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CCR Pediatric Oncology Series
Surveillance Recommendations for Children
with Overgrowth Syndromes and Predisposition
to Wilms Tumors and Hepatoblastoma
Jennifer M. Kalish
1
, Leslie Doros
2
, Lee J. Helman
3
, Raoul C. Hennekam
4
,
Roland P. Kuiper
5
, Saskia M. Maas
6
, Eamonn R. Maher
7
, Kim E. Nichols
8
,
Sharon E. Plon
9
, Christopher C. Porter
10
, Surya Rednam
9
, Kris Ann P. Schultz
11
,
Lisa J. States
12
, Gail E. Tomlinson
13
, Kristin Zelley
14
, and Todd E. Druley
15
Abstract
A number of genetic syndromes have been linked to increased
risk for Wilms tumor (WT), hepatoblastoma (HB), and other
embryonal tumors. Here, we outline these rare syndromes with at
least a 1% risk to develop these tumors and recommend uniform
tumor screening recommendations for North America. Specifi-
cally, for syndromes with increased risk for WT, we recommend
renal ultrasounds every 3 months from birth (or the time of
diagnosis) through the seventh birthday. For HB, we recommend
screening with full abdominal ultrasound and alpha-fetoprotein
serum measurements every 3 months from birth (or the time of
diagnosis) through the fourth birthday. We recommend that
when possible, these patients be evaluated and monitored by
cancer predisposition specialists. At this time, these recommenda-
tions are not based on the differential risk between different
genetic or epigenetic causes for each syndrome, which some
European centers have implemented. This differentiated approach
largely represents distinct practice environments between the
United States and Europe, and these guidelines are designed to
be a broad framework within which physicians and families can
work together to implement specific screening. Further study is
expected to lead to modifications of these recommendations. Clin
Cancer Res; 23(13); e115–e22. 2017 AACR.
See all articles in the online-only CCR Pediatric Oncology
Series.
Introduction
Overgrowth syndromes represent a heterogeneous group of
disorders that result in differing presentations based on the
developmental pathways and organ systems affected. Renal
tumors, typically Wilms tumors (WT), are reported in a number
of these disorders with variable frequencies ranging from 1% to
90%. Clinically identified malformations and syndromes account
for almost 18% of WT (1). In addition, several syndromes have an
increased risk for hepatoblastoma (HB). Previously, screening
guidelines have been largely based on those developed for Beck-
with–Wiedemann syndrome (BWS) and WT1-related disorders.
As part of the 2016 AACR Childhood Cancer Predisposition
Workshop, an international committee of geneticists, oncologists,
radiologists, and genetic counselors reviewed and made recom-
mendations for the management of children with the syndrome-
associated WT and other tumors present in these syndromes, and
offered recommendations for tumor screening based on current
published data and clinical practice. These recommendations
were designed to be uniform for each tumor type being screened
and to offer screening in cases with a 1% or greater risk when early
detection is minimally invasive and significantly improves
outcome.
Genetic Summary
Beckwith–Wiedemann syndrome (BWS) is a rare overgrowth
syndrome classically characterized by pre- and postnatal consti-
tutional and organ overgrowth, macroglossia, omphalocele/
umbilical hernia, facial nevus flammeus, hemihyperplasia, and
embryonal tumors (2). WT and HB are the most common tumor
types reported; however, additional tumors have been reported,
including neuroblastoma, rhabdomyosarcoma, pheochromocy-
toma, and adrenocortical carcinoma (3). Most cases of BWS
are mosaic, and clinical features typically vary between patients
with rare familial forms identified. Many cases of isolated
1
Division of Human Genetics, Children's Hospital of Philadelphia and the Depart-
ment of Pediatrics at the Perelman School of Medicine, University of Pennsyl-
vania, Philadelphia, Pennsylvania.
2
Cancer Genetics Clinic, Children's National
Medical Center, Washington, DC.
3
Center for Cancer Research and Pediatric
Oncology Branch, National Cancer Institute, Rockville, Maryland.
4
Department
of Pediatrics, University of Amsterdam, Amsterdam, the Netherlands.
5
Princess
M
axima Center for Pediatric Oncology, Utrecht, the Netherlands.
6
Department
of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.
7
Department of Medical Genetics, University of Cambridge, and Cambridge
NIHR Biomedical Research Centre, Cambridge, United Kingdom.
8
Department of
Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
9
Depart-
ment of Pediatrics/Hematology-Oncology, Baylor College of Medicine, Texas
Children's Hospital, Houston, Texas.
10
Department of Pediatrics, Emory Univer-
sity, Atlanta, Georgia.
11
Division of Cancer and Blood Disorders, Children's
Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.
12
Division of Radi-
ology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
13
Division
of Pediatric Hematology-Oncology and Greehey Children's Cancer Research
Institute, The University of Texas Health Science Center at San Antonio, San
Antonio, Texas.
14
Division of Oncology, Children's Hospital of Philadelphia,
Philadelphia, Pennsylvania.
15
Division of Pediatric Hematology and Oncology,
Washington University, St. Louis, Missouri.
Corresponding Author: Jennifer M. Kalish, Children's Hospital of Philadelphia,
3501 Civic Center Boulevard, CTRB Room 3028, Philadelphia, PA 19104. Phone:
215-590-1278; Fax: 267-425-7499; E-mail: kalishj@email.chop.edu
doi: 10.1158/1078-0432.CCR-17-0710
2017 American Association for Cancer Research.
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hemihyperplasia (IHH) are considered a more subtle presenta-
tion of BWS leading to a spectrum of features due to a variety of
structural, genetic, or epigenetic abnormalities localized to chro-
mosome 11, termed the "11p Overgrowth Spectrum." IHH can
have other non-11p causes as well. Several different clinical
scoring systems have been presented to clarify the clinical diag-
nosis of BWS (2, 4). The incidence of BWS is one in 10,500 births
(2), but with inclusion of the subtle cases with IHH, the incidence
is likely higher. BWS is caused by the dysregulation of growth
genes encoding both proteins and regulatory RNAs (H19, IGF2,
and CDKN1C) on chromosome 11p15 that are imprinted and,
therefore, normally expressed in a parent-of-origin–specific man-
ner. At least 85% of BWS cases are not inherited, and most are due
to epigenetic changes on chromosome 11p15, most commonly
gain of methylation at one imprinting control region, IC1 (H19/
IGF2:IG-DMR), or loss of methylation at a second imprinting
control region, IC2 (KCNQ1OT1:TSS-DMR). Paternal uniparental
isodisomy (pUPD11) for part or all of chromosome 11 (where
both copies of this region of chromosome 11 are derived from the
father) can also cause BWS. More rarely, mutations on the mater-
nally derived copy of CDKN1C, paternally inherited duplications
of the 11p15 region, or chromosomal rearrangements cause
hereditary BWS. Given the complexity of the genetics, we recom-
mend that any determination of recurrence risk for the parents or
adults with BWS or testing of relatives be performed by a genetics
health care professional.
Recent data from a large cohort of European patients with BWS
suggest there is a correlation between tumor risk and the genetic or
epigenetic cause of BWS, and it has been recommended that tumor
screening should be based on the genetic or epigenetic cause (3, 5).
Overall incidence of tumor risk is 5% to 10%, which represents an
averaged statistic, as risk in patients with gain of methylation at
IC1 was found to be 28%, whereas loss of methylation at IC2 was
2.6%, pUPD11 was 16%, and CDKN1C mutations was 6.7% (3).
Frequency of tumor type varies by genotype as well (3, 5). WT and
HB screening are recommended with abdominal/renal ultrasound
and alpha-fetoprotein (AFP) measurements. The frequency and
type of screening based on specific genetic or epigenetic changes
are debated due to the differences in the acceptable risk and health
care cultures in which the guidelines are implemented (6–8).
These factors and current data were discussed at length by the
international AACR workshop committee, and we acknowledge
that consequences of the present knowledge may lead to differ-
ences in guidelines in countries with different health cultures. In
the context of the United States, the committee recommends
uniform screening based on tumor type for which patients are at
risk, with the understanding that there is a need for continued
discussion and that future screening may be tailored based on
genetic cause and specific syndromes. Neuroblastoma screening is
recommended for patients with CDKN1C mutations with urine
catecholamines and chest radiographs, and those screening
recommendations are outlined in the article by Kamihara and
colleagues in this CCR Pediatric Oncology series (9). The incidence
of tumor types in BWS other than those noted above (i.e., WT and
HB) is not high enough to warrant specific screening recommen-
dations at this time.
Bohring–Opitz syndrome (BOS) is a rare genetic syndrome
characterized by severe growth and feeding problems, severe
developmental delay/intellectual disability, typical facial appear-
ance (trigonocephaly, retrognathia, prominent eyes with under-
developed supraorbital ridges, upslanting palpebral fissures,
depressed nasal bridge, anteverted nares, low-set and posteriorly
rotated ears, glabellar nevus flammeus, low anterior hairline),
microcephaly, forehead hirsutism, cleft lip and palate, retinal
abnormalities, flexion anomalies of upper limbs with radial head
dislocation and ulnar deviation of fingers ("BOS posture"), lower
limb anomalies, structural brain anomalies, and seizures (10–
15). About 40% of patients die in early childhood, typically from
unexplained bradycardia, obstructive apnea, or pulmonary infec-
tions. Hoischen noted that in those who survive past infancy,
distinctive facial features may fade over time (13). Females
outnumber males approximately 3:1, with no evidence for dif-
ference in viability (13).
Multiple studies have demonstrated the transforming capacity
of ASXL1 mutations, suggesting ASXL1 is a tumor-suppressor gene
(13, 15–19). Thus, there is an increased tumor risk in patients with
BOS. Two patients presented with bilateral WT with confirmed
ASXL1 mutations: one diagnosed at age 2 years and the other at
age 6 years. In the 43 cases reported by Russell and colleagues
(2015), two patients developed WT and one had nephroblasto-
matosis leading to a renal neoplasm incidence of 7% (15). The
small number of reported patients with BOS and high infant
mortality rate indicates that the true cancer risk may be higher
than reported. WT screening guidelines as used for BWS have
previously been recommended and the AACR workshop com-
mittee concurred with that recommendation (15).
Mulibrey (muscle, liver, brain, and eye) nanism is a rare,
autosomal recessive growth disorder with prenatal onset that
includes severe growth retardation, distinct dysmorphic features,
constrictive pericarditis, hepatomegaly, male infertility, insulin
resistance, and metabolic deficiencies (20, 21). Approximately
130 cases are known worldwide, with 89 originating from Finland
(20). Mulibrey nanism is caused by biallelic mutations in TRIM37
on chromosome 17q22.
Mulibrey nanism is associated with development of a wide
array of benign and malignant tumors. A systematic review
revealed a total of 210 tumors in 66 of the 89 (74%) reported
Finnish patients (21). Benign tumors included cysts within
various organs, peliosis of the liver, adrenal adenoma, para-
thyroid adenoma, thyroid nodules, pancreatic cystadenoma,
renal angiomyolipoma, ovarian fibrothecoma, pheochromocy-
toma, and central nervous system (CNS) Langerhans cell his-
tiocytosis (20). Thirteen (15%) of these patients developed
malignant tumors, including WT (n¼5; median age, 2.5 years;
range, 2.2–3.7 years), renal papillary carcinoma (n¼3; median
age, 22.3 years; range, 17–28 years), papillary thyroid carcino-
ma (n¼3; median age, 32.1; range, 28–40 years), and single
cases of medullary thyroid carcinoma, ovarian carcinoma,
endometrial carcinoma, and acute lymphoblastic leukemia
(20). On the basis of these results, screening for WT using
renal ultrasound was recommended by the AACR workshop
committee for children with Mulibrey nanism. Screening for
renal, thyroid, ovarian, and endometrial carcinomas could also
be considered for affected adults.
Perlman syndrome is a rare congenital overgrowth syndrome
inherited as an autosomal recessive trait (22–24). Characteristic
features include polyhydramnios, macrosomia, characteristic
facial dysmorphology (broad depressed nasal bridge, everted V-
shape upper lip, low-set ears, deep-set eyes, and prominent
forehead), renal dysplasia and nephroblastomatosis, and multi-
ple congenital anomalies. Fifty-three percent of children with
Perlman syndrome die in the neonatal period from a variety of
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causes including renal failure, hypoxia, and pulmonary hypopla-
sia (22–24). The kidneys show nephroblastomatosis in about
75% of cases (25). In those that survive the neonatal period,
developmental delay is common and most patients appear to
develop WT. On average, WT occurs at an early age (<2 years
compared with 3 to 4 years in sporadic WT), and bilateral WT are
common (55%; refs. 22, 24, 26).
Perlman syndrome may be differentiated from other congenital
overgrowth disorders such as BWS and Simpson–Golabi–Behmel
syndrome (SGBS) by the presence of features including fetal
ascites and characteristic facial dysmorphism in the absence of
macroglossia, anterior abdominal wall defects, polydactyly, and
other features. In addition, a molecular diagnosis of Perlman
syndrome can be made by the presence of inactivating mutations
in DIS3L2 on chromosome 2q37.1, whose product has been
implicated in miRNA degradation (27, 28). In view of the high
risk of WT, it has been suggested that children affected with
Perlman syndrome should be offered regular surveillance similar
to that for children with BWS (29).
SGBS is characterized by pre- and postnatal macrosomia, dis-
tinctive craniofacies (including macrocephaly, coarse facial fea-
tures, macrostomia, macroglossia, palatal abnormalities), and
commonly, mild-to-severe intellectual disability with or without
structural brain anomalies. Other variable findings include super-
numerary nipples,diastasis recti/umbilicalhernia, congenital heart
defects, diaphragmatic hernia, genitourinary defects, and gastro-
intestinal (GI) anomalies. Skeletal anomalies can include vertebral
fusion, scoliosis, rib anomalies, and congenital hip dislocation.
Hand anomalies can include large hands and postaxial polydac-
tyly. Physical features distinguishing SGBS from BWS are ocular
hypertelorism, a large mouth, coarse facial features, supernumer-
ary nipples, and persistent overgrowth throughout life.
SGBS is X-linked and caused by mutation or deletion of the
glypican genes GPC3 (30) or GPC4 (31). Although SGBS is
X-linked and generally restricted to males, the SGBS phenotype
has been observed in females (32, 33).
Tumor types seen in SGBS include multiple reports of WT and
nephroblastomatosis (34), five reports of liver tumors in children
(34–38), and neuroblastoma (39). One case of medulloblastoma
in SGBS has been reported (40). Currently, there do not appear to
be specific genotype–phenotype correlations, and deletions and
truncation mutations have been reported with and without tumor
development. Tumor screening similar to BWS screening has
previously been used in these patients (41). Some have also
suggested utilizing the b-HCG tumor marker due to previous
reports of germ cell tumors in SGBS; however, this is not a
widespread recommendation (35, 40). No screening recommen-
dations have been made for CNS tumors in SGBS.
Trisomy 18 (Edwards syndrome) is the second most common
constitutional chromosomal abnormality after trisomy 21, occur-
ring in 1:6,000 to 1:8,000 live births (42). Mosaic and partial
trisomy 18 also occur. Trisomy 18 is characterized by a variety of
major and minor malformations, growth retardation, psychomo-
tor delays, and intellectual disability (42, 43). Only 5% to 10% of
affected infants live past the first year, and the infants who survive
this period are at increased risk to develop benign and malignant
tumors (44). The high mortality rate is a result of many factors
including cardiac and renal malformations, feeding difficulties,
sepsis, and central apnea (45). Children with mosaic or partial
trisomy 18 have a higher life expectancy than the children with full
trisomy 18.
A systematic review found 45 malignancies in 56 patients,
mostly HB and WT (44). Nephroblastomatosis was also reported
in autopsies of infants with trisomy 18 who did not die from a WT
(46, 47). The risk for WT development is estimated to be approx-
imately 1% (48). Benign tumors, including cardiac and skin
tumors, have additionally been reported (44). The rate of cancer
in this population may be underestimated given the high infant
mortality rate observed. Cancer screening for trisomy 18 is con-
troversial given the poor prognosis and tendency to avoid surgery
and other invasive procedures. The AACR workshop committee
recommendations are outlined below.
WT1-related syndromes include WAGR (WT, aniridia, genito-
urinary abnormalities, retardation) syndrome, Denys–Drash Syn-
drome (DDS), and Frasier Syndrome (FS). WT1 encodes for a zinc
finger–containing protein with multiple isoforms (49, 50). This
protein acts as a transcription factor during development, regu-
lating cell growth and differentiation in the kidneys, gonads,
spleen, and mesothelium (49, 50). DDS and FS may represent
variations along a phenotypic spectrum (51). In all WT1-related
syndromes, inheritance is autosomal dominant, the penetrance is
mutation dependent, the expressivity is variable, and most muta-
tions are de novo.
WAGR syndrome is characterized by WT, aniridia, genitouri-
nary abnormalities, and intellectual disability (41). A significant
risk of nephropathy also exists (52). This constellation of features
is due to contiguous gene deletions in chromosome 11p13
including WT1, PAX6, and other genes. DDS is characterized by
WT, nephrotic syndrome (due to mesangial sclerosis), and ambig-
uous genitalia/gonadal dysgenesis (in affected individuals with
46,XY karyotype). The syndrome is predominantly caused by
missense mutations in exon 8 or 9 of WT1 (53, 54). FS is
characterized by focal segmental glomerulosclerosis and ambig-
uous genitalia/gonadal dysgenesis and risk of gonadoblastoma
(in affected individuals with 46,XY karyotype and dysgenetic
gonads). Mutations in the WT1 intron 9 donor splice site are
associated with this condition.
Overall, WT1 germline mutations (either somatic only or
inherited) are found in up to 11% of occurrences of WT (1, 55,
56). The median age of WT diagnosis is around 1 year of age in
WT1-affected individuals, about 2 to 3 years earlier than the age of
WT diagnosis in children without a germline WT1 mutation.
There have been reports of children with WT1 mutations devel-
oping WT up to 8 years of age (54). The risk of WT development
varies among the WT1-related syndromes. The risk of WT in
WAGR is approximately 50% (54). In DDS, it is greater than
90% (54). In FS, multiple cases of WT have been reported (54).
Several other genotype–phenotype correlations relevant to WT
risk have also been reported. The greatest risk for WT may be
related to truncating mutations in the exon 8/9 hotspot (57, 58).
Furthermore, the risk of bilateral WT is significantly greater with
truncating mutations than with missense mutations (57, 58).
WT1-related gonadoblastoma occurs in the context of disor-
dered sexual development in FS or DDS individuals with 46,XY
karotype. In these patients, the gonadoblastoma appears to be
directly related to the presence of gonadal dysgenesis and is
equally likely to occur in both FS and DDS, with an estimated
risk level greater than 40% (58, 59). Although most gonadoblas-
tomas develop in adolescents or young adults, occurrences in
children as young as infants have been described (59–61). The risk
of gonadoblastoma is low when the sex matches the karyotype
(58). However, an evaluation for gonadal dysgenesis is indicated
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in patients with karyotype 46,XY, and if present, gonadectomy is
generally recommended. Management of gonadoblastoma risk in
individuals with suspected gonadal dysgenesis per recent evi-
dence-based guidelines detailed elsewhere is recommended
(62). These guidelines encompass the initial evaluation for
gonadal dysgenesis (including hormonal assessment and imag-
ing) and considerations for the timing of gonadectomy. The AACR
workshop committee recommendations are discussed below.
Additional causes of WT include the presence of somatic
chromosome copy-number changes affecting chromosome
2q37 and for the MYCN gene at 2p24.3 (63–65). Germline
changes at these loci have also been reported in patients present-
ing with WT, and, therefore, WT risk should also be considered in
patients with germline MYCN copy-number gains (2p24.3) or
2q37 microdeletions (66, 67). The incidence of patients with these
genetic changes is rare, and the actual incidence of WT in these
populations needs further study. DICER1 mutations have also
been linked to WT, and further discussion of DICER1 can be found
in the article by Schultz and colleagues (68) in this series. Mosaic
variegated aneuploidy is another rare recessive set of disorders in
which WT has been reported in multiple patients (54).
There are several other overgrowth syndromes, including
PIK3CA-related overgrowth spectrum, Sotos syndrome, and
Weaver syndrome, for which incidental cases of cancer have been
reported. However, with cancer risk estimates below 1%, cancer
screening is not recommended. Weaver and Sotos syndromes are
discussed in the article by Villani and colleagues (69) in this series.
Cancer Screening/Surveillance Protocols
The AACR workshop recommendations reflect the health care
culture in North America and may differ from that of other parts of
the world. For instance, WT screening is recommended in North
America based on an acceptable risk model of 1% for all syn-
dromes as listed in Table 1. However, in Europe, a threshold of 2%
is typically used. These recommendations are based on the advan-
tage of having a consistent, inclusive, universal protocol that can
be effectively applied to all patients for a specific tumor type,
where screening is minimally invasive and the outcome of early
detection for a specific tumor type offers significant improvement
in morbidity and mortality. We acknowledge that uniform recom-
mendations may result in some patients being screened more
frequently and for a longer duration than some clinicians have
previously determined to be necessary. Therefore, these recom-
mendations should be discussed with each family, and the family
needs to be counseled in the context of their specific syndrome and
the tumor risk in their case by physicians and/or genetic counse-
lors' knowledgeable on this topic [see article by Druker and
colleagues in this series (70)]. Surveillance can be further tailored
on the basis of the disorder and knowledge regarding the specific
characteristics of the tumors that occur in the syndrome, especially
as the burden that accompanies any surveillance scheme is per-
ceived differently in some European countries.
Developing guidelines for tumor screening is challenging and
needs to take into account current data available for tumor risk
and the medical and societal context in which the screening is
being implemented. Although there is emerging evidence of
different cancer risks based on genetic or epigenetic subgroups
for certain syndromes, and several European countries now use
subgroup-specific recommendations for WT screening particular-
ly in BWS, these practices have not yet been adopted in the United
States. Thus, recommendations are likely to continue to evolve
over time. Furthermore, age ranges of tumor risk may vary
between syndromic versus sporadic causes of WT. However, to
simplify these screening recommendations, our AACR workshop
committee proposes a uniform screening approach for all syn-
dromes with a risk of WT greater than 1%. Additional screening for
HB by serum AFP measurement is recommended in BWS, trisomy
18, and SGBS.
These recommendations are based on screening that will lead to
earlier stage tumor detection (71, 72) and have been designed to
cover the age range in which 90% to 95% of tumors will present
(41). The interval of WT screening is based on the increased risk of
interval tumor development when screening is spaced beyond 4
months (73). As the rate of tumor growth is expected to be the
same regardless of age, the recommended frequency of screening
does not change as the patient ages. As further data are collected
and with improved access to and understanding of genetic testing
by both families and physicians, screening recommendations in
the future will likely evolve to incorporate distinctions based on
genetic causes of each syndrome and between different syndromic
causes of WT and HB.
The goal of the AACR workshop was to present screening
recommendations based on tumor type when the risk for a tumor
within a syndrome was above a specified threshold. These guide-
lines were meant to be uniform across a tumor type, not tailored to
a specific syndrome or genetic etiology. However, it is important
to note that the field of cancer genetics is learning that risk of a
specific tumor type varies by underlying syndrome, and even by
genetic cause within the same syndrome; therefore, additional
guidelines will be needed in the future to diversify screening based
on syndrome and genetic cause.
Table 1. WT risk associated with different overgrowth syndromes
Syndrome Recommended screening Risk of WT Median age of WT occurrence References
BWS WT, HB 4.1% 24 months (3, 5)
Hemihypertrophy WT, HB 3%–4% 37 months (83)
Bohring–Optiz WT 6.9% 24 months (15)
Mulibrey nanism WT 6.7% 30 months (20)
Perlman WT 75% <24 months (96, 97)
Simpson–Golabi–Behmel WT, HB 8% Undefined (34, 98)
Trisomy 18 WT, HB >1% 68 months
Most 5–9y
(44, 99)
WAGR WT 50% 22 months
Most <8y
(52–54, 100)
Denys–Drash WT >90% 12 months
Most <3y
(101)
Frasier WT Several cases Undefined (102)
Abbreviation: y, years.
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WT screening
The mean age from a large meta-analysis for WT diagnosis in
BWS is 24 months (3), and most will occur prior to age 4 years.
However, limited published data exist regarding the development
of WT in the 4- to 7-year age range. A combined study of 324
patients with WT and either BWS or IHH showed that 69% of WT
occurred prior to age 4 years, 81% before age 5 years, 87% before
age 6 years, and 93% prior to age 8 years (74). This cohort
represents a mixture of BWS and IHH patients with WT, and
molecular data were not provided. Therefore, it may be that causes
other than the 11p Overgrowth Spectrum were present in these
cohort participants and could be responsible for WT occurrence
after 4 years of age. Regardless, these data demonstrate that a range
of age distribution exists in patients with WT and a phenotype of
BWS and IHH, including a small but measurable percentage up to
the age of 8 years. These data are not included in the recent meta-
analyses due to the absence of molecular data (3, 5). It remains
challenging to determine the age to stop screening, because the age
of tumor formation does not follow a normal distribution based
on the median age of onset. As seen with neuroblastoma,
although the median age may be 2 years, 98% of tumors occur
before age 10 years, and, therefore, screening is recommended
until 10 years, as discussed in the article by Kamihara and
colleagues in this series (9). Taken together, these data suggest
that screening for WT should continue through age 6 to 7 years,
with more data needed to be collected to determine the exact age at
which to end screening.
For WT, starting at birth (or the time of diagnosis of the specific
syndrome), we recommend renal ultrasound screening including
the adrenal glands every 3 months through the child's seventh
birthday. For syndromes in which HB is also a risk (BWS/IHH,
trisomy 18, SGBS), full abdominal ultrasound instead of renal-
only ultrasound is recommended every 3 months through the
child's fourth birthday. After the fourth birthday, these patients
can be monitored with renal ultrasound every 3 months until the
seventh birthday. Physical examination by a specialist (geneticist
or pediatric oncologist) twice yearly is recommended and should
include ongoing education regarding tumor manifestations, rein-
forcing the rationale for screening and compliance with the
screening regimen, and other syndrome-specific manifestations.
HB screening
HB screening is recommended in BWS due to the increased
relative risk of 2,280 times that of the healthy population (75). For
HB in BWS, most HB occur within the first year, with the oldest
reported at 30 months (3); this suggests that HB screening could
start at birth and continue up to the fourth birthday. AFP screening
is sensitive for HB (76, 77) and can be used to distinguish
hemangiomas compared with HB detected by imaging
(78, 79). AFP elevation often precedes detection by ultrasound
(76, 80), as HB can grow rapidly and screening results in detection
at a lower stage (77, 81–83). Families appear to be comforted by
early diagnosis and regular medical checks (6), and HB detected at
earlier stages have better prognosis. Previous AFP interval screen-
ing recommendations have varied between 6 weeks and 3
months. In the general pediatric population, it has been recom-
mended that elevated AFPs be remeasured at 2- to 4-week intervals
to evaluate for pathologic causes of elevated AFP (84). In the BWS
population, AFP levels may be elevated above that in other
populations, but if a modest elevation is observed, repeat mea-
surements every 6 weeks have been recommended (85). These
recommendations are presented in the literature (2, 86), but no
systematic studies have demonstrated improved outcomes of 6
weeks versus 3 months in detecting HB. In some cases, more
frequent screening may be warranted (80).
For HB screening, we recommend full abdominal ultrasound
and simultaneous serum AFP screening every 3 months starting at
birth (or at the time of diagnosis) and continuing through the
child's fourth birthday for patients with BWS/IHH, trisomy 18,
and SGBS. The question of screening in the presence of familial
adenomatous polyposis is covered in the article by Achatz and
colleagues in this series (87). In monitoring AFP levels, the
individual value needs to be interpreted in the context of the
AFP trend over time, with an expectation of declining values
through infancy. Importantly, AFP results need to be interpreted
on the basis of normal BWS values, which tend to be elevated over
the first years of life compared with normal pediatric values (88–
90). AFP values also should be interpreted in the context of the
clinical picture, the age of the patient, and the most recent
imaging. In addition, interpretation should be done by, or in
consultation with, physicians familiar with AFP monitoring in
these syndromes, particularly geneticists and oncologists in cancer
predisposition programs. Small rises within the reference ranges
should not trigger additional testing, as these can be due to
intercurrent illness or other factors such as teething, which
emphasizes the importance of a good medical history taken at
the time AFP values are collected.
Large rises in AFP values (greater than 50–100 ng/mL) should
be further investigated, first with a repeat AFP in 6 weeks and a re-
examination of the most recent ultrasound imaging. Several
different intervals for repeat testing have been recommended in
a few reported cases, but it is unclear that repeating the AFP
measurement sooner than 6 weeks alters the clinical outcome
(80, 91). If two successive increases occur, further imaging by MRI
is recommended. In cases of significantly larger increases (greater
than 1,000 ng/mL), repeat testing to validate the value is recom-
mended, and if validated, one should proceed directly to addi-
tional imaging.
Radiologic considerations
Ultrasonography is the optimal screening tool used to detect a
mass in the liver or kidneys. It is widely available, lacks ionizing
radiation, and can be performed without sedation. Preparation
for an abdominal or renal ultrasound does not require fasting.
Ultrasonography has a high sensitivity for detecting hepatic
masses (92). The main diagnostic consideration in this pati-
ent population besides HB is infantile hepatic hemangioma,
a benign vascular neoplasm, seen with greater incidence in
BWS/IHH than the general population. Classic ultrasound fea-
tures of hemangioma include homogeneous echotexture, hyper
or hypoechoic, and increased peripheral vascularity on Doppler
interrogation. Hemangiomas can be solitary, multifocal, or dif-
fuse. Any atypical features such as lobulated margins, chunky
calcifications, heterogeneity indicating hemorrhage or necrosis, or
diminished vascularity raise the concern for HB, and correlation
with AFP should be performed (78, 79). In multifocal and diffuse
cases, the possibility of metastatic neuroblastoma should be
considered and an adrenal primary tumor should be excluded.
Patients with rising AFPs should be evaluated by MRI with a
hepatobiliary contrast agent or contrast-enhanced portal venous
phase CT. MRI is preferred due to the lack of ionizing radiation
and superior lesion characterization using multiphase contrast
Wilms Tumors and Hepatoblastoma Predisposition Surveillance
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enhancement and diffusion-weighted imaging. Contrast-
enhanced ultrasound using gas-filled microbubbles is an emerg-
ing tool used to evaluate liver lesions (93). An IV is required for
administration of the contrast agent, but sedation is not required.
Surgical considerations
In syndromic WT, given the increased recurrence risk in the
ipsilateral or contralateral kidney, nephron-sparing surgery is
recommended if possible (94). MRI is considered the ideal
imaging modality used for detection of multiple tumors and
nephrogenic rests and for preoperative evaluation in consider-
ation of partial nephrectomy. Infiltration of adjacent structures,
central location, tumor thrombus, tumor rupture, or collecting
system involvement are features that help the surgeon consider
whether a partial or complete nephrectomy is the correct choice
for the patient (95).
General considerations
Historically, most children with the disorders included in
this article were monitored by their general pediatricians and
only referred to oncology if a malignancy developed. Although
access to academic centers with multidisciplinary subspecialty
clinics may not always be practical or readily available, physi-
cians are encouraged to refer patients to such clinics if at all
possible. This heterogeneous group of rare disorders can dis-
play many subtle features with variable penetrance and is
accompanied by a rapidly expanding knowledge based on the
genetic, epigenetic, and therapeutic implications attendant
with each, making it very difficult for the general pediatrician
to stay abreast of the latest information. Once referred, screen-
ing can be performed locally, and the specialists can work with
the general pediatricians to manage any abnormal results and
the patients' ongoing screening.
Thus, critical imperatives in the surveillance of these conditions
are: (i) having longitudinal radiologic assessments performed by
the same group and evaluated by the same individuals (ideally
pediatric radiologists), and if warranted, (ii) having AFP values
performed in the same laboratory each time, as much as reason-
ably possible. Overall, outcomes for these patients will be opti-
mized by the longitudinal integration of clinical and research data
by groups providing uniform surveillance and intervention based
on the guidelines recommended herein.
In addition, in cases where a tumor develops, syndromic
patients should be considered in the context of both immediate
post-tumor screening and should return to pre-tumor screening
schedules once the initial post-tumor screening recommenda-
tions are completed. On the basis of current data, most of these
syndromes are not associated with an increased risk of adult-onset
cancers. Thus, as the child ages past the need for WT and HB
screening, there should be a discussion with the parents whether
further cancer screening is indicated.
Finally, as genetic and epigenetic understanding of the mech-
anism underlying tumor formation in these patients continues to
evolve, these screening recommendations are likely to be further
stratified. For those changes to occur, further discussion regarding
the role of "health care cultures," which includes determination of
acceptable risk, medical systems, and cultural context of medical
practice, needs to occur. This article is designed to providethe most
appropriate and broadest recommendations for this varied group
of patients susceptible to WT and HB. However, implementation
of these recommendations still falls to the individual physicians
within the medical environment and community in which they
practice. In addition, a critical part of the implementation of these
recommendations is the practitioner's discussion with the patient
and the patient's family regarding tumor screening.
Conclusions
In summary, we recommend specific WT and HB screening
guidelines for patients in the United States with genetic syn-
dromes that lead to a risk of 1% for these tumors. This screening
is recommended uniformly for all of these syndromes and should
be monitored by cancer predisposition experts whenever possible
and implemented in discussion with each patient and his or her
family. The next step to improve a patient-personalized screening
strategy for WT and HB will need to include collection of addi-
tional genetic and clinical outcome data to determine if screening
should be personalized based on genetic or epigenetic change for
many of the syndromes discussed above. As we implement these
screening programs in our pediatric communities, we will need to
continually reevaluate the effectiveness of these screening guide-
lines and adjust them as new information is collected.
Disclosure of Potential Conflicts of Interest
S.E. Plon is a consultant/advisory board member for Baylor Genetics. No
potential conflicts of interest were disclosed by the other authors.
Acknowledgments
The authors thank Kelly Duffy and Aesha Vyas for their technical support
in compilation of this article. In addition, the authors thank Matthew Deardorff
for insightful discussion and critical reading of this article.
Grant Support
This study was supported by NCI K08 CA1939915, Alex's Lemonade Stand
Foundation for Childhood Cancer, and St. Baldrick's Foundation (to J.M.
Kalish); European Research Council Advanced Researcher Award (to E.R.
Maher); and NCI 5P30CA054174-21 (to G.E. Tomlinson).
Received March 11, 2017; revised April 23, 2017; accepted May 9, 2017;
published online July 3, 2017.
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Jennifer M. Kalish, Leslie Doros, Lee J. Helman, et al.
Hepatoblastoma
Syndromes and Predisposition to Wilms Tumors and
Surveillance Recommendations for Children with Overgrowth
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