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Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma



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. Specifically, 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 recommendations 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 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
CCR Pediatric Oncology Series
Surveillance Recommendations for Children
with Overgrowth Syndromes and Predisposition
to Wilms Tumors and Hepatoblastoma
Jennifer M. Kalish
, Leslie Doros
, Lee J. Helman
, Raoul C. Hennekam
Roland P. Kuiper
, Saskia M. Maas
, Eamonn R. Maher
, Kim E. Nichols
Sharon E. Plon
, Christopher C. Porter
, Surya Rednam
, Kris Ann P. Schultz
Lisa J. States
, Gail E. Tomlinson
, Kristin Zelley
, and Todd E. Druley
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. Speci-
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 specic screening. Further study is
expected to lead to modications of these recommendations. Clin
Cancer Res; 23(13); e115e22. 2017 AACR.
See all articles in the online-only CCR Pediatric Oncology
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 identied 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-
withWiedemann 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 signicantly improves
Genetic Summary
BeckwithWiedemann syndrome (BWS) is a rare overgrowth
syndrome classically characterized by pre- and postnatal consti-
tutional and organ overgrowth, macroglossia, omphalocele/
umbilical hernia, facial nevus ammeus, 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 identied. Many cases of isolated
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.
Cancer Genetics Clinic, Children's National
Medical Center, Washington, DC.
Center for Cancer Research and Pediatric
Oncology Branch, National Cancer Institute, Rockville, Maryland.
of Pediatrics, University of Amsterdam, Amsterdam, the Netherlands.
axima Center for Pediatric Oncology, Utrecht, the Netherlands.
of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.
Department of Medical Genetics, University of Cambridge, and Cambridge
NIHR Biomedical Research Centre, Cambridge, United Kingdom.
Department of
Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
ment of Pediatrics/Hematology-Oncology, Baylor College of Medicine, Texas
Children's Hospital, Houston, Texas.
Department of Pediatrics, Emory Univer-
sity, Atlanta, Georgia.
Division of Cancer and Blood Disorders, Children's
Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.
Division of Radi-
ology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
of Pediatric Hematology-Oncology and Greehey Children's Cancer Research
Institute, The University of Texas Health Science Center at San Antonio, San
Antonio, Texas.
Division of Oncology, Children's Hospital of Philadelphia,
Philadelphia, Pennsylvania.
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:
doi: 10.1158/1078-0432.CCR-17-0710
2017 American Association for Cancer Research.
on August 28, 2017. © 2017 American Association for Cancer Research. Downloaded from
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-originspecic 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 specic genetic or epigenetic changes
are debated due to the differences in the acceptable risk and health
care cultures in which the guidelines are implemented (68).
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 specic 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 specic screening recommen-
dations at this time.
BohringOpitz 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 ssures,
depressed nasal bridge, anteverted nares, low-set and posteriorly
rotated ears, glabellar nevus ammeus, low anterior hairline),
microcephaly, forehead hirsutism, cleft lip and palate, retinal
abnormalities, exion anomalies of upper limbs with radial head
dislocation and ulnar deviation of ngers ("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, 1519). Thus, there is an increased tumor risk in patients with
BOS. Two patients presented with bilateral WT with conrmed
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 deciencies (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 brothecoma, 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, 2.23.7 years), renal papillary carcinoma (n¼3; median
age, 22.3 years; range, 1728 years), papillary thyroid carcino-
ma (n¼3; median age, 32.1; range, 2840 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 (2224). 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 (2224). 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 SimpsonGolabiBehmel
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 ndings 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), ve reports of liver tumors in children
(3438), and neuroblastoma (39). One case of medulloblastoma
in SGBS has been reported (40). Currently, there do not appear to
be specic genotypephenotype 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 rst 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 difculties,
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, DenysDrash Syn-
drome (DDS), and Frasier Syndrome (FS). WT1 encodes for a zinc
ngercontaining 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 signicant
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 genotypephenotype 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 signicantly 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 (5961). 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 (6365). 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 reect 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 specic tumor type,
where screening is minimally invasive and the outcome of early
detection for a specic tumor type offers signicant 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 specic 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 specic
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-specic 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 specied threshold. These guide-
lines were meant to be uniform across a tumor type, not tailored to
a specic syndrome or genetic etiology. However, it is important
to note that the eld of cancer genetics is learning that risk of a
specic 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)
BohringOptiz WT 6.9% 24 months (15)
Mulibrey nanism WT 6.7% 30 months (20)
Perlman WT 75% <24 months (96, 97)
SimpsonGolabiBehmel WT, HB 8% Undened (34, 98)
Trisomy 18 WT, HB >1% 68 months
Most 59y
(44, 99)
WAGR WT 50% 22 months
Most <8y
(5254, 100)
DenysDrash WT >90% 12 months
Most <3y
Frasier WT Several cases Undened (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 specic
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-specic 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 rst 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, 8183). 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 rst 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 50100 ng/mL) should
be further investigated, rst 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 signicantly 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
calcications, 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 Clin Cancer Res; 23(13) July 1, 2017 e119
on August 28, 2017. © 2017 American Association for Cancer Research. Downloaded from
enhancement and diffusion-weighted imaging. Contrast-
enhanced ultrasound using gas-lled 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. Inltration 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 difcult 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
stratied. 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.
In summary, we recommend specic 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 Conicts of Interest
S.E. Plon is a consultant/advisory board member for Baylor Genetics. No
potential conicts of interest were disclosed by the other authors.
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.
Syndromes and Predisposition to Wilms Tumors and
Surveillance Recommendations for Children with Overgrowth
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... (Maas et al., 2016). Unfortunately the authors misrepresented the advice on hepatoblastoma surveillance given for this subgroup by Kalish et al. (2017). Kalish et al. (2017) recommend abdominal ultrasounds (AUS) every 3 months until the 4th, rather than the 7th birthday. ...
... Unfortunately the authors misrepresented the advice on hepatoblastoma surveillance given for this subgroup by Kalish et al. (2017). Kalish et al. (2017) recommend abdominal ultrasounds (AUS) every 3 months until the 4th, rather than the 7th birthday. In addition, it is doubtful whether alpha-fetoprotein (AFP) measurements should be performed in this group, considering the updated recommendations by Brioude et al. (2018). ...
... [15][16][17][18][19][20][21] Due to this increased cancer risk, all patients with BWS are screened by liver ultrasound and serum α-fetoprotein (AFP) every 3 months from BWS diagnosis until four years of age. [22] BWS HB neoplasms may be different from those that arise sporadically in the nonsyndromic population. A meta-analysis of BWS HB cohorts observed that no individuals developed HB after 30 months of age. ...
... [23] All patients had their HB detected through increased AFP and/or a liver mass detected as part of the routine BWS tumor surveillance program. [22] Most of the tumors presented with a mixed fetal and embryonal histologic subtype (Table 1). In the present study, all patients who were affected by BWS HB were alive at last follow-up, with survival measured between 20 months to 15 years off therapy ( Table 1). ...
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Beckwith-Wiedemann Syndrome (BWS) is the most common human overgrowth disorder caused by structural and epigenetic changes to chromosome 11p15. Patients with BWS are predisposed to developing hepatoblastoma (HB). To better understand the mechanism of HB oncogenesis in this cancer predisposition background, we performed the first multi-dimensional study of HB samples collected from patients diagnosed with BWS. This multi-omic investigation of seven BWS HB and five matched nontumor BWS liver samples from 7 unique patients included examination of whole exome sequences, messenger RNA/microRNA expression, and methylation levels to elucidate the genomic, transcriptomic, and epigenomic landscape of BWS-associated HB. We compared the transcriptional profiles of the BWS samples, both HB and nontumor, to that of control livers. Genes differentially expressed across BWS tissues were identified as BWS HB predisposition factors; this gene group included cell cycle regulators, chromatin organizers, and WNT, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT members. We also compared transcriptional changes associated with non-syndromic HB carrying BWS-like 11p15 alterations compared to those without, as well as to BWS HB. Through this analysis, we identified factors specific to 11p15-altered HB oncogenesis, termed the BWS oncogenesis network. We propose that 11p15 alterations drive HB oncogenesis by initially dysregulating cell-cycle regulators and chromatin organizers, including histone deacetylase 1 (HDAC1), ATP-dependent helicase X, and F-Box and WD repeat domain containing 7. Furthermore, we found oncogenic factors such as dickkopf WNT signaling pathway inhibitor 1 and 4, WNT16, forkhead box O3 (FOXO3), and MAPK10 are differentially expressed in 11p15-altered HB in both the BWS and non-syndromic backgrounds. These genes warrant further investigation as diagnostic or therapeutic targets.
... Epidemiological data are limited, however a steady increase of 4.3% per year between 1992 and 2004 has been documented in children younger than 19 years. 2 This trend seems to continue into recent literature. Feng et al illustrate an annual percentage increase of 2.2% between 2000 and 2015. 2 Various explanations have been proposed: cases may be revealed by screening young children with the genetic propensity to develop HB, using abdominal ultrasound and alpha feto-protein (AFP) serology; 3,4 another likely contributor is the tremendous advance in neonatal medicine, improving the survival of infants who bear dual risk factors for HB development, prematurity and very low birth weight of <1500g. 1 A tumor of embryonal origin, HB, recapitulates the hepatic development of fetal life. 5 Its striking heterogeneity can be explained by its origin, arising from the aberrant division of both primary hepatoblasts and human fetal liver multipotent progenitor cells. ...
... In such circumstances, imaging should be taken in the clinical context of serum AFP levels, which fall post-treatment and tend to rise with recurrence and repetitive CT surveillance. 3,13,18 ...
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Hepatoblastoma (HB) is the most common malignancy within the rare cohort of pediatric primary liver tumors. It may arise sporadically or in association with germline mutations in specific genetic syndromes. Histogenesis recapitulates fetal hepatic development, however, this tumor can exhibit a markedly heterogeneous appearance both macroscopically and under the microscope. Histologic subtypes are classified based on morphologic appearance, with additional discrimination based on emerging molecular and immunohistochemical features. Numerous diagnostic pitfalls exist from clinical presentation through to ancillary testing; at all stages, the surgical pathologist must be discerning and open to collaboration with colleagues of different specialties. Problematic areas include the adequacy of tissue sampling, correlation of histology with radiologic appearance and alpha feto-protein (AFP) serology, forming a diagnostic consensus within the pediatric pathology community and choosing a shrewd immunohistochemical panel. This review discusses the sequence of events leading up to histologic assessment, and the nuances of microscopic evaluation. Along the way, pitfalls are highlighted, providing a tool for the surgical pathologists to support their individual approach.
... Hepatoblastoma (HB) is an embryonic liver malignant tumor, characterized by high-grade malignancy, rapid recurrence and metastasis and poor prognosis (Kalish et al. 2017;Sharma et al. 2017). At present, chemoradiotherapy in combination with surgical resection is the most common and effective treatment for HB (Trobaugh-Lotrario Katzenstein 2012). ...
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Hepatoblastoma (HB) is a common primary liver malignant tumor in children. Long non-coding RNAs (lncRNAs) are closely engaged in HB progression. The role and regulatory molecule mechanism of lncRNA small nucleolar RNA host gene 1 (SNHG1) in HB remain unclear. Through qRT-PCR or western blot, we found that SNHG1 and proviral integration site for moloney murine leukemia virus 3 (PIM3) were elevated but miR-6838-5p was decreased in HB cells. Cell biology experiments revealed that SNHG1 depletion or miR-6838-5p upregulation suppressed cell proliferation, migration, and invasion of HB cells. Mechanistically, luciferase activity assay validated that miR-6838-5p could interact with SNHG1 or PIM3. SNHG1 up-regulated PIM3 expression via sponging miR-6838-5p. Moreover, miR-6838-5p inhibitor abolished SNHG1 depletion-mediated suppression of malignant behaviors in HB cells. PIM3 overexpression neutralized miR-6838-5p mimics-mediated repression of malignant phenotypes in HB cells. Furthermore, miR-6838-5p overexpression suppressed RhoA activation, which was restored by PIM3 upregulation. What’s more, the results at the cellular level were further verified by nude mice tumor formation experiment. In conclusion, SNHG1 regulated miR-6838-5p/PIM3/RhoA axis to promote malignant phenotypes of HB, which might provide novel therapeutic target for HB treatment.
... and after testicular cancer treatment, ultrasound is valuable in monitoring the remaining testis.In conjunction with tumor markers, ultrasound is used to monitor for hepatoblastoma recurrence. Similarly, ultrasound is useful in patients with cancer predisposition syndromes or other conditions for routine surveillance.[24][25][26] Ultrasound is the primary modality for monitoring patients with Beckwith-Wiedemann syndrome for renal and liver tumors, Denys-Drash and von Hippel-Lindau syndrome patients for renal tumors, patients with multiple endocrine neoplasia syndrome, and patients with DICER 1 mutations for thyroid and other cancers.Patients with Li-Fraumeni syndrome are predisposed to develop a variety of tumors and also have greater sensitivity to the effects of ionizing radiation, making ultrasound (and MRI) especially valuable for their CT is a noninvasive cross-sectional imaging modality, utilizing ionizing radiation and cutting-edge computer reconstruction algorithms, which can rapidly create detailed multiplanar images of the body from the acquired volume data set. ...
Diagnostic imaging is essential in the diagnosis and management, including surveillance, of known or suspected cancer in children. The independent and combined roles of the various modalities, consisting of radiography, fluoroscopy, ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine (NM), are both prescribed through protocols but also function in caring for complications that may occur during or subsequent to treatment such as infection, bleeding, or organ compromise. Use of a specific imaging modality may be based on situational circumstances such as a brain CT or MR for a new onset seizure, chest CT for respiratory signs or symptoms, or US for gross hematuria. However, in many situations, there are competing choices that do not easily lend themselves to a formulaic approach as options; these situations depend on the contributions of a variety of factors based on a combination of the clinical scenario and the strengths and limitations of the imaging modalities. Therefore, an improved understanding of the potential influence of the imaging decision pathways in pediatric cancer care can come from comparison among the individual diagnostic imaging modalities. The purpose of the following material to is to provide such a comparison. To do this, pediatric imaging content experts for the individual modalities of radiography and fluoroscopy, US, CT, MRI, and NM will discuss the individual modality strengths and limitations.
... In addition, a prominent 'undiagnosed' population includes patients with features of BWS, who have neither received molecular confirmation of this diagnosis nor met the full clinical criteria (Brioude et al. 2018) (12 patients; 10.1% of undiagnosed). Many families in which this diagnosis is being considered elect to follow-up in the ECC for preventive tumor screening for Wilms' tumor and hepatoblastoma due to the increased risk of developing these types of tumors in the setting of BWS or other forms of hemihyperplasia (Brioude et al. 2018;Kalish et al. 2017). However, it is unclear how many may ultimately be diagnosed with BWS or another epigenetic condition. ...
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The multidisciplinary Epigenetics and Chromatin Clinic at Johns Hopkins provides comprehensive medical care for individuals with rare disorders that involve disrupted epigenetics. Initially centered on classical imprinting disorders, the focus shifted to the rapidly emerging group of genetic disorders resulting from pathogenic germline variants in epigenetic machinery genes. These are collectively called the Mendelian disorders of the epigenetic machinery (MDEMs), or more broadly, Chromatinopathies. In five years, 741 clinic visits have been completed for 432 individual patients, with 153 having confirmed epigenetic diagnoses. Of these, 115 individuals have one of 26 MDEMs with every single one exhibiting global developmental delay and/or intellectual disability. This supports prior observations that intellectual disability is the most common phenotypic feature of MDEMs. Additional common phenotypes in our clinic include growth abnormalities and neurodevelopmental issues, particularly hypotonia, attention-deficit/hyperactivity disorder (ADHD), and anxiety, with seizures and autism being less common. Overall, our patient population is representative of the broader group of MDEMs and includes mostly autosomal dominant disorders impacting writers more so than erasers, readers, and remodelers of chromatin marks. There is an increased representation of dual function components with a reader and an enzymatic domain. As expected, diagnoses were made mostly by sequencing but were aided in some cases by DNA methylation profiling. Our clinic has helped to facilitate the discovery of two new disorders, and our providers are actively developing and implementing novel therapeutic strategies for MDEMs. These data and our high follow-up rate of over 60% suggest that we are achieving our mission to diagnose, learn from, and provide optimal care for our patients with disrupted epigenetics.
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Beckwith-Wiedemann syndrome (BWS) is a pediatric overgrowth disorder which predisposes to tumor development.The following case study examined a prenatal finding of omphalocele with postnatal findings of macroglossia and cutaneous hemangioma, ultimately leading to a diagnosis of BWS.This case highlighted the features of BWS, the diagnostic principles and the importance of a multidisciplinary team approach to its management.
Purpose of review: Childhood cancer is rare, but it remains the leading cause of disease-related mortality among children 1-14 years of age. As exposure to environmental factors is lower in children, inherited genetic factors become an important player in the cause of childhood cancer. This review highlights the current knowledge and approach for cancer predisposition syndromes in children. Recent findings: Current literature suggests that 10-18% of paediatric cancer patients have an underlying genetic susceptibility to their disease. With better knowledge and technology, more genes and syndromes are being discovered, allowing tailored treatment and surveillance for the probands and their families.Studies have demonstrated that focused surveillance can detect early malignancies and increase overall survival in several cancer predisposition syndromes. Various approaches have been proposed to refine early tumour detection strategies while minimizing the burden on patients and families. Newer therapeutic strategies are being investigated to treat, or even prevent, tumours in children with cancer predisposition. Summary: This review summarizes the current knowledge about different cancer predisposition syndromes, focusing on the diagnosis, genetic counselling, surveillance and future directions.
Incidental liver lesions are identified in children without underlying liver disease or increased risk of hepatic malignancy in childhood. Clinical and imaging evaluation of incidental liver lesions can be complex and may require a multidisciplinary approach. This review aims to summarize the diagnostic process and follow-up of incidental liver lesions based on review of the literature, use of state-of-the-art imaging, and our institutional experience. Age at presentation, gender, alpha fetoprotein levels, tumor size, and imaging characteristics should all be taken into consideration to optimize diagnosis process. Some lesions, such as simple liver cyst, infantile hemangioma, focal nodular hyperplasia (FNH) and focal fatty lesions, have specific imaging characteristics. Recently, contrast-enhanced ultrasound (CEUS) was FDA-approved for the evaluation of pediatric liver lesions. CEUS is most specific in lesions smaller than 3 cm and is most useful in the diagnosis of infantile hemangioma, FNH, and focal fatty lesions. The use of hepatobiliary contrast in MRI increases specificity in the diagnosis of FNH. Recently, lesion characteristics in MRI were found to correlate with subtypes of hepatocellular adenomas and associated risk for hemorrhage and malignant transformation. Biopsy should be considered when there are no specific imaging characteristics of a benign lesion. Surveillance with imaging and AFP should be performed to confirm the stability of lesions when the diagnosis cannot be determined, and when biopsy is not feasible.
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Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li–Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop. Clin Cancer Res; 23(13); e98–e106. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.
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Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (APC and MUTYH), juvenile polyposis coli (BMPR1A and SMAD4), Peutz–Jeghers Syndrome (STK11/LKB1), and PTEN hamartoma tumor syndrome (PHTS; PTEN), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107–e14. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.
Mutations in the WT1 gene ere anticipated to explain the genetic basis of the childhood kidney cancer, Wilms' tumour (WT). Six years on, we revie 100 reports of intragenic WT1 mutations and examine the accompanying clinical phenotypes. While only 5% of sporadic Wilms' tumours have intragenic WT1 mutations, > 90% of patients with the Denys-Drash syndrome (renal nephropathy, gonadal anomaly, predisposition to WT) carry constitutional intragenic WT1 mutations. WT1 mutations have also been reported in juvenile granulosa cell tumour, non-asbestos related mesothelioma, desmoplastic small round cell tumour and, most recently, acute myeloid leukemia. Hum Mutat 9:209–225, 1997. © 1997 Wiley-Liss, Inc.
As the understanding of the genetic etiology of childhood cancers increases, the need for the involvement of experts familiar with the provision of genetic counseling for this population is paramount. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in pediatric cancer predisposition met to establish surveillance guidelines for children with cancer predisposition. Identifying for whom, when, why, and how these cancer predisposition surveillance guidelines should be implemented is essential. Genetic counselors invited to this workshop provide a genetic counseling framework for oncology professionals in this article. Points of entry and recommendations regarding the provision and timing of the initial and subsequent genetic counseling sessions are addressed. The genetic counseling and testing processes are reviewed, and the psychologic impact related to surveillance is explored. Pediatric cancer genetics will continue to grow and evolve as a field, and genetic counseling services will be vital to ensure appropriate identification and management of at-risk children moving forward. Clin Cancer Res; 23(13); e91–e97. ©2017 AACR. See all articles in the online-only Pediatric Oncology Series.
PTEN hamartoma tumor syndrome (PHTS),DICER1syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years.DICER1syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord-stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended.Clin Cancer Res; 23(12); e76-e82. ©2017 AACRSee all articles in the online-onlyCCRPediatric Oncology Series.
In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83–e90. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.
Beckwith–Wiedemann syndrome (BWS) is one of the most common cancer predisposition disorders. As a result, BWS patients receive tumor screening as part of their clinical management. Until recently, this screening has been employed uniformly across all genetic and epigenetic causes of BWS, including the utilization of ultrasonography to detect abdominal tumors and alpha-fetoprotein (AFP) to detect hepatoblastoma. The advancements in our understanding of the genetics and epigenetics leading to BWS has evolved over time, and has led to the development of genotype/phenotype correlations. As tumor risk appears to correlate with genetic and epigenetic causes of BWS, several groups have proposed alterations to tumor screening protocols based on the etiology of BWS, with the elimination of AFP as a screening measure and the elimination of all screening measures in BWS patients with loss of methylation at the KCNQ1OT1:TSS-DMR 2 (IC2). There are many challenges to this suggestion, as IC2 patients may have additional factors that contribute to risk of hepatoblastoma including fetal growth patterns, relationship with assisted reproductive technologies, and the regulation of the IC2 locus.
Simpson–Golabi–Behmel syndrome is an X-linked recessive overgrowth condition caused by alterations in GPC3 gene, encoding for the cell surface receptor glypican 3, whose clinical manifestations in affected males are well known. Conversely, there is little information regarding affected females, with very few reported cases, and a clinical definition of this phenotype is still lacking. In the present report we describe an additional case, the first to receive a primary molecular diagnosis based on strong clinical suspicion. Possible explanations for full clinical expression of X-linked recessive conditions in females include several mechanisms, such as skewed X inactivation or homozygosity/compound heterozygosity of the causal mutation. Both of these were excluded in our case. Given that the possibility of full expression of SGBS in females is now firmly established, we recommend that GPC3 analysis be performed in all suggestive female cases.