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INTRODUCTION.

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American Journal of Medical Genetics Part C (Semin. Med. Genet.) 137C:1 –3 (2005)
I N T R O D U C T I O N
Overgrowth syndromes have become more important in pediatrics and
medical genetics. The subject has been
highlighted at several medical genetics
meetings. Papers on overgrowth were
delivered at the plenary session of the
Birth Defects Conference in San Antonio, Texas in 1996. The Manchester
Birth Defects Conference held in
Manchester, England in 1996 also had
overgrowth syndromes as one major
focus. The 1997 Robert J. Gorlin Conference on Dysmorphology was devoted
entirely to overgrowth syndromes and
the conference papers were published as
an issue of the American Journal of Medical
Genetics [Cohen, 1998]. A general book
on overgrowth syndromes appeared
more recently [Cohen et al., 2002].
This issue of the Seminar Series,
titled Overgrowth Syndromes: An Update, consists of the following articles:
*
*
*
*
*
*
Valérie Cormier-Daire M.D., Ph.D. is a
medical geneticist in the Department of
Medical Genetics of Necker Enfants Malades
Hospital in Paris, France. She first trained in
Pediatrics and then in Medical Genetics. Her
Ph.D. was focused on mitochondrial disorders. She spent 1 year in Los Angeles at
the Skeletal Dysplasia Registry. She is now
involved in clinical and research activities in
the skeletal dysplasia field and has a particular interest in syndromes and overgrowth
conditions. She is the co-author of more than
140 articles in the medical and scientific
literature.
Dr. M. Michael Cohen Jr is professor
emeritus of Pediatrics at Dalhousie University
in Halifax, Nova Scotia, Canada and associate editor of the American Journal of Medical
Genetics. His interests include clinical genetics, pathology, and health care in developing countries. His research interests include
bone disorders, overgrowth syndromes,
and central nervous system anomalies. He
is the author or co-author of more than
350 articles in the medical and scientific
literature; author, co-author, or editor of 14
books; and author or co-author of more than
40 book chapters.
*Correspondence to: Dr. M. Michael
Cohen Jr, Dalhousie University, 5981 University Avenue, Halifax, Nova Scotia B3H 3J5,
Canada. E-mail: michael.cohen@dal.ca
DOI 10.1002/ajmg.c.30059
ß 2005 Wiley-Liss, Inc.
*
Clinical and Molecular Overlap in
Overgrowth Syndromes, by Geneviève Baujat, Sylvie Rossignol,
Damien Sanlaville, Stanislas Lyonnet, Martine Le Merrer, Arnold
Munnich, Christine Gicquel, Laurence Colleaux, and Valérie CormierDaire.
Beckwith–Wiedemann Syndrome,
by Rosanna Weksberg, Cheryl
Shuman, and Adam C. Smith.
NSD1 Mutations in Sotos Syndrome,
by Francesca Faravelli
Fragile X Syndrome, by Alessandra
Terracciano, Pietro Chiurazzi, and
Giovanni Neri.
Proteus Syndrome: An Update, by
M. Michael Cohen Jr.
Risk of Tumorigenesis in Overgrowth Syndromes: A Comprehensive Review, by Pablo Lapunzina.
Tumor Predisposition in Costello
Syndrome, by Karen Gripp.
There are a number of different
ways to interpret overgrowth syndromes. Classification systems have been
proposed by Cohen [1982], Beighton
[1988], and Weaver [1994] (Table I).
Because of molecular advances, such
classificatory schemes appear to be outmoded. At present, it is recommended
that overgrowth definition and classification be loose, and simply serve as an
organizing principle for review and
discussion [Cohen et al., 2002].
Overgrowth syndromes, which are
less common than syndromes with
growth deficiency, tend to share several
characteristics in common. First, overgrowth is often (but not always) present
at birth and persists into postnatal life.
Second, weight is as important as length.
Third, most overgrowth syndromes
are associated with various anomalies.
Fourth, some syndromes are associated
with neoplasia. Finally, mental deficiency may be a feature in some cases
[Cohen, 1981, 1989, 1999].
Most overgrowth results from (a)
an increased number of cells, (b) hypertrophy, (c) an increase in the interstitium, most commonly excessive fluid,
as in fetal hydrops, or (d) some combination of these factors. In overgrowth
syndromes, for example, Beckwith–
Wiedemann syndrome, Sotos syndrome, or Weaver syndrome, excessive
TABLE I. Overgrowth Syndromes: Definition and Classification
Cohen [1982]
Beighton [1988]
Weaver [1994]
Familial tall stature
Prenatal onset overgrowth
Postnatal onset overgrowth
Intrinsic cellular hyperplasia versus humorally mediated hyperplasia
Generalized overgrowth
Obesity
Localized overgrowth
Digital overgrowth
Generalized overgrowth
Regional overgrowth
Parameter-specific overgrowth
From Cohen et al. [2002].
2
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)
INTRODUCTION
TABLE II. Some Disorders With Non-Classical Types of Overgrowth
Disorders
Overgrowth features
Neurofibromatosis, type 1
Fragile X syndrome
Marfan syndrome, type 1
Marfan syndrome, type 2
Congenital contractural arachnodactyly
Gene involved
Neurofibromas; variably macrocephaly, hemihyperplasia of limb or digit
Birthweight may be elevated; adult males have tall stature, relative
macrocephaly, large testes
Tall stature, long limbs, arachnodactyly
Tall stature, long limbs, arachnodactyly
Tall stature, long limbs, arachnodactyly
NF1
FMR1
FBN1
TGFbR2
FBN2
Data from Cohen et al. [2002] and OMIM [2004].
cellular proliferation predominates and
can be demonstrated or inferred to have
occurred [Cohen, 1981, 1989, 1999].
An expected consequence of cellular
overgrowth is that cell cultures from
affected persons manifest the growth
excess. An example is Elejalde syndrome
in which cultured fibroblasts complete
the cell cycle in 63% of the normal time
[Elejalde et al., 1977]. However, in a
preliminary study of Perlman syndrome,
cell growth rate was not increased in
fibroblasts. Negative findings may be
explained by (a) non-expression in
fibroblasts, (b) switching off of the
mutant gene, or (c) possible expression
of the mutant gene in some other way
[Neri et al., 1985].
In addition to the classical overgrowth syndromes discussed above,
several other disorders with non-classical types of overgrowth are known,
including type 1 neurofibromatosis,
fragile X syndrome, type 1 Marfan syndrome, type 2 Marfan syndrome, and
congenital contractural arachnodactyly
(Table II).
Molecular studies of fibroblast
growth factor receptor 3 (FGFR3) provide an intriguing example of how a
single gene can cause overgrowth or
growth deficiency, depending on particular human mutations and on mouse
model study. The function of FGFR3
can be deduced from the Fgfr3/
knockout mouse, which is overgrown
with excessively long femora and elongated vertebrae, resulting in a long tail
[Deng et al., 1996]. Thus, the normal
function of FGFR3 is to regulate endochondral ossification by ‘‘putting the
brakes’’ on growth. Mutations for
short-limb skeletal dysplasias on FGFR3
(hypochondroplasia,
achondroplasia,
and thanatophoric dysplasia) are gainof-function mutations that ‘‘put the
brakes’’ on growth even more to various
degrees [Naski et al., 1996; Webster and
Donoghue, 1996]. Some chromosomal
anomalies that result in overgrowth
TABLE III. Chromosomal Anomalies Associated With Overgrowth
and Undergrowtha
Overgrowth
Undergrowth
Gene
dup(4)(p16)
dup(15)(qter)
dup(X)(p22.3)
del(4)(p16)
del(15)(qter)
del(X)(p22.3)
IGF1R
SHOX
a
Several other chromosomal anomalies may also result in overgrowth: translocation,
inversion, or duplication of 11p15 (Beckwith–Wiedemann syndrome); i(12p) mosaicism
(Pallister–Hall syndrome); dup(5p); dup (12p); dup (12)(q11 ! q15); but also
del(5)(q35)(NSD1); del(15)(q25-q26)(IGF1R); and del(22)(q13)(SSTR3).
when duplicated and undergrowth
when deleted suggest the possibility of
dosage effects (Table III).
Molecular delineation of several
overgrowth syndromes includes GPC3
mutations in Simpson–Golabi–Behmel
syndrome; PTEN mutations in Bannayan–Riley–Ruvalcaba syndrome; and
NSD1 mutations in Sotos syndrome.
The molecular basis of Beckwith–
Wiedemann syndrome, the classic overgrowth syndrome, is complex, involving
deregulation of imprinted genes found
in two domains within the 11p15
region: telomeric Domain 1 (IGF2
and H19) and centromeric Domain
2 (KCNQ1, KCNQ1OT1, and
CDKN1C) [Cohen et al., 2002; Weksberg, 2002; Weksberg et al., 2005].
Molecular delineation of craniosynostosis syndromes by FGFRs has clarified some issues, but has also ‘‘muddied
the waters’’ because, for example, mutations in FGFR2 can have overlapping
phenotypes [Cohen, 2004]. Similarly,
the molecular delineation of overgrowth
syndromes has clarified some issues, but
has also ‘‘muddied the waters.’’ Phenotypic/molecular overlap has been shown
for Bannayan–Riley–Ruvalcaba syndrome and Cowden syndrome, now
best thought of as Bannayan–Riley–
Ruvalcaba/Cowden syndrome or PTEN
hamartoma–tumor syndrome [Marsh
et al., 1997, 1999]. NSD1 mutations
occur not only in Sotos syndrome, but
also in some cases of Weaver syndrome,
and rarely in other overgrowth syndromes, including Beckwith–Wiedemann syndrome [Douglas et al.,
2003; Turkmen et al., 2003; Baujat
INTRODUCTION
et al., 2004]. Baujat et al. [2004]
identified NSD1 mutations in 4% of
Beckwith–Wiedemann cases (n ¼ 52)
and 11p15 abnormalities in 10% of
Sotos syndrome cases (n ¼ 20). To date,
overlap appears to occur in a minority of
cases. Further studies with a larger group
of patients will help establish the degree
of overlap. We can also expect the molecular delineation of other overgrowth
syndromes in the future.
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pp 18-303, Addendum, pp 373–376.
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)
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Valérie Cormier-Daire
M. Michael Cohen, Jr.*
Guest Editors
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