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NSD1 mutations in Sotos syndrome.

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American Journal of Medical Genetics Part C (Semin. Med. Genet.) 137C:24 –31 (2005)
A R T I C L E
NSD1 Mutations in Sotos Syndrome
FRANCESCA FARAVELLI*
Sotos syndrome is a genetic disorder characterized by a typical facial appearance, macrocephaly, accelerated
growth, developmental delay, and a variable range of associated abnormalities. The NSD1 gene was recently
found to be responsible for Sotos syndrome, and more than 150 patients with NSD1 alterations have
been identified. A significant ethnic difference is found in the prevalence of different types of mutation, with a
high percentage of microdeletions identified in Japanese Sotos syndrome patients and with intragenic mutations
in most non-Japense patients. NSD1 aberrations are rather specific for Sotos syndrome, but have also been
detected in patients lacking one or more major criteria of the disorder, namely overgrowth, macrocephaly, and
advanced bone age. Thus, new diagnostic criteria should be considered. Studies have reported different
frequencies of mutations versus non-mutations in Sotos syndrome, thus indicating allelic or locus hetereogeneity.
Although some authors have suggested genotype/phenotype correlations, further studies are needed.
ß 2005 Wiley-Liss, Inc.
KEY WORDS: overgrowth syndromes; intragenic mutations; microdeletions; neoplasia; genotype/phenotype correlations; Weaver
syndrome; Beckwith–Wiedemann syndrome
INTRODUCTION
Sotos syndrome (OMIM 117550) was
described in 1964 in five patients with
prenatal and postnatal overgrowth, characteristic facial appearance, advanced
bone age, and developmental delay [Sotos
et al., 1964], but most authors quote the
report by Schlesinger [1931] as the first
case. Hundreds of cases were subsequently
reported.
Facial features are characterized by a
high anterior hairline, frontal bossing,
downslanting palpebral fissures, and prominent mandible [Sotos et al., 1964; Cole
and Hughes, 1994; Allanson and Cole,
1996]. Additional features include neonatal hypotonia, poor feeding, jaundice,
congenital heart defects, seizures, and
scoliosis [Cole and Hughes, 1994; Opitz
et al., 1998]. It remains to be determined
Francesca Faravelli received her M.D.
degree at the University of Genoa, Italy and
trained in Medical Genetics in Genoa and in
London, at the Institute of Child Health. She
works as a clinical geneticist in the Department of Human Genetics of Galliera Hospital
in Genoa. Her main field of interest is
dysmorphology.
*Correspondence to: Francesca Faravelli,
SC Genetica Umana, Ospedale Galliera, Italy.
DOI 10.1002/ajmg.c.30061
ß 2005 Wiley-Liss, Inc.
to what extent Sotos syndrome is a
cancer-predisposing syndrome [Hersh
et al., 1992; Noreau et al., 1998; Cohen,
1999; Yule, 1999].
Phenotypic overlap with other
overgrowth syndromes is known, particularly with Weaver syndrome, characterized by abnormal facial features,
metaphyseal flaring of the femurs,
camptodactyly, deep-set nails, hoarse
low-pitched cry, and advanced bone
age [Weaver et al., 1974; Cole et al.,
1992; Opitz et al., 1998].
In 2002, the gene for Sotos syndrome
was identified [Kurotaki et al., 2002] in a
patient carrying an apparently balanced
de novo translocation (5;8)(q35;q24.1)
[Imaizumi et al., 2002]. Since then,
microdeletions of NSD1 and intragenic
mutations have been identified in more
than 150 patients [Kurotaki et al., 2002;
Douglas et al., 2003; Hoglund et al., 2003;
Kamimura et al., 2003; Kurotaki et al.,
2003; Nagai et al., 2003; Rio et al., 2003;
Turkmen et al., 2003; Cecconi et al.,
2005].
In 2002, the gene for Sotos
syndrome was identified in a
patient carrying an apparently
balanced de novo translocation.
Since then, microdeletions of
NSD1 and intragenic
mutations have been identified
in more than 150 patients.
NSD1 GENE AND PROTEIN
The NSD1 gene was isolated and
characterized in 2001 [Kurotaki et al.,
2001]. It represents the human homolog
of the mouse Nsd1 gene (Nuclear
receptor-binding SET Domain containing protein 1). It was identified in 1998
in a search for factors mediating the
transcriptional response induced by
binding of ligands to nuclear receptors
(NRs) [Huang et al., 1998]. It encodes
the NSD1 protein, which belongs to an
emerging family of proteins that include
NSD2 (or MMSET and WHSCR1)
[Chesi et al., 1998] and NSD3 [Angrand
et al., 2001]. NSD2 is located in 4p16.3
in the Wolf–Hirschorn syndrome critical region of deletion [Stec et al., 2000];
NSD3 maps to 8p12. The three
genes have similar functional domains.
They have all been involved in human
malignancies, suggesting a key role in
ARTICLE
controlling cell growth and differentiation. The NSD1 gene has been isolated
recently in the context of a fusion
transcript with the nucleoporin gene
(NUP98) in a recurrent translocation in
patients with de novo childhood acute
myeloid leukemia [Jaju et al., 1999,
2001]. The NSD2 gene was disrupted
in a t(4;14) translocation associated with
lymphoid multiple myeloma [Chesi
et al., 1998] and NSD3 is amplified in
several tumor-derived cell lines and
primary breast carcinomas [Angrand
et al., 2001]. Recently, NSD3 has also
been identified as a translocation partner
of NUP98 in acute myeloid leukemia
[Rosati et al., 2002].
NSD1 has an open reading frame of
8,088 base pairs, consists of 23 exons, and
is translated into a 2,696 amino acid
protein [Kurotaki et al., 2001]. It contains
multiple functional domains, including
the SET domain (SU[VAR]3–9, Enhancer of Zeste, Trithorax), initially identified
in Drosophila genes involved in chromatin-mediated regulation during development [Tschiersch et al., 1994; reviewed in
Jenuwein, 2001]. It also contains a SETassociated Cys-rich (SAC) domain adjacent to the SET domain, typical of
proteins functioning as histone-methyltransferases (HMTases) [Rea et al., 2000].
Other functional domains are represented
by five plant homeodomain (PHD): zinc
finger-like motifs interacting with chromatin and two PWWP domains thought
to be involved in protein–protein interaction [Aasland et al., 1995; Stec et al.,
2000]. Finally, the NSD1 gene contains
two distinct NR interaction domains
(NID): NIDL and NIDþL that exhibit
binding properties of NIDs found in NR
corepressors and coactivators [Huang
et al., 1998]. This suggests that NSD1
may function as a bifunctional transcriptional regulator that can activate or repress
transcription in response to ligand binding
[Huang et al., 1998].
The expression pattern of NSD1
revealed the presence of two different
transcripts (9.0 kb and 10.0 kb) in
various fetal and adult tissues, including
brain, kidney, skeletal muscle, spleen,
thymus, and lung. To gain further
insights into its biological function,
Nsd1 deficient mice have recently been
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)
generated by gene disruption [Rayasam
et al., 2003]. Homozygous mutant
embryos fail to complete gastrulation,
indicating that NSD1 is essential for
early post-implantation development.
By contrast, heterozygous mutant
miceþ/ are viable, fertile, and display
early normal growth rate [Rayasam et al.,
2003], indicating that the Sotos phenotype in mice may be milder than in
humans. Furthermore, the SET domain
represents a novel HMTase domain
with a specific histone methyltransferase
activity [Rayasam et al., 2003].
NSD1 ABERRATIONS IN
SOTOS SYNDROME
Kurotaki et al. [2002] cloned the 5q35
breakpoint of a translocation (5;8) in a
Sotos syndrome patient and demonstrated that the NSD1 gene was disrupted in this rearrangement. The same
authors identified microdeletions encompassing NSD1 as the major cause of
Sotos syndrome in Japanese patients.
This finding was subsequently confirmed in a larger series of Japanese
patients [Kurotaki et al., 2003], but not
in European patients who tended to
harbor intragenic mutations [Douglas
et al., 2003; Kurotaki et al., 2003; Rio
et al., 2003; Turkmen et al., 2003;
Cecconi et al., 2005].
Table I shows the frequency of
NSD1 aberrations in reported patients
and clinical criteria used for their
selection. Although most authors refer
to the criteria suggested by Cole and
Hughes [1994], that is a typical facial
gestalt, overgrowth, macrocephaly, and
advanced bone age, some differences
are found in published series, and this
probably explains the variability in the
overall detection rate of mutations in
Sotos syndrome (35%–90%). In particular, most reports distinguish a class of
typical Sotos syndrome patients and one
of Sotos-like patients. The second group
refers to individuals lacking one or
more major criteria including, in some
instances, the typical facial gestalt. In this
group, a few patients with mutations
have been identified and this can be
explained by the subsequent observation
that a typical facial gestalt represents a
25
constant criterion in individuals with
NSD1 aberrations (see section titled
Clinical Features in Patients With
NSD1 Alterations).
A variable proportion of patients
with a clinical diagnosis of Sotos syndrome do not show alterations in NSD1.
This is likely due, at least in part, to allelic
heterogeneity with some patients having
underlying aberrations undetectable by
means of currently used screening techniques. A partial deletion of the gene
A variable proportion of
patients with a clinical
diagnosis of Sotos syndrome
do not show alterations in
NSD1. This is likely due,
at least in part, to allelic
heterogeneity with some
patients having underlying
aberrations undetectable by
means of currently used
screening techniques.
detected by use of quantitative multiplex
PCR of short fluorescent fragments
(QMPSF) has recently been described
in one such patient [Drouin-Garraud
et al., 2003]. However, it cannot be
excluded that locus heterogeneity exists
in this disorder. Baujat et al. [2004]
described anomalies of the 11p15 region
in two patients with a clinical diagnosis
of Sotos syndrome, though neither was
typical of the condition. The first
patients, with documented paternal
uniparental disomy of the 11p15 region,
had previously been published as a
Sotos-like phenotype with absence of
advanced bone age [Amiel et al., 2002,
their case 3]. It remains to be determined
whether some cases of Sotos syndrome
are allelic to Beckwith–Wiedemann
syndrome.
The NSD2 and NSD3 genes were
recently tested as potential candidates for
NSD1-negative Sotos syndrome patients
based on strong sequence similarities
to the NSD1 gene. No mutations or
26
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)
ARTICLE
TABLE I. Reported Frequencies of NSD1 Aberrations in Sotos Syndrome Patients
Intragenic mutations
Typical SoS
Kurotaki et al. [2002]
Kurotaki et al. [2003]a
Japanese patients
Non-Japanese patients
Douglas et al. [2003]b
Rio et al. [2003]c
Turkmen et al. [2003]d
Cecconi et al. [2005]e
SoS-like
4/38 (10%)
11/95
5/17
26/37
14/23
19/21
16/24
(12%)
(29%)
(70%)
(61%)
(90%)
(66%)
3/13 (23%)
2/10 (20%)
0/9
Deletions
Typical SoS
SoS-like
Overall frequency of NSD1
aberrations in typical SoS
20/30 (67%)
(77%)
49/95 (52%)
1/17 (6%)
2/37 (5%)
2/23 (9%)
—
1/24 (4%)
60/95 (63%)
6/17 (35%)
28/37 (76%)
16/23 (69%)
19/21 (90%)
17/24 (70%)
1/13 (7%)
4/10 (4%)
0/9
SoS: Sotos syndrome.
Clinical criteria adopted as follows:
a
Typical Sotos: typical facial gestalt, mental retardation, and overgrowth.
b
Typical Sotos: presence of four criteria of: typical facial gestalt, height >97th centile, OFC >97th centile, bone age >90th centile,
developmental delay, congenital anomalies, or malformations; Sotos-like: some atypical characteristics, primarily concerning facial features.
c
Typical Sotos: presence of four criteria: typical facial gestalt, overgrowth >97th centile, OFC >97th centile, advanced bone age; Sotos-like:
lacking bone age and overgrowth.
d
Typical Sotos: presence of four criteria of five: typical facial gestalt, overgrowth >97th centile, OFC >97th centile, advanced bone age,
developmental delay.
e
Typical Sotos: presence of four of five major criteria: typical facial gestalt, overgrowth >97th centile, OFC >97th centile, advanced bone
age, developmental delay; Sotos-like: some atypical characteristics, primarily concerning facial features.
This estimate is as reported from the authors.
deletions were identified in 78 patients
with overgrowth [Douglas et al., 2004].
NSD1 MICRODELETIONS
Microdeletions encompassing the
NSD1 gene have been reported in
approximately 50% of Japanese patients
and in less than 10% of non-Japanese
patients [Table II]. Preferential paternal
Microdeletions encompassing
the NSD1 gene have been
reported in approximately 50%
of Japanese patients and in less
than 10% of non-Japanese
patients.
origin of microdeletions has been noted
[Douglas et al., 2003, Miyake et al.,
2003, Rio et al., 2003], as for other de
novo mutations and structural chromosomal abnormalities [Chandley, 1991].
A common-sized 2 Mb deletion is
very frequent in Japanese patients and
two complex low-copy repeats (LCRs)
have been identified at both common
deletion breakpoints [Kurotaki et al.,
2003]. The size, structure, orientation,
and extent of sequence identity of these
LCRs have been fully characterized and
a non-allelic homologous recombination (NAHR) between directly oriented
LCRs subunits have been demonstrated
to mediate the common deletion
[Kurotaki et al., 2005; Visser et al.,
2005]. Investigating 33 non-Japanese
NSD1 microdeletion cases, TattonBrown et al. [in press] confirmed that
although the majority of cases have a
same-sized deletion, a high proportion
of non-recurrent microdeletions of variable size exist [Douglas et al., 2003;
Kurotaki et al., 2003] and suggested
possible mechanistic difference in the
generation of the microdeletion among
different populations. The reason for
these discrepancies and for the observed
difference in frequency of the common
deletion remains to be determined. To
date, no instances of familial transmis-
sion of an NSD1 microdeletion have
been reported.
NSD1 INTRAGENIC
MUTATIONS
More than 100 distinct intragenic mutations in NSD1 have been identified
[Kurotaki et al., 2002; Douglas et al.,
2003; Nagai et al., 2003; Rio et al., 2003;
Turkmen et al., 2003; Cecconi et al.,
2005]. No mutational hot spots are
present in the gene and mutations are
widespread through the 23 exons with a
few recurring changes described in small
numbers of unrelated patients. Most
mutations have a truncating effect on
the protein. A minority of missense
mutations affecting functional domains
have been identified. Finally, all mutations arose de novo, with the exception
of three familial cases with documented
transmission of the phenotype from an
affected parent [Douglas et al., 2003;
Hoglund et al., 2003; Kurotaki et al.,
2003]. Table II summarizes all reported
intragenic mutations.
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)
TABLE II. Reported NSD1 Intragenic Mutations
Mutation
Splice-site
IVS8-2A ! G
IVS15-1G ! C
IVS15-1G ! T
IVS16-2delA
IVS19-2A ! G
6151þ1G ! A
Deletion
896delC
1171delC
1727delA
1807delT
2053-2057del
2363delG
2386delGAAA
2432delG
2576delAT
2760delTAGG
3141delC
3160delA
3197delC
3273delT
3355delC
3383delCT
3536delA
3541delGAAA
3708delTTGT
3841delC
3844delTTGGAinsGATC
4139delAAGTCinsCTG
4806delTGTTAAA
4883delT
4895delG
5341delC
6001delC
6302delA
6532delTGCCCCAGC
Nonsense
1130G ! A
1310C ! G
1318C ! T
1492C ! T
1492C ! T
1810C ! T
1828C ! T
2323C ! T
3063T !A
3091C ! T
3214C ! T
3886A !T
Protein change
(where reported)
Exon
Mutation analysis
in parents
Reference
Skip ex9/ frameshift
—
Skip ex16/frameshift
—
Skip ex20/frameshift
Skip ex20
Int 8
Int 15
Int 15
Int 16
Int 19
Int 20
Neg
—
—
Neg [m]
Neg
Neg
5
2
5
2
5
1
Frameshift
Q391fsX418
N576fsX598
Frameshift
Frameshift
Frameshift
E796fsX805
Frameshift
H859fsX873
Frameshift
Frameshift
Frameshift
Frameshift
Frameshift
Frameshift
S1128fsX1129
Frameshift
Frameshift
Frameshift
Frameshift
Frameshift
Frameshift
Frameshift
M1628fsX1641
Frameshift
Frameshift
L2001fsX2001
K2101fsX2149
2178-2180delCPS
2
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
6
6
7
13
13
13
16
19
22
23
Pos [f]
Neg
—
—
—
Neg
Pos [m]
—
—
Neg
Neg [m]
—
Neg
—
Neg
—
Neg
—
Neg
Neg
Neg
Neg
Neg
Neg [m]
—
Neg
—
Neg
Familial
8
2
2
6
6
3
4
4
2
3
5
5
3
6
3
2
1, 5
5
3
3
3
3
5
2
5
4
2
2
5
W377X
S437X
R440X
R498X
R498X
R604X
Q610X
Q775X
C1021X
R1031X
R1072X
K1296X
4
5
5
5
5
5
5
5
5
5
5
6
—
Neg
Neg
—
—
Neg
Neg
Neg
Neg
Neg
Neg
Neg
6
1
3
2
5
2
4
2
3
3, 5
3
6
(Continued )
27
28
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)
ARTICLE
TABLE II. (Continued )
Mutation
3958C ! T
3964C ! T
4411C ! T
4417C ! T
4885C ! T
5194G ! T
5229G ! A
5332C ! T
5431C ! T
5611A !T
5861G ! A
6013C ! T
Insertion
2807-8insA
3549-50insT
4160insC
4390delATATins8
4769insT
5008-9insG
5398insT
5744-5insT
5998insT
6431-2ins17
6450-1insC
Missense
4411C ! G
4847A !T
4910T ! C
5022C ! G
5060T !A
5178T ! C
5179G ! C
5375G ! T
5386G ! T
5684G ! A
5773T ! C
5864G ! A
5951G ! A
5990A ! G
6014G ! A
6049C ! T
6050G ! A
6429C ! G
6499T ! C
6548G ! C
6680C ! T
Protein change
(where reported)
Exon
Mutation analysis
in parents
Reference
R1320X
R1322X
R1471X
R1473X
Q1629X
E1732X
W1743X
R1778X
R1811X
K1871X
W1954X
R2005X
7
7
10
10
13
15
15
16
16
17
18
20
Neg
Neg
Neg [m]
Neg
—
—
—
—
Neg
Neg
Neg
Neg
7
6
2
2
5
5
6
2
3
5
2
5
Y936fsX936
E1184fsX1184
Frameshift
Frameshift
Frameshift
A1670fsX1672
Frameshift
M1915fsX1919
Frameshift
A2144fsX2155
K2151fsX2165
5
5
7
10
13
14
16
18
19
22
22
—
—
Neg
Neg
Neg
—
Neg
Neg
Neg
Neg
Neg [m]
2
2
5
3
6
2
5
2
1
2
2
R1471G
H1616L
L1637P
C1674W
I1687N
P1726L
A1725P
G1792V
V1796F
C1895Y
C1925R
G1955D
R1984Q
Y1997C
R2005Q
R2017W
R2017Q
H2143E
C2167R
C2183S
P2227L
10
13
13
14
14
15
15
16
16
18
18
18
19
19
20
20
20
22
23
23
23
—
Neg
Neg
—
Neg
—
—
Neg
Neg
Neg
Neg [m]
Neg
Neg
Neg
Neg
Neg
Neg
Neg
—
Neg
—
4
2
2
2
3
4
4
2
5
4
2
3
3
3
2
3
2
2
4
2
4
Neg, negative; Neg [m], only the mother examined; Neg [f], only the father examined; Pos [m], positive in the mother; Pos [f], positive in
the father; —, not examined.
References: 1, Kurotaki et al. [2002]; 2, Douglas et al. [2003]; 3, Rio et al. [2003]; 4, Kurotaki et al. [2003]; 5, Turkmen et al. [2003]; 6,
Kamimura et al. [2003]; 7, Nagai et al. [2003]; 8, Hoglund et al. [2003].
ARTICLE
CLINICAL FEATURES IN
PATIENTS WITH NSD1
ALTERATIONS
Detailed clinical information is available
for a subset of 86 patients with NSD1
alterations (58 patients with intragenic
mutations and 28 with deletions)
[Hoglund et al., 2003; Nagai et al.,
2003; Rio et al., 2003; Turkmen et al.,
2003; Cecconi et al., 2005].
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)
series. However, a substantial proportion
of patients with confirmed Sotos syndrome are described as having a normal
or moderately advanced bone age (25%,
n ¼ 69). Patients with NSD1 aberrations
and reduced bone age have also been
identified [Tatton-Brown and Rahman,
2004]. Because of this data, advanced
bone age is not considered a mandatory
diagnostic criterion.
DEVELOPMENTAL DELAY
CRANIOFACIAL FEATURES
In Sotos syndrome, the most striking
facial feature is the overall gestalt [Cole
and Hughes, 1994], which includes high
and bossed forehead, downslanting palpebral fissures, highly arched palate, and
a small pointed chin, which becomes
more prominent with age [Allanson and
Cole, 1996; Tatton-Brown and Rahman, 2004]. Clinical analysis of reported patients with a confirmed NSD1
abnormality suggests that the facial
phenotype is the most constant feature.
OVERGROWTH AND
MACROCEPHALY
Overgrowth and macrocephaly are
major criteria for the diagnosis of Sotos
syndrome [Cole and Hughes, 1994].
Most authors define overgrowth in
Sotos syndrome as height >97th centile
or þ2 SD. A significant proportion of
patients with NSD1 alterations do not
satisfy this criterion. Some authors
postulated that overgrowth could be less
evident in patients with a microdeletion.
Although available data are partially
consistent with this hypothesis, such as
absent overgrowth in 92% (n ¼ 58)
with intragenic mutations and 21%
(n ¼ 28) with microdeletions, analysis
of a larger series is needed. Macrocephaly (>97th centile) is absent in about
7% (n ¼ 85). Information about parental
height and head circumferences is rarely
available.
ADVANCED BONE AGE
A unified method of bone age assessment and criteria for the definition of
advanced bone age are absent in reported
A formal assessment of the degree of
intellectual impairment has rarely been
performed, although all patients are described as having some degree of mental
retardation/developmental delay.
ASSOCIATED CONGENITAL
ANOMALIES
Congenital heart defects and urogenital
abnormalities are relatively frequent, and
the type of NSD1 alteration may
influence their frequency. Congenital
heart defects were reported in 8.7%
(n ¼ 23) of patients with intragenic
mutations [Rio et al., 2003] and in
55.5% (n ¼ 27) of patients with microdeletions [Nagai et al., 2003; Rio et al.,
2003]. The most frequent defect is
patent ductus arteriosus with or without atrial septal defect. Variability in the
Congenital heart defects were
reported in 8.7% of patients
with intragenic mutations and
in 55.5% of patients with
microdeletions. The most
frequent defect is patent ductus
arteriosus with or without
atrial septal defect.
prevalence of congenital heart defects
has been noted in different populations
(40%–50% in Japanese and 8%–10% in
non-Japanese patients) [Kaneko et al.,
1987; Noreau et al., 1998; Tsukahara
et al., 1999]. Some authors have postulated that a second gene in the deleted
29
region might be involved in the pathogenesis of structural heart abnormalities
[Visser and Matsumoto, 2003]. However, recent data on patients with intragenic mutations and a high prevalence of
congenital heart defects (7/16 patients)
[Cecconi et al., 2005] do not support this
hypothesis.
Haploinsufficiency of the 5q31qter region is associated with a high
frequency of congenital heart defects
[Kleczkowska et al., 1993; Stratton et al.,
1994; Pauli et al., 1999]. The NKX2.5
gene, whose mutations are associated
with congenital heart defects and atrioventricular conduction defects, is localized to this region [Schott et al., 1998;
Benson et al., 1999] and has been
indicated as being responsible for the
cardiac phenotype [Schafer et al., 2001];
most of these deletions involve NSD1,
which could itself contribute to the
presence of congenital heart defects in
these patients.
NEOPLASIA
Two patients with confirmed Sotos and
neuroblastoma have been reported, one
with a 5q35 microdeletion and another
with an intragenic mutation [Nagai et al.,
2003; Turkmen et al., 2003]. A third
patient with ganglioglioma and a microdeletion has been noted [Deardorff et al.,
2004]. Three sacroccygeal teratomas,
one ganglioneuroma, one neuroblastoma, and one case of acute lymphocytic
leukemia have occurred in childhood,
and one small cell lung cancer at 22 years
of age occurred in a series of NSD1
positive cases [Tatton-Brown and Rahman, 2004]. These data support the
association of Sotos syndrome and
malignancy. A larger series is necessary
to establish a more accurate tumor
prevalence.
GENOTYPE–PHENOTYPE
CORRELATION IN SOTOS
SYNDROME
As discussed above, some preliminary
suggestions have been made about
genotype–phenotype correlation in
Sotos syndrome. The facial features have
been suggested to be coarser in microdeleted patients, although this is highly
30
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)
subjective [Douglas et al., 2003]. A more
severe degree of mental retardation but
less frequent and pronounced overgrowth has been recorded in microdeleted patients [Douglas et al., 2003;
Nagai et al., 2003; Rio et al., 2003]. A
higher incidence of congenital heart
defects and urologic anomalies has been
observed in patients with microdeletions
[Nagai et al., 2003; Rio et al., 2003],
although these are also reported with
variable frequency in patients with
intragenic mutations [Rio et al., 2003;
Cecconi et al., 2005]. Careful clinical
evaluation of larger series of patients is
needed to verify these observations.
NSD1 ABERRATIONS IN
OTHER OVERGROWTH
PHENOTYPES
NSD1 aberrations were demonstrated in
one-third of investigated patients with a
diagnosis of Weaver syndrome (6/18)
[Douglas et al., 2003; Rio et al., 2003;
Turkmen et al., 2003]. Reported features of mutated patients, when available, included deep-set nails (three
cases), camptodactyly (three cases), small
chin with deep horizontal skin crease
(two cases), and metaphyseal widening
(two cases). Further data are needed to
verify if both disorders are actually allelic
or if some heterogeneity exists in the
pathogenesis of Weaver syndrome. No
NSD1 alterations were demonstrated in
nearly 50 patients with non-specific
overgrowth phenotype [Douglas et al.,
2003; Rio et al., 2003; Cecconi et al.,
2005]. NSD1 mutations have been
reported in two patients classified clinically as having Beckwith–Wiedemann
syndrome [Baujat et al., 2004].
OPEN ISSUES AND FUTURE
PROSPECTS
Available data leave many issues about
Sotos syndrome and the NSD1 gene
unanswered. To date, the reason for
differences in mutation type among
different populations is undetermined.
In all ethnic groups, a proportion of
patients with a clinical diagnosis of Sotos
syndrome do not have detectable NSD1
aberrations and it is not known if this is
due to allelic or locus heterogeneity. A
definitive genotype–phenotype correlation awaits further studies.
In the future, it will be important to
better understand the functional role of
the NSD1 gene and pathogenetic
mechanisms in Sotos syndrome, to
identify other factors that mediate
phenotypic variability in the presence
of similar genotypes, and to determine
whether the NSD1 gene is a major
contributor to other overgrowth
phenotypes, such as Weaver syndrome.
A large series of patients with confirmed
aberrations in the NSD1 gene will
allow a better estimate of the neoplastic risk and possibly an understanding
of other factors that may influence this
risk.
ACKNOWLEDGMENTS
I thank Nazneen Rahman for helpful
comments and for collaboration.
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