultrasounds and AFP measurements every 3 months
until the 4th birthday;
•renal ultrasounds every 3 months until the 7th birthday.
Although the utility of AFP screening has been debated (Duffy,
Deardorff, & Kalish, 2017; Kalish & Deardorff, 2016; Maas et al.,
2016; Mussa & Ferrero, 2015, 2017), previous reports highlight the
usefulness of this measure in detecting hepatoblastoma before detec-
tion by ultrasonography (Clericuzio et al., 2003; Mussa et al., 2011;
Zarate et al., 2009) thus downgrading tumor stage at diagnosis
(Clericuzio et al., 2003; Trobaugh-Lotrario, Venkatramani, & Feusner,
2014), which is why we advocate for AFP in our tumor surveillance
recommendations. Recent evidence shows that hepatoblastoma in
patients with BWSp occurs before the age of 30 months (Mussa,
Duffy, Carli, Ferrero, & Kalish, 2019), so guidelines may be further
amended to reduce the length of AFP screening and full abdominal
ultrasounds. AFP norms in BWS were recently published to aid in
interpretation of values when screening (Duffy, Cohen, Elci, & Kalish,
2019). There are also additional recommendations for patients with
CDKN1C mutations due to a risk for development of neuroblastoma
(urine HVA/VMA and chest X-rays; Kalish, Doros, et al., 2017b), how-
ever further data are needed for this patient population.
4.6.3 |Multidisciplinary team approach
Patients with BWSp can be affected by a variety of clinical features
requiring a multidisciplinary team approach. At time of suspected diag-
nosis, patients should be evaluated for which clinical features are pre-
sent and referred to other specialists as appropriate. In patients with
macroglossia, referral to a plastic surgeon for consideration for tongue
reduction is warranted, as approximately half of patients with mac-
roglossia in our cohort required a tongue reduction. Referral to a pulmo-
nologist for polysomnography is also warranted in patients with
macroglossia, as a high prevalence of obstructive sleep apnea (OSA) in
children with BWSp and macroglossia has been observed (Cielo, Duffy,
Taylor, Marcus, & Kalish, 2019). Patients with LO should be referred to
an orthopedist to evaluate for an associated leg length (Brioude et al.,
2018). Referrals to nephrology and/or urology may be warranted in
some patients, as renal and genitourinary issues have been reported in
patients with BWS (Goldman et al., 2002; Mussa et al., 2012; Tong
et al., 2017; Wong, Cuda, & Kirsch, 2011). Other referrals to specialists
should be made according to clinical features present. Cardiac and renal
evaluation is recommended to screen for congenital lesions (Brioude
14 DUFFY ET AL.

et al., 2018). While there are no specific developmental associations
with BWS, hyperinsulinism and prematurity can both cause delays so
developmental evaluation is recommended if there are any concerns.
Adult management is largely focused on specific clinical concerns and
genetic counseling regarding family planning, especially if the genetic
etiology is not known (Brioude et al., 2018). A recent study indicates
that early surgical management of BWS features including tongue
reduction, treatment of leg length difference, and orchiopexy are impor-
tant to prevent later complications (Gazzin et al., 2019). Further study is
warranted to improve recommendations for adult management.
Another challenging aspect of BWS is the best strategy to manage
partially discordant twins. Current recommendations include evaluat-
ing both twins for clinical features of BWS and testing the patients
with a clinical score of greater than 4 including at least one cardinal
feature (Cohen et al., 2019). Screening is currently recommended for
clinically affected twins but not for a twin without clinical features
unless molecular testing is positive in a tissue other than blood
(Cohen et al., 2019).
5|CONCLUSION
Although the BWS consensus scoring system was designed with the
goal to recognize BWS as a spectrum and aid in diagnosis, our results
suggest that this scoring system may benefit may from modifications
to improve its utility. Further delineation of the full spectrum suggests
the need for updating the scoring methodology especially for patients
presenting with hyperinsulinism or a tumor as more of these patients
may fall into the spectrum than previously considered.
ACKNOWLEDGMENTS
The authors thank the patients and their families for participating in
this study. Funding was provided by K08 CA193915, St Baldrick's
Foundation Scholar award and Alex's Lemonade Stand Foundation.
CONFLICT OF INTERESTS
The authors have no conflicts of interest relevant to this article to dis-
close. Author J.L.C. was a one-time consultant for Sobi, Inc.
ORCID
Jennifer M. Kalish https://orcid.org/0000-0003-1500-9713
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How to cite this article: Duffy KA, Cielo CM, Cohen JL, et al.
Characterization of the Beckwith-Wiedemann spectrum:
Diagnosis and management. Am J Med Genet Part C. 2019;
1–16. https://doi.org/10.1002/ajmg.c.31740
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