Seminars in Cell & Developmental Biology 53 (2016) 115–125

Contents lists available at ScienceDirect

Seminars in Cell & Developmental Biology

journal homepage: www.elsevier.com/locate/semcdb

Review

Altered FGF signalling in congenital craniofacial and skeletal disorders

Shahida Moosa a,b , Bernd Wollnik a,b,∗
a
Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
b
Institute of Human Genetics, University of Cologne, Cologne, Germany

a r t i c l e i n f o a b s t r a c t

Article history: The fibroblast growth factor (FGF) signalling pathway has been the focus of intense genetic and functional
Received 31 August 2015 research for several decades. The emerging data implicate FGF signalling in diverse regulatory processes,
Accepted 7 December 2015 both in the developing embryo as well as in the adult organism. Alterations in this tightly regulated path-
Available online 11 December 2015
way can lead to a number of pathological conditions, ranging from well-recognized congenital disorders
to cancer. In order to mediate their cellular processes, FGFs signal through a subfamily of tyrosine kinase
Keywords:
receptors, called FGF receptors (FGFRs). In humans, four FGFRs are described, and, to date, mutations in
FGF signalling
FGFR1, FGFR2, and FGFR3 have been shown to underlie human developmental disorders. FGFs/FGFRs are
FGFR1
FGFR2
known to be key players in both endochondral and intramembranous bone development. In this review,
FGFR3 we focus on the major developmental craniofacial and skeletal disorders which result from altered FGF
Bone development signalling.
Craniosynostosis © 2015 Published by Elsevier Ltd.
Skeletal dysplasia

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
2. General aspects of FGF/FGFR signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
3. FGF/FGFR signalling in cranial suture development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
3.1. FGFR-related craniosynostosis spectrum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
3.1.1. Apert syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
3.1.2. Crouzon syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
3.1.3. Pfeiffer syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
3.1.4. Jackson–Weiss syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
3.1.5. Beare–Stevenson cutis gyrata syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
3.1.6. Antley–Bixler syndrome type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
3.1.7. Muenke syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
3.1.8. Crouzon syndrome with acanthosis nigricans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
4. FGF/FGFR signalling in skeletal development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
4.1. FGFR-related skeletal dysplasia spectrum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
4.1.1. Achondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
4.1.2. Hypochondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
4.1.3. Thanatophoric dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
4.1.4. Severe achondroplasia with developmental delay and acanthosis nigricans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
4.1.5. Osteoglophonic dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
4.1.6. Bent bone dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
4.1.7. Lacrimo-auriculo-dento-digital syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
4.1.8. Camptodactyly–tall stature–hearing loss syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
5. Therapeutic outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

∗ Corresponding author at: Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany.
E-mail address: bernd.wollnik@med.uni-goettingen.de (B. Wollnik).

http://dx.doi.org/10.1016/j.semcdb.2015.12.005
1084-9521/© 2015 Published by Elsevier Ltd.
116 S. Moosa, B. Wollnik / Seminars in Cell & Developmental Biology 53 (2016) 115–125

6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

1. Introduction affinities and specificities for the different FGF ligands [23]. It has
been shown that these isoforms are expressed in a tissue-specific
The mammalian fibroblast growth factor (FGF) family comprises manner. The so-called “c” isoform of the receptors is predominantly
a group of 18 structurally related proteins, which play important expressed in skeletal tissues.
roles in the regulation of a variety of cellular processes [1–3]. FGFs FGFs can bind to the extracellular domain of the inactive FGFR
are highly conserved and have been identified in many species, monomer and, in the presence of heparan sulphate, induce FGFR
ranging from nematodes to humans. The first member of the FGF dimerization [24,25]. The receptor dimerization causes the two
family was described in 1973 and named for its ability to induce intracellular kinase domains of the two FGFRs to phosphorylate
proliferation in 3T3 fibroblasts [4]. To date, FGF signalling has been each other on specific tyrosine residues (see Fig. 1). This process of
shown to be important for a growing list of fundamental pro- FGFR activation then initiates a complex cascade of further intra-
cesses in embryonic development and organ formation, as well as cellular signalling through several downstream pathways [7,26].
in adult tissue homeostasis [5]. FGFs play a critical role in embry- The most well-studied of these pathways include (i) the phospho-
onic morphogenesis by regulating cell proliferation, differentiation, lipase C␥ (PLC␥) pathway, (ii) the RAS-MAP kinase pathway, which
senescence and migration. In the adult organism, FGFs are cru- includes ERK1/2, p38 and JNK kinases, and (iii) the PI3 kinase/AKT
cial for example for angiogenesis, tissue repair, wound healing, pathway (see Fig. 2). The activities of these signal transduction
cholesterol metabolism, and serum phosphate regulation [6,7]. pathways vary depending on the cell type, although the activation
Furthermore, altered FGF/FGFR signalling has been linked to the of the RAS-MAP kinase pathway has been observed in all cell types.
aetiology of several cancers [8]. Key components of the FGF signalling are the docking protein FGF-
FGFs mediate their cellular processes through a subfamily of receptor substrate 2 (FRS2) and the signalling enzyme PLC␥. Most
tyrosine kinase receptors, named FGF receptors (FGFRs). In humans, of these phosphorylation transduction pathways target transcrip-
four FGFRs are described and congenital disease-associated muta- tion factors within the nucleus, thereby affecting gene expression,
tions have been identified in FGFR1, FGFR2, and FGFR3. Although cell proliferation, differentiation and survival (see Fig. 2).
mutations in several of the FGF genes have also been linked to The complexity and diverse functions of the FGF/FGFR path-
congenital syndromes, the focus of this review will be on the way further explain the wide range of congenital disorders
FGFR-related groups of skeletal dysplasias and craniosynostosis observed when the pathway is disturbed. Germline mutations in
syndromes. the FGF/FGFR genes result in at least 24 distinct human congeni-
Linking dysregulated FGF signalling to disease has opened up tal disorders. Prominent amongst them are groups of syndromes
avenues for further research into therapeutic options that act with skeletal, cranial and limb abnormalities. Disorders associated
directly or indirectly on this pathway and/or its downstream tar- with deafness, endocrine abnormalities, renal abnormalities and
gets. Promising first evidence exists for the use of compounds neurological disease have also been described (listed in Table 1).
targeting the FGF/FGFR pathway in the development of therapies The skeletal effects are primarily a consequence of altered endo-
for achondroplasia and certain cancer types. A brief overview of chondral ossification, resulting in short-limbed dwarfism, while the
the current therapeutic options for the group of FGFR3 skeletal craniosynostosis effects are thought to be a consequence of altered
dysplasias is provided at the end of this review. intramembranous ossification, leading to premature fusion of one
or several cranial sutures.
2. General aspects of FGF/FGFR signalling
3. FGF/FGFR signalling in cranial suture development
The many important cellular functions and processes controlled
by FGF signalling infer that the growth factor signalling pathway is The human skull consists of five bones: paired frontal bones,
highly complex. In mammals, the FGF family comprises 18 ligands paired parietal bones, and the occipital bone, in addition to lateral
acting through FGFRs, their high-affinity binding partners. FGFs contributions from the squamous part of the temporal bone and the
interact with heparan sulphate proteoglycans. While paracrine greater wing of the sphenoid bone (see Fig. 3). These bones form
FGFs have a high affinity for heparan sulphate and require hep- by intramembranous ossification. During embryonic development,
aran sulphate for signalling [9–13], endocrine FGFs, demonstrate a the bones grow and expand, but do not fuse. The unossified junc-
lower affinity for heparan sulphate and rely on Klotho co-receptors tions between the calvarial bones are known as sutures. Before skull
to elicit their metabolic effects [14–18]. bones fuse later in postnatal development, the intervening sutures
Proteins of the FGFR family share a highly conserved structure ensure the growth potential of the skull to be able to accommodate
with an extracellular domain that contains three immunoglobulin the underlying growing and developing brain. Growth at the sites of
(Ig)-like domains (designated D1, D2, and D3), a single trans- the sutures involves the maintenance of a population of proliferat-
membrane domain and a split cytoplasmic tyrosine kinase domain ing osteoprogenitor cells. These osteoprogenitor cells differentiate
[19,20]. FGF binding occurs at the second and third Ig-like domains into osteoblasts, which express type I collagen, bone sialoprotein,
(D2 and D3) and the linker between these domains. A stretch of and osteocalcin, and synthesize and secrete bone matrix. There-
negatively charged amino acids in the linker connecting the D1 fore, sutures are a major site of intramembranous bone growth and
and D2 domains is termed the acid box. Furthermore, a conserved function as growth centres for the continuously expanding skull.
positively charged region in the D2 domain serves as the binding FGF signalling is crucial for normal morphogenesis, develop-
site for heparan sulphate or heparin. The D3 domain is encoded by ment and growth of the craniofacial skeleton [27–30]. It is well
two separate exons: exon IIIa encodes the N-terminal part of the understood that the expression of the FGFs and their receptors
D3 domain, while the C-terminal part is encoded by either exon is temporally and spatially regulated during development. From
IIIb or IIIc [21,22]. FGFR1-3 undergo alternative splicing in their studying mouse development, we know that Fgf2, Fgf4 and Fgf9 are
D3 domains, thereby generating receptor isoforms with different important players during embryonic cranial vault development
 S. Moosa, B. Wollnik / Seminars in Cell & Developmental Biology 53 (2016) 115–125 117

Fig. 1. FGFR activation. FGF binding to the FGFR induces receptor dimerization, juxtaposing the intracellular tyrosine kinase domains of the FGFR receptors, so that
phosphorylation and activation of the kinase domain can occur.

Fig. 2. FGFR signalling pathways. The downstream signal transduction pathways activated by phosphorylated FGFRs. These phosphorylated tyrosine kinase residues are
then specifically bound by a number of intracellular signal transduction proteins. The major direct substrates of activated FGFR kinase are FRS2 and PLC␥ (their pathways
are indicated by the red arrows). The cellular responses to the main downstream intracellular signalling pathways are indicated.

[31,32]. Fgf18 and Fgf20 are also expressed in developing calvarial
bones [33–36]. Moreover, Fgf18 knockout mice display abnormal
skull development [33,34]. Fgf18 is first detected in calvarial mes-
enchymal cells and later in development is expressed in osteogenic
mesenchyme and in differentiated osteoblasts on the endosteal
and periosteal surface of skull bones [33,34]. Fgfr1 is expressed in
the mesenchyme of the calvarium and also in osteoblasts. Fgfr2
is expressed at ossification sites in differentiating osteoblasts
[35–40]. Fgfr1 and Fgfr2 are crucial in regulating the morphology
and maintaining the patency of craniofacial sutures, acting in
concert with other key players [31,32]. During calvarial bone
development Fgfr3 is expressed at low levels in sutural osteogenic
fronts, but at a later stage than Fgfr1 and Fgfr2 [38,41].
It is therefore not surprising that dysregulation of the FGF/FGFR
pathway caused by mutations in genes encoding FGFRs, and in par-
ticular FGFR1 and FGFR2 (and to a lesser extent FGFR3) leads to
syndromes associated with premature calvarial intramembranous
ossification causing craniosynostosis.
3.1. FGFR-related craniosynostosis spectrum
Premature ossification and thereby obliteration of the cranial
sutures results in craniosynostosis. Craniosynostosis occurs with
a prevalence of approximately 1 in 2500 births and is a feature
in over 100 distinct syndromes [42,43]. Craniosynostosis is classi-
fied as either simple (only one fused suture) or complex (multiple
sutures involved); primary (abnormality inherent in the sutural
biology) or secondary (due to external influences); and syndromic
(in combination with other dysmorphic features) or isolated.
The vast majority of mutations in the FGFR genes which have
been described to cause various craniosynostosis syndromes
tend to be heterozygous missense mutations that confer overall
118 S. Moosa, B. Wollnik / Seminars in Cell & Developmental Biology 53 (2016) 115–125

Table 1
Disorders associated with dysregulated FGF/FGFR signalling.

Gene Mechanism Disorder Inheritance OMIM

FGF3 LoF Deafness, microtia, microdontia AR 610706

FGF5 LoF Trichomegaly AR 190330
FGF8 LoF Hypogonadotropic hypogonadism 6 with/without anosmia (Kallmann syndrome) AD 612702
FGF9 LoF Multiple synostoses syndrome 3 AD 612961
FGF10 LoF Lacrimo-auricular-dento-digital syndrome (LADD) AD 180920
LoF Aplasia of the lacrimal and salivary glands (ALSG) AD 149730
FGF14 LoF Spinocerebellar ataxia type 27 (SCA27) AD 609307
FGF16 LoF Metacarpal 4–5 fusion X-linked 309630
FGF17 LoF Hypogonadotropic hypogonadism 20 with/without anosmia AD 615270
FGF20 LoF Renal hypodysplasia/aplasia 2 AR 615721
FGF23 GoF Hypophosphatemic rickets AD 193100
LoF Familial hyperphosphatemic tumoral calcinosis AR 211900

FGFR1
Skeletal dysplasias
GoF Osteoglophonic dysplasia AD 166250
Craniosynostosis
GoF Jackson–Weiss syndrome AD 123150
GoF Pfeiffer syndrome AD 101600
Other
LoF Hartsfield syndrome AD 615465
LoF Hypogonadotropic hypogonadism 2 with or without anosmia AD 147950
Undefined Trigonocephaly 1 AD 190440

FGFR2
Skeletal dysplasias
GoF Bent bone dysplasia AD 614592
Craniosynostosis
GoF Antley–Bixler syndrome without genital anomalies or disordered steroidogenesis AD 207410
GoF Apert syndrome AD 101200
GoF Beare–Stevenson cutis gyrata syndrome AD 123790
GoF Craniofacial-skeletal-dermatological dysplasia AD 101600
GoF Crouzon syndrome AD 123500
GoF Jackson–Weiss syndrome AD 123150
GoF Pfeiffer syndrome AD 101600
GoF Saethre–Chotzen syndrome AD 101400
GoF Scaphocephaly, maxillary retrusion, and mental retardation AD 609579
Other
LoF LADD syndrome AD 149730

FGFR3
Skeletal dysplasias
GoF Achondroplasia AD 100800
GoF Hypochondroplasia AD 146000
GoF SADDAN AD 616482
GoF Thanatophoric dysplasia type 1 AD 187600
GoF Thanatophoric dysplasia type 2 AD 187601
Craniosynostosis
GoF Crouzon with acanthosis nigricans AD 612247
GoF Muenke syndrome AD 602849
Other
GoF CATSHL AD 610474
LoF LADD syndrome AD 149730

Abbreviations: AD: autosomal dominant; AR: autosomal recessive; LoF: loss-of-function; GoF: gain-of-function; OMIM: Online Mendelian Inheritance in Man.

gain-of-function properties on the affected receptors. Although
premature differentiation of the osteoblasts bordering the cranial
suture mesenchyme may be the most important factor leading to
the development of craniosynostosis, the resulting pathophysio-
logical processes are complex and include increased proliferation,
differentiation and apoptosis of the osteoblasts [38,44].
Craniosynostosis syndromes are associated with mutations in
three of the four members of the FGFR family, namely FGFR1,
FGFR2, and FGFR3. FGFR2 is the most frequently mutated, with most
mutations mapping to the D3 domain and the D2–D3 linker. Fre-
quent mutations causing Crouzon syndrome, Pfeiffer syndrome,
or Jackson–Weiss syndrome involve the gain or loss of a cys-
teine residue [45–47]. This results in an unpaired-cysteine residue
which facilitates the formation of intermolecular disulphide bonds
causing ligand-independent FGFR dimerization, phosphorylation,
and signalling [45,48,49]. Furthermore, there are numerous other
mutations which act by perturbing the folding of the D3 domain,
thereby exposing the conserved cysteines of the domain. These
residues then engage in disulphide-linked dimerization and recep-
tor activation [47].
The FGFR-related syndromes are all autosomal dominant dis-
orders and include: Antley-Bixler syndrome (ABS2) [51,52], Apert
syndrome (ACS1) [50,53], Beare–Stevenson syndrome (BSVS)
[54,55], Crouzon syndrome with acanthosis nigricans (CAN) [56],
Crouzon syndrome (CFD1) [57,58], Jackson–Weiss syndrome (JWS)
[59,60], Muenke syndrome (MNKES) [61], and Pfeiffer syndrome
(ACS5) [60,62–64] (see Table 1). The majority of mutations are
found in FGFR2 and are de novo in origin. Interestingly, the de
novo mutations most often arise on the paternal allele and are
strongly associated with an increased paternal age [65]. Mutations
in FGFR2 enhance receptor activation through several mecha-
nisms, including constitutive ligand-independent dimerization,
enhancing the intrinsic tyrosine kinase activity of the intracellular
kinase domain, enhancing binding affinity of the receptor for FGFs
 S. Moosa, B. Wollnik / Seminars in Cell & Developmental Biology 53 (2016) 115–125
Fig. 3. Schematic presentation of the calvarial bones and sutures. Also shown are the deformities resulting from synostosis of a particular suture. The arrows indicate the
directions of skull growth.
and compromising ligand binding specificity [66–69]. The major
FGFR-related craniosynostosis syndromes are summarized below.
3.1.1. Apert syndrome
Apert syndrome (ACS1; OMIM 101200) was first described by
Apert in 1906 [50]. The syndrome is characterized by premature
fusion of the bilateral coronal sutures, complex symmetrical syn-
dactyly of hands and feet, and developmental delay in addition
to other associated features [70]. ACS1 is caused by heterozy-
gous gain-of-function mutations in FGFR2, with two mutations
(p.Ser252Trp and p.Pro253Arg) being particularly frequent (hot-
spot mutations). These mutations confer gain-of-function effects
on FGFR2 in a ligand-dependent manner by compromising ligand
binding specificity [71,72]. Again, the vast majority of ACS1-causing
mutations arise de novo on the paternal allele, providing evidence
for advanced paternal age effects. Rarely, familial forms with auto-
somal dominant inheritance have been described.
3.1.2. Crouzon syndrome
First described by Crouzon in 1912, Crouzon syndrome (CFD1;
OMIM 123500) is characterized by varying degrees of craniosynos-
tosis, typical facial features (Crouzonoid facies) and the absence of
major abnormalities of the hands and feet [57,58,70]. The pheno-
type in CFD1 can vary, even amongst family members, and can be
very mild in some cases. It is also caused by gain-of-function muta-
tions in FGFR2, which result for example in ligand-independent,
disulphide-linked receptor dimerization and activation [73].
3.1.3. Pfeiffer syndrome
Although Pfeiffer syndrome (ACS5; OMIM 101600) was origi-
nally described in 1964, its underlying cause was only discovered
several decades later [62]. Pfeiffer syndrome is caused by heterozy-
gous mutations in either FGFR1 or FGFR2 [63,64,74,75]. Affected
individuals have characteristic hand and foot abnormalities, such
119
as broad thumbs and halluces, brachydactyly and variable degrees
of syndactyly. Several clinical subtypes have been delineated, with
the classic type 1 being compatible with life, while patients with
types 2 (cloverleaf skull) and 3 demise early [76]. All patients with
FGFR1-related Pfeiffer syndrome have the same gain-of-function
mutation (p.Pro252Arg) in the D2–D3 linker region of FGFR1, which
results in increased receptor affinity for ligand binding [72]. The
Pfeiffer syndrome mutations in FGFR2 overlap with those caus-
ing Crouzon syndrome (p.Cys278Phe and p.Cys342Tyr mutations
cause both syndromes); however, the majority of severely affected
patients with Pfeiffer syndrome have one of the following FGFR2
mutations, which result in ligand-independent activation of the
receptor: p.Trp290Cys, p.Tyr340Cys, p.Cys342Arg or p.Ser351Cys
[77]. Other mutations, including the p.Asp321Ala have been shown
to compromise FGFR2 binding specificity in addition to enhancing
ligand-binding affinity of the receptor [71,72].
3.1.4. Jackson–Weiss syndrome
Jackson–Weiss syndrome (JWS; OMIM 123150) is character-
ized by variable craniosynostosis, tarsal and/or metatarsal fusion,
facial dysmorphism and broad halluces with normal hands [59].
The syndrome was first described in an Amish kindred in 1976
[59]. Since then, numerous other patients have been described in
the literature. Clinically, JWS patients resemble those with Pfeif-
fer syndrome. JWS is caused by mutations in FGFR1 [78] and FGFR2
[60]. The mutations result in excessive receptor activation by, for
example, enhancing the affinity of the receptor for ligand binding
[72].
3.1.5. Beare–Stevenson cutis gyrata syndrome
Beare–Stevenson cutis gyrata syndrome (BTVS; OMIM 123790)
is a rare form of syndromic craniosynostosis with cutis gyrata, acan-
thosis nigricans, and ear and anogenital anomalies [54,55,79]. BTVS
occurs due to heterozygous mutations in FGFR2, the most common
120 S. Moosa, B. Wollnik / Seminars in Cell & Developmental Biology 53 (2016) 115–125
of which are the p.Ser372Cys and p.Tyr375Cys mutations located
near the receptor’s membrane insertion point. These mutations
result in ligand-independent receptor activation [80,81].
3.1.6. Antley–Bixler syndrome type 2
Antley–Bixler syndrome type 2 (ABS2; OMIM 207410) is the
exclusively skeletal form of Antley–Bixler syndrome caused by
heterozygous mutations in FGFR2 [52]. The syndrome is mainly
characterized by craniosynostosis, facial dysmorphism and skeletal
abnormalities, such as radiohumeral synostosis [51,82].
3.1.7. Muenke syndrome
Muenke syndrome (MNKES; OMIM 602849) is a syndromic form
of craniosynostosis which clinically resembles both Jackson–Weiss
and Pfeiffer syndromes. It is characterized by uni- or bicoronal
synostosis, macrocephaly, facial dysmorphism, and developmental
delay. A single mutation in FGFR3 causes MNKES (p.Pro250Arg) [61].
The FGFR3 MNKES p.Pro250Arg substitution is the exact equivalent
of the Apert syndrome p.Pro253Arg substitution in FGFR2 and the
Pfeiffer syndrome p.Pro252Arg mutation in FGFR1; hence, like the
corresponding FGFR1 and FGFR2 mutations, this MNKES mutation
causes a gain in binding affinity of FGFR3 for ligand [72].
3.1.8. Crouzon syndrome with acanthosis nigricans
Crouzon syndrome with acanthosis nigricans, also termed
Crouzonodermoskeletal syndrome (CAN; OMIM 612247), is char-
acterized by typical Crouzon-like features in addition to acanthosis
nigricans, which develops during childhood [56]. Affected individ-
uals may also develop other symptoms, such as cementomas of the
jaw, which are atypical for classic Crouzon syndrome [83]. A single
mutation in FGFR3 (Ala391Glu), which maps to the C-terminal end
of the transmembrane helix, underlies this syndrome [84].
4. FGF/FGFR signalling in skeletal development
Endochondral ossification is the process by which the appen-
dicular skeleton, facial bones, vertebrae and medial clavicles are
formed. In contrast to intramembranous ossification, it is a two-
step process. First chondrocytes form cartilaginous primordia in
which osteoblasts differentiate and continue the process of ossifica-
tion. This conversion of the cartilaginous primordial template into
bone involves several developmental steps. FGF/FGFR signalling
was recognized as a crucial component during endochondral bone
formation, when the underlying cause of achondroplasia, a het-
erozygous mutation in FGFR3, was first discovered [85,86]. Since
then, many other skeletal dysplasias have been attributed to muta-
tions in members of the FGF and FGFR families (Table 1).
A number of FGFs are expressed in developing endochondral
bone. FGF2 was the first of the FGFs to be isolated from chon-
drocytes in the developing growth plate [87]. Expression of Fgf2
can be observed in osteoblasts and periosteal cells [88,89]; but
no role has been established for Fgf2 in chondrogenesis [90]. Fgf9
is also expressed in chondrocytes [91,92]. However, Fgf9 knock-
out mice do not display any skeletal abnormalities at birth [93].
A number of studies have shown that other members of the FGF
family, for example Fgf7, Fgf8, Fgf17 and Fgf18, are expressed in
developing endochondral bone tissue, and at least for one of these,
namely Fgf18, essential roles in chondrogenesis and osteogenesis
have been demonstrated [33,34,94–96].
In chondrocytes, Fgfr3 expression is initiated in the differenti-
ated core of mesenchyme. At the same time, Fgfr2 is also expressed.
During the epiphyseal growth plate formation, Fgfr1 is expressed
to further differentiate the chondrocytes and enable chondrocyte
growth. It is interesting to note that the expression domains of Fgfr1
and Fgfr3 are distinct: Fgfr1 is expressed in the hypertrophic chon-
drocytes, while Fgfr3 is expressed in the proliferating chondrocytes
[97,98]. Thus, Ffgr1 is implicated in regulating the survival and rate
of differentiation of hypertrophic chondrocytes [38,97]. Fgfr3 on
the other hand, is implicated in directly regulating chondrocyte
proliferation and possible differentiation [38,97,99]. It was shown
that activation of FGFR3 induces several downstream pathways,
for example, the signal transducer and activator of transcription
(STAT), RAS/MAP kinase (MAPK), and PLC␥ pathways (see Fig. 2)
[7,100–103]. Moreover, chondrocyte proliferation is thought to be
inhibited by STAT signals, while RAS/MAP kinase signals nega-
tively influence proliferation and disrupt terminal differentiation
and post-mitotic matrix synthesis [101,104–106]. Studies suggest
that FGFR3 exerts its negative growth effect mainly during the
growth phase of bone, when it inhibits the proliferation and differ-
entiation of chondrocytes in developing bone [107,108]. Moreover,
FGFR3 is also implicated in premature terminal differentiation of
chondrocytes, thus reducing the pool of chondrocytes available to
form cartilage [104,109].
It thus appears that the normal action of FGFR3 is to suppress
bone growth. Fgfr3 knockout mice have elongated hind limbs and
tails [98,110]. Heterozygous mutations in FGFR3 have been shown
to result mainly in a constitutive activation of the receptor [49,111],
increased ligand-binding affinity [71,112], altered specificity for
FGF binding [66], or direct activation of the tyrosine kinase domains
[68,69,113].
4.1. FGFR-related skeletal dysplasia spectrum
Since the discovery of the underlying genetic cause of achon-
droplasia in 1994 [85,86], dysregulated FGFR signalling has been
implicated in a growing number of skeletal disorders. Most muta-
tions in the FGFR genes are inherited in an autosomal dominant
manner and exhibit a gain-of-function mechanism of action,
although there are notable exceptions (see Table 1).
Mutations in FGFR3 underlie the so-called achondroplasia fam-
ily of skeletal disorders, which includes hypochondroplasia (HCH),
achondroplasia (ACH), severe achondroplasia with developmen-
tal delay and acanthosis nigricans (SADDAN) and thanatophoric
dysplasia types 1 (TD1) and 2 (TD2). These disorders represent
a spectrum of severity in the clinical and radiological presenta-
tion from mild (HCH) to severe (ACH and SADDAN) and neonatally
lethal (TD1 and TD2) (see Fig. 4). Evidence suggests that the phe-
notypic differences in severity among these disorders may be due
to the respective mutations causing varying degrees of ligand-
independent activation [69,114]. Moreover, mutations in different
domains of FGFR3 may have differing effects on the signal trans-
duction pathways initiated by the receptor.
It is interesting to note the presence of “hot-spot” muta-
tions in both FGFR2 and FGFR3. A common hot-spot in FGFR3,
the Lys650 residue is located just two residues from the A-
loop tyrosines. Substitutions at this conserved lysine lead
to TD2 (p.Lys650Glu), SADDAN (p.Lys650Met), and HCH
(p.Lys650Asn, p.Lys650Gln, p.Lys650Thr). Chen et al. [69]
were able to show that the Lys650 mutations enhance the
intrinsic activity of the FGFR3 kinase in the following order:
Lys650Glu > Lys650Met > Lys650Asn − Lys650Gln > Lys650Thr
which correlates well with the clinical spectrum of severity of
these disorders [69].
Further FGFR-related skeletal disorders include FGFR1-related
osteoglophonic dysplasia, FGFR2-related bent bone dysplasia, and
LADD syndrome, which is genetically heterogeneous and linked to
mutations in FGF10, FGFR2 and FGFR3 (see Table 1).
4.1.1. Achondroplasia
Achondroplasia (ACH; OMIM 100800) is the most common form
of dwarfism in humans. Affected individuals have short stature
due to predominantly rhizomelic shortening of the limbs. They
 S. Moosa, B. Wollnik / Seminars in Cell & Developmental Biology 53 (2016) 115–125 121

Fig. 4. Radiographs of the FGFR3-related skeletal dysplasias. The spectrum of severity ranges from mild in HCH (not shown), to more severe in ACH (A–C), to very severe in
SADDAN (D–F) and invariably lethal in TD1 (G) and TD2 (H) (radiographs kindly provided by Professor Gen Nishimura, Tokyo, Japan).
122 S. Moosa, B. Wollnik / Seminars in Cell & Developmental Biology 53 (2016) 115–125
also have macrocephaly, frontal bossing and midface hypoplasia
[115]. ACH is an autosomal dominant disorder caused by mutations
in FGFR3 [85,86], with approximately 99% of patients harbouring
the heterozygous gain-of-function p.Gly380Arg mutation, which
results in ligand-independent receptor activation [49]. Around 80%
of affected individuals have achondroplasia due to a de novo occur-
rence of mutations in FGFR3; the remainder have inherited the
mutation from an affected parent. Homozygous achondroplasia is
a very severe, perinatally lethal condition.
4.1.2. Hypochondroplasia
Hypochondroplasia (HCH; OMIM 146000) is an autosomal dom-
inant disorder which is phenotypically milder than ACH. HCH is
also characterized by short stature and rhizomelic shortening of
the extremities. HCH can be distinguished from ACH on clinical
and radiological grounds [116], although the diagnosis may be dif-
ficult to make, especially in young infants. Several heterozygous
mutations in FGFR3 cause HCH, although the p.Asn540Lys is partic-
ularly common [115]. Once again, a gain-of-function mechanism is
involved, albeit to a lesser extent than in the more severe FGFR3-
related syndromes, as has been shown in functional studies of
the underlying mutations [69,114]. The p.Asn540Lys mutation, for
example, was shown to target the so-called “molecular brake” at
the kinase hinge region that inhibits the ability of the kinase to
adopt its active conformation [69].
4.1.3. Thanatophoric dysplasia
There are two subtypes of thanatophoric dysplasia, which are
distinguished on clinical, radiological and genetic grounds [117].
Thanatophoric dysplasia type 1 (TD1; OMIM 187600) is a severe
short-limbed form of dwarfism which is usually lethal in the neona-
tal period [118]. TD1 is characterized by severe micromelia with
bowing of the long bones, severe platyspondyly and “French tele-
phone handle”-shaped femurs. Thanatophoric dysplasia type 2
(TD2; OMIM 187601) is distinguished from TD1 by the presence
of a cloverleaf skull and relatively straight femurs. Both conditions
are caused by mutations in FGFR3 [119]. The most common TD1
mutations affect the extracellular domain of FGFR3, while the most
common TD2 mutation, namely p.Lys650Glu, affects the tyrosine
kinase domain. The crystal structure of the FGFR3 kinase domain
harbouring the p.Lys650Glu mutation shows that this mutation sta-
bilizes the active state conformation of the kinase activity, thereby
increasing the kinase activity of the affected receptor [120]. The
TD1 and TD2 mutations impart greater activation of the receptor
than the mutations causing ACH and HCH.
4.1.4. Severe achondroplasia with developmental delay and
acanthosis nigricans
Severe achondroplasia with developmental delay and acantho-
sis nigricans (SADDAN; OMIM 616482) is a rare but severe skeletal
dysplasia. SADDAN is characterized by marked short stature, tibial
bowing, profound developmental delay and acanthosis nigricans.
The severity of SADDAN approaches that of TD1 [116,121]; how-
ever, unlike TD1 and TD2, patients with SADDAN usually survive
past infancy. The associated acanthosis nigricans is not evident in
early childhood but develops only later. Molecular analysis is thus
crucial to make the diagnosis. An FGFR3 p.Lys650Met mutation has
been identified in affected individuals [69,116,121]. This substitu-
tion of lysine by methionine has been shown to markedly enhance
the intrinsic activity of the FGFR3 kinase [69].
4.1.5. Osteoglophonic dysplasia
Osteoglophonic dysplasia (OGD; OMIM 166250) is a rare form
of syndromic dwarfism, associated with rhizomelic shortening of
the limbs, craniosynostosis and dysmorphic facial features, which
include frontal bossing and a deeply depressed nasal bridge [122]. It
is the only skeletal dysplasia associated with activating mutations
in FGFR1 [123]. The OGD-causing mutations affect highly con-
served residues in the extracellular juxtamembrane region of the
receptor (p.Tyr372Cys), the C-terminal portion of the D3 domain
(p.Asn330Ile) or the transmembrane domain (p.Cys379Arg). In the
case of the p.Tyr372Cys mutation, White et al. [123] were able
to show enhanced basal activity and increased ligand-induced
receptor activation in cell-based assays. Mutations affecting the
homologous position in FGFR3 of the FGFR1 Cys379 are responsible
for the majority of cases of ACH [85,86].
4.1.6. Bent bone dysplasia
Bent bone dysplasia (BBDS; OMIM 614592) is a perinatally lethal
skeletal dysplasia, clinically characterized by bent long bones,
craniosynostosis, dysmorphic facial features and osteopenia. Het-
erozygous mutations in FGFR2 were identified as the cause of BBDS
[124]. The identified mutations which map to the transmembrane
region of FGFR2 decrease FGFR2 plasma membrane signalling, but
do not affect nuclear localization of the mutant receptor. As a conse-
quence of the FGFR2 mutations, enhanced nuclear occupancy of the
receptor occurs at the ribosomal DNA promoter, where it induces
enhanced rDNA transcription [125].
4.1.7. Lacrimo-auriculo-dento-digital syndrome
Autosomal dominant lacrimo-auriculo-dento-digital syndrome
(LADD; OMIM 149730) is a genetically heterogeneous syndrome
caused by heterozygous mutations in FGF10, FGFR2 and FGFR3 [126].
Clinically, patients with LADD syndrome typically present with
lacrimal duct aplasia, dysplastic ears associated with hearing loss
in 50% of cases, dental abnormalities, and digital malformations
mainly affecting the thumbs [127]. In contrast to the syndromes
described above, the mutations in the FGF/FGFR pathway associ-
ated with LADD syndrome are hypofunctional and loss-of-function
mutations, and a dominant-negative effect was described for muta-
tions in FGFR2 and FGFR3 (see Table 1). The mutations described by
Rohmann et al. [126] in these FGFR proteins are specifically located
within the tyrosine kinase domain of the receptors. Thus, for exam-
ple, heterozygosity for either the FGF10 or the FGFR2 mutations in
LADD syndrome leads to reduced FGFR2 kinase activity and hence
reduced FGFR2 signalling [128]. The LADD phenotype is recapit-
ulated in conditional knockout Fgfr2 and Fgf10 animals. Milunsky
et al. [129] described a family in which the daughter had typical
features of LADD syndrome, but her mother only had aplasia of
the lacrimal and salivary glands (ALSG; OMIM 180920). They iden-
tified a heterozygous mutation in the FGF10 gene in the family,
thus providing evidence that LADD and ASLG are part of the same
phenotypic spectrum [129].
4.1.8. Camptodactyly–tall stature–hearing loss syndrome
The camptodactyly, tall stature, hearing loss syndrome (CAT-
SHL; OMIM 610474) is another syndrome caused by mutations in
FGFR3. Both heterozygous [130] and homozygous [131] mutations
in the kinase domain of FGFR3 have been identified in families with
CATSHL. Clinically, patients with CATSHL have tall stature, hear-
ing loss and camptodactyly and may have developmental delay.
Mice homozygous for an Fgfr3-null allele display similar pheno-
typic features to patients with CATSHL. Both Toydemir et al. [130]
and Makrythanasis et al. [131] postulate a loss-of-function mech-
anism for the identified mutations. Their findings provide insight
into how abnormal FGFR3 signalling can cause a human phenotype
opposite to the well-understood short stature skeletal dysplasias,
thus implicating dysregulated FGFR3 in the promotion as well as
inhibition of endochondral bone development.
 S. Moosa, B. Wollnik / Seminars in Cell & Developmental Biology 53 (2016) 115–125
5. Therapeutic outlook
Since the discovery of the FGFR3 mutation causing achondropla-
sia, effective therapies for the FGFR3-related disorders have been
sought. Research has been based on the premise that direct or
indirect inhibition of the FGFR3 signalling pathway would provide
options for treatment. Several approaches have been attempted
in the past few years aiming to directly inhibit the FGFR3 kinase
activity, but unfortunately with little success. More recently, as
more information has become available on FGFR3 signalling and
its downstream pathways and targets, novel therapeutic options
have emerged, which show promise. They include C-type natri-
uretic peptide (CNP)-mediated antagonism of FGFR3 downstream
signals, chemical inhibition of FGFR3 tyrosine kinase activity and
antibody blockade of FGFR3 activation. There are currently clinical
trials underway to evaluate the effect of BMN-111 in patients with
achondroplasia. BMN-11 is a CNP agonist, which was found to nor-
malize skeletal growth in achondroplasia mouse models [132,133].
In chondrocytes, CNP signals through its receptor, natriuretic pep-
tide receptor 2 (guanylate cyclase B), which inhibits the MAP kinase
pathway and thus regulates skeletal growth. This makes it an
attractive target for therapeutic intervention. Overexpression of
CNP results in skeletal overgrowth through attenuation of FGFR3
signalling [132,134].
Very recently, statins were identified as a possible drug to
improve chondrogenic differentiation of induced pluripotent stem
cells derived from patients with thanatophoric dysplasia [135]. Fur-
thermore, achondroplasia mice treated with a class of statins show
increased long bone and anteroposterior skull lengths [135]. The
underlying mechanism by which statins exert their effects on bone
tissue is still poorly understood, but the possibility of future statin-
based therapies is intriguing.
6. Conclusion
This paper has reviewed the major congenital skeletal and cra-
niosynostosis disorders associated with dysregulated FGF/FGFR
signalling. It is anticipated that ongoing research will improve our
understanding of the underlying pathophysiology of these disor-
ders and that this will facilitate the discovery of novel therapeutic
targets for FGF/FGFR-related disorders. There are already promis-
ing trials underway for the treatment of achondroplasia which we
anticipate will bring much hope and relief to affected individuals
and their families.
Acknowledgements
We thank Karin Boss for critically reading the manuscript and
Professor Gen Nishimura (Tokyo, Japan) for kindly providing us
with the images. This work was supported by the German Fed-
eral Ministry of Education and Research (BMBF) by grant number
01GM1211A (E-RARE network CRANIRARE-2) to B.W.
References
[1] Coulier F, Pontarotti P, Roubin R, Hartung H, Goldfarb M, Birnbaum D. Of
worms and men: an evolutionary perspective on the fibroblast growth factor
(FGF) and FGF receptor families. J. Mol. Evol 1997;44:43–56.
[2] Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their recep-
tors and signaling. Endocr. Relat. Cancer 2000;7:165–97.
[3] Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol 2001. Reviews
3005.
[4] Armelin HA. Pituitary extracts and steroid hormones in the control of 3T3 cell
growth. Proc. Natl. Acad. Sci. U.S.A 1973;70:2702–6.
[5] Givol D, Eswarakumar VP, Lonai P. Molecular and cellular biology of FGF
signaling. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, editors. Inborn Errors
of Development – The Molecular Basis of Clinical Disorders of Morphogenesis.
Oxford: Oxford University Press; 2003. p. 367–79.
123
[6] Yu C, Wang F, Kan M, Jin C, Jones RB, Weinstein M, et al. Elevated cholesterol
metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase
receptor FGFR4. J. Biol. Chem 2000;275:15482–9.
[7] Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth
factor receptors. Cytokine Growth Factor Rev 2005;16:139–49.
[8] Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and
therapy. Nat. Rev. Drug Discov 2009;8:235–53.
[9] Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM. Cell surface, heparin-like
molecules are required for binding of basic fibroblast growth factor to its high
affinity receptor. Cell 1991;64:841–8.
[10] Rapraeger AC, Krufka A, Olwin BB. Requirement of heparan sulphate for
bFGF-mediated fibroblast growth and myoblast differentiation. Science
1991;252:1705–8.
[11] Ornitz DM, Yayon A, Flanagan JG, Svahn CM, Levi E, Leder P. Heparin is required
for cell-free binding of basic fibroblast growth factor to a soluble receptor and
for mitogenesis in whole cells. Mol. Cell. Biol 1992;12:240–7.
[12] Spivak-Kroizman T, Lemmon MA, Dikic I, Ladbury JE, Pinchasi D, Huang
J, et al. Heparin-induced oligomerization of FGF molecules is responsi-
ble for FGF receptor dimerization, activation, and cell proliferation. Cell
1994;79:1015–24.
[13] Lin X, Buff EM, Perrimon N, Michelson AM. Heparan sulphate proteoglycans
are essential for FGF receptor signaling during Drosophila embryonic devel-
opment. Development 1999;126:3715–23.
[14] Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita
T, et al. Klotho converts canonical FGF receptor into a specific receptor for
FGF23. Nature 2006;444:770–4.
[15] Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, et al.
Regulation of fibroblast growth factor-23 signaling by Klotho. J. Biol. Chem
2006;281:6120–3.
[16] Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, et al. Tissue-
specific expression of ␤Klotho and fibroblast growth factor (FGF) receptor
isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem
2007;282:26687–95.
[17] Nakatani T, Ohnishi M, Razzaque MS. Inactivation of klotho function induces
hyperphosphatemia even in presence of high serum fibroblast growth factor
23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model.
FASEB J 2009;23:3702–11.
[18] Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate KC, Mangelsdorf DJ,
et al. ␤Klotho is required for fibroblast growth factor 21 effects on growth
and metabolism. Cell Metab 2007;16:387–93.
[19] Hunter T. Signaling—2000 and beyond. Cell 2000;100:113–27.
[20] Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell
2000;103:211–25.
[21] McKeehan WL, Kan M. Heparan sulfate fibroblast growth factor receptor com-
plex: structure–function relationships. Mol. Reprod. Dev 1994;39:62–81.
[22] Wang F, Lu W, McKeehan K, Mohamedali K, Gabriel JL, Kan M, et al. Common
and specific determinants for fibroblast growth factors in the ectodomain of
the receptor kinase complex. Biochemistry 1999;38:160–71.
[23] Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM.
Receptor specificity of the fibroblast growth factor family: the complete mam-
malian FGF family. J. Biol. Chem 2006;281:15694–700.
[24] Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase
activity. Cell 1990;61:203–12.
[25] Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon
A, et al. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a
dual role for heparin in FGFR binding and dimerization. Mol. Cell 2000;6:
743–50.
[26] Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and
intramembranous bone development and human genetic disease. Genes Dev
2002;16:1446–65.
[27] Wilkie AO. Craniosynostosis: genes and mechanisms. Hum. Mol. Genet
1997;6:1647–56.
[28] Morriss-Kay GM. Derivation of the mammalian skull vault. J. Anat
2001;199:143–51.
[29] Nie X, Luuko K, Kettunen P. FGF signalling in craniofacial development and
developmental disorders. Oral Dis 2006;1282:102–11.
[30] Hatch NE. FGF signalling in craniofacial biological control and patholog-
ical craniofacial development. Crit. Rev. Eukaryot. Gene Expr 2010;20:
295–311.
[31] Kim HJ, Rice DP, Kettunen PJ, Thesleff I. FGF-BMP-, and Shh-mediated
signalling pathways in the regulation of cranial suture morphogenesis and
calvarial bone development. Development 1998;125:1241–51.
[32] Johnson D, Iseki S, Wilkie AOM, Morriss-Kay GM. Expression patterns of Twist
and Fgfr1-2 and -3 in the developing mouse coronal suture suggest a key role
for Twist in suture initiation and biogenesis. Mech. Dev 2000;91:341–5.
[33] Liu Z, Xu J, Colvin JS, Ornitz DM. Coordination of chondrogenesis and osteo-
genesis by fibroblast growth factor 18. Genes Dev 2002;16:859–69.
[34] Ohbayashi N, Shibayama M, Kurotaki Y, Imanishi M, Fujimori T, Itoh N, et al.
FGF18 is required for normal cell proliferation and differentiation during
osteogenesis and chondrogenesis. Genes Dev 2002;16:870–9.
[35] Hajihosseini MK, Heath JK. Expression patterns of fibroblast growth factors-
18 and -20 in mouse embryos is suggestive of novel roles in calvarial and limb
development. Mech. Dev 2002;113:79–83.
[36] Hughes SE. Differential expression of the fibroblast growth factor (FGFR)
multigene family in normal human adult tissues. J. Histochem. Cytochem
1997;45:1005–19.
124 S. Moosa, B. Wollnik / Seminars in Cell & Developmental Biology 53 (2016) 115–125
[37] Britto JA, Chan JC, Evans RD, Hayward RD, Thorogood P, Jones BM. Fibro-
blast growth factor receptors are expressed in craniosynostotic sutures. Plast.
Reconstr. Surg 1998;101:540–3.
[38] Delezoide AL, Benoist-Lasselin C, Legeai-Mallet L, Le Merrer M, Munnich A,
Vekemans M, et al. Spatio-temporal expression of FGFR 1, 2 and 3 genes during
human embryo-fetal ossification. Mech. Dev 1998;77:19–30.
[39] Iseki S, Wilkie AOM, Morriss-Kay GM. Fgfr1 and Fgfr2 have distinct differen-
tiation and proliferation-related roles in the developing mouse skull vault.
Development 1999;126:5611–20.
[40] Marie PJ, Debiais F, Hay E. Regulation of human cranial osteoblast phenotype
by FGF-2, FGFR-2 and BMP-2 signaling. Histol. Histopathol 2002;17:877–85.
[41] Rice DP, Aberg T, Chan Y, Tang Z, Kettunen PJ, Pakarinen L, et al. Integration
of FGF and TWIST in calvarial bone and suture development. Development
2000;127:1845–55.
[42] Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D. Genetic study
of nonsyndromic coronal craniosynostosis. Am. J. Med. Genet 1995;55:500–4.
[43] Boulet SL, Rasmussen SA, Honein MA. A population-based study of cra-
niosynostosis in metropolitan Atlanta, 1989–2003. Am. J. Med. Genet
2008;146A:984–91.
[44] Holmes G, Rothschild G, Roy UB, Deng CX, Mansukhani A, Basilico C. Early
onset of craniosynostosis in an Apert mouse model reveals critical features of
this pathology. Dev. Biol 2009;328:273–84.
[45] Wilkie AO, Morriss-Kay GM, Jones EY, Heath JK. Functions of fibroblast growth
factors and their receptors. Curr. Biol 1995;5:500–7.
[46] Galvin BD, Hart KC, Meyer AN, Webster MK, Donoghue DJ. Constitu-
tive receptor activation by Crouzon syndrome mutations in fibroblast
growth factor (FGFR)2 and FGFR2/New chimeras. Proc. Natl. Acad. Sci. U.S.A
1996;93:7894–9.
[47] Robertson SC, Meyer AN, Hart KC, Galvin BD, Webster MK, Donoghue DJ.
Activating mutations in the extracellular domain of the fibroblast growth
factor receptor 2 function by disruption of the disulfide bond in the third
immunoglobulin-like domain. Proc. Natl. Acad. Sci. U.S.A 1998;95:4567–72.
[48] Muenke M, Schell U. Fibroblast-growth-factor receptor mutations in human
skeletal disorders. Trends Genet 1995;11:308–13.
[49] Naski MC, Wang Q, Xu J, Ornitz DM. Graded activation of fibroblast growth
factor receptor 3 by mutations causing achondroplasia and thanatophoric
dysplasia. Nat. Genet 1996;13:233–7.
[50] Apert ME. De l’acrocephalosyndactylie. Bull. Mem. Soc. Med. Hop. Paris
1906;23:1310–20.
[51] Antley RM, Bixler D. Trapezoidocephaly, midface hypoplasia and cartilage
abnormalities with multiple synostoses and skeletal fractures. Birth Defects
Orig. Artic. Ser 1975;XI:397–401.
[52] Chun K, Siegel-Bartelt J, Chitayat D, Phillips J, Ray PN. FGFR2 mutation asso-
ciated with clinical manifestations consistent with Antley–Bixler syndrome.
Am. J. Med. Genet 1998;77:219–24.
[53] Wilkie AOM, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, et al.
Apert syndrome results from localized mutations of FGFR2 and is allelic with
Crouzon syndrome. Nat. Genet 1995;9:165–72.
[54] Beare JM, Dodge JA, Nevin NC. Cutis gyratum, acanthosis nigricans and other
congenital anomalies: a new syndrome. Br. J. Dermatol 1969;81:241–7.
[55] Stevenson RE, Ferlauto GJ, Taylor HA. Cutis gyratum and acanthosis nigri-
cans associated with other anomalies: a distinctive syndrome. J. Pediatr
1978;92:950–2.
[56] Breitbart AS, Eaton C, McCarthy JG. Crouzon’s syndrome associated with acan-
thosis nigricans: ramifications for the craniofacial surgeon. Ann. Plast. Surg
1989;22:310–5.
[57] Crouzon O. Dysostose cranio-faciale hereditaire. Bull. Mem. Soc. Med. Hop.
Paris 1912;33:545–55.
[58] Reardon W, Winter RM, Rutland P, Pulleyn LJ, Jones BM, Malcolm S. Mutations
in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat.
Genet 1994;8:98–103.
[59] Jackson CE, Weiss L, Reynolds WA, Forman TF, Peterson JA. Craniosynostosis
midfacial hypoplasia, and foot abnormalities: an autosomal dominant phe-
notype in a large Amish kindred. J. Pediatr 1976;88:963–8.
[60] Jabs EW, Li X, Scott AF, Meyers G, Chen W, Eccles M, et al. Jackson–Weiss
and Crouzon syndromes are allelic with mutations in fibroblast growth factor
receptor 2. Nat. Genet 1994;8:275–9.
[61] Muenke M, Gripp KW, McDonald-McGinn DM, Gaudenz K, Whitaker LA,
Bartlett SP, et al. A unique point mutation in the fibroblast growth factor
receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am. J.
Hum. Genet 1997;60:555–64.
[62] Pfeiffer RA. Dominant erbliche Akrocephalosyndaktylie. Z. Kinderheilk
1964;90:301–20.
[63] Muenke M, Schell U, Hehr A, Robin NH, Losken HW, Schinzel A, et al. A com-
mon mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer
syndrome. Nat. Genet 1994;8:269–74.
[64] Rutland P, Pulleyn LJ, Reardon W, Baraitser M, Hayward R, Jones B, et al. Iden-
tical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome
phenotypes. Nat. Genet 1995;9:173–6.
[65] Glaser RL, Jiang W, Boyadjiev SA, Tran AK, Zachary AA, Van Maldergem L, et al.
Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome
and Pfeiffer syndrome. Am. J. Hum. Genet 2000;66:768–77.
[66] Yu K, Herr AB, Waksman G, Ornitz DM. Loss of fibroblast growth factor recep-
tor 2 ligand-binding specificity in Apert syndrome. Proc. Natl. Acad. Sci. U.S.A
2000;97:14536–41.
[67] Ibrahimi OA, Zhang F, Eliseenkova AV, Itoh N, Linhardt RJ, Mohammadi M. Bio-
chemical analysis of pathogenic ligand-dependent FGFR2 mutations suggest
distinct pathophysiological mechanisms for craniofacial and limb abnormal-
ities. Hum. Mol. Genet 2004;13:2313–24.
[68] Chen H, Ma J, Li W, Eliseenkova AV, Chonfeng X, Neubert TA, Todd Miller W,
Mohammadi M. A molecular brake in the kinase hinge region regulates the
activity of receptor tyrosine kinases. Mol. Cell 2007;27:717–30.
[69] Chen H, Huang Z, Dutta K, Blais S, Neubert TA, Li X, Cowburn D, Traaseth
NJ, Mohammadi M. Cracking the molecular origin of intrinsic tyrosine kinase
activity through analysis of pathogenic gain-of-function mutations. Cell Rep
2013;4:376–84.
[70] Johnson D, Wilkie AO, Craniosynostosis, Eur J. Hum. Genet 2011;19:369–76.
[71] Ibrahimi OA, Eliseenkova AV, Plotnikov AN, Yu K, Ornitz DM, Mohammadi
M. Structural basis for fibroblast growth factor receptor 2 activation in Apert
syndrome. Proc. Natl. Acad. Sci. U.S.A 2001;98:7182–7.
[72] Ibrahimi OA, Zhang F, Eliseenkova AV, Linhardt RJ, Mohammadi M. Proline
to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke
craniosynostosis syndromes through enhancement of FGF binding affinity.
Hum. Mol. Genet 2004;13:69–78.
[73] Kan SH, Elanko N, Johnson D, Cornejo-Roldan L, Cook J, Reich EW, et al.
Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spec-
trum of mutations in patients with syndromic craniosynostosis. Am. J. Hum.
Genet 2002;70:472–86.
[74] Schell U, Hehr A, Feldman GJ, Robin NH, Zackai EH, de Die-Smulders C, et al.
Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome.
Hum. Mol. Genet 1995;4:323–8.
[75] Lajeunie E, Ma HW, Bonaventure J, Munnich A, Le Merrer M, Renier D. FGFR2
mutations in Pfeiffer syndrome. Nat. Genet 1995;9:108 (Letter).
[76] Cohen Jr MM. Pfeiffer syndrome update, clinical subtypes, and guidelines for
differential diagnosis. Am. J. Med. Genet 1993;45:300–7.
[77] Lajeunie E, Heuertz S, El Ghouzzi V, Martinovic J, Renier D, Le Merrer M, et al.
Mutation screening in patients with syndromic craniosynostoses indicates
that a limited number of recurrent FGFR2 mutations accounts for severe forms
of Pfeiffer syndrome. Eur. J. Hum. Genet 2006;14:289–98.
[78] Roscioli T, Flanagan S, Kumar P, Masel J, Gattas M, Hyland VJ, et al. Clinical
findings in a patient with FGFR1 P252R mutation and comparison with the
literature. Am. J. Med. Genet 2000;93:22–8.
[79] Hall BD, Cadle RG, Golabi M, Morris CA, Cohen Jr MM. Beare–Stevenson cutis
gyrata syndrome. Am. J. Med. Genet 1992;44:82–9.
[80] Przylepa KA, Paznekas W, Zhang M, Golabi M, Bias W, Bamshad MJ, et al. Fibro-
blast growth factor receptor 2 mutations in Beare–Stevenson cutis gyrata
syndrome. Nat. Genet 1996;13:492–4.
[81] Fonseca R, Costa-Lima MA, Cosentino V, Orioli IM. Second case of
Beare–Stevenson syndrome with an FGFR2 ser372cys mutation. Am. J. Med.
Genet 2008;146A:658–60.
[82] McGlaughlin KL, Witherow H, Dunaway DJ, David DJ, Anderson PJ. Spectrum
of Antley–Bixler syndrome. J. Craniofac. Surg 2010;21:1560–4.
[83] Cohen Jr MM. Let’s call it ‘Crouzonodermoskeletal syndrome’ so we won’t be
prisoners of our own conventional terminology. Am. J. Med. Genet 1999;84:74
(Letter).
[84] Meyers GA, Orlow SJ, Munro IR, Przylepa KA, Jabs EW. Fibroblast growth fac-
tor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with
acanthosis nigricans. Nat. Genet 1995;11:462–4.
[85] Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, et al. Mutations
in the gene encoding fibroblast growth factor receptor-3 in achondroplasia.
Nature 1994;371:252–4.
[86] Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, et al. Mutations in
the transmembrane domain of FGFR3 cause the most common genetic form
of dwarfism, achondroplasia. Cell 1994;78:335–42.
[87] Sullivan R, Klagsbrun M. Purification of cartilage-derived growth factor by
heparin affinity chromatography. J. Biol. Chem 1985;260:2399–403.
[88] Hurley MM, Abreu C, Gronowicz G, Kawaguchi H, Lorenzo J. Expression and
regulation of basic fibroblast growth factor mRNA levels in mouse osteoblastic
MC3T3-E1 cells. J. Biol. Chem 1994;269:9392–6.
[89] Sabbieti MG, Marchetti L, Abreu C, Montero A, Hand AR, Raisz LG, et al.
Prostaglandins regulate the expression of fibroblast growth factor-2 in bone.
Endocrinology 1999;140:434–44.
[90] Montero A, Okada Y, Tomita M, Ito M, Tsurukami H, Nakamura T, et al. Dis-
ruption of the fibroblast growth factor-2 gene results in decreased bone mass
and bone formation. J. Clin. Invest 2000;105:1085–93.
[91] Colvin JS, Feldman B, Nadeau JH, Goldfarb M, Ornitz DM. Genomic organiza-
tion and embryonic expression of the mouse fibroblast growth factor 9 gene.
Dev. Dyn 1999;216:72–88.
[92] Garofalo S, Kliger-Spatz M, Cooke JL, Wolstin O, Lunstrum GP, Moshkovitz SM,
et al. Skeletal dysplasia and defective chondrocyte differentiation by targeted
overexpression of fibroblast growth factor 9 in transgenic mice. J. Bone Miner.
Res 1999;14:1909–15.
[93] Colvin JS, Green RP, Schmahl J, Capel B, Ornitz DM. Male-to-female sex rever-
sal in mice lacking fibroblast growth factor 9. Cell 2001;104:875–89.
[94] Mason IJ, Fuller-Pace F, Smith R, Dickson C. FGF-7 (keratinocyte growth factor)
expression during mouse development suggests roles in myogenesis, fore-
brain regionalisation and epithelial-mesenchymal interactions. Mech. Dev
1994;45:15–30.
[95] Finch PW, Cunha GR, Rubin JS, Wong J, Ron D. Pattern of keratinocyte growth
factor and keratinocyte growth factor receptor expression during mouse fetal
 S. Moosa, B. Wollnik / Seminars in Cell & Developmental Biology 53 (2016) 115–125
development suggests a role in mediating morphogenetic mesenchymal-
epithelial interactions. Dev. Dyn 1995;203:223–40.
[96] Xu J, Lawshe A, MacArthur CA, Ornitz DM. Genomic structure, mapping, activ-
ity and expression of fibroblast growth factor 17. Mech. Dev 1999;83:165–78.
[97] Peters KG, Werner S, Chen G, Williams LT. Two FGF receptor genes are
differentially expressed in epithelial and mesenchymal tissues during limb
formation and organogenesis in the mouse. Development 1992;114:233–43.
[98] Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P. Fibroblast growth factor
receptor 3 is a negative regulator of bone growth. Cell 1996;84:911–21.
[99] Naski MC, Ornitz DM. FGF signaling in skeletal development. Front. Biosci
1998;3:D781–94.
[100] Su WC, Kitagawa M, Xue N, Xie B, Garofalo S, Cho J, et al. Activation of Stat1
by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type
II dwarfism. Nature 1997;386:288–92.
[101] Sahni M, Ambrosetti DC, Mansukhani A, Gertner R, Levy D, Basilico C. FGF
signaling inhibits chondrocyte proliferation and regulates bone development
through the STAT-1 pathway. Genes Dev 1999;13:1361–70.
[102] Hart KC, Robertson SC, Kanemitsu MY, Meyer AN, Tynan JA, Donoghue DJ.
Transformation and Stat activation by derivatives of FGFR1, FGFR3, and
FGFR4. Oncogene 2000;19:3309–20.
[103] Choi DY, Toledo-Aral JJ, Lin HY, Ischenko I, Medina L, Safo P, et al. Fibroblast
growth factor receptor 3 induces gene expression primarily through Ras-
independent signal transduction pathways. J. Biol. Chem 2001;276:5116–22.
[104] Minina E, Kreschel C, Naski MC, Ornitz DM, Vortkamp A. Interaction of FGF
Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hyper-
trophic differentiation. Dev. Cell 2002;3:439–49.
[105] Murakami S, Balmes G, McKinney S, Zhang Z, Givol D, de Crombrugghe B.
Constitutive activation of MEK1 in chondrocytes causes Stat1-independent
achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse pheno-
type. Genes Dev 2004;18:290–305.
[106] Zhang R, Murakami S, Coustry F, Wang Y, de Crombrugghe B. Constitutive
activation of MKK6 in chondrocytes of transgenic mice inhibits prolifera-
tion and delays endochondral bone formation. Proc. Natl. Acad. Sci. U.S.A
2006;103:365–70.
[107] Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP, et al. BMP
and Ihh/PTHrP signalling interact to coordinate chondrocyte proliferation and
differentiation. Development 2001;128:4523–34.
[108] Dailey L, Laplantine E, Priore R, Basilico C. A network of transcriptional and
signaling events is activated by FGF to induce chondrocyte growth arrest and
differentiation. J. Cell Biol 2003;161:1053–66.
[109] Dailey L, Ambrosetti D, Mansukhani A, Basilico C. Mechanisms underly-
ing differential responses to FGF signaling. Cytokine Growth Factor Rev
2005;16:233–47.
[110] Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM. Skeletal over-
growth and deafness in mice lacking fibroblast growth factor receptor 3. Nat.
Genet 1996;12:390–7.
[111] Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I,
et al. A novel skeletal dysplasia with developmental delay and acanthosis
nigricans is caused by a lys650-to-met mutation in the fibroblast growth
factor receptor 3 gene. Am. J. Hum. Genet 1999;64:722–31.
[112] Anderson J, Burns HD, Enriquez-Harris P, Wilkie AO, Heath JK. Apert syndrome
mutations in fibroblast growth factor receptor 2 exhibit increased affinity for
FGF ligand. Hum. Mol. Genet 1998;7:1475–83.
[113] Neilson KM, Friesel R. Ligand-independent activation of fibroblast growth
factor receptors by point mutations in the extracellular, transmembrane, and
kinase domains. J. Biol. Chem 1996;271:25049–57.
[114] Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, et al.
Distinct missense mutations of the FGFR3 lys650 codon modulate receptor
kinase activation and the severity of the skeletal dysplasia phenotype. Am. J.
Hum. Genet 2000;67:1411–20.
125
[115] Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M,
et al. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am.
J. Hum. Genet 1995;56:368–73.
[116] Walker BA, Murdoch JL, McKusick VA, Langer Jr LO, Beals RK. Hypochon-
droplasia. Am. J. Dis. Child 1971;122:95–104.
[117] Norman AM, Rimmer S, Landy S, Donna D. Thanatophoric dysplasia of the
straight-bone type (type 2). Clin. Dysmorphol 1992;1:115–20.
[118] Maroteaux P, Lamy M, Robert JM. Le nanisme thanatophore. Presse Med
1967;75:2519–24.
[119] Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, et al.
Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibro-
blast growth factor receptor 3. Nat. Genet 1995;9:321–8.
[120] Huang Z, Chen H, Blais S, Neubert TA, Li X, Mohammadi M. Structural mimicry
of a-loop tyrosine phosphorylation by a pathogenic FGF receptor 3 mutation.
Structure 2013;21:1889–96.
[121] Zankl A, Elakis G, Susman RD, Inglis G, Gardener G, Buckley MF, et al. Prena-
tal and postnatal presentation of severe achondroplasia with developmental
delay and acanthosis nigricans (SADDAN) due to the FGFR3 lys650met muta-
tion. Am. J. Med. Genet 2008;146A:212–8.
[122] Beighton P, Cremin BJ, Kozlowski K. Osteoglophonic dwarfism. Pediatr. Radiol
1980;10:46–50.
[123] White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, et al. Muta-
tions that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone
elongation. Am. J. Hum. Genet 2005;76:361–7.
[124] Merrill AE, Sarukhanov A, Krejci P, Idoni B, Camacho N, Estrada KD, et al.
Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient
canonical FGF signaling. Am. J. Hum. Genet 2012;90:550–7.
[125] Neben CL, Idoni B, Salva JE, Tuzon CT, Rice JC, Krakow D, et al. Bent bone
dysplasia syndrome reveals nucleolar activity for FGFR2 in ribosomal DNA
transcription. Hum. Mol. Genet 2014;23:5659–71.
[126] Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nurnberg G, Lew ED, et al.
Mutations in different components of FGF signaling in LADD syndrome. Nat.
Genet 2006;38:414–7.
[127] Hollister DW, Klein SH, Dejager HJ, Lachman RS, Rimoin DL. The lacrimo-
auriculo-dento-digital syndrome. J. Pediatr 1973;83:438–44.
[128] Lew ED, Bae JH, Rohmann E, Wollnik B, Schlessinger J. Structural basis for
reduced FGFR2 activity in LADD syndrome: implications for FGFR autoinhi-
bition and activation. Proc. Natl. Acad. Sci. U.S.A 2007;104:19802–7.
[129] Milunsky JM, Zhao G, Maher TA, Colby R, Everman DB. LADD syndrome is
caused by FGF10 mutations. Clin. Genet 2006;69:349–54.
[130] Toydemir RM, Brassington AE, Bayrak-Toydemir P, Krakowiak PA, Jorde LB,
Whitby FG, et al. A novel mutation in FGFR3 causes camptodactyly, tall stature,
and hearing loss (CATSHL) syndrome. Am. J. Hum. Genet 2006;79:935–41.
[131] Makrythanasis P, Temtamy S, Aglan M, Otaify GA, Hamamy H, Antonarakis
SE. A novel homozygous mutation in FGFR3 causes tall stature, severe lateral
tibial deviation, scoliosis, hearing impairment, camptodactyly, and arachn-
odactyly. Hum. Mutat 2014;35:959–63.
[132] Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, et al.
Overexpression of CNP in chondrocytes rescues achondroplasia through a
MAPK-dependent pathway. Nat. Med 2004;10:80–6.
[133] Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, et al.
Evaluation of therapeutic potential of a CNP analog in a Fgfr3 mouse model
recapitulating achondroplasia. Am. J. Hum. Genet 2012;91:1108–14.
[134] Bocciardi R, Giorda R, Buttgereit J, Gimelli S, Divizia MT, Beri S, et al. Overex-
pression of the C-type natriuretic peptide (CNP) is associated with overgrowth
and bone anomalies in an individual with balanced t(2;7) translocation. Hum.
Mutat 2007;28:724–31.
[135] Yamashita A, Morioka M, Kishi H, Kimura T, Yahara Y, Okada M, et al.
Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature
2014;513:507–11.