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ReviewJ M Wit and others Genetics of short stature 174 :4 R145–R173
MECHANISMS IN ENDOCRINOLOGY
Novel genetic causes of short stature
Jan M Wit1, Wilma Oostdijk1, Monique Losekoot2, Hermine A van Duyvenvoorde2,
Claudia A L Ruivenkamp2 and Sarina G Kant2
Departments of 1Paediatrics and 2Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden,
The Netherlands
Invited Author’s profile
Professor Jan Maarten Wit is currently Professor Emeritus and honorary staff member of the DepPaediatrics at Leiden University Medical Centre, The Netherlands. Trained as a paediatric endocrinserved as an Associate Professor of Paediatric Endocrinology in Utrecht and Full Professor/Chairman ofin Leiden. Most of his research has been focused on the diagnosis and management of growth disordeafter his PhD thesis (Responses to growth hormone therapy), he founded the Dutch Growth HormonGroup and the Dutch Growth Hormone Research Foundation’s bureau, instrumental in conductingmulticentre clinical trials on the efficacy and safety of growth hormone treatment. In Leiden, he leprojects on regulation of the epiphyseal growth plate and on referral criteria and diagnostic guidelinechildren, but the main subject focus over the last 10 years has been the elucidation of novel genetic cauand tall stature.
www.eje-online.org � 2016 European Society of EndocrinologyDOI: 10.1530/EJE-15-0937 Printed in Great Britain
Published by Bioscientifica Ltd.
Correspondence
should be addressed
to J M Wit
Abstract
The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic
hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure.
In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate.
We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and
fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting
disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone
deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several
novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH
insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered.
Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations
cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors
(FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause
disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also
rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other
syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal
abnormalities, CNVs, and imprinting disorders.
artoloParse Anuds f
ses
European Journal of
Endocrinology
(2016) 174, R145–R173
Introduction
The fast technological development has caused a flood of
novel discoveries in genetic causes of congenital disorders,
including syndromic and non-syndromic forms of short
stature. In the first decade of the 21st century, the genetic
toolbox was expanded by whole genome single nucleotide
polymorphism (SNP) array (1) and array-comparative
ment ofgist, he
ediatrics. Shortlydvisorymerous
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Review J M Wit and others Genetics of short stature 174 :4 R146
genomic hybridization (array-CGH) (2) for the detection
of microdeletions or microduplications (copy number
variants (CNVs)), the former of which is also able to detect
uniparental disomy. In the second decade an even more
successful tool became available – whole exome sequen-
cing (WES) – for the detection of gene variants as possible
causes of congenital disorders (3, 4, 5, 6), with a good
diagnostic yield in well-selected patients (6). In general,
WES is performed in an index patient and his/her parents
(a ‘trio’), and (if available) affected and non-affected
siblings, to limit the number of informative variants in
the bioinformatic analysis.
At the same time, information about genes associated
with linear growth was collected through non-clinical
research, in particular through genome-wide association
studies (GWAS) and animal and in vitro experiments on
epiphyseal growth plate (GP) function. GWAS have shown
that common SNPs at over 400 loci contribute to variation
in normal adult stature, albeit with a small effect size per
locus (7). Many of these genes, but also others, have
appeared in gene expression studies in the various zones
of the GP (8, 9).
For this review we chose to focus on discoveries made
in the last 10 years (up to August 2015), against the
background of earlier findings, as summarized in previous
reviews by our group (10, 11, 12, 13) and others (5, 14, 15,
16, 17) (for search strategy see section at the end of the
article). The tables offer the formal names of the disorders
and codes according to online Mendelian inheritance in
man (OMIM) (http://www.ncbi.nlm.nih.gov/omim), and
we aimed at providing the most recent relevant references.
In line with a recent review paper (17), we structured
this review according to a diagnostic classification centred
on the GP. In the GP, chondrocytes proliferate, hyper-
trophy, and secrete cartilage extracellular matrix, under
the influence of endocrine and paracrine factors. Thus, in
this review successively hormones, paracrine factors,
matrix molecules, intracellular pathways, and fundamen-
tal cellular processes will be discussed, followed by CNVs
and imprinting disorders. Because the GP is the structure
where linear growth takes place, we prefer this patho-
physiologic classification above the multiple reported
alternative classifications, for example proportionate vs
disproportionate short stature; with or without micro-
cephaly (18); prenatal vs postnatal onset of growth
retardation (19); or growth hormone (GH) deficiency or
insensitivity (20).
A complicating factor in the classification of mono-
genic disorders is that a variety of mutations in one gene
can result in a broad phenotypic spectrum, sometimes
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including different clinical entities, previously defined as
separate conditions (‘allelic heterogeneity’). On the other
hand, one clinical disorder can be caused by mutations in
different genes (‘locus heterogeneity’) (14). Furthermore,
mutations in some genes not only impair GP development
and/or function but also non-skeletal structures, causing
associated congenital anomalies (syndromic short
stature) (17).
The last decades have taught us that with time the
clinical phenotype of genetic defects tends to become
more variable than initially assumed. The rapid increase
of the use of SNP arrays and WES in the coming years, and
the expected appearance of whole genome sequencing
(WGS), RNA sequencing, and methylation assays, will
certainly lead to the discovery of many more novel causes
of short stature, as well as a further expansion of the
clinical phenotypes associated with genetic and epigenetic
variants.
Genetic defects of the GH–insulin-likegrowth factor 1 axis
The GH––insulin-like growth factor 1 (IGF1) axis is an
important pathway in the regulation of linear growth, and
defects have been found in virtually all components of this
cascade. Tables 1 and 2 show conditions associated with
GH or IGF1 signalling, divided into three categories: i) GH
deficiency (GHD); ii) GH insensitivity (GHI) and decreased
expression or biologic activity of IGF1 or IGF2; and iii)
IGF1 insensitivity. For various genes, a publicly available
database has been established (www.growthgenetics.com)
(21), and clinicians and geneticists are encouraged to
upload clinical and genetic data of additional cases.
GH deficiency
Table 1 shows the gene defects that have been associated
with GHD. Many of the proteins encoded by these
genes are associated with GHD as part of combined
pituitary hormone deficiency (CPHD), and function as
pituitary transcription factors (for detailed information on
associated clinical features and MRI appearances see (5, 22,
23, 24)). A novel endocrine syndrome discovered by our
group, immunoglobulin superfamily member 1 (IGSF1)
deficiency syndrome, is primarily characterized by central
hypothyroidism and macroorchidism, but can also
present with hypoprolactinaemia and transient partial
GHD (25, 26). The association of Netherton syndrome
with GH and prolactin deficiency suggests that a defect of
LEKT1 (encoded by SPINK5) may increase the degradation
Table 1 Causes of GHD.
Disordera Gene(s) Clinical features Inheritance References
GHD and potential for CPHDCPHD-1 (613038) POU1F1 GH, PRL, var. TSH def. AR, AD (5, 22, 23)CPHD-2 (262600) PROP1 GH, PRL, TSH, LH, FSH, var. ACTH def.
Pituitary can be enlarged.AR (5, 22, 23)
CPHD-3 (221750) LHX3 GH, TSH, LH, FSH, PRL def. Sensorineural hearingloss, cervical abnormalities, short stiff neck
AR (5, 22, 23)
CPHD-4 (262700) LHX4 GH, TSH, ACTH def. AD, AR (5, 22, 23)Septo-optic dysplasia (CPHD-5)(182230)
HESX1 Optic nerve hypoplasia, pituitary hypoplasia,midline abnormalities of brain, absent corpuscallosum and septum pellucidum
AR, AD (5, 22, 24)
CPHD-6 (613986) OTX2 TSH, GH, LH, FSH, var. ACTH and PRL def. AD (5, 22, 24)Axenfeld–Rieger syndrome type 1(180500)
PITX Coloboma, glaucoma, dental hypoplasia,protuberant umbilicus, brain abnormalities,var. pituitary def.
AD (22)
Optic nerve hypoplasia andabnormalities of the centralnervous system (206900)
SOX2 Var. GHD, hypogonadism, anophthalmia,developmental delay
AD (22, 24)
X-linked panhypopituitarism(312000, 300123)
SOX3dupb GHD or CHPD, mental retardation XLR (5, 22, 24)
Dopa-responsive dystonia due tosepiapterin reductase deficiency(612716)
SPR Diurnally fluctuating movement disorder,cognitive delay, neurologic dysfunction,GH and TSH def.
AR (237)
Holoprosencephaly 9 (610829) GLI2 Holoprosencephaly, craniofacial abnormalities,polydactyly, single central incisor, partial agen-esis corpus callosum (or hypopituitarism only)
AD (5, 22)
IGSF1 deficiency syndrome(300888)
IGSF1 TSH, var. GH and PRL def.; macroorchidism XLR (26)
Netherton syndrome (256500) SPINK5 Var. GH and PRL def. AR (27)Pallister–Hall syndrome (146510) GLI3 Hypothalamic hamartoma, central polydactyly,
visceral malformationsAD (5)
FGF8 Holoprosencephaly, septo-optic dysplasia,Moebius syndrome
AR (5, 24)
FGFR1 Hypoplasia pituitary, corpus callosum, oculardefects
AD (5, 238)
PROKR2 Var. hypopituitarism AD (238)HMGA2 Severe GHD, ectopic posterior pituitary AD (239, 240)GRP161 Pituitary stalk interruption syndrome, intellectual
disability, sparse hair in frontal area, hypo-telorism, broad nasal root, thick alae nasi, nailhypoplasia, short fifth finger, 2–3 toe syndactyly,hypopituitarism
AR (241)
Isolated GHD or bioinactivityIsolated GHD, type IB (612781) GHRHR Low serum GH AR (240, 242)Isolated GHD, type 1A (262400) GH1 No serum GH, often anti-GH ab AR (240, 242)Isolated GHD, type IB (612781) GH1 Low serum GH AR (240, 242)Isolated GHD, type II (173100) GH1 Var. height deficit and pituitary size; other pituitary
deficits can developAD (240, 242)
Isolated GHD, type III (307200) BTK, SOX3 GHD with agammaglobulinemia XLR (240, 242)Isolated partial GHD (615925) GHSR Var. serum GH and IGF1 AR, AD (39, 41)Kowarski syndrome (bioinactiveGH syndrome) (262650)
GH1 high GH; def. of IGF1, IGFBP-3, and ALS AD (242)
Almstrom syndrome (203800) ALMS1 50% of cases are GHD AR (35)RNPC3 Severe GHD, hypoplasia anterior pituitary AR (33)IFT172 Functional GHD, retinopathy, metaphyseal
dysplasia, hypertensionAR (34)
AD, autosomal dominant; AR, autosomal recessive; def., deficiency; GHBP, growth hormone binding protein; GHD, growth hormone deficiency;IGF1, insulin-like growth factor 1; IGFBP-3, IGF binding protein-3; PRL, prolactin; var., variable; XLR, X-linked recessive.aName (number) according to OMIM. For clinical and radiological features of the various conditions, see (5, 22, 23, 24).bThis condition can also be caused by SOX3 polyalanine deletions and expansions.
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Table 2 Causes of GH insensitivity or IGF insensitivity.
Disordera Gene(s) Clinical features Inheritance References
GH insensitivityLaron syndrome (262500) GHR Variable height deficit and GHBP,
midfacial hypoplasia;[GH, YIGF1,IGFBP-3 and ALS
AR (AD) (46, 242)
GH insensitivity with immuno-deficiency (245590)
STAT5B Midfacial hypoplasia, immuno-deficiency; [GH and PRL; YIGF1,IGFBP-3 and ALS
AR (55)
Multisystem, infantile-onsetautoimmune disease (615952)
STAT3 (act) Associated with early-onset multi-organautoimmune disease
AD (68, 69)
X-linked severe combinedimmunodeficiency (300400)
IL2RG GH normal, low IGF1, non-respondingto GH injections
XLR (243, 244)
IGF1 deficiency (608747) IGF1 SGA, microcephaly, deafness; [GH andIGFBP-3; variable IGF1
AR (13)
Severe growth restriction withdistinctive facies (616489)
IGF2 Y[/nl GH, IGFBP3; nl IGF1 Pat inheritance (82)
ALS deficiency (615961) IGFALS Mild height deficit; GH?,YIGF1, IGFBP-3and ALS
AR (59)
PAPP-A2 Microcephaly, skeletal abnormalities,[GH, IGF1, IGFBP-3, and ALS
AR (84)
Immunodeficiency 15 (615592) IKBKB Immunodeficiency; YIGF1 and IGFBP-3 AR, AD (65)IGF insensitivityResistance to insulin-like growthfactor 1
IGF1R SGA, microcephaly; [/nl GH, IGF1, andIGFBP-3
AD, AR (85)
act, activating; AD, autosomal dominant; ALS, acid-labile subunit; AR, autosomal recessive; GH, growth hormone; GHBP, growth hormone binding protein;IGF1, insulinlike growth factor 1; IGFBP-3, insulin-like growth factor binding protein 3; SGA, small for gestational age; XLR, X-linked recessive.aName (number) according to OMIM.
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Review J M Wit and others Genetics of short stature 174 :4 R148
of these hormones in pituitary cells by human tissue
kallikreins before they enter the circulation (27). Other
causes of CPHD include mutations in GLI3, FGF8, FGFR1,
PROKR2, HMGA2, and GRP161 (Table 1).
Isolated GHD mutations in the genes encoding GH
(GH1) or GH releasing hormone receptor (GHRHR) can be
found in up to 34% in familial cases (28). GH1 mutations
can either lead to classical GHD (types IA, IB, and II) or
bioinactive GH syndrome. While in the past the latter
diagnosis was used without good experimental evidence,
recent reports have shown that this is a real condition,
characterized by normal or even elevated circulating GH
levels, and in some cases also associated with partial GHI
(28, 29, 30).
The most common cause of type IA GHD is a
homozygous GH1 deletion; in most of such patients
anti-GH antibodies develop with GH treatment. However,
several other aberrations of GH1 have been described. The
less severe type IB GHD is caused by mutations of GH1 or
GHRHR, and a dominant form of GHD (type II) is usually
caused by skipping of exon 3 resulting in production of a
17.5-kDa isoform of GH with a dominant negative effect
(28). The X-linked type III GHD is associated with
agammaglobulinaemia, and has been associated with
mutations in BTK (31) and SOX3 (32).
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Isolated GHD can also be caused by biallelic mutations
in RNPC3, which encodes a minor spliceosome protein
required for U11/U12 small nuclear ribonucleoprotein
(snRNP) formation and splicing of U12-type introns (33).
Compound heterozygosity for a gene encoding a protein
important for ciliary function (IFT172) can cause
functional GHD, pituitary hypoplasia, and ectopic pos-
terior pituitary (34), and also Alstrom syndrome, caused
by a mutation of ALMS1 encoding a protein localized to
the centrosomes and basal bodies of ciliated cells (35) is
associated with GHD. GHD has also been documented
in a congenital malformation syndrome associated with a
paternal deletion of 6q24.2–q25.2 (36), complete general-
ized glucocorticoid resistance (37), and mitochondrial
diseases (38).
A still insufficiently defined cause of GHD is a
mutation of the gene encoding the Ghrelin receptor
(GHSR) (reviewed in (39)). The variability of clinical
phenotypes (GHD, idiopathic short stature (ISS) and
constitutional delay of growth and puberty (CDGP)) and
incomplete segregation of the mutations with the pheno-
type still cast doubt on the role of GHSR mutations in
causing short stature, although functional studies do
suggest that GHSR mutations may decrease GH secretion
(40, 41, 42), implying that GHSR mutations may
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contribute to the genetic aetiology of children originally
considered ISS (41).
GHI and decreased expression or biologic activity of
IGF1or IGF2
Table 2 shows the various syndromes presenting with
insensitivity to GH or IGF1. The first discovered cause
of GHI was Laron syndrome, usually caused by a
homozygous mutation of the gene encoding the GH
receptor (GHR) (43, 44, 45). Since then more than 70
mutations in O300 cases have been found with mutations
in extracellular, transmembrane, and intracellular parts of
the GHR (46, 47). In most cases serum GH binding protein
(GHBP) is absent, except in cases with a mutation in the
intracellular or transmembrane part of the protein. While
the classical form causes severe growth failure, there are
milder forms as well, for example caused by an intronic
base change leading to the activation of a pseudoexon
sequence and insertion of 36 new amino acids within the
receptor extracellular domain (48, 49, 50) or by hetero-
zygous GHR mutations causing a dominant negative effect
(51, 52, 53).
In 2003 the first patient with a homozygous loss-
of-function mutation of the gene encoding the main
component of the intracellular GH signalling pathway
(STAT5B) was found (54), and since then ten patients have
been reported in seven families (55). Most have an
additional immunodeficiency and pulmonary fibrosis
(56). Heterozygosity for a STAT5B mutation leads to a
slightly lower height (57).
Another well-defined cause of GHI is a defect in
IGFALS, encoding acid-labile subunit (ALS) which forms
with IGF binding protein 3 (or 5) and IGF1 (or IGF2) a
ternary complex in the circulation (58, 59). Children with
ALS deficiency show a mild growth failure, delayed
puberty, undetectable serum ALS, low serum IGF1, and
even lower IGF binding protein 3 (IGFBP-3) (59), and
variable osteopenia and hyperinsulinism (60, 61, 62).
Heterozygosity for IGFALS variants causes a one S.D. lower
height (60, 62, 63) and may be responsible for a subset of
children previously considered having ISS (64).
GHI may also be caused by a mutation in the gene
encoding IkBa (IKBKB), presenting with short stature,
GHI, severe immune deficiency and other features (65) or a
PRKCA duplication, in a patient with a mosaic de novo
duplication of 17q21–25 (66) (reviewed in (67)). Further-
more, activating STAT3 mutations may be not only
associated with early-onset multi-organ autoimmune
disease, but also with growth failure (68, 69).
Homozygous deletions or missense mutations of
IGF1 (encoding IGF1) resulting in a complete loss-of-
function (70, 71) cause a severe prenatal and postnatal
growth failure, developmental delay, microcephaly, and
sensorineural deafness. Patients with a homozygous
hypomorphic mutation (72) or specific heterozygous
mutations (73, 74) presented with less severe growth failure
and normal hearing (reviewed in (75)). Heterozygous
carriers of IGF1 mutations or deletions are w1 S.D. shorter
than non-carriers (71, 73, 74, 76).
With regard to IGF2, it is assumed that in most
children with Silver–Russell syndrome the pre- and post-
natal growth restriction is caused by deficient expression
of the paternally expressed gene encoding IGF2 (IGF2) (77,
78), usually through H19 hypomethylation. Such children
can have relatively high serum IGF1 and IGFBP-3,
suggesting partial IGF1 resistance (79, 80). In contrast,
Silver–Russell syndrome patients carrying a maternal
uniparental disomy of chromosome 7 (UPD7) usually
present with low levels of IGF1 (79, 81). Very recently, the
first family with a paternally inherited IGF2 mutation
and growth restriction was reported, indicating that
IGF2 not only is a mediator of intrauterine development
but also contributes to postnatal growth (82). This
confirmed an earlier observation of a patient with a
paternally transmitted severe intrauterine growth retar-
dation (IUGR) with a translocation breakpoint disrupting
regulation of IGF2 (83).
Another novel finding is that a homozygous mutation
of the gene encoding the protease PAPPA-2 (PAPPA2) is
associated with mild short stature, presumably by insuffi-
cient availability of free IGF1 (84).
IGF1 insensitivity
Numerous cases have been reported of heterozygous
mutations or deletions of the gene encoding the receptor
for IGF1 (and IGF2) (IGF1R) (reviewed in (75, 85)). Clinical
features include prenatal growth failure persisting after
birth, microcephaly, and serum IGF1 in the upper half of,
or above, the normal range. On GH treatment serum IGF1
can become very high, which may probably be accepted
because of the decreased sensitivity. We estimate that
IGF1R defects can be found in w3% of short children born
small for gestational age (SGA) (86). A homozygous or
compound heterozygous IGF1R mutation leads to a more
severe phenotype (87, 88, 89, 90). In theory, IGF1
insensitivity may also be caused by mutations downstream
of the IGF receptor, or by defective microRNA regulation
of IGF1 signalling (91).
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Genetic defects affecting signalling of otherhormones regulating GP function
Congenital disorders of thyroid hormone signalling
include primary hypothyroidism (thyroid dysgenesis or
dyshormonogenesis) and thyroid hormone resistance.
If undiagnosed, congenital hypothyroidism leads to very
severe growth failure (92), but in most middle- and high-
income countries early detection by neonatal screening
will prevent this, as well as the severe consequences for
mental development. Presently known genetic causes of
thyroid dysgenesis and dyshormonogenesis have recently
been reviewed (17, 93).
Children with thyroid hormone resistance caused by
mutations of THRB (encoding the beta form of the thyroid
hormone receptor (TRb)) usually show normal growth, but
in severe cases short stature has been observed (94).
In contrast, all reported children with mutations in
THRA (encoding TRa) are short. Further clinical features
include delayed mental and bone development, consti-
pation, and relatively low serum T4 and high serum T3
levels (elevated T3/T4 ratio) (95, 96). An opposite serum
thyroid hormone profile (elevated T4 and low-normal or
slightly decreased T3) is seen in a homozygous or
compound heterozygous mutation of SECISBP2 (SBP2)
(encoding an iodothyronine deiodinase), associated with
short stature and responding to GH and T3 treatment (97).
It is well known that growth failure can be caused by
excessive exposure to glucocorticoids, due to Cushing
syndrome or pharmacological doses of corticosteroids.
A discussion of newly discovered genetic causes of ACTH-
dependent and independent Cushing syndrome is outside
the scope of this paper (for recent findings, see (98, 99)).
Homozygous or compound heterozygous mutations of the
gene encoding the insulin receptor (INSR) cause Donohue
syndrome (Leprechaunism) (100).
Genetic defects affecting paracrine factorsin the GP
Paracrine regulation plays a major role in the GP, and only
part of its complexity is presently understood. Most of the
genetic defects of paracrine pathways result in some form
of skeletal dysplasia, of which 436 conditions, caused by
defects in 364 genes, have been listed in the 2015 revision
of the nosology of genetic skeletal disorders (101).
Disproportionate short stature is one of the main features
of most of these conditions. Therefore, in the clinical
assessment of the short individual, not only accurate
measurements of height and head circumference have to
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be carried out, but also of sitting height and arm span, and
the same measurements should be performed in the
parents. The length of upper and lower arms and legs,
and hands and feet, should be at least visually assessed,
and possibly measured and compared with normative
charts (a relatively short upper arm and leg is called
rhizomelia, in contrast to mesomelia if forearm and lower
leg are relatively short). A series of skeletal radiographs
usually gives important clues for the diagnosis (15, 102,
103, 104). Most forms of skeletal dysplasia show short-
limb dwarfism, in contrast to type I and II collageno-
pathies which are characterized by short-trunk dwarfism
(14). Because a comprehensive review of these conditions
is beyond the scope of this article, only a few relatively
common conditions are discussed (Table 3).
Fibroblast growth factor signalling
Several fibroblast growth factors (FGFs) and their receptors
play a role in the GP (9, 105). Best known is the FGF
receptor-3 (encoded by FGFR3), which acts as a negative
regulator of GP chondrogenesis (106, 107). Consequently,
heterozygous activating mutations in FGFR3 impair bone
elongation and lead to a spectrum of disorders, reflecting
the degree of activation of the FGFR3 mutation. The best
known examples are thanatophoric dysplasia, achondro-
plasia, and hypochondroplasia, each associated with
different locations of the mutation. The clinical presen-
tation of hypochondroplasia is milder and more variable
than achondroplasia and includes rhizomelic limb
shortening, limitation of elbow extension, brachydactyly,
relative macrocephaly, generalized laxity, and specific
radiologic features (5, 108). We recently reported a novel
activating FGFR3 mutation in a family with proportionate
short stature (109).
Bone morphogenetic protein signalling
Bone morphogenetic proteins (BMPs), also known as
growth and differentiation factors (GDFs), belong to the
transforming growth factor-beta (TGFb) superfamily of
paracrine factors. The BMPs regulate a multitude of
processes in skeletal development, including spatial
regulation of proliferation and differentiation in the GP,
and a BMP signalling gradient across the GP may
contribute to the progressive differentiation of resting to
proliferative to hypertrophic chondrocytes (9). Inacti-
vating mutations in the genes for several BMPs, their
receptors, and antagonists cause various forms of skeletal
dysplasias, particularly brachydactylies.
Table 3 Examples of genetic defects affecting paracrine factors in the growth plate.
Disordera Gene(s) Clinical features Inheritance References
FGF signalingPfeiffer syndrome, acrocephalo-syndactyly, type V (101600)
FGFR1, FGFR2 Craniosynostosis with characteristicanomalies of the hands and feet(three types)
AD (245)
Thanatophoric dysplasia type I(187600)
FGFR3 (act) Severe short-limb dwarfism syndrome usuallylethal in the perinatal period
AD (9)
Achondroplasia (100800) FGFR3 (act) Rhizomelic limb shortening, frontal bossing,midface hypoplasia, exaggeratedlumbar lordosis, limited elbow extension,genu varum, trident hand
AD (9)
Hypochondroplasia (146000) FGFR3 (act) Short-limbed dwarfism, lumbar lordosis,short and broad bones, caudal narrowingof interpediculate distance of lumbar spine
AD (9, 108, 246)
Short stature FGFR3 (act) Relative macrocephaly for height AD (109)BMP signalingBrachydactyly A1 (112500) IHH, GDF5,
BMPR1BMiddle phalanges rudimentary or fused with
terminal phalanges, short proximalphalanges thumbs and big toes
AD (247)
Brachydactyly A2 (112600) BMPR1B, BMP2,GDF5
Malformations of middle phalanx of indexfinger, anomalies of second toe
AD (248)
Brachydactyly C (113100) GDF5, CDMP1 Deformity of middle and proximal phalanges(II, III), hypersegmentation of proximalphalanx
AD (249)
WNT signalingRobinow syndrome (268310) ROR2, WNT5A Frontal bossing, hypertelorism, broad nose,
short-limbed dwarfism, vertebralsegmentation, genital hypoplasia
AR, AD (112)
Brachydactyly, Type B1 (113000) ROR2 Short middle phalanges, terminal phalangesrudimentary or absent; deformed thumbs,big toes
AD (113)
PTHrP-IHH pathwayBrachydactyly, type E2 (613382) PTHLH Short stature and learning difficulties AD (116)Blomstrand chondro-dysplasia(215045)
PTHR1 Short limbs, polyhydramnios, hydrops fetalis,facial anoma-lies, increased bone density,advanced skeletal maturation
AR (117)
Jansen type of meta-physealchondrodys-plasia (156400)
PTHR1 (act) Severe short stature, short bowed limbs,clinodactyly, prominent upper face,small mandible; hypercalcemia andhypophosphatemia
AD (118)
Brachydactyly type A1 (112500) IHH, GDF5,BMPR1B
Middle phalanges rudimentary or fused withterminal phalanges. Short proximalphalanges of thumbs, big toes
AD (119)
Acrocapitofemoral dysplasia(607778)
IHH Variable short stature, short limbs withbrachydactyly, relatively large headcircumference
AR (119)
Albright hereditary osteodystrophy(103580)
GNAS Pseudohypoparathyroidism, type Ia/c.Caused by loss of function of Gs-alphaisoform of GNAS on maternal allele.For further details see Table 8
Imprinted (228)
Acrodysostosis 1 (101800) PRKAR1A Severe brachydactyly, facial dysostosis, nasalhypoplasia, advanced bone age, obesity,resistance to multiple hormones
AD (121)
CNP-NPR2 pathwayAcromesomelic dysplasia,Maroteaux type (602875)
NPR2 Disproportionate shortening of middlesegments (forearms and forelegs) anddistal segments (hands and feet)
AR (124)
(Dis)proportionate short stature NPR2 Moderate short stature, short forearms andforelegs
AD (130)
AD, autosomal dominant; AR, autosomal recessive; act, activating.aName (number) according to OMIM.
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WNT signalling
The receptor tyrosine kinase-like orphan receptor 2 (RoR2) is
part of a conserved family of tyrosine kinase-like receptors
that serve as receptors for noncanonical WNT ligands,
participating in developmental processes like cell move-
mentand cellpolarity (110, 111). Homozygous mutations of
ROR2 or heterozygous mutations of WNT5A cause Robinow
syndrome (112) and dominant ROR2 mutations cause
brachydactyly, Type B1 (113).
PTHrP–IHH pathway
Parathyroid hormone related peptide (PTHrP) and Indian
Hedgehog (IHH) form a negative feedback loop within the
GP that regulates chondrocyte hypertrophy and prolifer-
ation (114, 115). Heterozygous loss-of-function mutations
in PTHLH, encoding PTHrP, and inactivating and activat-
ing mutations in PTHR1 (encoding the parathyroid
hormone receptor-1) cause various short stature syn-
dromes (116, 117, 118), as well as inactivating and
activating mutations of IHH (119, 120). Heterozygous
missense mutations in PRKAR1A and PDE4D cause
acrodysostosis 1 and 2 respectively, with or without
hormone resistance (121, 122).
CNP–NPR2 pathway
One of the most interesting breakthroughs in the field
of growth genetics is the unravelling of the role of
C-natriuretic peptide (CNP, encoded by NPPC) and its
receptors in GP function. CNP is a local, positive regulator
of GP function, and SNPs in NPPC and in the gene encoding
one of its receptors (NPR3) show a significant association
with adult height in GWAS (123). Homozygous inactivat-
ing mutations of NPR2 (encoding the main CNP receptor)
cause a severe skeletal dysplasia, acromesomelic dysplasia,
Maroteaux type (124). Initial observations that relatives
heterozygous for NPR2 mutations of patients with acrome-
somelic dysplasia are shorter than non-carriers (125), were
confirmed by recent studies (126, 127, 128, 129). The
phenotype of heterozygous NPR2 mutations is similar to
that of patients with SHOX haploinsufficiency (Leri–Weill
syndrome), with short forearms and lower legs
(mesomelia), except for the absence of Madelung deformity
(130). Heterozygous NPR2 mutations may explain 2–3% of
cases with assumed ISS (129) and probably more if one of
the parents has a similar phenotype.
Unravelling of the role of this pathway in linear
growth has led to potential therapeutic consequences for
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children with achondroplasia. Binding of CNP to NPR2
stimulates the receptor guanylyl cyclase activity thereby
increasing synthesis of cGMP, activating the type II cGMP-
dependent protein kinase (131), which in turn leads to
inhibition of the MAPK pathway, thus antagonizing FGFR
signalling (132). In a mouse model of achondroplasia,
CNP had beneficial effects (133), and clinical trials with a
long-acting CNP analogue are in progress in children with
achondroplasia.
Genetic defects affecting cartilageextracellular matrix
A unique characteristic of chondrocytes is that they
secrete an extracellular matrix containing specific
collagens, non-collagenous proteins and proteoglycans,
which are vital to normal GP function. This extracellular
matrix not only provides the compressible, resilient
structural properties of cartilage, but also interacts with
signalling molecules to regulate GP chondrogenesis (17).
Mutations in several genes encoding matrix proteins
and proteoglycans have been shown to lead to growth
disorders (Table 4). Mutations in ACAN, encoding aggre-
can, show a gene-dose effect: homozygous mutations
cause a severe skeletal dysplasia, spondyloepimetaphyseal
dysplasia aggrecan type (134), while heterozygous
mutations can present as a milder skeletal dysplasia,
spondyloepiphyseal dysplasia type Kimberley, or as short
stature without evident radiographic skeletal dysplasia
(135). This latter form is associated with an advanced bone
age and early cessation of growth (17, 135).
Some disorders, such as the genetically heterogeneous
brachyolmia, tend to affect the spine more than the long
bones, for example mutations in PAPSS2 encoding a
sulphotransferase, required for sulphation of a variety of
molecules, including cartilage glycosaminoglycans and
DHEA (136, 137).
Genetic defects of intracellular pathways
Various intracellular pathways play a role in chondrocyte
differentiation in the GP, and examples of disorders in
such pathways are listed in Table 5.
For the clinician, the relatively frequent aberrations of
the gene encoding short stature homeobox (SHOX)
(located at the tip of the X and Y chromosome, and
transmitted in a pseudoautosomal fashion) are most
relevant. SHOX acts as a transcriptional activator and,
like in NPR2 mutations, a gene-dose effect is apparent:
homozygous or compound heterozygous inactivating
Table 4 Examples of genetic defects affecting cartilage extracellular matrix.
Disordera Gene(s) Clinical features Inheritance References
Acromicric dysplasia (102370) FBN1 Severe short stature, short hands and feet,joint limitations, skin thickening
AD (250, 251)
Geleophysic dysplasia-2 (614185) FBN1 Severe short stature, short hands and feet,joint limitations, skin thickening, heartinvolvement
AD (250, 251)
Brachyolmia type 4 with mildepiphyseal and metaphysealchanges (spondyloepimeta-physeal dysplasia, Pakistanitype) (612847)
PAPSS2 Short trunk, normal intelligence and facies;rectangular vertebral bodies with irregularendplates and narrow intervertebral discs,precocious calcification of rib cartilages,short femoral neck, mildly shortenedmetacarpals, and mild epiphyseal andmetaphyseal changes of the tubular bones
AR (137, 252)
Hurler syndrome (607014) IDUA Skeletal deformities, corneal clouding,hepatosplenomegaly, psychomotor delay
AR (253)
Metaphyseal chondro-dysplasia,Schmid type (156500)
COL10A1 Short stature, widened growth plates,bowing of long bones
AD (254)
Multiple epiphyseal dysplasia 1–6 COMP, COL9A2,COL9A3, SLC26A2,MATN3, COL9A1
Short-limbed dwarfism, joint pain andstiffness and early onset osteoarthritis
AD (255)
Pseudoachondro-plasia (177170) COMP Disproportionate short stature, deformity oflower limbs, brachydactyly, loose joints,ligamentous laxity, vertebral anomalies,osteoarthritis
AD (256)
Spondyloepiphyseal dysplasiacongenita (183900)
COL2A1 Multiple presentations AD (257)
Spondyloepimetaphy-sealdysplasia aggrecan type(612813)
ACAN Relative macrocephaly, severe midfacehypoplasia, almost absent nasal cartilage,relative prognathism, slightly low-set,posteriorly rotated ears; short neck, barrelchest, mild lumbar lordosis; rhizomelia andmesomelia
AR (134)
Spondyloepiphyseal dysplasiatype Kimberley (608361)
ACAN Proportionate short stature, stocky habitus,progressive osteoarthropathy
AD (258)
Short stature with advancedbone age
ACAN Advanced bone age, premature growthcessation
AD (135)
Weill–Marchesani syndrome(613195, 608328)
ADAMTS10, FBN1 Spherophakia, lenticular myopia, ectopialentis, joint stiffness, brachydactyly
AR (259)
AD, autosomal dominant; AR, autosomal recessive.aName (number) according to OMIM.
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SHOX mutations cause Langer mesomelic dysplasia, while
heterozygous mutations or deletions of SHOX cause a
milder skeletal dysplasia, Leri–Weill dyschondrosteosis
(with the classic Madelung deformity of the wrist) or
present clinically as ISS. It is assumed that most of the
growth failure characteristic for Turner syndrome is
caused by heterozygous SHOX deletion. Body proportions
are usually mildly affected (mesomelia) but can be within
the normal range (138). Various clinical prediction rules
have been proposed to select patients for testing (139, 140,
141, 142), but the high variability of the clinical
presentation limits their predictive value (5). SHOX
mutations account for 2–15% of individuals presenting
with ISS (143). Since usually SHOX defects are transmitted
from one of the parents, physical examination of the
parents is essential, including height, sitting height,
arm span, forearm length, and presence of Madelung
deformity.
Heterozygous deletions of the downstream and
upstream enhancer of SHOX cause a similar phenotype as
defects of SHOX itself (144, 145, 146, 147, 148, 149), and the
growth response to GH treatment is even better in children
carrying a deletion of the SHOX enhancer than in carriers
of a SHOX defect (150). The consequences of increased
copies of SHOX are less clear (146, 150, 151, 152, 153).
A second intracellular pathway that plays a role in
cellular proliferation and differentiation of GP chondro-
cytes is the Ras/MAPK signalling pathway, which inte-
grates signals from several growth factors including GH,
FGFs, CNP, and EGF (154, 155). Activation of this pathway
results in a number of overlapping syndromes, called
‘rasopathies’, including Noonan, LEOPARD, Costello,
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Table 5 Examples of genetic defects affecting intracellular pathways.
Disordera Gene(s) Clinical features Inheritance References
SHOX aberrationsLanger mesomelic dysplasia (249700) SHOX Severe limb aplasia or hypoplasia of
the ulna and fibula, and a thickenedand curved radius and tibia
AR (138)
Leri–Weill dyschon-drosteosis(127300)
SHOX Mesomelia, Madelung wrist deform-ity, or mild body disproportion
AD (138, 149)
RasopathiesNoonan syndrome 1–8 PTPN11, KRAS,
SOS1, RAF1,NRAS, BRAF,RIT1
Facial dysmorphism, wide spectrum ofcongenital heart defects
AD (157, 260, 261)
LEOPARD syndrome1 (151100)2 (611554)3 (613707)
PTPN11,RAF1,BRAF
Multiple lentigines, electrocardio-graphic conduction abnormalities,ocular hypertelorism, pulmonicstenosis, abnormal genitalia,sensorineural deafness
AD (260)
Costello syndrome (218040) HRAS Coarse facies, distinctive hand postureand appearance, feeding difficulty,failure to thrive, cardiac anomalies,developmental delay
AD (260)
Cardio-facio-cutaneous syndrome(115150)
BRAF, KRAS Distinctive facial appearance, heartdefects, mental retardation
AD (260)
Neurofibromatosis-Noonansyndrome (601321)
NF1 Features of both conditions AD (260)
Neurofibromatosis type I (162200) NF1 Cafe-au-lait spots, Lisch nodules ineye, fibroma-tous skin tumours;short in 13%; large headcircumference in 24%
AD (262)
Coffin–Lowry syndrome (303600) RPS6KA3 Mental retardation, skeletalmalformations, hearing deficit,paroxysmal movement disorders
XLR (261)
Other syndromesAarskog–Scott syndrome(faciogenital dysplasia) (305400)
FGD1 Hypertelorism, shawl scrotum,brachydactyly
XLR (263)
Alstrom syndrome (203800) ALMS1 Retinal photoreceptor degeneration,sensorineural hearing imparment,obesity, insulin resistance
AR (35)
Campomelic dysplasia (114290) SOX9 Congenital bowing and angulation oflong bones, other skeletal andextraskeletal defects
AD (264)
Congenital disorders of glycosylation Multiple genes(O76)
Multisystem disorders caused bydefects in biosynthesis of glyco-conjugates
AR (168)
Kabuki syndrome 1 (147920) and 2(300867)
KMT2D, KDM6A Long palpebral fissures, eversion oflateral third of the lower eyelids,broad and depressed nasal tip, largeprominent earlobes, cleft or high-arched palate, scoliosis, short fifthfinger, persistence of fingerpads,radiographic abnormalities ofvertebrae, hands, and hip joints,recurrent otitis media in infancy
AD (265)
Kenny–Caffey syndrome type 1(244460) and 2 (127000)
TBCE, FAM111A Craniofacial anomalies, small handsand feet, hypocalcemia, hypopara-thyroidism, cortical thickening oflong bones with medullary stenosis,delayed closure of anterior fonta-nel, eye abnormalities, transienthypocalcemia. Gene encodestubulin-specific chaperone E.
ARAD
(6, 266)
AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.aName (number) according to OMIM.
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cardio-facio-cutaneous, and neurofibromatosis–Noonan
syndrome, all characterized by postnatal growth failure
of varying degree (156, 157). Mutations in these genes can
also cause short stature without obvious clinical features
(158). Inhibition of IGF1 release via GH-induced ERK
hyperactivation or EGF-induced PI3K/AKT/GSK-3b stimu-
lation may contribute to short stature in patients with
PTPN11 mutations (159, 160).
Genetic aberrations in several other intracellular
pathways play a role in short stature syndromes. For
example, mutations in FGD1, encoding a guanine nucleo-
tide exchange factor of the Rho/Rac family of small
GTP-binding proteins, cause the X-linked form of
Aarskog–Scott syndrome (faciogenital dysplasia) (161),
although in only 18% of clinically suspected cases a
mutation was found (162). FGD1 activates MAP3K mixed-
lineage kinase 3 (MLK3), which regulates ERK and p38
MAPK, which in turn phosphorylate and activate the
master regulator of osteoblast differentiation, RUNX2
(163). FGD1 is involved in the regulation of the formation
and function of invadopodia and podosomes, which are
cellular structures devoted to degradation of the extra-
cellular matrix in tumour and endothelial cells (164).
Inactivating mutations in SOX9 cause a severe skeletal
dysplasia, campomelic dysplasia. The encoded protein
and its distant relatives SOX5 and SOX6 also activate the
genes for cartilage-specific extracellular matrix com-
ponents (165).
Congenital disorders of glycosylation (CDG) are a
rapidly expanding family of genetic diseases due to defects
in the synthesis of the glycan moiety of glycoproteins and
glycolipids and in their attachment to proteins and lipids.
Most CDG are multisystem disorders, and many are
associated with skeletal abnormalities, including short
stature and microcephaly (166, 167, 168).
Genetic defects in fundamental cellularprocesses
Mutations in genes encoding proteins involved in
fundamental cellular processes can produce severe global
growth deficiencies, termed primordial dwarfisms, which
affect not just the GP but multiple other tissues and
typically impair both pre- and post-natal growth (17).
Several of these syndromes are associated with a normal
head circumference, but many are microcephalic. In some
syndromes, DNA repair defects are prominent. Some
examples are presented in Tables 6 and 7, classified
according to head size and DNA repair.
Syndromes with (usually) normal head circumference
CHARGE syndrome is caused by heterozygous mutations
in CHD7 (169) or SEMA3E (170). CHD7 is a transcriptional
regulator that binds to enhancer elements in the nucleo-
plasm, and also functions as a positive regulator of rRNA
biogenesis in the nucleolus (171).
Patients diagnosed with Coffin–Siris syndrome have a
broad clinical variability, and at present mutations in six
genes have been reported, all encoding components of the
SWI/SNF complex (172, 173). The gene associated with
Floating–Harbor syndrome (SRCAP) encodes a component
of SWI/SNF chromatin remodelling complexes (174, 175).
The KBG syndrome is caused by a heterozygous
mutation in ANKRD11 (176), encoding a member of a
family of ankyrin repeat-containing cofactors that
interacts with p160 nuclear receptor coactivators and
inhibits ligand-dependent transcriptional activation (177).
Mulibrey nanism (referring to muscle, liver, brain and
eye) is caused by homozygous mutations in TRIM37,
which encodes a peroxisomal protein that mono-ubiqui-
tinates histone H2A, a chromatin modification associated
with transcriptional repression (178). In contrast to a
promising short-term effect of GH treatment, the effect on
adult height is modest (5 cm) (179).
SHORT syndrome is caused by mutations in PIK3R1
(p85-alpha). In addition to regulating PI3K function,
p85-alpha and p85-beta regulate the function of XBP-1,
a transcription factor that orchestrates the unfolded protein
response following endoplasmic reticulum stress (180).
SOFT syndrome, caused by homozygous POC1A
mutations, is associated with severe pre- and post-natal
short stature, symmetric shortening of long bones,
triangular facies, sparse hair, and short, thickened distal
phalanges (181, 182).
Three-M syndrome is caused by defects in one of three
genes: CUL7 (encoding a ubiquitin ligase) (183), OBSL1
(encoding a cytoskeletal adaptor) (184) or CCDC8 (encoding
a protein possibly linked to CUL7 through the adaptor
protein OBSL1) (185, 186). The products of these genes play
a critical role in maintaining microtubule integrity with
defects leading to aberrant cell division (17, 187).
Microcephalic primordial dwarfism
Microcephalic primordial dwarfism is characterized
by severe pre- and post-natal growth retardation accom-
panied by microcephaly (18).
For Cornelia de Lange syndrome, five types have been
distinguished, and the same applies to Meier–Gorlin
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Table 6 Examples of genetic defects in fundamental cellular processes.
Disordera Gene(s) Clinical features Inheritance References
Syndromes with (usually) normal head circumferenceCHARGE syndrome(214800)
CHD7, SEMA3E Choanal atresia, malformations of heart,inner ear and retina
AD (267)
Coffin–Siris syndrome(135900)
SMARCB1, SMARCA4,SMARCA2, ARID1A,ARID1B
Developmental delay, speech impairment,coarse facial features, hypertrichosis,hypoplastic fifth fingernails or toenails,agenesis of the corpus callosum
AD (172)
Floating–Harbor syndrome(136140)
SRCAP Delayed bone age and speech, triangular face,deep-set eyes, long eyelashes, bulbous nose,wide columella, short philtrum, thin lips
AD (174, 175)
KBG syndrome (148050) ANKRD11 Macrodontia of upper central incisors, distinc-tive craniofacial findings, skeletal anomalies,global developmental delay, seizures,intellectual disability
AD (176)
Mulibrey nanism (253250) TRIM37 Progressive cardiomyopathy, characteristic facialfeatures, failure of sexual maturation, insulinresistance with DM2, increased risk forWilms tumor
AR (178)
SHORT syndrome (269880) PIK3R1 hyperextensibility of joints, inguinal hernia,ocular depression, teething delay
AD (180)
Short stature, onycho-dysplasia, facial dys-morphism, hypotri-chosis(SOFT, 614813)
POC1A Severely short long bones, peculiar faciesassociated with paucity of hair, triangularfacies, nail anomalies, short, thickened distalphalanges. Relative macrocephaly inchildhood, microcephaly in adulthood
AR (181, 182)
Three-M syndrome 1(273750), 2 (612921),3 (614205)
CUL7, OBSL1, CCDC8 Facial features, normal mental development,long, slender tubular bones, reducedanteroposterior diameter of vertebralbodies, delayed bone age
AR (183, 184,185, 186)
Microcephalic primordial dwarfismCornelia de Langesyndrome 1–5
NIPBL, SMC1A, SMC3,RAD21, HDAC8
Low anterior hairline, arched eyebrows,synophrys, ante-verted nares, maxillaryprognathism, long philtrum, thin lips, ‘carp’mouth, upper limb anomalies.
AD (190)
Meier–Gorlin syndrome 1–5 ORC1, ORC4, ORC6,CDT1, CDC6
Bilateral microtia, and aplasia or hypoplasia ofthe patellae, normal intelligence
AR (192, 268)
MOPD I (210710) U4atac Neurologic abnormalities, including mentalretardation, brain malformations, ocular/auditory sensory deficits
AR (5, 193)
MOPD II (210720) PCNT Radiologic abnormalities, absent or mild mentalretardation in comparison to Seckelsyndrome, truncal obesity, diabetes,moyamoya, small loose teeth
AR (5, 194, 269)
Microcephaly and chorio-retinopathy, 1 (251270),2 (616171)
TUBGCP6, PLK4 Retinopathy. The gene encodes PLK4 kinase,a master regulator of centriole duplication.
AR (270)
Rett syndrome (312750) MECP2 Almost exclusively in females. Arresteddevelopment (6–18 months), loss of speech,stereotypic movements, microcephaly,seizures, mental retardation.
XLD (271)
Rubinstein–Taybi syndrome1 (180849), 2 (613684)
CREBBP, EP300 Mental retardation, broad thumbs and halluces,dysmorphic facial features
AD (272)
Seckel syndrome 1–8 ATR, RBBP8, CENPJ,CEP152, CEP63, NIN,DNA2, ATRIP
Mental retardation, characteristic ‘bird-headed’facial appearance
AR (5, 18, 195)
Short stature with micro-cephaly and distinctivefacies (615789)
CRIPT Frontal bossing, high forehead, sparse hair andeyebrows, telecanthus, proptosis, antevertednares, flat nasal bridge
AR (273)
AD, autosomal dominant; AR, autosomal recessive; DM2, diabetes mellitus type 2; MOPD, microcephalic osteodysplastic primordial dwarfism; IUGR,intrauterine growth retardation; XLR, X-linked recessive.aName (number) according to OMIM.
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Table 7 Examples of genetic defects in fundamental cellular processes: DNA repair defects.
Disordera Gene(s) Clinical features Inheritance References
Bloom syndrome (210900) RECQL3 Sun-sensitive, telangiectatic, hypo- andhyperpigmented skin, predisposition tomalignancy,chromosomal instability
AR (274)
Cockayne syndrome A, B, XPG/CS(five types)
ERCC8, ERCC6, ERCC5,ERCC3, ERCC4
Cutaneous photosensitivity, thin, dry hair,progeroid appearance, pigmentary retino-pathy, sensorineural hearing loss, dentalcaries
AR (272)
Fanconi anemia (multiple types) FANCA and multiplegenes
Heterogeneous disorder causing genomicinstability, abnormalities in major organsystems, bone marrow failure, highpredisposition to cancer
AR (275, 276)
Hutchinson–Gilford progeriasyndrome (176670)
LMNA Low body weight, early loss of hair, lipo-dystrophy, scleroderma, decreased jointmobility, osteolysis, facial features thatresemble aged persons
AD (277)
Hypomorphic PCNA mutation PCNA Hearing loss, premature aging, telangiecta-sia, neurodegeneration, photosensitivityby nucleotide excision repair defect
AR (278)
Immunoosseous dysplasia,Schimke type (242900)
SMARCAL1 Spondyloepiphyseal dysplasia, numerouslentigines, slowly progressive immunedefect, immune-complex nephritis
AR (279)
Natural killer cell and gluco-corticoid deficiency with DNArepair defect (609981)
MCM4 Variant of familial glucocorticoid deficiency:hypocortisolemia, increased chromosomalbreakage, NK cell deficiency
AR (280, 281)
Nijmegen breakage syndrome(251260)
NBS1 Microcephaly, growth retardation, immuno-deficiency, predisposition to cancer
AR (282)
Ovarian dysgenesis 4 MCM9 Hypergonadotropic hypogonadism, genomicinstability
AR (283)
Rothmund–Thomson syndrome RECQL4 Skin atrophy, telangiectasia, hyper- andhypopigmentation, congenital skeletalabnormalities, premature aging
AR (284)
X-linked mental retardation-hypotonic facies syndrome(309580)
ATRX Mental retardation, dysmorphic facies,hypogonadism, deafness, renal anomalies,mild skeletal defects
XLR (285)
Defective nonhomologous end-joining (NHEJ) DNA damagerepair
LIG4, NHEJ1, ARTEMIS,DNA-PKCs, XRCC4,PRKDC
Radiosensitive, severe combined immuno-deficiency
AR (197, 198,199, 273,286, 287)
AD, autosomal dominant; AR, autosomal recessive; DM2, diabetes mellitus type 2; IUGR, intrauterine growth retardation; XLR, X-linked recessive; MOPD,Microcephalic osteodysplastic primordial dwarfism.aName (number) according to OMIM.
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Review J M Wit and others Genetics of short stature 174 :4 R157
syndrome (188, 189, 190, 191, 192). Microcephalic osteo-
dysplastic primordial dwarfism (MOPD) type I is caused by
mutations in RNU4ARAC, encoding a small nuclear RNA
that is part of the minor spliceosome and necessary for
proper splicing of U12-dependent introns (193). Mutations
in the gene encoding pericentrin (PCNT) cause MOPD type
II (5, 194). Seckel syndrome is caused by mutations in many
different genes encoding proteins involved in DNA damage
response or centrosomal function (reviewed in (5, 18, 195)).
DNA repair defects
Many syndromes associated with abnormal DNA repair
present with short stature (Table 7). The best known
example is Bloom syndrome, caused by a mutation in the
gene encoding DNA helicase RecQ protein-like-3 (RECQL3).
Cells of these patients show an increased frequency of
chromosomal breaks, and the elevation in the rate of sister
chromatid exchanges is used as a diagnostic test. Other
syndromes include Cockayne syndrome, Fanconi anaemia,
and Rothmund–Thomson syndrome. Fanconi anaemia is a
clinically and genetically heterogeneous disorder that
causes genomic instability. Characteristic clinical features
include developmental abnormalities in major organ
systems, early-onset bone marrow failure, and a high
predisposition to cancer. The cellular hallmark is hypersen-
sitivity to DNA crosslinking agents and high frequency of
chromosomal aberrations.
An important pathway for the repair of DNA double-
stranded breaks is non-homologous end-joining (196),
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and mutations in several genes encoding proteins
involved in this process have been discovered in short
individuals, including LIG4 and XRCC4 mutations
(197, 198, 199). XRCC4 mutations are also associated
with hypergonadotrophic hypogonadism (199).
Chromosomal abnormalities, CNVs, andimprinting disorders associated with shortstature
Chromosomal abnormalities
Most guidelines on clinical workup of children with short
stature advise to perform routine karyotyping in females
with unexplained short stature, to detect Turner syndrome.
Indeed, it is very important to diagnose Turner syndrome,
given the comorbidities (partly potentially life-threaten-
ing) and efficacy of GH treatment. However, the diagnostic
yield in females with isolated short stature is low (estimated
at 4% (200)), so that several clinicians have doubted if this
would be cost-effective (201, 202, 203, 204). In fact, even in
the presence of clear guidelines for diagnostic studies in
short children, karyotyping was only performed in w50%
of cases in a Dutch study (205). Potentially useful criteria for
a cost-effective selection of short girls for this expensive test
may include a large distance between height SDS and target
height SDS (e.g., O2 S.D.) (206), delayed puberty and any
indication of physical stigmata. Deletions of the long arm
of the Y chromosome, or X/XY mosaicisms in phenotypic
females or males, are associated with short stature
(207, 208, 209, 210). However, in short males the
diagnostic yield of karyotyping is low (3%) (200).
Besides numerical aberrations of sex chromosomes,
several other chromosome abnormalities associated
with short stature are detectable with routine karyotyping,
e.g., Down syndrome (trisomy 21), Edwards syndrome
(trisomy 18), Patau syndrome (trisomy 13), and trisomy 17
mosaicism (211).
Copy number variants
As alluded to in the introduction, CNVs can be detected by
array-CGH (2) or SNP arrays (1). With these methods,
many new microdeletion and microduplication syn-
dromes have been identified, and several novel genes
associated with short stature as part of contiguous
gene syndromes have been discovered. Examples include
the observation that EPHA4 haploinsufficiency is
responsible for short stature observed in children with
Waardenburg syndrome caused by a chromosome
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2q35q36.2 deletion (212), and a possible role of dupli-
cations of EPAS and RHOQ on chromosome 2p21 in severe
short stature and delayed bone age (213). For Dubowitz
syndrome, a presumed autosomal recessive disorder
characterized by microcephaly, developmental delay,
growth failure, and a predisposition to allergies and
eczema, no unifying genetic alteration has been identified,
but in a subset of individuals diagnosed with this
syndrome deletions at 19q13 were found (214). Relatively
frequent contiguous gene deletion (and occasionally
duplication) syndromes are listed in Table 8.
Apart from these relatively well documented syn-
dromes, there may be many more. Four recent studies
(153, 215, 216, 217) showed that w10% of patients with ISS
carry a disease-causing CNV, and in short children
microdeletions (in contrast to microduplications) are
significantly more frequent than in controls (218). However,
for individual cases one often remains uncertain whether
their growth failure is due to the encountered CNV, and
which of the genes is responsible for it. Comparison with
previously reported patients and databases like DatabasE of
Chromosomal Imbalance and Phenotype in Humans using
Ensembl Resources (DECIPHER; http://decipher.sanger.uk)
and European Cytogeneticists Association Register of
Unbalanced Chromosome Aberrations (ECARUCA; http://
www.ecaruca.net) may give hints for candidate genes.
Imprinting disorders and uniparental disomy
Examples of imprinting disorders are shown in Table 9.
The best known example of a growth disorder associated
with an imprinting disorder is the Silver–Russell syn-
drome, which is most commonly caused by hypomethyla-
tion of an imprinting control region on the paternal allele
of chromosome 11p15.5, controlling the methylation of
the IGF2 and H19 genes (219). However, also multilocus
loss-of-methylation can occur (220, 221). Other genetic
causes include uniparental (maternal) disomy of chromo-
some 7 (UPD7) (79) and a mutation in the paternally
imprinted gene CDKN1C (222). CDKN1C mutations are
also associated with the IMAGe syndrome, characterized
by intrauterine growth restriction, metaphyseal dysplasia,
congenital adrenal hypoplasia, and genital anomalies
(223), and a syndrome of pre and postnatal growth failure
and early-onset diabetes mellitus (224). The clinical
spectrum of Silver–Russell syndrome is considerably
broader than thought before, and lack of intrauterine
growth restriction should not automatically result in
exclusion from molecular testing (225).
Table 8 Examples of contiguous gene deletion or duplication syndromes associated with short stature.
Disordera Location Clinical features References
Recurrent rearrangements of 1q21.1 1q21.1del Intellectual disability, autism spectrum disorder,microcephaly, cardiac abnormalities, cataracts
(288)
2p16p22 microduplication syndrome 2p16p22dup Delayed bone age, facial dysmorphism. Role ofEPAS and RHOQ?
(213)
Wolf–Hirschhorn syndrome (194190) 4p16.3del ‘Greek warrior helmet’, epicanthal folds, shortphiltrum, downturned corners of mouth,micrognathia, seizures. Mitochondrial defect byLETM1 haploinsufficiency
(289, 290)
Chromosome 4q21 deletion syndrome(613509)
4q21del Neonatal muscular hypotonia, severe psychomotorretardation, severely delayed speech, broadforehead, frontal bossing, hypertelorism, shortphiltrum, downturned corners of mouth
(291)
Cri-du-chat syndrome (123450) 5p15.2ter del High-pitched catlike cry, microcephaly, round face,ocular hypertelorism, micrognathia, epicanthalfolds, low-set ears, hypotonia, severe psychomotorretardation. CTNND2?
(292)
Short stature, microce-phaly, speechdelay
5q35.2q35.3dup Microcephaly, speech delay. Reciprocal to commonSotos syndrome deletion (increased NSD1function?)
(293)
Williams–Beuren syndrome (194050) 7q11.23del Supravalvular aortic stenosis, intellectual disability,distinctive facial features
(294)
Trichorhinophalangeal syndrome, type II(Langer–Giedion syndrome) (150230)
8q21.11q24.13del Large, laterally protruding ears, bulbous nose,elongated upper lip, sparse scalp hair, wingedscapulae, multiple cartilaginous exostoses,redundant skin, intellectual disability. TRPS1, EXT1?
(295)
WAGR syndrome (194072) 11p13del Aniridia, hemihypertrophy, Wilms tumor,cryptorchidism. PAX6, WT1?
(296)
12q14 microdeletion syndrome 12q14del Developmental delay, osteopoikilosis. HMGA2? (297, 298)Chromosome 13q14 deletion syndrome
(613884)13q14del Retinoblastoma, mental impairment, high forehead,
prominent philtrum, anteverted earlobes(299)
Frias syndrome (609640) 14q22.1q22.3del Exophthalmia, palpebral ptosis, hypertelorism, shortsquare hands, small broad great toes. BMP4?
(300)
Distal 14q duplication syndrome 14q32.2-qter Mild developmental delay, high forehead, hyper-telorism, dysplastic ear helices, short philtrum, cupidbow upper lip, broad mouth, micrognathia
(230)
Smith–Magenis syndrome (182290) 17p11.2del Brachycephaly, midface hypoplasia, prognathism,hoarse voice, speech delay, hearing loss, psycho-motor retardation, behavioral problems. RAI1?Can be associated with GHD
(301)
Miller–Dieker lissencephaly syndrome(247200)
17p13.3del Lissencephaly, microcephaly, wrinkled skin overglabella and frontal suture, prominent occiput,narrow forehead, downward slanting palpebralfissures, small nose and chin, cardiac malformations,hypoplastic male external genitalia, seizures. CRK?
(302, 303)
17q21q25 duplication syndrome 17q2125dup Developmental delay, distal arthrogryposis.GH insensitivity, disturbed STAT5B, PI3K, andNF-kappaB signaling. Role of PRKCA mRNAoverexpression?
(66, 304)
Chromosome 18p deletion syndrome(146390)
18p11del Intellectual disability, round face, dysplastic ears, widemouth, abnormalities of teeth, limbs, genitalia,brain, eyes, heart
(305)
Chromosome 18q deletion syndrome(601808)
18q22.3q23del Congenital aural atresia, GHD, intellectual disability,reduced white-matter myelination, foot deformities
(306, 307)
Velocardiofacial syndrome (192430) 22q11.2del Highly variable phenotype. Central deletions: cardiacdisorders, learning delays, dysmorphic facialfeatures, hypernasal speech, velopalatalinsufficiency, hypocalcemia, hypoparathyroidism,psychiatric disorders; roleof TBX1? Distal: role of MAPK1?
(308, 309)
GHD, growth hormone deficiency; WAGR syndrome, Wilms tumor, Aniridia, genitourinary anomalies, and mental retardation syndrome.aName (number) according to OMIM.
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Table 9 Examples of imprinting disorders.
Disordera Genetics Clinical features References
Silver–Russell syndrome (180860) Hypomethylation of imprintingcontrol region on paternalallele of 11p15.5 controlingmethylation of IGF2 and H19
Severe IUGR, triangular shapedface, broad forehead, bodyasymmetry, variety of minormalformations
(79, 219, 220, 229, 310)
Maternal UPD7 (SRS, 7p11.2)Silver–Russell syndrome or IMAGe
syndrome (614732) or IUGR Cearly-onset diabetes mellitus
Mutation in paternally imprintedgene CDKN1C
IUGR, metaphyseal dysplasia,adrenal hypoplasia congenita,genital anomalies; or onlySilver–Russell syndrome; orIUGR and early-adulthood-onset diabetes with normaladrenal function
(222, 224)
Prader–Willi syndrome (176270) Loss of expression of paternalcopies of imprinted genes(SNRPN, NDN), and others(15q11–q13) by deletion,maternal UPD, imprintingcenter defect, or Robertsoniantranslocation
Intellectual disability, seizures,poor gross and fine motorcoordination, behavioralproblems, sleep disturbances,high pain threshold
(226)
Pseudohypoparathyroidismtype 1a/c (103580)
Heterozygous GNAS1 (20q13.32)mutation inherited frommother
Resistance to parathyroidhormone and other hormones
(228)
Pseudohypoparathyroidismtype 1b (603233)
Both alleles have a paternal-specific imprinting pattern onboth parental alleles
Resistance to PTH is present with-out signs of Albright hereditaryosteodystrophy
Pseudopseudohypopara –thyroidism (612463)
Heterozygous GNAS1 mutationinherited from father
Albright hereditary osteodystro-phy without multiple hormoneresistance, brachydactyly
Temple syndrome (616222) Maternal UPD14 (14q32) Low birth weight, hypotonia,motor delay, feeding problemsearly in life, early puberty,reduced adult height, broadforehead, short nose with widenasal tip, small hands and feet
(153, 229)
IUGR, intrauterine growth retartdation.aName (number) according to OMIM.
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Another well-known example is Prader–Willi syn-
drome, a contiguous gene syndrome. There are three
main genetic subtypes: a paternal chromosome 15q11q13
deletion (65–75% of cases), a maternal UPD of chromo-
some 15 (20–30% of cases), and an imprinting defect
(1–3%). It is now thought that deletion of the paternal
copies of the imprinted genes SNRPN, NDN, and possibly
others within the chromosome region 15q11q13, are
responsible for the phenotype (226). GH secretion can be
low and GH treatment has positive effects on linear
growth and body composition (227).
Loss-of-function mutations of GNAS, coding for the
a-subunit of the Gs protein, is associated with a spectrum
of growth disorders (228). The term pseudohypopara-
thyroidism indicates a group of heterogeneous disorders
whose common feature is represented by impaired
signalling of various hormones (primarily PTH) that
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activate cAMP-dependent pathways via Gsa protein. The
two main subtypes of PHP (types Ia and Ib) are caused by
molecular alterations within or upstream of the imprinted
GNAS gene, which encodes Gsa and other translated and
untranslated products. Patients who inherited a GNAS
mutation from their father develop Albright hereditary
osteodystrophy (AHO) without multiple hormone resist-
ance (pseudopseudohypoparathyroidism), characterized
by brachydactyly and short stature. In contrast, patients
who inherited the mutation from their mother, addition-
ally develop resistance to PTH and other hormones
(pseudohypoparathyroidism type 1a or 1c). This difference
is caused by the tissue-specific imprinting of GNAS.
In pseudohypoparathyroidism type 1b only resistance to
PTH is present without signs of AHO, due to an imprinting
defect of GNAS with silencing of the maternal allele,
affecting mainly the renal tubules.
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Besides UPD7, there is another UPD syndrome that is
associated with short stature and various additional clinical
features: maternal UPD14 (Temple syndrome) (229). This
syndrome shares similarities with the distal 14q dupli-
cation phenotype (Table 8) (230). We showed that such
diagnoses can be found using SNP array technology in
children who had been considered ISS (153).
There may be many more epigenetic disorders
associated with short stature. In a study on 79 patients
with suspected Silver–Russell syndrome or unexplained
short stature/intrauterine growth restriction, 37% showed
a methylation abnormality in eleven imprinted loci. The
commonest finding was a loss of methylation at H19, and
a gain of methylation at IGF2R was significantly more
observed than in controls (231). Another example is the
epigenetic control of several parts of the IGF1 signalling
pathway. The IGF1 P2 promotor is an epigenetic quan-
titative trait locus (QTL), and methylation of a cluster of
six CGs located within the proximal part of this promoter
shows a strong negative association with serum IGF1 and
growth (232). In children with ISS CG-137 methylation in
this promoter contributed 30% to the variance of the IGF1
response to GH in an IGF1 generation test (233).
Diagnostic approach
In agreement with Dauber et al. (5), we believe that genetic
testing to identify rare monogenic causes of short stature is
important for various reasons: i) it can end the diagnostic
workup and the family’s uncertainty about the cause of
the condition; ii) it may alert the clinician to other
medical comorbidities; iii) it is invaluable for genetic
counselling; and iv) it may have implications for therapy
(e.g., some conditions, such as Bloom syndrome, are
contraindications for GH treatment (234)). With respect
to the question of who should undergo genetic testing, the
clinician should take several factors into consideration
that increase the likelihood of a monogenic cause of short
stature (5). The severity of the growth failure, presence of
additional abnormalities, presence of sibling or parent
with similar features, and consanguinity may be the most
important indicators.
The genetic evaluation of short stature is well
described in a recent review, which also presents a useful
diagnostic algorithm (5) in a step-wise fashion. If a
particular genetic aetiology or syndrome is suspected,
based on clinical features such as birth size, head
circumference, body proportions, and inheritance pattern,
a single gene-based test or gene panel is usually indicated.
We estimate that this applies to a limited number of
patients, since in the majority short stature is probably
of polygenic origin. If there is no strong suspicion on a
certain genetic diagnosis, or if initial testing showed no
abnormality – while a monogenic disorder appears very
likely – the clinician can either accept the diagnosis
‘apparent ISS’ or proceed on a hypothesis-free approach.
To arrive at this decision, various considerations apply,
including the availability of DNA from other family
members, informed consent, local infrastructure, and
financial aspects. It is noteworthy that presently limited
information is available about the sensitivity, specificity
and cost-effectiveness of this approach, while it is
important that the ethical aspects are properly dealt
with, for example appropriate informed consent forms
including information about handling incidental find-
ings. For details we refer to recently published guidelines
for diagnostic next-generation sequencing (235).
The hypothesis-free approach consists of two steps.
First, an array-cGH or SNP array is carried out, to search for
CNVs and uniparental disomies (with SNP-arrays) (1). Even
if no CNV is found, the results are useful for the analysis
of the second step, WES. For example, SNP arrays provide
information about homozygous regions, which can be
used in the bioinformatic analyses of the WES data,
particularly if a recessive condition is suspected. If a
potentially causative gene variant is found, it should be
confirmed by Sanger sequencing. After confirmation,
cosegregation studies in affected and non-affected relatives
should be performed, and if confirmatory, functional
studies are usually indicated to provide final proof.
However, we expect that in the coming years further
reduction of costs of next generation sequencing
technologies will render this step-wise approach super-
fluous, so that WES will be used as a tool to identify
small mutations as well as CNVs and homozygous
regions. The next step that the field will probably take
is WGS which, in combination with RNA sequencing of
the whole transcriptome and sequencing-based DNA
methylation analysis of the whole genome, will provide
additional information. It will probably lead to further
novel insights in the causes of short stature, if the ability
to interpret sequence variants outside the exome can be
improved.
Conclusion
In the past decade, many novel gene defects have been
found in association with multiple clinical disorders
associated with short stature, which has enormously
expanded the ability of clinicians to obtain a diagnosis
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Review J M Wit and others Genetics of short stature 174 :4 R162
in their patients. A more widespread use of currently
available genetic tools will certainly lead to a further
increase of clinical syndromes associated with genetic
aberrations. We agree with Lu et al. (236) and Dauber et al.
(5) that clinical use of sequencing data may reduce the cost
of care, result in more specific treatment guidelines and
avoidance of costly diagnostic and therapeutic procedures,
and reduce variance in diagnosis and treatment outcomes
between academic medical centres and community
hospitals and clinics.
Declaration of interest
J M Wit has served as consultant for Pfizer, Biopartners, OPKO, Versartis,
Teva, Merck-Serono, and Ammonett and has received speaker’s honoraria
from Pfizer, Versartis, Merck-Serono, Lilly and Sandoz. W Oostdijk received
unrestricted grant support from Novo Nordisk, Ipsen and Ferring. The other
authors have nothing to disclose.
Funding
This review did not receive any specific grant from any funding agency in
the public, commercial or not-for-profit sector.
Search Strategy
The search strategy started with updating information on genetic causes of
short stature described in previous reviews (10, 11, 13) and others (5, 14, 15,
16, 17), through OMIM and PubMed. Novel genetic causes were found with
the following search strategy (courtesy J. Schoones, Leiden):
(("body size"[Majr] OR Body Size[ti] OR "body height"[Majr] OR body
height[Ti] OR "body height"[ti] OR (growth[ti] NOT ("growth factor"[ti]
OR "growth factors"[ti]))) AND ("child"[MeSH Terms] OR child[Text Word]
OR children[Text Word] OR "infant"[MeSH Terms] OR infant[Text Word] OR
infants[Text Word] OR pediatric[tiab] OR paediatric[tiab]) NOT (obese
OR obesity OR obes* OR mice[tiab] OR animal[tiab] OR animals[tiab] OR
cattle[tiab] OR bovine[tiab] OR cows[tiab] OR pigs[tiab] OR birds[tiab]
OR fish[tiab] OR snakes[tiab] OR squirrels[tiab] OR cow[tiab] OR pig[tiab]
OR bird[tiab] OR fishes[tiab] OR snake[tiab] OR squirrel[tiab]) AND
english[la] AND ("genetics"[Subheading] OR "genetics"[tw] OR "genetics"
[mesh] OR "Genetic Techniques"[mesh])) AND ("2005/01/01"[PDAT]:
"3000/12/31"[PDAT]) NOT ("cell growth"[tw] OR "Cell Transformation,
Neoplastic"[mesh] OR "Cell Proliferation"[mesh] OR "Gene Expression
Regulation, Neoplastic"[mesh] OR "Cell Movement"[mesh]).
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Received 18 September 2015
Revised version received 2 November 2015
Accepted 16 November 2015
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