REVIEW

CURRENT
OPINION Overgrowth syndromes
Orla M. Neylon, George A. Werther, and Matthew A. Sabin

Purpose of review
Human growth ensues from a complex interplay of physiological factors, in the wider setting of varying
genetic traits and environmental influences. Intensive research in these divergent areas, and particularly
in the field of genetics, continues to clarify the molecular basis of disorders which result in overgrowth,
and it is therefore timely to provide a review of these findings.
Recent findings
This article provides an overview of the factors which regulate growth, followed by a discussion of the
more commonly encountered overgrowth syndromes and their genetic basis as it is understood at the
current time. There is also an added focus on recently discovered genetic associations in some conditions,
such as Weaver, Perlman and Proteus syndromes.
Summary
New discoveries continue to be made regarding the genetic basis for many overgrowth syndromes and the
development of a much needed molecular classification system for overgrowth may become possible as the
interlinking functions of these genes on growth are unravelled. As there exists a wide spectrum of
syndromes, disorders resulting in overgrowth can represent a diagnostic and therapeutic challenge, from
those causing prenatal overgrowth with a poor prognosis to less severe genetic aberrations which are
identified in later childhood or adult life.
Keywords
imprinting, overgrowth, syndromes, tall stature

INTRODUCTION phosphorylating enzymes called cyclin-dependent

&

Somatic growth is dependent on an increase in
both cell size and number, although the interplay
between multiple mechanisms involved in its
regulation remains incompletely understood at a
molecular level. Overgrowth per se can be taken
to mean either tall stature or generalized/localized
overgrowth of tissues, and, while overgrowth con-
ditions are relatively rare, their study offers unique
opportunities to gain new insights into growth
regulation, as well as the identification of possible
individualized benefits for affected probands
kinases (CDKs) [1 ]. In general, their actions are
counterbalanced by inhibitory ‘gatekeepers’, such
as PTEN (phosphatase and tensin homologue),
which halts further cell replication upon detection
of aberrant DNA. At a cellular level, the control
of cell replication is tightly controlled, with uncon-
trolled upregulation of cell division being associated
with cancer and/or overgrowth.
Linear growth during childhood occurs pri-
marily from chondrocyte differentiation and repli-
cation at the growth plate in the distal epiphyseal
&

and families. Within this review, we describe the and central metaphyseal regions of long bones [2 ].
control of linear growth and the most commonly This process terminates with growth plate calcifica-
described genetic aberrations resulting in over- tion and fusion at the end of puberty. Childhood
growth syndromes. growth is stimulated by human growth hormone

NORMAL REGULATION OF CELLULAR
DIVISION AND LINEAR GROWTH
Tissue growth is dependent upon cell division in a
process which results in the transfer of the parent
cell’s genome into two identical daughter cells
(mitosis). The cell replication cycle is classically
divided into four mitotic phases, each directed by
Murdoch Childrens Research Institute, Royal Children’s Hospital and
University of Melbourne, Parkville, Victoria, Australia
Correspondence to Dr Matthew A. Sabin, Department of Endocrinology
and Diabetes, Royal Children’s Hospital, 50 Flemington Road, Parkville,
VIC 3052, Australia. Tel: +61 3 9345 5951; fax: +61 3 9345 6240;
e-mail: matthew.sabin@mcri.edu.au
Curr Opin Pediatr 2012, 24:505–511
DOI:10.1097/MOP.0b013e3283558995

1040-8703 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-pediatrics.com

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Endocrinology and metabolism
KEY POINTS
 The clinical phenotype of overgrowth syndromes is
quite variable and requires careful evaluation in
suspected cases.
 Unlike short stature, no clear molecular classification
system has yet been developed.
 Many overgrowth syndromes have an associated risk
of malignancy.
(hGH), which is secreted in a pulsatile manner from
the anterior pituitary, primarily under the control of
hypothalamic growth hormone releasing hormone.
hGH influences linear growth by acting on the
growth plate directly, as well as through insulin-like
growth factor (IGF) I, which is secreted from
the liver upon hGH stimulation. IGF-I circulates
bound to IGF-binding protein (IGFBP) 3 in a ternary
complex, the critical integrity of which is main-
tained by an acid/labile subunit (ALS). Insulin and
insulin-like signalling regulate systemic nutrient
sensing [3,4] and IGF-I is a critical determinant of
growth in childhood [5], whereas IGF-II plays a more
influential role prenatally [6].
Growth in infancy is predominantly nutrition-
ally regulated, whereas growth hormone, IGF-I
and thyroid hormone play equally prominent roles
in mid-childhood [7]. Thyroid hormones also exert
growth-promoting effects at the growth plate. Sex
steroids regulate pubertal growth, with eventual
fusion being principally determined by increased
local levels of oestrogen (in both men and women)
[8]. The progress of ossification can be directly
visualized by an assessment of skeletal maturation,
which is usually obtained from a plain radiograph
film of the nondominant wrist. This can then
be compared with standardized charts (such as
Greulich and Pyle [9]), giving a bone age with which
to compare the individual’s chronological age. In
the absence of an underlying syndrome known to
affect skeletal growth, this information is invaluable
in the determination of an individual’s current
health and future growth potential. Specifically
designed tables allow bone age to be used to estimate
final height [10].
Eventual adult height is principally determined
by genetic potential, although other environmental
(e.g. nutritional status) and endocrine/metabolic
factors (e.g. thyroid status, timing of puberty, etc.)
are known to play important roles. An interesting
example of the tight genetic regulation of growth
is the highly imprinted region of 11p15.5, which is
divided into two distinct domains. In domain 1,
normally the IGF-II gene is expressed only by the
506 www.co-pediatrics.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
paternal allele, whereas a gene counterbalancing
its effects (H19) is expressed exclusively from the
maternal allele [11]. IGF-II acts to promote foetal
growth, whereas H19 expression from the maternal
allele is thought to protect against having a large
baby, which could compromise the mother’s health.
The second domain consists of the maternally
expressed CDKN1C gene, which acts as an in-utero
negative regulator of cell growth and as a postnatal
tumour-suppressor gene. There are two other
imprinted regulatory genes in domain 2, KCNQ1
and KCNQ1OT1, which are paternally expressed
and regulate maternal gene expression. Epigenetic
alterations leading to reduced expression of
CDKN1C can act as a ‘double-negative’, resulting
in overgrowth. Perturbations in this region are also
responsible for cases of Beckwith–Wiedemann syn-
drome (BWS) as described below, and reciprocally
for the short stature seen in cases of Silver–Russell
syndrome.
TALL STATURE AND OVERGROWTH
SYNDROMES
Tall stature has been associated with occupational
success [12], which is presumably why referrals for
evaluation of tall stature are encountered far less
often than those for short stature. Children or
adolescents whose height exceeds the 97th centile
may also need assessment, though, particularly if
they are outside their predicted genetic height
potential and if tall stature is causing emotional
distress. Genetic height potential can be estimated
from a sex-adjusted mid-parental height (MPH)
calculation, which adjusts for the 13 cm difference
between the mean adult man and woman. This sex-
adjusted MPH is calculated by taking the average of
the parents’ heights and, if the child is a boy, adding
6.5 cm to this figure; conversely, if the child is a girl,
6.5 cm is subtracted. Plotting this calculated figure
on the adult end of the growth chart gives an
estimation of genetic height percentile expectation.
Comparison of height/height prediction with a
same-sex sibling may also be helpful in identifi-
cation of children with abnormal stature.
Commonest causes of tall stature are familial,
or growth acceleration driven by overnutrition,
but potential endocrinopathies should also be
considered. Commoner causes such as precocious
puberty, hyperthyroidism or congenital adrenal
hyperplasia may be uncovered, or rarer conditions
such as a growth hormone secreting adenoma,
familial glucocorticoid deficiency or the even rarer
aromatase deficiency. The latter has provided
important insight into the crucial actions of oestro-
gen at the growth plate. Loss of function mutations
Volume 24  Number 4  August 2012
 Overgrowth syndromes Neylon et al.

at CYP19A1 cause human aromatase deficiency molecular interactions underlying growth may
and resultant oestrogen deficiency. Affected male enable this to be achieved in the future. In the
individuals display tall stature with eunuchoid meantime, attempts are currently being made by
proportions, delayed bone age and osteoporosis. the European Society of Paediatric Endocrinology to
Treatment is with closely monitored oestrogen organize these types of disorders into a classification
replacement therapy [13,14]. system by phenotype in order to assist the practising
&
Figure 1 [15 ] displays a recently devised clinician. A description now follows of the most
algorithm for the assessment of tall stature and commonly encountered overgrowth syndromes,
overgrowth. Overgrowth presenting at birth may ordered according to their typical timing of clinical
be related to the intrauterine environment, the presentation.
prime example being an infant of a diabetic mother.
However, a specific overgrowth syndrome should
also be considered in any child with tall stature or SYNDROMES EXHIBITING OVERGROWTH
increased length, regardless of age, particularly if IN THE NEONATAL PERIOD
associated with learning difficulties or dysmorphic Syndromes more usually exhibiting overgrowth in
features. There is a wide assortment of genetic syn- the neonatal period include the following.
dromes currently described which have overgrowth
as a predominant feature, but their organization
into an obvious molecular classification system Beckwith–Wiedemann syndrome
is still difficult. It is possible that aberrant IGF BWS [OMIM#130650] should be suspected in an
signalling may represent a common link towards infant with macrosomia, macroglossia and an
providing the needed structural framework for this abdominal wall deficit, commonly exomphalos or
concept, and further clarification of the complex umbilical hernia. Hyperinsulinaemic hypoglycaemia

Height SDS > +2SDS Height < +2SDS

or but
Height-TH > +2SDS typical dysmorphic features

Dysmorphic?

No Yes

(Recent) growth acceleration? Disproportionate?

No
Yes

Height-TH > +2SDS? Puberty signs? No Yes

No Yes No Yes
Overgrowth syndromes
Klinefelter syndrome
Overgrowth syndromes Marfan syndrome
Sotos syndrome Marfan type II syndrome
Weaver syndrome CCA/Beals syndrome
Obesity Pituitary gigantism Precocious puberty Nevo syndrome Homocystinuria
Familial tall stature
Oestrogen deficiency/insensitivity Hyperthyroidism Pseudoprecocious Beckwith-Wiedemann syndrome Lujan Fryns syndrome
puberty Simpson-Golabi-Behmel syndrome
Constitutional PTEN-Hamartoma syndrome Other
advance in puberty Oestrogen deficiency or
insensitivity

FIGURE 1. Diagnostic flow chart for the differential diagnosis of tall stature and overgrowth syndromes. Chart modified from
Visser et al. [15 ]. Height-TH, current height percentile >2 SDS from target height percentile, the latter based on mid-parental
&

height calculation; SDS, standard deviation score.

1040-8703 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-pediatrics.com 507

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Endocrinology and metabolism
is reported in one-third to one-half of cases and
other associated features include posterior helical
ear pits or creases, hemihypertrophy, polycythae-
mia, cryptorchidism and variable organomegaly.
Somatic mosaicism may account for phenotypic
variability.
BWS is caused by alterations in the normal
dosage balance of a number of genes clustered at
11p15, a highly imprinted region of the genome,
which, as previously discussed, is organized into
two separately controlled domains. An estimated
85% of individuals with BWS have sporadic
mutations, the remainder displaying an autosomal
inherited pattern with maternal preferential trans-
& Weaver et al. first described this syndrome
mission [15 ]. BWS is a classical example of an
imprinting disorder, where genes are expressed
preferentially according to their ‘parent of origin’,
a process controlled by epigenetic mechanisms
(factors which influence the function or expression
of a gene without changing its structure, such as
methylation, noncoding RNA or histone modifi-
cation) [16]. Perturbation of genes at 11p15 occurs
through several different mechanisms including
uniparental disomy, maternally derived transloca-
tions and inversions, paternal duplications and
methylation defects. Essentially, these errors can
lead to biallelic (over)expression of IGF-2 or
reduction of CDKN1C expression with the resulting
BWS phenotype [17]. Neonatal issues in children
with BWS are significant, with a mortality rate
estimated as high as 21%, but surviving children
are healthy and may have normal intelligence.
Individuals have a risk of embryonal tumours
(Wilms and hepatoblastoma) of approximately
7.5% and screening in childhood is recommended,
particularly during the first 4 years [18].
Sotos syndrome
Sotos syndrome (cerebral gigantism) is relatively
rare with an incidence estimated at 1 in 15 000
[OMIM#117550]. It is caused by haploinsufficiency
of the gene NSD-1 (location 5q35.2–35.3) in
60–90% of cases and transmitted in an autosomal
dominant manner, although approximately 95% of
cases are due to de-novo mutations [19]. Mutations
vary by ethnicity, but include intragenic point
mutations (85%), whole-gene deletions (10%) and
exon deletions (5%) of NSD-1. How this results in
overgrowth is unclear, but growth hormone
secretion is normal, with varying serum levels of
IGF-I and ALS reported [20].
A characteristic triangular facies with marked
prognathism, combined with prenatal and post-
natal overgrowth, macrocephaly and intellectual
disability are considered the most reproducible
508 www.co-pediatrics.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
clinical features of Sotos syndrome. A diagnostic
scoring system has been developed [19]. Other
associated features include a high arched palate,
an advanced bone age and a high incidence of
central nervous system, cardiovascular and genito-
urinary malformations. Tumour risk is reported as
between 2 and 4%, usually presenting before the age
of 8–10 years, and periodic surveillance is recom-
mended [21]. These tumours include leukaemia,
lymphoma, neuroblastoma and sacrococcygeal
teratoma [22].
Weaver syndrome
[OMIM#277590] in 1974 in two boys, who both
displayed prenatal and postnatal overgrowth associ-
ated with markedly advanced bone age and macro-
cephaly. Other features comprise camptodactyly,
mild developmental delay and expressive language
difficulties. Significant overlap exists with Sotos
syndrome, but there are distinct differences in
facial appearance and dental maturation (which is
not advanced in Weaver syndrome, as opposed to
Sotos syndrome). There are some reports of NSD-1
mutations in affected individuals [23,24], but
whole-exome sequencing has recently identified
mutations in the EZH2 gene in two families and
&&
one classical proband [25 ]. Akin to NSD-1, this
gene codes for a histone methyltransferase, which
epigenetically acts to repress gene transcription
&&
[26 ]. Although EZH2 somatic mutations have been
identified in myeloid malignancies, overall the risk
of malignancy in Weaver syndrome is not currently
thought to be increased.
Simpson–Golabi–Behmel syndrome
Simpson–Golabi–Behmel syndrome [OMIM#
312870] is an X-linked recessive disorder caused by
mutations or deletions in the glypican 3 (GPC3) gene
located at Xq26.2. The GPC3 product is a heparan
sulfate proteoglycan anchored to the cell surface,
which appears to conduct a critical role in the
regulation of cell growth and division. Phenotypic
variability extends from a severe neonatal form, in
which babies often die in utero, to less severe forms
in which individuals survive into adulthood.
Affected individuals exhibit prenatal and postnatal
overgrowth with an adult height more than 97th
centile [27]. Other features include a characteristic
facies with macrocephaly, ocular hypertelorism,
epicanthic folds, broad nasal bridge, macrostomia
and macroglossia. Individuals sometimes also dis-
play syndactyly, cardiac defects (especially septal),
supernumerary nipples and cleft lip or palate. Intel-
lectual disability is common and tumour risk is
Volume 24  Number 4  August 2012

estimated at 7.5%, with 3-monthly surveillance
recommended [28]. Increased risk for Wilms tumour,
neuroblastoma, hepatocellular carcinoma and gona-
doblastoma is described [29].
Perlman syndrome
The molecular basis for the rare Perlman syndrome
[OMIM#267000] is unknown, but inheritance is
presumed to be autosomal recessive. It is character-
ized by polyhydramnios, foetal macrosomia, neph-
romegaly, hyperinsulinaemic hypoglycaemia and
dysmorphic facies (prominent forehead, deep-set
eyes and a broad depressed nasal bridge). Prognosis
is poor with a high neonatal mortality rate. There is
a high incidence of Wilms tumour (65%) in those
who survive infancy and growth patterns quickly
revert to the normal/low-normal range, inferring
that this also may not represent a true disorder of
overgrowth [30]. A recently published study has
identified germline mutations in DIS3L2 in patients
&&
with Perlman syndrome [31 ]. DIS3L2 is an exori-
bonuclease with cell growth and division regulatory
functions, overexpression of which has also been
detected in sporadic Wilms tumour.
Pallister–Killian syndrome
Pallister–Killian syndrome (PKS) [OMIM#601803] is
an extremely rare syndrome first described in 1976
and also known as tetrasomy 12p. PKS is character-
ized by multiple congenital anomalies including
pigmentary skin changes, severe intellectual dis-
ability and the mosaic presence of a tissue-limited
isochromosome 12p. Usually the supernumerary iso-
chromosome 12p is of maternal origin and isolated
from skin fibroblasts [32]. At least five patients have
had lymphocyte mosaicism for an isochromosome
12p, but this is usually not the case [33]. An older
maternal age effect has been suggested. Other clinical
features include seizures, hypotonia, contractures
with advancing age, a flat, broad nasal root with
anteverted nares and a long philtrum with a thin
upper lip displaying a distinct ‘cupid-bow’ shape.
Postnatal deceleration of length and head circum-
ference usually occurs.
OVERGROWTH SYNDROMES USUALLY
IDENTIFIED IN CHILDHOOD
Overgrowth syndromes which are more usually
identified in childhood include the following.
Klinefelter syndrome
Klinefelter syndrome is the most commonly
inherited disorder of sex chromosome aneuploidy,
1040-8703 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Overgrowth syndromes Neylon et al.
with a prevalence of 1.09–1.72 cases per 1000 births.
However, it is estimated that only 25–50% of cases
are diagnosed postnatally [34], with 21% diagnosed
prenatally and the other diagnostic peak (14.2%) at
30–34 years of age, generally secondary to investi-
&
gation of male infertility [35 ]. There is a wide
phenotypic spectrum, but a karyotype should
ideally be requested where tall boys have clinical
features such as small testes, pubertal failure or
arrest, gynaecomastia and variable cognitive/beha-
vioural difficulties in problem-solving, language or
planning [36]. Affected men have an increased risk
of germ cell tumours and breast cancer, as well as
auto-immune conditions. Klinefelter syndrome is
caused by the addition of one or more X chromo-
somes to the normal male 46XY karyotype, often
from nondysjunction errors. Most (80%) result in a
47,XXY karyotype, but other variants are reported,
including 48,XXXY, 48,XXYY, 49,XXXXY or 46XY/
47XXY mosaicism. In a study of 39 men with
47,XXY karyotype, 53% of this nondysjunction
appeared secondary to paternal meiosis I errors,
34% to maternal meiosis I errors, 9% to maternal
meiosis II errors and 3% to a postzygotic mitotic
error [37].
Tall stature in Klinefelter syndrome is primarily
due to increased leg length and has been attributed
to a dose-dependent effect of the short stature
homeobox gene located on the X chromosome,
which affects skeletal growth (haploinsufficiency
conversely can explain short stature in girls with
Turner syndrome 45X) [38]. Longer CAG repeats of
the androgen receptor have been described and
associated with both a later onset of puberty in
affected boys and paternal origin of the extra X
chromosome [39]. Serum gonadotropins are elevated
due to primary testicular failure and testosterone
replacement from puberty onwards is often needed,
primarily to prevent the long-term effects of
hypogonadism on bone density. This has no effect
on infertility, which is due to profound loss of germ
cells during early-to-mid-pubertal maturation [40].
Occasionally, foci of isolated spermatogenesis are
located in the tubules, offering potential for IVF
using intracytoplasmic sperm injection from micro-
testicular extracted sperm [41]. A 46% success rate has
been described using this technique and all offspring
were reported to have a normal karyotype [42].
PTEN-hamartoma syndrome
Also known as Bannayan–Riley–Ruvalcaba syn-
drome [OMIM#153480], PTEN-hamartoma syn-
drome is an autosomal dominant disorder caused
by haploinsufficiency of the PTEN gene on chromo-
some 10. This acts as a tumour-suppressor gene by
www.co-pediatrics.com 509
 Endocrinology and metabolism
producing a phosphatase which prevents cells
from replicating too rapidly [43]. Clinical features
include hamartomas of the intestine, haemangio-
mas, lipomatosis, penile macules and macroce-
phaly. Final height is normal secondary to growth
deceleration during childhood, raising the question
as to whether this represents a true overgrowth
syndrome. PTEN aberrations are responsible for
80% of cases of the adult-onset cancer syn-
drome Cowden syndrome as well as 20% of cases
of Proteus syndrome. Tumour surveillance recom-
mendations in children are unclear, but should be
undertaken in a similar manner to adults with
Cowden syndrome.
Other syndromes
A number of other conditions are described where
overgrowth can be a predominant feature. Marfan
syndrome, Loeys–Dietz syndrome and related
conditions are described in detail in an accompany-
ing review in this issue. Approximately 50% of
individuals affected with neurofibromatosis type 1
exhibit tall stature, and microdeletions in 17q11
are associated with overgrowth as well as a more
severe NF-1 phenotype (5% of all NF-1) [44]. Less
prevalent syndromes and regional overgrowth are
also described.
The autosomal recessive Nevo syndrome
[OMIM#601450] is caused by loss-of-function
mutations in the PLOD1 gene, and is considered
an allelic disorder with Ehlers–Danlos, kypho-
scoliotic form [45]. This gene product enhances
cross-linkage of collagen molecules, increasing
the stability of connective tissue. Affected infants
display prenatal and postnatal overgrowth, kypho-
sis, moderate hypotonia, talipes and oedematous
extremities. Intelligence is normal and final height
outcomes are not yet described. Management
involves symptomatic treatment of musculoskeletal
issues.
Regional overgrowth is also described in
conditions such as Klippel–Trenaunay–Weber
syndrome, wherein areas of localized tissue
hypertrophy occur in association with an under-
lying vascular malformation. These conditions
are not thought to represent true overgrowth dis-
orders.
Also worth noting, Proteus syndrome has its
onset in childhood and is characterized by dispro-
portionate, asymmetric overgrowth of body regions
starting during the first year of life [OMIM#176920].
Cerebriform connective tissue naevi are patho-
gnomic and there is a high risk of deep venous
thrombosis. Diagnostic criteria have been devel-
&
oped, but management remains difficult [46 ].
510 www.co-pediatrics.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The cause is as yet unknown, but theorized to be
secondary to somatic mosaicism of a gene defect
which is lethal in the nonmosaic form. A recent
report suggests an association with mutations in
AKT1, again discovered through exome sequencing
&&
[47 ].
CONCLUSION
Disorders of overgrowth are clinically quite variable
in presentation and the underlying pathogenetic
causes are often unclear. This likely reflects the
diversity of factors which regulate the molecular
control of growth and the cell cycle. The majority
of overgrowth conditions described arise from dys-
regulation at a cellular level, with an associated
attendant risk of malignancy. Hence, incorporating
a proactive cancer screening plan in the medical
treatment of these children is often necessary. Mul-
tidisciplinary team involvement is recommended
due to the complexity of these cases and genetic
counselling is a valuable resource for families.
Hormonal treatment aimed at limiting final height
has been generally unsuccessful and associated with
unacceptable side effects.
New genetic associations with tall stature are
constantly emerging, for example small supernum-
&
erary ring chromosomes [48 ], and, with increasing
technological advances, further elucidation of the
molecular mechanisms of these conditions will be
discovered. This has recently occurred as demon-
strated in both Weaver and Perlman syndromes.
It is interesting that children conceived using
assisted reproduction techniques are reported to
exhibit a slightly higher risk of imprinting disorders
[49] and evidence is emerging that IVF-conceived
children are taller than expected during childhood,
with elevated levels of serum IGF-I and IGF-II [50].
Future research is this area is clearly required.
The study of overgrowth syndromes offers
an exciting window into the complex factors
orchestrating the process of growth itself, and offers
hope to improve the clinical management of
affected children.
Acknowledgements
M.A.S. is supported through a National Health
and Medical Research Council Health Professional
Training Fellowship (APP1012201), and the Murdoch
Childrens Research Institute is supported in part by the
Victorian Government’s Operational Infrastructure
Support Program.
Conflicts of interest
There are no conflicts of interest.
Volume 24  Number 4  August 2012

REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 551–552).
1. Domingo-Sananes MR, Kapuy O, Hunt T, Novak B. Switches and latches: a
& biochemical tug-of-war between the kinases and phosphatases that control
mitosis. Philos Trans R Soc Lond B Biol Sci 2011; 366:3584–3594.
Interesting overview of mitosis, with the proposal that phosphate regulation is an
integral part of the mitotic switch, as opposed to just suppressing futile ongoing
cycles of dephosphorylation/phosphorylation.
2. Spath S-S, Andrade AC, Chau M, Nilsson O. Local regulation of growth plate
& cartilage. Endocr Dev 2011; 21:12–22.
Elucidates recent progress in paracrine control mechanisms at the growth plate.
3. Hietakangas V, Cohen SM. Regulation of tissue growth through nutrient
sensing. Annu Rev Genet 2009; 43:389–410.
4. Barbieri M, Bonafe M, Franceschi C, Paolisso G. Insulin/IGF-I-signaling
pathway: an evolutionarily conserved mechanism of longevity from yeast to
humans. Am J Physiol Endocrinol Metab 2003; 285:E1064–E1071.
5. Ohlsson C, Mohan S, Sjogren K, et al. The role of liver-derived insulin-like
growth factor-I. Endocr Rev 2009; 30:494–535.
6. Rikken B, van Doorn J, Ringeling A, et al. Plasma levels of insulin-like growth
factor (IGF)-I, IGF-II and IGF-binding protein-3 in the evaluation of childhood
growth hormone deficiency. Horm Res 1998; 50:166–176.
7. Nilsson O, Marino R, De Luca F, et al. Endocrine regulation of the growth
plate. Horm Res 2005; 64:157–165.
8. Chagin AS, Savendahl L. Estrogens and growth: review. Pediatr Endocrinol
Rev 2007; 4:329–334.
9. Greulich W, Pyle S. Radiographic atlas of skeletal development of the hand
and wrist. Stanford, California: Stanford University Press; 1950.
10. Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age:
revised for use with the Greulich–Pyle hand standards. J Pediatr 1952;
40:423.
11. Weksberg R, Shuman C, Beckwith JB. Beckwith–Wiedemann syndrome. Eur
J Hum Genet 2010; 18:8–14.
12. Judge TA, Cable DM. The effect of physical height on workplace success and
income: preliminary test of a theoretical model. J Appl Psychol 2004;
89:428–441.
13. Bilezikian JP, Morishima A, Bell J, Grumbach MM. Increased bone mass as a
result of estrogen therapy in a man with aromatase deficiency. N Engl J Med
1998; 339:599–603.
14. Carani C, Qin K, Simoni M, et al. Effect of testosterone and estradiol in a man
with aromatase deficiency. N Engl J Med 1997; 337:91–95.
15. Visser R, Kant SG, Wit JM, Breuning MH. Overgrowth syndromes: from
& classical to new. Pediatr Endocrinol Rev 2009; 6:375–394.
Excellent clinical reference of overgrowth syndromes, summarizing much original
work.
16. Martı́n-Subero JI. How epigenomics brings phenotype into being. Pediatr
Endocrinol Rev 2011; 9:506.
17. Choufani S, Shuman C, Weksberg R. Beckwith–Wiedemann syndrome. Am J
Med Genet C Semin Med Genet 2010; 154C:343–354.
18. DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in
children from the Beckwith–Wiedemann Syndrome Registry. J Pediatr 1998;
132 (3 Pt 1):398–400.
19. de Boer L, Kant SG, Karperien M, et al. Genotype–phenotype correlation in
patients suspected of having Sotos syndrome. Horm Res 2004; 62:197–207.
20. de Boer L, Hoogerbrugge CM, van Doorn J, et al. Plasma insulin-like growth
factors (IGFs), IGF-binding proteins (IGFBPs), acid-labile subunit (ALS) and
IGFBP-3 proteolysis in individuals with clinical characteristics of Sotos
syndrome. J Pediatr Endocrinol 2004; 17:615–627.
21. Gracia Bouthelier R, Lapunzina P. Follow-up and risk of tumors in overgrowth
syndromes. J Pediatr Endocrinol 2005; 18 (Suppl 1):1227–1235.
22. Tatton-Brown K, Rahman N. Sotos syndrome. Eur J Hum Genet 2007;
15:264–271.
23. Rio M, Clech L, Amiel J, et al. Spectrum of NSD1 mutations in Sotos and
Weaver syndromes. J Med Genet 2003; 40:436–440.
24. Douglas J, Hanks S, Temple IK, et al. NSD1 mutations are the major cause of
Sotos syndrome and occur in some cases of Weaver syndrome but are rare in
other overgrowth phenotypes. Am J Hum Genet 2003; 72:132–143.
25. Gibson WT, Hood RL, Zhan SH, et al. Mutations in EZH2 cause Weaver
&& syndrome. Am J Hum Genet 2012; 90:110–118.
Three de-novo mutations in EZH2 described &&
in two families, adding credence to
the publication of Tatton-Brown et al. [26 ].
26. Tatton-Brown K, Hanks S, Ruark E, et al. Germline mutations in the oncogene
&& EZH2 cause Weaver syndrome and increased human height. Oncotarget
2011; 2:1127–1133.
New report using exome-sequencing to demonstrate the link between EZH2
mutations and Weaver syndrome. These data provide further connections between
histone modifications and regulation of growth.
1040-8703 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Overgrowth syndromes Neylon et al.
27. Neri G, Moscarda M. Overgrowth syndromes: a classification. Endocr Dev
2009; 14:53–60.
28. Scott RH, Walker L, Olsen OE, et al. Surveillance for Wilms tumour in at-risk
children: pragmatic recommendations for best practice. Arch Dis Child 2006;
91:995–999.
29. Garganta CL, Bodurtha JN. Report of another family with Simpson–Golabi–
Behmel syndrome and a review of the literature. Am J Med Genet 1992;
44:129–135.
30. Alessandri J-L, Cuillier F, Ramful D, et al. Perlman syndrome: report,
prenatal findings and review. Am J Med Genet A 2008; 146A:2532–
2537.
31. Astuti D, Morris MR, Cooper WN, et al. Germline mutations in DIS3L2 cause
&& the Perlman syndrome of overgrowth and Wilms tumour susceptibility. Nat
Genet 2012; 44:277–284.
A previously unknown susceptibility locus was mapped and germline mutations in
DIS3L2 identified for the first time in individuals with Perlman syndrome. Functional
studies demonstrated that underexpression of this gene was associated with
cellular growth enhancement.
32. Struthers JL, Cuthbert CD, Khalifa MM. Parental origin of the isochromo-
some 12p in Pallister–Killian syndrome: molecular analysis of one
patient and review of the reported cases. Am J Med Genet 1999; 84:
111–115.
33. Theisen A, Rosenfeld JA, Farrell SA, et al. aCGH detects partial tetrasomy of
12p in blood from Pallister–Killian syndrome cases without invasive skin
biopsy. Am J Med Genet A 2009; 149A:914–918.
34. Abramsky L, Chapple J. 47,XXY (Klinefelter syndrome) and 47,XYY:
estimated rates of and indication for postnatal diagnosis with implications
for prenatal counselling. Prenat Diagn 1997; 17:363–368.
35. Herlihy AS, Halliday JL, Cock ML, McLachlan RI. The prevalence and
& diagnosis rates of Klinefelter syndrome: an Australian comparison. Med J
Aust 2011; 194:24–28.
Important work illustrating the high rate of underdiagnosis in Klinefelter syndrome.
36. Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter’s syndrome.
Lancet 2004; 364:273–283.
37. Jacobs PA, Hassold TJ, Whittington E, et al. Klinefelter’s syndrome:
an analysis of the origin of the additional sex chromosome using molecular
probes. Ann Hum Genet 1988; 52 (Pt 2):93–109.
38. Ogata T, Matsuo N, Nishimura G. SHOX haploinsufficiency and overdosage:
impact of gonadal function status. J Med Genet 2001; 38:1–6.
39. Wikstrom AM, Painter JN, Raivio T, et al. Genetic features of the X chromo-
some affect pubertal development and testicular degeneration in adole-
scent boys with Klinefelter syndrome. Clin Endocrinol (Oxf) 2006; 65:
92–97.
40. Houk CP, Rogol A, Lee PA. Fertility in men with Klinefelter syndrome.
Pediatr Endocrinol Rev 2010; 8 (Suppl 1):182–186.
41. De Sanctis V, Ciccone S. Fertility preservation in adolescents with
Klinefelter’s syndrome. Pediatr Endocrinol Rev 2010; 8 (Suppl 1):178–
181.
42. Schiff JD, Palermo GD, Veeck LL, et al. Success of testicular sperm extraction
(corrected) and intracytoplasmic sperm injection in men with Klinefelter
syndrome [Erratum appears in J Clin Endocrinol Metab 2006; 91:4027].
J Clin Endocrinol Metab 2005; 90:6263–6267.
43. Chu EC, Tarnawski AS. PTEN regulatory functions in tumor suppression and
cell biology. Med Sci Monit 2004; 10:RA235–RA241.
44. Spiegel M, Oexle K, Horn D, et al. Childhood overgrowth in patients
with common NF1 microdeletions. Eur J Hum Genet 2005; 13:883–
888.
45. Giunta C, Randolph A, Al-Gazali LI, et al. Nevo syndrome is allelic to the
kyphoscoliotic type of the Ehlers-Danlos syndrome (EDS VIA). Am J Med
Genet A 2005; 133A:158–164.
46. Thomason JL, Abramowsky CR, et al. Proteus syndrome: three case
& reports with a review of the literature. Fetal Pediatr Pathol 2012; 31:145.
Most recent reported cases of this exceedingly rare syndrome. This article
demonstrates the common pattern of initial misdiagnosis, as well as the clinical
spectrum of Proteus syndrome.
47. Lindhurst MJ, Sapp JC, Teer JK, et al. A mosaic activating mutation in AKT1
&& associated with the Proteus syndrome. N Engl J Med 2011; 365:611–
619.
This article reports the important discovery of a link between AKT1 and tissues
affected by the overgrowth in Proteus syndrome. A previously described link with
PTEN mutations and Proteus syndrome is now generally felt not to be accurate,
but AKT1 may represent a connection between the two, given that PTEN
underexpression results in activation of AKT1.
48. Melis D, Genesio R, Del Giudice E, et al. Selective cognitive impairment and
& tall stature due to chromosome 19 supernumerary ring. Clin Dysmorphol
2012; 21:27–32.
Report of the phenotype and molecular cytogenetic analysis in a patient with the
smallest de-novo constitutional ring of chromosome 19.
49. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with
Beckwith–Wiedemann syndrome and epigenetic alterations of LIT1 and
H19. Am J Hum Genet 2003; 72:156–160.
50. Miles HL, Hofman PL, Peek J, et al. In vitro fertilization improves child-
hood growth and metabolism. J Clin Endocrinol Metab 2007; 92:3441–
3445.
www.co-pediatrics.com 511