doi:10.1136/jmg.38.12.810
2001;38;810-819J. Med. Genet.
Megan P Hitchins, Philip Stanier, Michael A Preece and Gudrun E Moore
aetiology and candidate chromosomal regions
Silver-Russell syndrome: a dissection of the genetic
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Review article
Silver-Russell syndrome: a dissection of the
genetic aetiology and candidate chromosomal
regions
Megan P Hitchins, Philip Stanier, Michael A Preece, Gudrun E Moore
Abstract
The main features of Silver-Russell syn-
drome (SRS) are pre- and postnatal
growth restriction and a characteristic
small, triangular face. SRS is also accom-
panied by other dysmorphic features
including fifth finger clinodactyly and
skeletal asymmetry. The disorder is clini-
cally and genetically heterogeneous, and
various modes of inheritance and abnor-
malities involving chromosomes 7, 8, 15,
17, and 18 have been associated with SRS
and SRS-like cases. However, only chro-
mosomes 7 and 17 have been consistently
implicated in patients with a strict clinical
diagnosis of SRS. Two cases of balanced
translocations with breakpoints in
17q23.3-q25 and two cases with a
hemizygous deletion of the chorionic
somatomammatropin gene (CSH1) on
17q24.1 have been associated with SRS,
strongly implicating this region. Maternal
uniparental disomy for chromosome 7
(mUPD(7)) occurs in up to 10% of SRS
patients, with disruption of genomic im-
printing underlying the disease status in
these cases. Recently, two SRS patients
with a maternal duplication of 7p11.2-p13,
and a single proband with segmental
mUPD for the region 7q31-qter, were
described. These key patients define two
separate candidate regions for SRS on
both the p and q arms of chromosome 7.
Both the 7p11.2-p13 and 7q31-qter regions
are subject to genomic imprinting and the
homologous regions in the mouse are
associated with imprinted growth pheno-
types. This review provides an overview of
the genetics of SRS, and focuses on the
newly defined candidate regions on chro-
mosome 7. The analyses of imprinted
candidate genes within 7p11.2-p13 and
7q31-qter, and gene candidates on distal
17q, are discussed.
(J Med Genet 2001;38:810­819)
Keywords: Silver-Russell syndrome; imprinting;
mUPD(7); candidates
Table 1 Clinical features and their reported frequencies in SRS. and genetic subgroups of SRS. The percentage of SRS features in two separate groups of
SRS patients are listed.3 4
These figures could not be combined as certain clinical conditions were not examined consistently in both sets of patients. These
serve as a reference for the frequency of features observed in specific genetic categories of SRS patients mentioned in the text. Where the patient number is
small the frequencies are given as fractions, not percentages. Traits either not reported or not evaluated are blank. Non-SRS features apparent in the
SRS-like patients with abnormalities of chromosomes 18 and 8 are not included, but discussed in the text
Clinical feature
SRS
n=143
SRS
n=50
mUPD(7)
n=24
r(15)
n=2
t(17q25)
n=2
Deletion
CSH1
n=1
18+
mosaic
n=1
Deletion
(18p11)
n=1
Deletion
(8q11-13)
n=1
Major
Low birth weight (<-1 SD) 94% 94% 87.5% 2/2 2/2 1/1 1/1 1/1 1/1
Short stature (<-1 SD) 99% 86% 100% 2/2 2/2 1/1 1/1 0/1 1/1
Triangular face 79% >62% 29% 2/2 2/2 1/1 1/1 Atypical 1/1
Minor
Clinodactyly V 68% 56% 37.5% 2/2 2/2 0/1 0/1 1/1 1/1
Relative macrocephaly 64% 70% 71 % 0/2 2/2 1/1 1/1 0/1 0/1
Ear anomalies 53% 21% 0/2 2/2 0/1 1/1 Atypical 1/1
Skeletal asymmetry 51% 34% 45% 0/2 2/2 1/1 1/1 1/1 0/1
Brachydactyly V 48% 25% 0/2 0/2 0/1 0/1 0/1 0/1
Downward slanting corners of mouth 46% 0% 2/2 1/2 1/1 0/1 Atypical 0/1
Muscular hypotrophy/tonia 45% 12.5% 0/2 1/2 0/1 0/1 0/1 0/1
Motor/neuropsychological delay 37% 38% 23% 2/2 0/2 1/1 1/1 1/1 1/1
Irregular spacing of teeth 28% 4% 0/2 0/2 0/1 0/1 1/1 0/1
Simian crease 25% 0% 0/2 0/2 0/1 0/1 0/1 0/1
Squeaky voice 22% 4% 0/2 0/2 0/1 0/1 0/1 0/1
Syndactyly 19% 0% 0/2 1/2 0/1 0/1 1/1 0/1
Café au lait naevi 19% 4% 4% 1/2 0/2 0/1 0/1 1/1 0/1
Early or precocious puberty 13% 0% 0/1 0/1
Genital abnormalities 36% 1/2 0/2 1/2 1/1 1/1 0/1
Speech delay 20% 25% 1/1 0/1
Camptodactyly 22% 1/1 0/1
Feeding diYculties 56% 33% 1/1 1/1
References 3 4 51, 52, 59 19, 20 28, 29 35 13 17 18
J Med Genet 2001;38:810­819810
Department of Fetal
and Maternal
Medicine, Institute of
Reproductive and
Developmental
Biology, Faculty of
Medicine, Imperial
College,
Hammersmith
Hospital, Du Cane
Road, London
W12 0NN, UK
M P Hitchins
P Stanier
G E Moore
Division of
Biochemistry,
Endocrinology and
Metabolism, Institute
of Child Health,
University College
London, London, UK
M A Preece
Correspondence to:
Dr Hitchins,
m.hitchins@ic.ac.uk
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Silver-Russell syndrome (SRS) is a clinically
and genetically heterogeneous disorder of
growth with a spectrum of additional dysmor-
phic features. SRS may comprise diVerent dis-
orders with clinically similar phenotypes or
may result from disruption of diVerent compo-
nents of a single biochemical or endocrinologi-
cal pathway, in either case reflecting its genetic
heterogeneity. This review focuses on the influ-
ence of genomic imprinting in SRS and recent
progress in defining two candidate SRS regions
on both the p and q arms of chromosome 7.
The investigation of imprinted genes on
chromosome 7 and candidate genes from other
chromosomal locations are also discussed with
regard to their potential role in SRS.
Clinical features of Silver-Russell
syndrome
SRS is a congenital disorder characterised by
intrauterine and postnatal growth retardation
in association with a number of dysmorphic
features first described in 1953 by Silver et al1
and in 1954 by Russell.2
The syndrome is
clinically heterogeneous and diagnosis may be
subjective. Two recent reviews provide details
of the spectrum and frequency of the various
clinical manifestations of SRS in two large
groups of patients.3 4
Wollmann et al3
addition-
ally reviewed the growth characteristics of 386
SRS patients. Table 1 lists the clinical features
of SRS and their frequencies, as determined in
these two reviews.3 4
Low birth weight, short
stature resulting from postnatal growth retar-
dation, and a characteristic, small, triangular
face were observed in the vast majority of
patients. Clinodactyly of the fifth finger,
relative macrocephaly owing to sparing of cra-
nial growth, and facial, limb, or body asymme-
try were also frequently observed. Although no
strict diagnostic criteria for SRS have been
established, presence of the three major
features plus one or more of the minor
confirmatory features (such as clinodactyly or
asymmetry) are generally required for a
positive diagnosis.3­5
However, none of these
traits is absolute and there are a small number
of diagnosed SRS patients in whom a major
feature is absent, but several of the minor ones
are present. A recent novel observation is the
presence of bilateral camptodactyly with termi-
nal interphalangeal contractures in 10 of 31
classical SRS patients.4
Genetic heterogeneity
The majority of SRS cases are sporadic.5
How-
ever, in a review of 197 SRS probands, 19%
had more than one aVected person in the fam-
ily, providing evidence for a genetic cause.6
DiVerent modes of inheritance have also been
suggested on the basis of family histories, indi-
cating that SRS is genetically heterogeneous
(reviewed by Duncan et al6
). Autosomal reces-
sive transmission appears likely in several fami-
lies in which there is more than one aVected sib
but the parents are phenotypically normal.
Consanguinity between the normal parents in
four unrelated Arab families with two or more
SRS oVspring supports transmission of an
autosomal recessive mutation in these cases.7 8
Autosomal and X linked dominant inheritance
patterns have also been suggested in SRS.6 9 10
In their review, Duncan et al6
describe 23 fami-
lies with 38 SRS patients. In 17 of these, mul-
tiple maternal relatives either had full SRS or a
partial phenotype.6
Autosomal dominant in-
heritance, with intrafamilial variation in ex-
pression owing to incomplete penetrance or
gene pleiotropy is one possibility. Alternatively,
the primarily female transmission of this disor-
der in these families is suggestive of an X linked
dominant form. While paternal inheritance of
SRS has been described, no male to male
transmission has been documented.6 10
Hy-
pogonadism accompanying SRS in males may
be a factor in reducing male transmission of
SRS. Nevertheless, this means that X linked
dominant and autosomal dominant inherit-
ance patterns may be indistinguishable in these
families.6
In view of recent evidence to suggest
that genomic imprinting plays a role in certain
SRS patients,11
an imprinted mode of inherit-
ance may be invoked in some SRS families with
more than one aVected. Certainly the predomi-
nant maternal transmission of SRS is compat-
ible with a matrilineal mode of inheritance
owing to genomic imprinting.
Concordance for SRS in a pair of mono-
zygotic twins and discordance in dizygotic
twins lends some weight to a genetic basis for
this syndrome (reviewed by Duncan et al6
).
However, the report of a pair of monozygotic
twins discordant for SRS is confounding. This
may be solely because of environmental
factors. Placental pathology, including hypo-
trophy, a single umbilical artery, and velamen-
tous cord insertion was observed in the growth
restricted twin fetus during pregnancy.12
How-
ever, the continuation of growth retardation
postnatally is diYcult to explain if purely envi-
ronmental circumstances are involved. Alterna-
tively, genetic factors such as a postzygotic
mutation event or mosaicism, in concert with
environmental factors, may be the cause of the
disease phenotype in only one twin.
While genetic factors are evident in familial
cases of SRS, the genetic contribution to the
majority of isolated patients is diYcult to
assess. It is possible that some of these patients
who are karyotypically normal have inherited
recessive mutations, or have new dominant
mutations, although there is no evidence of a
parental age eVect to support the latter.5
Structural chromosome abnormalities in
patients with SRS or SRS-like features
The majority of SRS patients have a normal
karyoptype. However, a small number of
patients with SRS, or features reminiscent of
SRS, have been described with structural
abnormalities of diVerent chromosomes, fur-
ther illustrating the genetic heterogeneity of
this disorder. These chromosomal disruptions
provide clues regarding the location of the
genes involved in SRS, aiding a positional
cloning or positional candidate approach to
identifying these. Several candidate genes
mapping in these regions have been identified
and analysed for involvement in SRS.
SRS review 811
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CHROMOSOMES 18 AND 8 WITH SRS-LIKE
PHENOTYPE
A single case with SRS has been reported in
association with trisomy 18 mosaicism.13
The
diagnosis was made on the basis that the
patient had the three major SRS features plus
asymmetry (table 1), but additionally pre-
sented with characteristics of the trisomy 18
syndrome including low set ears, developmen-
tal delay, failure to thrive, a prominent occiput,
and characteristic dermatoglyphics. The geni-
tal anomalies observed in this patient are com-
mon to both disorders.13
Several cases of
trisomy 18 mosaicism have been documented
with a SRS-like phenotype including low birth
weight and congenital asymmetry, but these
may represent overlapping features between
the SRS and trisomy 18 syndromes.14­16
One patient diagnosed with SRS on the basis
of IUGR and several minor SRS features
(listed in table 1) has been described with a
deletion of the short arm of chromosome 18.
However, this patient did not have short
stature. Furthermore, the facial dysmorphism,
large, low set ears, and mental retardation
observed were atypical of SRS.17
This patient
was lacking two major SRS features so does not
strictly fit the SRS phenotype.
One SRS-like patient has been described
with a paternally inherited deletion of chromo-
some 8q11-13. This patient had all the major
features of SRS and fifth finger clinodactyly,
but was microcephalic and had additional non-
SRS features.18
It is likely that the SRS charac-
teristics observed in cases with chromosome 8
and 18 anomalies are a subset of the multitude
of clinical manifestations displayed. These
patients are likely to have a distinct non-SRS
clinical entity, which merely shares some of the
SRS features. Thus, it is debatable as to
whether these cases should still be considered
SRS, as they tend to cause confusion rather
than clarity when considering genetic aeti-
ology.
RING CHROMOSOME 15 AND DELETIONS OF 15q
Two patients with a distinct SRS phenotype
have been identified with a r(15).19 20
Both
patients had the three major SRS features and
additional minor ones (table 1). A hemizygous
deletion of the insulin-like growth factor
receptor I gene (IGFIR), localised to 15q26.3,
was identified in one of these cases analysed
molecularly.20
A number of SRS-like patients have also
been described with deletions of distal 15q or a
ring chromosome 15 (r(15)) with accompany-
ing deletions of 15q subbands.21­24
Several SRS
features overlap with those seen in patients
with the r(15) syndrome including IUGR,
short stature, triangular facies, digital anoma-
lies such as fifth finger clinodactyly, and café au
lait naevi. However, there are diVerences
between the two syndromes. Patients with a
r(15) may additionally present with micro-
cephaly, hypertelorism, and mental retardation
not common to SRS, with absence of other
SRS characteristics such as skeletal asymmetry,
downturned corners of the mouth, and preco-
cious puberty.21 23 24
The size of the deleted sections of distal 15q
in r(15) syndrome patients are variable, but
where these included IGFIR, the patients were
severely pre- and postnatally growth re-
tarded.21 23 24
The insulin-like growth factor
(IGF) family, consisting of insulin, IGF1 and
IGF2, their receptors IGF1R and IGF2R, and
six IGF binding proteins (IGFBPs), plays a
crucial role in regulation of fetal and neonatal
growth and development.25 26
It was hypoth-
esised that hemizygous loss of the IGFIR gene
was responsible for the phenotype in the two
SRS patients with r(15) and the shared features
between SRS and r(15) syndrome patients.
IGFIR was also proposed as a candidate for
SRS in patients with normal karyotypes.20
However, no hemizygous deletions were identi-
fied in a total of 38 such SRS patients, screened
in two separate studies.24 27
Furthermore, no
mutations were identified in two exons encod-
ing crucial active sites within the protein in 33
probands, indicating that this gene cannot be
largely responsible for SRS in other groups of
patients.27
DISTAL CHROMOSOME 17q
Two patients with severe SRS have been
described with reciprocal translocations involv-
ing distal chromosome 17q, with the break-
points originally localised to 17q25.28 29
Both
patients had several minor SRS traits in
addition to the three major criteria (table 1).
The first case had an apparently balanced
translocation (17;20)(q25;q13) inherited from
the phenotypically normal father.28
The second
case had a de novo translocation
(1;17)(q31;q25).29
The translocation break-
point in the latter case has now been cloned
and the localisation refined to 17q23.3-q24.30
Two members of the growth factor receptor
bound protein (GRB) family of genes, GRB2
and GRB7, which map to 17q25.1 and
17q21.1 respectively, have been analysed as
candidates for SRS. The GRB proteins interact
with various receptor tyrosine kinases within
the insulin and IGFI signal transduction axes,
and so play a role in mitogenesis (reviewed by
Daly et al31
). GRB2 and the guanine nucleotide
exchange factor, Sos, form a complex, which
interacts with the insulin receptor substrate I
(IRS-I), and thus regulates Ras activation in
the first steps of the insulin signalling path-
way.32
Minor structural anomalies of GRB2 and
GRB7 have been excluded in 36 SRS patients
with normal karyotypes (M Hitchins, unpub-
lished data). GRB2 was screened for mutations
of the coding region by two groups, in a total of
29 SRS patients, but none was found, indicat-
ing that these genes do not play a significant
role in SRS33
(M Hitchins, unpublished data).
However, the potential eVects of the two
reported translocations on expression of these
genes has not been investigated. The growth
hormone (GH) gene cluster, including the GH
gene and the chorionic somatomammotropin
hormone (CSH) genes CSH1 and CSH2, are
located on chromosome 17q24.1.34
A patient
with classical SRS (table 1) has been reported
with a paternally inherited deletion of the
CSH1 gene.35
Recently, a second case with a
812 Hitchins, Stanier, Preece, et al
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similar deletion has been identified (T Egger-
mann, personal communication). CSH1, or
placental lactogen, is produced in the placental
syncytiotrophoblast and secreted into the fetal
and maternal circulation. Low levels of placen-
tal lactogen during pregnancy have been asso-
ciated with pathological conditions including
IUGR, diabetes, and pre-eclampsia, but these
may be because of associated factors such as
placental infarction restricting maternal-fetal
circulation (reviewed by Handwerger36
). Sev-
eral cases with normal phenotypes at birth have
been reported with absence of placental
lactogen during pregnancy owing to CSH1
deletions on both chromosome 17 homologues
in the fetus.37 38
Thus, the significance of the
hemizygous CSH1 deletion in the two SRS
patients is unclear, but may have contributed to
the syndrome in combination with other
genetic or environmental factors. Infarction of
the placenta, for instance, was noted in the first
case.35
Deletion of CSH1 in association with
SRS is rare and similar deletions have been
ruled out in 106 SRS patients to date35
(T Egg-
ermann, personal communication; M Hitch-
ins, unpublished data).
Chromosome 7 and genomic imprinting
in SRS
UNIPARENTAL DISOMY AND GENOMIC IMPRINTING
Uniparental disomy (UPD) is the rare inherit-
ance of both copies of one particular chromo-
some from a single parent.39
UPD occurs
through two main mechanisms, following a
non-disjunction event during meiosis. (1)
Fusion of a disomic gamete with a normal
monosomic one, with subsequent loss of one of
the extra homologues from the trisomic
conceptus, is termed "trisomic rescue". Unipa-
rental heterodisomy, which is the inheritance of
two diVerent homologues from one parent, that
is, both grandparental copies, arises through
this mechanism. This may also be accompa-
nied by the observation of trisomy mosaicism
in the placenta.40
(2) Fusion of a nullisomic
gamete with a normal one forming a mono-
somic zygote, followed by mitotic duplication
of the existing homologue in the conceptus, is
termed "monosomy rescue". This mechanism
results in two replica copies of the original
parental homologue, referred to as uniparental
isodisomy. UPD may be a mixture of hetero-
and isodisomy owing to recombination at
meiosis I. UPD can also occur through a
mitotic error after fertilisation. This may result
in segmental disomy following somatic recom-
bination, or may be accompanied by trisomy
mosaicism or partial supernumerary
chromosomes.41­43
Genetic disorders as a consequence of UPD
may occur through two distinct mechanisms.
(1) Recessive mutations can be reduced to
homozygosity owing to isodisomy of the locus
if the transmitting parent is a heterozygous car-
rier. (2) Disruption of expression of genes sub-
ject to genomic imprinting can occur, in both
iso- and heterodisomy, where the chromosome
in question contains an imprinted region.
Genomic imprinting is defined as the diVer-
ential expression of a gene or chromosomal
region according to the parental origin of
inheritance. Imprinted genes are expressed
from a single parental allele (fig 1A), such that
in UPD there may be absence of an active copy
on the parental homologue that is missing, or
overexpression on the duplicate parental chro-
mosome (fig 1B). Imprinted genes tend to be
clustered together in regions in which their
expression is co-ordinately regulated and are
associated with sites of parental allele specific
methylation of the DNA. A regularly updated
catalogue of imprinted genes may be found at
www.otago.ac.nz/IGC.44
Imprinted genes and
regions are also generally conserved in evolu-
tion. Imprinted regions in the mouse have been
defined by the use of reciprocal translocations
to derive embryos that are uniparental for spe-
cific subchromosomal regions, which give rise
to a noticeable phenotype.45
There are cur-
rently 14 defined regions of "non-
complementation", which require both paren-
tal complements for normal growth and
development, spread over eight diVerent
mouse chromosomes. A map of these im-
printed regions and genes in the mouse, with
the human homology map, is available at
www.mgu.har.mrc.ac.uk/imprinting/
imprinting.html.
MATERNAL UNIPARENTAL DISOMY FOR
CHROMOSOME 7 AND SRS
Maternal UPD for chromosome 7
(mUPD(7)), that is, the inheritance of both
homologues from the mother, occurs in 7-10%
of SRS cases.46 47
The first cases of mUPD(7)
were ascertained through diagnosis of recessive
disorders, but prompted researchers to screen
for UPD(7) among the SRS population. Two
cases with cystic fibrosis (CF) resulting from
maternal isodisomy for chromosome 7, for
which the mothers were CFTR mutation carri-
ers, were the first cases of UPD to be
described.48 49
Both patients had primordial
growth retardation, which could not be attrib-
uted to CF alone, and other features of SRS. A
third patient with a collagen disorder and
Figure 1 Possible consequences of maternal uniparental
disomy for chromosome 7 in Silver-Russell syndrome.
Maternal and paternal chromosome homologues are
depicted by vertical lines in red and blue, respectively. Genes
are represented by squares and arrows denote
transcriptional activity. Expression of biallelic genes are not
aVected by mUPD. There is a double dose of maternally
expressed imprinted genes in mUPD. If one of these is
involved in growth suppression it might account for SRS.
There is absence of transcription of paternally expressed
imprinted genes in mUPD as these are silent on the
maternal allele. Absence of a paternally expressed growth
promoter could cause SRS.
SRS review 813
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marked short stature was found to have mixed
maternal hetero- and isodisomy for chromo-
some 7, with a homozygous mutation of the
COL1A2 gene.50
Screens of entire SRS patient
cohorts for mUPD(7) have subsequently been
carried out and at least 40 cases of mUPD(7)
in association with SRS (or SRS features) have
been published.40 43 46­56
Some researchers ex-
cluded mUPD(7) in their group of patients,57
which helped in determining the frequency of
this occurrence more accurately. UPD involv-
ing chromosomes 2, 6, 9, 14, 16, 20, and 22 in
association with SRS have also been investi-
gated, but ruled out.55 57 58
Some cases of SRS with mUPD(7) have a
mild or incomplete phenotype.4 47 59
Features
appearing milder or less frequently in
mUPD(7) patients include the facial dysmor-
phism, asymmetry, clinodactyly and other dig-
ital abnormalities, café au lait spots, precocious
puberty, squeaky voice, and tooth anomalies, as
listed in table 1.51 52 59
However, mUPD(7)
patients experienced severe feeding diYculties
in the first few years of life, speech delay, and
excessive sweating. These patients may com-
prise a more homogeneous group that are
clinically distinguishable from other SRS pa-
tients.4 47 59
MECHANISM CAUSING SRS IN mUPD(7)
The mechanism by which mUPD(7) causes
SRS has been investigated. Cases with biparen-
tal inheritance of chromosome 7, but with con-
fined placental mosaicism for trisomy 7 as a
consequence of "trisomic rescue" were found
to have normal birth weights. This excluded
the possibility that IUGR in SRS is the result of
malfunction of a trisomy 7 placenta.40
Two
patients with paternal UPD(7) (pUPD(7))
have been reported with recessive disorders
owing to isodisomy at mutant recessive loci.
The first patient had congenital chloride
diarrhoea but had normal growth patterns.60
The second child had CF with complete situs
inversus and immotile cilia in addition, and had
poor growth at 6 months of age most likely as a
consequence of his recessive phenotype.61
The
lack of a distinct growth phenotype in the
patients with pUPD(7), in contrast to the con-
sistent severe growth retardation seen in
mUPD(7), implicates imprinted genes in the
aetiology of SRS in these cases.
To diVerentiate between unmasking of a
recessive allele by isodisomy and disruption of
genomic imprinting as the cause of SRS,
Preece et al11
analysed the full length of the
chromosome 7 homologues in five mUPD(7)
cases for regions of consistent isodisomy.11
Forty polymorphic markers distributed along
the entire chromosome 7, at an average genetic
interval of 4.5 cM, were analysed in each
patient. The chromosomes 7 were mixed
hetero- and isodisomy in each case, but no
region of isodisomy was common to all five
patients. This study excluded recessive muta-
tions as the cause of SRS in cases with
mUPD(7), indicating that an imprinting defect
is the most likely cause for this disorder.11
SRS
could be caused by the absence of expression of
a gene involved in growth promotion that is
active exclusively on the paternal allele, or by
excess of a maternally expressed imprinted
gene that is involved in growth inhibition (fig
1B).
Two separate candidate regions for SRS
on chromosome 7
Maternal UPD(7) in SRS has involved the
whole chromosome in the majority of cases.
Thus, until recently, regions of human chro-
mosome 7 that were homologous to imprinted
regions in the mouse provided the main clue as
to the location of imprinted genes that play a
role in SRS. DiVerent segments of human
chromosome 7 share homology with regions
from 10 diVerent mouse chromosomes includ-
ing 2, 4, 5, 6, 7, 10, 11, 12, 13, and 16. These
are detailed at www.ncbi.nlm.nih.gov/
Homology/human7.html/. However, just two
regions on human 7 share homology with
definitive mouse imprinted regions; human
7p11.2-p13 is homologous to mouse proximal
chromosome 11 and human 7q21-qter has a
conserved region on proximal mouse chromo-
some 6 (fig 2). Both these regions in mice are
associated with growth phenotypes. These
regions aid in the selection of candidate genes
for SRS and enable the study of imprinting
processes that may contribute to SRS in the
mouse system.
Recently the identification of key SRS
patients with anomalies of 7p11.2-p13 and
7q31-qter has defined these two intervals as
separate candidate regions for SRS. It is inter-
esting to note that these two segments share
homology with the aforementioned mouse
imprinted regions.
THE 7p11.2-p13 REGION AND CANDIDATE GENES
Two patients with SRS have been identified
with duplications of 7p12.1-p13.62 63
In the first
case, the proband and her mother had an
inverted interstitial duplication of this region.
The SRS proband had relatively low birth
weight, marked short stature, mild facial asym-
metry, and fifth finger clinodactyly. The
mother, whose duplication had arisen de novo
on the grandpaternal chromosome, also had
mild features of SRS, including short stature
and fifth finger clinodactyly.62
The second
report was of a de novo tandem duplication of
the region 7p11.2-p13 on the maternally
derived homologue, in a SRS patient present-
ing with pre- and postnatal growth restriction,
small triangular face, and fifth finger clinodac-
tyly, but no asymmetry.63
In both cases the
duplicated region encompassed the insulin-like
growth factor binding protein 1 (IGFBP1) and
the growth factor receptor bound protein 10
gene (GRB10). The epidermal growth factor
receptor gene (EGFR) lay outside the duplica-
tions (fig 2).62 63
Each of these genes had previ-
ously been proposed as candidates for SRS as
they are important in the regulation of growth
and development and their murine homo-
logues map within the conserved imprinted
region on proximal mouse chromosome 11.
Mice with maternal disomy/duplication for
proximal 11 (MatDp.prox11) are 30% smaller
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than their normal littermates, possibly repre-
senting the growth restriction seen in SRS.
Conversely, mice with paternal disomy for this
region (PatDp.prox11) are 30% larger than
normal.64
Although pUPD(7) is not associated
with a growth phenotype in humans, there are
other imprinted genes within proximal mouse
11 whose human homologues map to chromo-
somes other than 7, which may account for the
overgrowth in PatDp.prox 11 mice. For exam-
ple, the paternally expressed U2af1-rs1 gene
with a human equivalent U2AF1-RS1 on chro-
mosome 5 is a candidate for this excessive
growth in these mice (fig 2).64
EGFR was previously shown to be an
unlikely candidate for SRS on the basis that it
was not imprinted during human fetal develop-
ment.65
That EGFR is not within the dupli-
cated region in the two recently described SRS
patients corroborates this (fig 2).62 63
IGFBP1
and IGFBP3 have similarly been shown to be
expressed from both parental alleles in human
fetal tissues, so were deemed unlikely to
contribute to SRS.66 67
Furthermore, in a
screen of 49 SRS patients, no mutations of
either IGFBP1 or IGFBP3 were identified.68
The GRB10 gene was considered a prime
candidate for SRS on the basis of its function as
a growth inhibitor and its imprinting status in
the mouse. GRB10 is a member of a family of
growth factor receptor bound protein genes,
which includes GRB2 and GRB7 on chromo-
some 17, and has at least four protein isoforms.
GRB10 interacts with several tyrosine receptor
kinase growth factor receptors including the
insulin receptor, IGF1R, EGFR, and the plate-
let derived growth factor receptor, causing
downregulation of growth.69 70 71
Grb10 was
identified in a systematic screen for maternally
expressed imprinted genes by subtractive
hybridisation of cDNAs derived from a normal
mouse embryo with those from an androge-
netic embryo (with a paternal genetic comple-
ment). Expression specifically from the mater-
nal allele was confirmed in the mouse.72
Imprinted expression of GRB10 in human fetal
development was found to be both tissue and
isoform specific. A novel isoform was identified
Figure 2 Candidate imprinted regions for Silver-Russell syndrome on human chromosome 7 and homologous imprinted
regions in mouse. An ideogram of human chromosome 7 is shown with vertical black bars indicating the two SRS
candidate regions on both the p and q arm. Candidate (or previous candidate) genes for SRS are labelled on the left in their
approximate mapping locations. Imprinted genes are in bold. Mouse homologous regions to the two SRS candidate regions
are depicted on the right. Mouse chromosome regions displaying non-complementation phenotypes with two maternal (and
no paternal) copies and two paternal (and no maternal) copies are shown by dashed lines. These regions are defined by the
mouse reciprocal translocations T(11;13)41Ad (chromosome 11),64
T(4;6)77H, and T(6;13)6Ad (chromosome 6).82
The
approximate positions of mouse imprinted gene homologues are also indicated.
Human
chromosome 7
Homologous mouse
imprinted regions
Chromosome 11
Mat Pat
7p11.2­p13
Duplicated in
2 SRS patients
Prenatal
growth
retardation
Prenatal
overgrowth
Homologous to
human 7p11.2­p13
Homologous to
human chromosome 5
7p31­qter
Segmental mUPD
in 1 SRS patient
22
21
15.3
15.2
15.1
14
T41Ad
13
12
11.2
11.1
11.1
11.21
11.22
11.23
21.1
21.2
21.3
22
31.1
31.2
31.3
32
33
34
35
36
p
q
IGFBP3
EGFR
SGCE
IGFBP1
Grb10
U2af1
-rs1
MEST
CITI
­2COP
­2CoP
Mit1
Mest

GRB10
Chromosome 6
Mat PatEarly
embryonic
lethality
Growth
retardation
T77H
Sgce
T6Ad
SRS review 815
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in fetal skeletal muscle, which was maternally
expressed.73
In contrast, GRB10 was paternally
expressed in fetal brain and spinal cord, but
biallelic in all other major fetal organs and tis-
sues.73 74
The role that GRB10 may play in SRS
is diYcult to discern on the basis of this
imprinting profile. Yoshihashi et al75
reported a
maternally transmitted P95S amino acid sub-
stitution in GRB10 in two unrelated Japanese
SRS patients,75
but this was not found in a fur-
ther 161 SRS subjects.76
This substitution was
subsequently shown to be a rare polymorphism
in the Japanese population and unlikely to be
causative of SRS.77
No mutations of GRB10
have been identified in a total of 139 SRS
patients screened for the entire coding region
of the gene, indicating that it does not contrib-
ute significantly to SRS.73­76
Disruption of
imprinted expression of GRB10, through
altered methylation for instance, has not been
investigated and remains a possibility. Since
imprinted genes tend to occur in clusters, it is
likely that other imprinted genes exist in the
7p11.2-p13 candidate region, which may be
responsible for SRS in cases with and without
mUPD(7).
DiVerent opinions regarding whether the
SRS phenotype in patients with a duplication
of 7p11.2-p13 is attributable to an imprinting
eVect have been put forward. Monk et al63
stated that duplication of this region in SRS
provided evidence for involvement of a mater-
nally expressed growth suppressor gene, as
opposed to a growth promoter gene active on
the paternal allele, assuming these cases have a
common aetiology with mUPD(7) patients.
However, others have suggested that SRS may
be instead the result of an extra copy of this
region.43 62
The 7p12.1-p13 duplication in the
SRS proband described by Joyce et al62
was of
paternal origin in the proband's mother, who
also had SRS characteristics. However, the
mother's clinical phenotype was mild and may
have been caused by duplication or disruption
of non-imprinted contiguous genes, which may
contribute to some of the minor features asso-
ciated with SRS. A SRS patient with maternal
isodisomy 7 and ring chromosome 7 (r(7))
mosaicism has been reported. The r(7) con-
sisted of the 7p11-q11 region and was
identified as paternal in origin. It is most likely
that mitotic duplication of the maternal 7
homologue occurred in the zygote that was
essentially monosomic, with just a partial
paternal chromosome 7 to correct for chromo-
some number. Mosaicism for the r(7) probably
reflected the instability of supernumerary par-
tial chromosomes during cell replication.
Although mUPD(7) was considered the under-
lying cause of SRS, the authors suggested that
genes in the 7p11-q11 region were not involved
in SRS since a paternal copy was present.43
However, the behaviour of genes in ring
chromosomes is not clear, and so a paternal
copy in some cells may not compensate fully
for loss of a complete paternal homologue.78
It
is plausible that partial trisomy for chromo-
some 7 may be responsible for aspects of the
SRS phenotype in this patient, in the same way
that trisomy mosaicism for distal chromosome
11 may cause hemihypertrophy in Beckwith-
Wiedemann syndrome patients with segmental
pUPD for 11p15.5.41 42
No evidence for low
level trisomy 7 mosaicism has been identified
in four SRS patients with mUPD(7), though
further mUPD(7) patients should be screened,
especially those with asymmetry, before this
can be ruled out as a contributory mechanism
for SRS.79
THE 7q31-qter REGION AND CANDIDATE GENES
Two patients with SRS or some of the major
SRS features have been reported with mUPD
restricted to the q arm of chromosome 7.80 81
This suggests that the imprinted genes respon-
sible for SRS in patients with mUPD(7) for the
entire chromosome are located on the q arm
and that the p arm may not involve an imprint-
ing aetiology. A unique patient was reported
with isochromosomes of 7p and 7q, showing
homozygosity at all chromosome loci investi-
gated. Paternal isodisomy was found for the 7p
arm and the 7q arm was maternally isodisomic.
The patient did not have IUGR, but became
growth retarded postnatally, had mild limb
asymmetry, slight fifth finger clinodactyly, and
a triangular shaped face. The authors hypoth-
esised that a maternal contribution to the p
arm was necessary for normal fetal growth in
utero, but that imprinted genes on the q arm
were responsible for the additional SRS
features noted in this patient.80
Recently, a
patient with typical SRS including severe
IUGR, short stature, relative macrocephaly,
slightly triangular face with downturned cor-
ners of the mouth, mild fifth finger clinodac-
tyly, abnormal spacing of the teeth and a
squeaky voice, but no asymmetry, was de-
scribed with segmental maternal isodisomy for
the region 7q31-qter. This report shows that
mUPD for this small interval on chromosome
7 causes a clinically definitive SRS phenotype,
including several of the minor features.81
The
finding of mUPD restricted to 7q31-qter in
this SRS patient indicates that two separate
regions on chromosome 7 can independently
cause SRS, with the telomeric region of the q
arm most certainly involving an imprinting
defect (fig 2).
The human 7q21-qter region is homologous
to proximal mouse chromosome 6, which
shows two distinct imprinted phenotypes in
mice with maternal UPD. These are defined by
two translocation breakpoints, with the proxi-
mal region between the centromere and the
T77H breakpoint, and the distal region
between the T77H and T6Ad translocation
breakpoints (fig 2). The distal imprinting
segment is associated with pre- and postnatal
growth restriction in mice with maternal
disomy.82
This region contains a cluster of
imprinted genes including the paternally ex-
pressed mesoderm specific transcript gene
(Mest/Peg1)83
and the nonclathrincoatprotein
gene ( -2Cop), which is maternally expressed
in mouse, in contrast to its human homologue.
Two untranslated paternally expressed tran-
scripts Mit1 and -2Cop antisense, which over-
lap -2Cop, have also been reported in mouse.84
Mest was first identified in mice by subtractive
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hybridisation of cDNAs from a normal mouse
embryo with those from a parthenogenetic
embryo (with just a maternal genetic compo-
nent) in a screen for paternally expressed
genes.83
Mice with a paternally inherited muta-
tion of the Mest gene have IUGR and the
female oVspring themselves show abnormal
maternal behaviour, with impaired placen-
tophagia.85
The human homologue MEST has
thus been proposed and investigated as a
candidate for SRS.86
Human MEST87
and -2 COP88
both map to
7q32 (fig 2). MEST is paternally expressed in
embryos and all major fetal organs, but was
found to be biallelic in adult lymphocytes.89 90
Two diVerent isoforms of MEST have since
been identified in lymphocytes, one of which is
biallelically expressed while the other is tran-
scribed specifically from the paternal allele.
Functional absence of MEST was shown in
SRS patients with mUPD(7) by analysing this
latter isoform in patient lymphoblasts.91
How-
ever, no mutations of MEST have been identi-
fied in 49 SRS patients. MEST has a diVeren-
tially methylated 5' CpG island, thought to
regulate expression, with hypermethylation of
the inactive maternal allele.90
Although patients
with mUPD(7) only have the methylated
maternal alleles at this site, no epigenetic
alterations were identified in 35 non-mUPD(7)
SRS patients, suggesting that their regulation
of MEST was normal. These data indicated
that MEST is unlikely to play a major role in
SRS, although it may still contribute to the
phenotype in mUPD(7) patients.86
The -2
COP gene is paternally expressed in all major
fetal organs, with the exception of brain and
liver, where biallelic expression was noted. -2
COP was screened for mutations in 42 SRS
patients. A substitution was observed in one
SRS patient, which was not identified in 98
normal subjects, but this was present on the
inactive maternally derived allele, so was unre-
lated to the SRS phenotype.88
A non-translated
paternally expressed transcript, CIT1, con-
tained within an intron of -2 COP, has also
recently been reported.92
Intensive physical and
transcript mapping within 7q32 will help to
identify other genes which may be subject to
imprinting in this region.93
Is 7q21 a novel imprinted region?
A novel imprinted region may exist at 7q21.
This is suggested by the homology between this
region and the proximal imprinted region on
mouse chromosome 6, between the centromere
and T77H translocation breakpoint (fig 2).
Maternal disomy for this region causes early
embryonic lethality.82
This segment contains
the paternally expressed -sarcoglycan gene
(Sgce).94
The human homologue SGCE maps
to 7q21, but its imprinting status is unknown.95
Furthermore a paternally expressed gene,
PEG10, has recently been identified which
maps to 7q21 near to SGCE. PEG10 appears to
be derived from a retrotransposon.96
Although
these genes may be located within a third
imprinted region on chromosome 7, this lies
proximal to the candidate imprinted region
defined by segmental mUPD of 7q31-qter in
SRS, and no chromosomal anomalies involving
7q21 have been associated with SRS to date.
Conclusions
The Silver-Russell syndrome is both clinically
and genetically heterogeneous, with diVerent
modes of inheritance and chromosomal loca-
tions involved. This makes identification of the
genes responsible diYcult. Recent progress has
been made on chromosome 7, defining two
separate candidate regions, 7p11.2-p13 and
7q31-qter. A definitive role for genomic
imprinting has been indicated in the 7q31-qter
region, as a result of the observation of mater-
nal uniparental disomy specifically for this
interval in a single SRS patient. This case
suggests that the 7q31-qter region alone may
be responsible for SRS in patients with mUPD
for the entire chromosome 7. Two imprinted
genes within the disomic region, MEST and
-2 COP, have been investigated as candidates
for SRS, but there has been no direct evidence
to show either is responsible for the phenotype.
Currently there are conflicting opinions re-
garding the underlying basis for SRS in
patients with structural anomalies of the
7p11.2-p13 region, with some arguing against
a role for imprinting. However, this region
contains one imprinted gene, which has been
implicated in SRS, GRB10, though its potential
involvement in the disorder remains uncertain.
It may be the case that both the 7q31-qter and
7p11.2-p13 candidate regions cause SRS
through disruption of imprinting. Since im-
printed genes tend to be clustered in groups,
there are likely to be other imprinted genes in
both chromosome 7 candidate regions, which
will require investigation for a role in SRS. The
identification and analysis of additional SRS
patients presenting with unique chromosomal
abnormalities involving chromosome 7 will
further define the candidate intervals. It is
plausible that, as a variable phenotype, no sin-
gle gene is responsible for all the features of
SRS in any person. SRS may be a contiguous
gene disorder, or where imprinting is involved,
be the result of disruption of expression of sev-
eral co-regulated imprinted genes within an
imprinted region. Identification of the gene or
genes causing SRS in one of the associated
chromosomal locations (in particular on 7p,
7q, or chromosome 17) should aid consider-
ably in the identification of the other genes
involved on diVerent chromosomes, by provid-
ing information on the growth and develop-
mental pathway aVected.
We would like to thank Colin Beechey of the MRC Mammalian
Genetics Unit, Harwell for his help with fig 2. Megan Hitchins
is funded as a postdoctoral fellow by the Dunhill Medical Trust.
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