MECHANISMS IN ENDOCRINOLOGY Novel genetic causes of short

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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.

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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

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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

researchor shortof short

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http://dx.doi.org/10.1530/EJE-15-0937

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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

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http://www.ncbi.nlm.nih.gov/omim

http://www.growthgenetics.com

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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.


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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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.


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Table 3 Examples of genetic defects affecting paracrine factors in the growth plate.


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


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Table 4 Examples of genetic defects affecting cartilage extracellular matrix.


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.


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.


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.


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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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).


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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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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

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Accepted 16 November 2015

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