Abstract
Osteochondrodysplasias are a heterogeneous group of disorders. To date, more than 450 skeletal conditions have been characterized. Many of the skeletal dysplasias arise during the prenatal period and are able to be diagnosed by ultrasonography. Fibroblast growth factor (FGF) signaling, including the ligands and their receptors, plays an important role in the function of chondrocytes and osteocytes that contribute to bone patterning. Two of the most common types of skeletal dysplasias are achondroplasia and thanatophoric dysplasia, emphasizing the importance of FGF signaling in skeletal development. This chapter focuses on the many distinct skeletal disorders arising from mutations in the FGF receptor (FGFR) family of genes that are responsible for forms of syndromic and non-syndromic craniosynostosis and chondrodysplasias.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Osteochondrodysplasias
- Skeletal dysplasia
- Fibroblast growth factor
- FGF
- Fibroblast growth factor receptor
- FGFR
- Achondroplasia
- Thanatophoric dysplasia
- Craniosynostosis
- Chondrodysplasias
Introduction
Osteochondrodysplasias are a heterogeneous group of disorders. To date, greater than 450 skeletal conditions have been characterized [1– 3]. Many of the skeletal dysplasias arise during the prenatal period and can be clinically diagnosed by ultrasonography. The perinatal prevalence of skeletal dysplasias is conservatively suggested to be 2.3 in 10,000 with estimates as high as 1 in 4,000–5,000 births [4, 5]. Fibroblast growth factor (FGF ) signaling, including the ligands and their receptors, play an important role in the function of chondrocytes and osteocytes that contribute to bone patterning. Two of the most common types of skeletal dysplasias are achondroplasia and thanatophoric dysplasia, emphasizing the importance of FGF signaling in skeletal development [6]. Since mutations found in the FGF receptor (FGFR) genes result in some of the most common types of skeletal dysplasias, genetic testing is an effective diagnostic tool for determination of the type of skeletal dysplasia and establishing recurrence risks. This chapter focuses on the many distinct skeletal disorders arising from mutations in the FGFR family of genes that are responsible for forms of syndromic and non-syndromic craniosynostosis and chondrodysplasias.
Fibroblast Growth Factor Signaling
The FGF signaling pathway plays a prominent role in the growth and shaping of the skeletal system through regulation of chondro- and osteoblastogenesis [7]. Twenty-three known FGF family members act as ligands to the FGFRs to influence cellular proliferation and differentiation. The FGF ligands interact with four high-affinity receptors (FGFR1 through -4). Signaling is initiated by a FGFR monomer that binds to a FGF ligand, which requires heparin sulfate proteoglycan to facilitate the interaction [9]. FGF ligands bind to the FGFRs with different affinities and specificities [8]. Ligand binding induces homodimerization of the receptors and autophosphorylation of the tyrosine residues located in the cytoplasmic domain to propagate the intracellular signal [10, 11].
FGF Receptors
FGFRs are membrane-bound receptor tyrosine kinases. Of the four receptors, only mutations in FGFR1, -2, and -3 (OMIM *136350, *176943, *134934) result in skeletal disorders (Fig. 12.1). The structures of the FGFR paralogs are very similar (Table 12.1). The FGFR paralogs share the same organization consisting of three immunoglobulin-like extracellular domains denoted as IgI, IgII, and IgIII, a membrane traversing hydrophobic region, and a bifurcated intracellular tyrosine kinase domain that propagates the signal to downstream pathways (Fig. 12.2a). The three immunoglobulin-like regions are stabilized by cysteine-cysteine disulfide bonds. The FGFR1-3 genes produce alternative splicing of the IgIII domain, which generates two isoforms that exhibit tissue-specific expression. The amino aspect of the IgIII region is referred to as IgIIIa. The carboxy half of the IgIII loop contains one of two alternate exons (Fig. 12.2b) denoted as IgIIIb and IgIIIc that code for the C-terminal region of the IgIII domain [12, 13]. The two isoforms preferentially bind to particular FGF ligands and are differentially expressed in epithelial and mesenchymal tissues during development [14]. Studies indicate that it is the FGFR2c and FGFR3c isoforms, expressed in the mesenchyme, that are particularly involved in proper bone patterning [15].
Molecular Basis of Disease
Mutations in the FGFR1, -2, and -3 genes account for approximately 15–20 % of all craniosynostosis and chondrodysplasias. FGFR-related skeletal anomalies are a result of gain-of-function variants that constitutively activate the receptor function [16–18]. Activated FGFRs receptors cause increased cellular proliferation and premature osteoblast differentiation [19–21]. The FGFR constitutive activation is by either a FGF ligand-dependent or -independent mechanism. Ligand-dependent mechanisms arise due to mutations that improve binding of FGF ligands and dimerization of the receptors prolonging signaling activity [22]. Alternatively, ligand-independent mechanisms include the following: (1) enhancement of receptor dimerization due to an immunoglobulin domain structural change such as a gain or loss of a cysteine residue within the loops; (2) augmentation of dimerization due to intramembrane domain changes in amino acid charge that increases hydrogen bonding; and (3) alterations in the kinase domain causing constitutively active phosphorylation [23–25].
Mutations causing FGFR-related craniosynostosis and/or chondrodysplasia tend to cluster in specific domains of the receptors (Fig. 12.2a). These clusters illustrate the importance of the domains in receptor function. Analogous mutations found in each of the different FGFRs tend to mirror phenotypic effects between the receptors. However, distinctions between analogous mutations in the different receptors and their phenotypes reveal their independent roles during normal skeletogenesis.
Craniosynostosis and Chondrodysplasia
Craniosynostosis
Craniosynostosis arises from the premature fusion of one or more of the cranial sutures resulting in a dysmorphic skull. Distortions of the skull arise from uneven growth patterns between the sutures and depend on the location and timing of the fusion events [26]. The cranial sutures are the leading edges of the growing intramembranous bones that comprise the skull vault or calvaria. The calvaria consists of the left and right frontal, squamous occipital, squamous temporal, and the left and right parietal bones that will form the neurocranium (Fig. 12.3). At birth, the frontal bones are separated by the metopic suture. The coronal suture separates the frontal bones from the left and right parietal bones. The lambdoid suture separates the parietals from the occipital bone. The suture leading edges function as ossification centers. The calvaria of the neurocranium that forms the desmocranium ossifies as intramembranous bone forming the vault of the neurocranium. Normally, the metopic suture begins to close after the first year and closure is completed by the seventh year, generating the frontal bone [27]. The sagittal, coronal, and lambdoidal sutures generally complete fusion between 20 and 40 years of age. De novo or autosomal dominantly inherited mutations in the FGFR1–3 genes that enhance signaling result in the inhibition of the osteogenic proliferation program, thereby causing premature fusion of cranial sutures [28]. Mutations associated with isolated nonsyndromic forms of craniosynostosis have been found in each of the FGFR1–3 genes [29–31].
Nonsyndromic or isolated single-suture forms of craniosynostosis are more common than syndromic and number 1 in 2,100–3,000 live births [17]. Sagittal synostosis is the most common, followed by coronal, metopic, and then lambdoid suture synostosis (Fig. 12.4) [32, 33]. Nonsyndromic craniosynostosis is heterogeneous and many of the causes remain unknown. Often full sequencing of the FGFR genes may be requested to rule out the receptors and potentially detect de novo mutations.
Chondrodysplasias
In addition to influencing the growth of the neurocranium, FGF signaling also participates in the development of the skeletal system exemplified by its role in the growth of the long bones of the appendicular skeleton. Dominantly inherited and de novo gain-of-function mutations result in varying degrees of dwarfism as illustrated by particular FGFR3 mutations that cause hypochondroplasia and achondroplasia. Observed in both craniosynostosis and chondrodysplasia cases, germline mutations due to advanced paternal age are a significant contributor to these disorders [34, 35].
Clinical Utility of Testing
Syndromic forms of FGFR-related craniosynostosis and chondrodysplasia are diagnosed clinically, based on their well-described phenotypes. Three-dimensional ultrasonography is able to detect early skeletal anomalies, including short bones, premature skull fusion, and other characteristic syndromic features [6, 36]. Molecular testing is performed to confirm the diagnosis and provide recurrence risks in pregnancies with either suspected germline mosaic transmission in families with a history of a previously affected fetus, or in families with an affected parent and a 50 % probability of passing on the deleterious allele. In such cases of inheritance, examination of the contributing parent may reveal a mild phenotype. For severe cases, de novo mutations occurring in the male germline may be responsible. Advanced paternal age is known to increase the risk of having affected offspring. Generally, targeted mutation analysis is sufficient to confirm a well-characterized phenotype and is the first tier of testing. Sequencing of all the exons may be performed if no mutation is found initially.
Available Assays
Different methods have been developed to identify mutations within the FGFR genes. The vast majority of mutations are missense and nonsense, with splicing and in-frame small insertions and deletions being much rarer. Detection methods include targeted mutation analysis, scanning of specific exons, and sequencing of all the coding regions as well as their intron/exon boundaries. Targeted analysis is based on testing the patient’s DNA for previously described mutations. Using restriction fragment length polymorphism (RFLP) methods, regions of interest within the coding sequences can be amplified by polymerase chain reaction (PCR) and digested with restriction endonucleases that would characteristically identify specific mutations based on altered banding patterns observed by gel electrophoresis and staining (Fig. 12.5). Incomplete digestion of a restriction site may lead to aberrant results and an incorrect heterozygosity interpretation; therefore, both positive and negative digestion controls are essential for RFLP analysis. Alternatively, allele-specific oligonucleotide PCR with primers targeted to wild-type alleles and previously characterized mutations may be performed, resulting in identifiable amplicon patterns. The drawback to targeted analysis is that mutations outside the scope of the assay will be missed.
Mutation scanning by denaturing high-performance liquid chromatography (DHPLC) has been employed to screen the exons of the FGFR genes whereby patient’s profiles suggest potential mutations in comparison to unaffected and affected controls. Issues arise in scanning techniques such as DHPLC as well as high-temperature melting profiles and single-stranded conformational polymorphism in their inability to identify specific mutations or distinguish between known mutations and rare polymorphisms. Unique profiles identifying potential mutations must then be directly sequenced. Sequence analysis of the coding exons is the most comprehensive of the methods ensuring that any point mutation and small deletions and duplications will be identified within the amplified regions. Massively parallel sequencing, using next-generation sequencing platforms, also offers the option to perform sequence analysis on many samples concurrently through barcoding of individual patient’s DNA and using bioinformatics to separate the reads by patient and analyze the sequence data.
Deletion/duplication analysis may be performed by multiplex ligation-dependent probe amplification or exon level array-based comparative genomic hybridization and then confirmed by quantitative PCR. These methods measure the relative amounts of each exonic region where probes are placed, comparing the quantitative results to internal controls, usually housekeeping gene(s) found on other chromosomes.
Interpretation of Test Results
The majority of FGFR mutations causing skeletal dysplasia are point mutations. Interpretation of novel missense variants is becoming easier as the knowledge base grows. To date, there are approximately 155 known mutations within the FGFR1-2-3 that cause skeletal dysplasias. Current lists of mutations are available in the Human Gene Mutation Database (www.biobase-international.com/product/hgmd). Databases that include polymorphisms, such as dbSNP (www.ncbi.nlm.nih.gov/projects/SNP/), the 1000 Genomes Project (www.1000genomes.org/), and exome sequencing projects (Exome Aggregation Consortium [ExAC], exac.broadinstitute.org; Exome Variant Server, http://evs.gs.washington.edu/EVS/), provide information on the genetic variants and their frequencies in the general population [37, 38]. Variants of unknown significance can be evaluated using predictive algorithms that may provide insight into whether they are benign or pathogenic. These predictions take into consideration the biochemical properties of the amino acid change, including size, charge, polarity, steric constraints, and evolutionary conservation of the residue within the protein domain. Internet-based predictive tools, including PolyPhen2, SIFT, and Mutation Taster, provide analysis of the probable functional consequences of missense variants [39–41]. The results of these prediction tools have to be considered as one piece of evidence.
Rare splicing mutations causing skeletal dysplasia have been documented. Mutations, such as the synonymous change p.Ala344Ala (c.1032G>A) in the immunoglobulin IIIc (IgIIIc) domain of FGFR2, activate a cryptic splice donor site (Fig. 12.2b) [42]. Conversely, weakening the endogenous donor site (c.1084+3A>G and c.1084+1G>A) induces exon skipping and preferential splicing of the IgIIIb isoform [43–45]. Similarly, FGFR2 mutations causing Pfeiffer syndrome affect the IgIIIc acceptor site (c.940-2A>G or A>T) [46]. Unknown variants found in the intronic regions of the gene can be analyzed through splicing algorithms, such as the Human Splice Finder (www.umd.be/HSF/) [47] and Netgene2 (www.cbs.dtu.dk/services/NetGene2/) [48], to predict their influence on the precursor mRNA.
Laboratory Issues
Commercial test kits for analyzing the FGFR genes are not available, so testing is performed using laboratory developed tests. Test development and validation may be achieved using cell lines obtained from the Coriell Cell Repository (http://ccr.coriell.org). Proficiency testing is available through the College of American Pathologists Molecular Genetics Laboratory sequencing surveys. Additionally, interlaboratory sample exchanges and internal repeat testing of blinded samples can be used to meet the proficiency testing requirements.
FGFR-Related Skeletal Syndromes
Apert Syndrome
Apert syndrome (OMIM#101200), also known as acrocephalosyndactyly, is characterized by craniosynostosis, facial hypoplasia, broad thumbs and great toes, and digit fusion of the hands and feet (syndactyly) described as a “mitten-hand” malformation. As the most common of the craniosynostosis syndromes, Apert syndrome accounts for approximately 4.5 % of all cases with an occurrence estimated as 1 in 65,000 to 80,000 [49, 50]. The majority of cases result from de novo mutations attributed to increasing paternal age [51].
The majority of cases (99 %) are caused by one of two point mutations in the FGFR2 gene [52]. The common mutations are p.Ser252Trp, which accounts for approximately two-thirds of the cases, and p.Pro253Arg accounting for one third of cases. These mutations, located at the IgII-IgIII linker region, enhance ligand binding affinity [9]. Rarer mutations have been observed surrounding these two mutations in the linker region. Diagnostic testing can be performed by targeted Sanger sequencing.
Apert syndrome is clinically diagnosed. Identification of the specific mutation helps in determining the potential risk for further affected pregnancies due to germline mosaicism. With an affected parent, there is a 50 % probability that a pregnancy will result in an affected child.
Pfeiffer Syndrome
Patients presenting with Pfeiffer Syndrome (OMIM#101600) exhibit brachycephaly, hypertelorism, ocular proptosis, a flat midface, broad thumbs, and medially deviated great toes, and occasionally with hearing loss and variable cutaneous syndactyly [17]. Pfeiffer syndrome is a genetically heterogeneous disorder. Mutations have been found in both FGFR1 and FGFR2. FGFR2 mutations account for 95 % of patients’ mutations. One activating mutation, p.Pro252Arg in the FGFR1 gene, accounts for approximately 5 % of the diagnosed patients. Mutations in FGFR2 are found in the IgIIIa and IgIIIc regions as well as the tyrosine kinase domain, and tend to be phenotypically more severe than the FGFR1-derived phenotype.
Crouzon Syndrome With or Without Acanthosis Nigricans
Crouzon syndrome (OMIM#123500) patients have multiple suture fusions or coronal fusions causing brachycephaly, trigonocephaly, and rare reports of cloverleaf skull malformation also known as kleeblattschädel [53, 54]. Attributes typically include hypertelorism, a small midface, beaked nose and protrusion of the eyes. Hands and feet are generally normal. Heterozygous mutations in the FGFR2 gene show high penetrance and variability of the phenotype within families. Approximately half of the cases are inherited and the other half arise from de novo mutations. Increasing paternal age is a contributing factor for de novo mutations [35]. The prevalence is estimated as 1 in 65,000 live births [55].
Patients with Crouzon syndrome with acanthosis nigricans (OMIM#612247) are typically female, display hyperpigmentation of the skin, hyperkeratosis, and other skin findings. A specific FGFR3 heterozygous mutation, p.Ala391Glu, has been identified and is located in the transmembrane domain [56].
Muenke Syndrome
Muenke syndrome (OMIM#602849) displays incomplete penetrance and a variable phenotype even within families [57]. Prevalence in the population is estimated to be 1 in 30,000 live births. Sporadic and familial cases have been reported. Characteristics include bi- or unicoronal synostosis, midfacial hypoplasia, ptosis, and downslanting palpebral fissures. Some affected individuals have additional features that may include sensorineural hearing loss, developmental delay, brachydactyly, and coned epiphyses in the hands and feet. Muenke craniosynostosis is a result of a specific heterozygous mutation, p.Pro250Arg, found in the linker region between domains IgII and IgIII of FGFR3 [58–61]. Targeted testing may be performed by sequencing the seventh exon of FGFR3 or by RFLP analysis using the MspI endonuclease.
Beare-Stevenson Syndrome
Beare-Stevenson (OMIM#123790), also known as cutis gyrate syndrome of Beare and Stevenson, is a rare and severe disorder. Patients characteristically have body-wide skin furrows (cutis gyrate), acanthosis nigricans, skin tags, bifid scrotum, and anogenital anomalies. The craniosynostosis may be severe and present as a cloverleaf skull with hypertelorism, a broad nasal bridge, cleft palate, and hypodontia. Two heterozygous point mutations in the FGFR2 gene, p.Ser372Cys and p.Tyr375Cys, account for 50–60 % of cases, suggesting locus heterogeneity. The resulting cysteine residues are thought to increase ligand-independent dimerization. These de novo mutations are analogous to the mutations in FGFR3 causing thanatophoric dysplasia. An intragenic deletion, c.1506del63, has recently been described and is proposed to alter gene splicing in favor of the IgIIIb isoform of FGFR2. Loss of the 21 amino acids encoded by exons 8 and 9 is suggested to cause aberrant expression of FGFR2b [62].
Jackson-Weiss Syndrome
Jackson-Weiss Syndrome (OMIM#123150), inherited in an autosomal dominant manner, has been most prominently described in an extended Amish family with a p.Ala344Gly mutation in the IgIIIc domain of FGFR2 [63–66]. Fully penetrant with variable severity, the characteristics of the syndrome include craniosynostosis with facial anomalies, broad great toes, and webbing of the second and third toes [67]. A few reports suggest mutations in FGFR2 and FGFR1 exhibit phenotypic traits similar to Jackson-Weiss syndrome indicating that Crouzon, Jackson-Weiss, and Pfeiffer syndromes may represent a spectrum of craniosynostotic and digit malformations [68, 69].
Antley-Bixler Syndrome Type 2
Antley-Bixler syndrome (ABS; trapezoidocephaly-synostosis syndrome) is a rare and severe heterogeneous disorder with mutations found in both the FGFR2 gene (autosomal dominant; type 2; OMIM#207410) and the cytochrome P450 oxidoreductase (POR) gene (autosomal recessive; type 1; OMIM#201750). ABS type 2 is characterized by craniosynostosis of the coronal and lambdoid sutures, midfacial hypoplasia, radiohumeral and digit fusions, exophthalmos, and arachnodactyly [70, 71]. The mutations associated with ABS include p.Trp290Cys and p.Ser351Cys, both found in the IgIII domain of the FGFR2 gene [72]. Mutations at these positions also have been associated with the milder phenotype of Crouzon syndrome [73].
Osteoglophonic Dysplasia
Osteoglophonic dysplasia (Fairbank-Keats syndrome; OMIM#166250), a very rare disorder, is typified by variable craniosynostosis and rhizomelic dwarfism with a “hollowed-out” appearance of the tubular bones on radiographs, depression of the nasal bridge, unerupted teeth, frontal bossing, and prognathism similar to achondroplasia. Mutations in FGFR1 are found in the conserved amino acids clustered in the C-terminal region of the IgIII immunoglobulin domain, the linker region, and the transmembrane domain. The FGFR1 p.Tyr372Cys mutation is analogous to both the FGFR2 p.Tyr375Cys mutation that causes Beare-Stevenson syndrome and the p.Tyr373Cys FGFR3 mutation that causes thanatophoric dwarfism type 1, indicating the importance of that amino acid position in the functional role of the receptors [74].
Achondroplasia
Achondroplasia (OMIM#100800) arises from mutations in the FGFR3 gene that inhibit chondrocyte proliferation within the endochondral growth plate resulting in the shortening of long bones. Achondroplasia is the most common form of FGFR-related short-limbed dwarfism [75, 76], with an occurrence of 1 in 10,000 to 30,000 live births [4, 5]. Two common variants, c.1138G>A (~98 %) and c.1138G>C (1–2 %), result in a p.Gly380Arg mutation in the transmembrane domain of FGFR3 [77]. The achondroplasia mutation is the most common de novo disease-causing mutation known. There is a strong paternal origin for the mutation, mostly in fathers over the age of 35 years [34]. A second mutation, described in several published accounts, suggests that p.Gly375Cys also causes achondroplasia [78–80].
Testing for the c.1138G>A mutation may be performed by RFLP digestion of exon 10 with the SfcI restriction enzyme. It has been noted, however, that complete digestion is not consistently observed for the assay and other molecular methods may be required to differentiate between the G>A and the G>C mutations, the heterozygous form, and the lethal homozygous form [81–83].
Severe Achondroplasia, Developmental Delay, and Acanthosis Nigricans (SADDAN)
Severe achondroplasia, developmental delay and acanthosis nigricans (SADDAN; OMIM#187600), is caused by a c.1949A>T mutation (p.Lys650Met) in FGFR3. The substitution of a methionine residue at position 650 differentiates SADDAN from type 2 thanatophoric dysplasia, which arises from a glutamic acid substitution at the same position (c.1948A>G; Lys650Glu). The SADDAN amino acid change induces constitutive kinase activity that is threefold greater than normal [84].
Hypochondroplasia
Hypochondroplasia (OMIM#146000) is clinically diagnosed as a mild form of skeletal dysplasia. Clinical diagnosis is usually by short limbs detected on ultrasonography, which prompts diagnostic testing. The FGFR3 c.1138G>A mutation that causes achondroplasia has been found in about 5 % of hypochondroplasia cases. FGFR3 mutations account for only 50–70 % of cases, suggesting genetic heterogeneity. Of those mutations in FGFR3, 70 % are a recurrent p.Asn540Lys amino acid change located in the tyrosine kinase 1 domain (TK1), while others are rarer. Testing may be performed by RFLP analysis of an exon 13 PCR product, which will detect the two c.1659C>A/G, p.N540K mutations. A BspMI restriction site is abolished by the c.1620C>A mutation, and the c.1620C>G mutation creates a novel AluI restriction site [85]. The other known mutations may be detected by sequencing exons 10, 13, and 15 of FGFR3.
Thanatophoric Dysplasia
Thanatophoric dysplasia (TD) is the most common lethal condition of short-limbed skeletal dysplasia with a distorted head and has an estimated incidence of 1 in 20,000 to 50,000 live births. Two types of TD are clinically diagnosed based on ultrasound and radiographic findings [86–88]. Type 1 (OMIM#187600) patients have prominently curved femurs, while type 2 (OMIM#187601) patients typically have a severe form of craniosynostosis often referred to as a cloverleaf skull and a small chest [89].
Several different gain-of-function mutations in FGFR3 cause TD type 1. Mutations p.Arg248Cys, p.Ser249Cys, p.Ser371Cys, and p.Tyr373Cys create novel cysteine residues in the extracellular and intramembranous domains, while other mutations causing TD type 1, such as p.Ter807Arg, p.Ter807Cys, p.Ter807Gly, p.Ter807Ser, and p.Ter807Trp, obliterate the stop codon resulting in extension of the intracellular domain by an additional 141 amino acids [90, 91].
TD type 2 is caused by the FGFR3 transition mutation c.1948A>G, coding for p.Lys650Glu [92, 93]. The mutation causes multiple cranial sutures to fuse prematurely resulting in a cloverleaf skull malformation. The importance of the lysine 650 codon, situated in the tyrosine kinase-domain activation loop of FGFR3, is emphasized by the wide range of clinical phenotypes observed based, on the different amino acid substitutions and their ability to influence kinase activity. Similar to the previously mentioned SADDAN p.Lys650Met mutation, substitution of the lysine 650 for a glutamine or asparagine residue is associated with a milder hypochondrodysplasia phenotype [94].
Bent Bone Dysplasia: FGFR2 Type
Bent bone dysplasia-FGFR2 type (OMIM#614592) has recently been attributed to two heterozygous mutations in the FGFR2 transmembrane domain, c.1172T>G (p.Met391Arg) and c.1141T>G (p.Tyr381Asp) that reduce its localization to the plasma membrane [95]. A phenotype of perinatal lethality with hypertelorism, midface hypoplasia, micrognathia, prematurely erupted prenatal teeth, low-set posteriorly rotated ears, and clitoromegaly in females. Distinct radiological findings include coronal craniosynostosis with poorly mineralized calvaria, curved appendicular skeletal defects, and clavicle hypoplasia. The nuances of the genotype-phenotype correlations are observed in the mutation of the tyrosine 381 residue to asparagine (p.Tyr381Asn, c.1141T>A) that causes Crouzon syndrome [96]. These studies suggest a spectrum of severity for altered FGFR2 activity.
Other FGFR-Associated Disorders
In addition to the activating mutations resulting in craniosynostosis and chondrodysplasia, loss-of-function mutations in the FGFR genes cause a variety of different syndromes.
CATSHL Syndrome
Dominantly inherited, camptodactyly, tall stature, scoliosis, and hearing loss (CATSHL; OMIM#610474) is caused by a FGFR3 p.Arg621His heterozygous missense mutation residing within the tyrosine kinase domain generating a loss-of-function that promotes endochondral bone growth [97]. Recently, a novel homozygous FGFR3 c.1167C>A p.Thr546Lys, mutation has been described as also causing skeletal overgrowth [98].
Kallmann Syndrome
Hypogonadotropic hypogonadism, also known as Kallmann syndrome (OMIM#308700), is a heterogenic disorder with mutations found most commonly in the KAL gene (KAL1, X-linked; OMIM *300836) as well as FGFR1 (KAL2, OMIM#147950). Other genes that account for 5 % or less of cases include PROKR2, PROK2, CHD7, and FGF8, while an additional five genes are known to account for the autosomal recessive form. Sensitivity of testing for clinically diagnosed Kallmann syndrome is approximately 30 % for the aforementioned genes [99]. Loss-of-function mutations in FGFR1 account for approximately 10 % of cases of type 2 Kallmann Syndrome with deletions being rare contributors to the disorder. Kallmann syndrome exhibits a 5:1 male to female ratio with an incidence of approximately 1 in 8,000 to 10,000 in males and 1 in 40,000 to 50,000 in females [100, 101]. Patients characteristically have olfactory bulb dysgenesis (anosmia) and hypogonadotropic hypogonadism, with boys also having micropenis and cryptorchidism. Mutations in the FGFR1 gene also may result in cleft lip and/or palate, agenesis of the teeth, and digital malformations [102].
LADD Syndrome
Lacrimo-auriculo-dento-digital (LADD) syndrome (OMIM#149730; Levy-Hollister syndrome) is a dominant, heterogeneous disorder with mutations found in the FGF10 gene as well as the tyrosine kinase domains of FGFR2 (p.Ala648Thr, p.Ala628Thr) and FGFR3 (p.Asp513Asn) [103–105]. Variants in the receptor kinase domain associated with LADD syndrome reduce phosphorylation activity [106]. Affected individuals typically exhibit hypoplasia/aplasia of the tear and salivary ducts, malformed ears and deafness, hypodontia, and digital anomalies mostly affecting the thumbs [107–109].
References
Superti-Furga A, Steinmann B, Gitzelmann R, Eich G, Giedion A, Bucher HU, Wisser J. A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia. Eur J Pediatr. 1995;154(3):215–9.
Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabel B, Superti-Furga A. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011;155(5):943–68.
Krakow D. Skeletal Dysplasias. Clin Perinatol. 2015;42:301–19.
Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet. 1986;23(4):328–32.
Stoll C, Dott B, Roth M-P, Alembik Y. Birth prevalence rates of skeletal dysplasias. Clin Genet. 1989;35(2):88–92.
Krakow D, Alanay Y, Rimoin LP, Lin V, Wilcox WR, Lachman RS, Rimoin DL. Evaluation of prenatal-onset osteochondrodysplasias by ultrasonography: A retrospective and prospective analysis. Am J Med Genet A. 2008;146A(15):1917–24.
Ornitz DM, Itoh N. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015;4(3):215–66.
Spivak-Kroizman T, Lemmon MA, Dikic I, Ladbury JE, Pinchasi D, Huang J, Jaye M, Crumley G, Schlessinger J, Lax I. Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation. Cell. 1994;79(6):1015–24.
Mohammadi M, Olsen SK, Ibrahimi OA. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev. 2005;16(2):107–37.
Plotnikov AN, Schlessinger J, Hubbard SR, Mohammadi M. Structural basis for FGF receptor dimerization and activation. Cell. 1999;98(5):641–50.
Pellegrini L, Burke DF, von Delft F, Mulloy B, Blundell TL. Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature. 2000;407(6807):1029–34.
Givol D, Yayon A. Complexity of FGF receptors: genetic basis for structural diversity and functional specificity. FASEB J. 1992;6(15):3362–9.
Orr-Urtreger A, Bedford MT, Burakova T, Arman E, Zimmer Y, Yayon A, Givol D, Lonai P. Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev Biol. 1993;158(2):475–86.
Delezoide AL, Benoist-Lasselin C, Legeai-Mallet L, Le Merrer M, Munnich A, Vekemans M, Bonaventure J. Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification. Mech Dev. 1998;77(1):19–30.
Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005;16(2):139–49.
Webster MK, Donoghue DJ. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 1996;15(3):520–7.
Muenke M, Gripp K, McDonald-McGinn D, Gaudenz K, Whitaker L, Bartlett S, Markowitz R, Robin N, Nwokoro N, Mulvihill J, Losken H, Mulliken J, Guttmacher A, Wilroy L, Clarke R, Hollway G, Adès L, Haan E, Mulley J, Cohen M, Bellus G, Francomano C, Moloney D, Wall S, Wilkie A, Zackai E. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum Genet. 1997;60(3):555–64.
Cohen MM. Some chondrodysplasias with short limbs: molecular perspectives. Am J Med Genet. 2002;112(3):304–13.
Legeai-Mallet L, Benoist-Lasselin C, Delezoide A-L, Munnich A, Bonaventure J. Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia. J Biol Chem. 1998;273(21):13007–14.
Legeai-Mallet L, Benoist-Lasselin C, Munnich A, Bonaventure J. Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias. Bone. 2004;34:26–36.
Holmes G, Rothschild G, Roy UB, Deng C-X, 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.
Monsonego-oran E, Adar R, Feferman T, Segev O, Yayon A. The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation. Mol Cell Biol. 2000;20(2):516–22.
Sorokin A, Lemmon MA, Ullrich A, Schlessinger J. Stabilization of an active dimeric form of the epidermal growth factor receptor by introduction of an inter-receptor disulfide bond. J Biol Chem. 1994;269(13):9752–9.
Hart KC, Robertson SC, Donoghue DJ. Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation. Mol Biol Cell. 2001;12:931–42.
Ratisoontorn C, Fan GF, McEntee K, Nah DD. Activating (P253R, C278F) and dominant negative mutations of FGFR2: differential effects on calvarial bone cell proliferation, differentiation, and mineralization. Connect Tissue Res. 2003;44 Suppl 1:292–7.
Cohen MM. No man’s craniosynostosis: the arcana of sutural knowledge. J Craniofac Surg. 2012;23(1):338–42. 310.1097/SCS.1090b1013e318241dbc318244.
Sperber G, Sperber S, Guttmann G. Craniofacial embryogenetics and development. Shelton, CT: People’s Medical Publishing House; 2010.
Ornitz DM. Regulation of chondrocyte growth and differentiation by fibroblast growth factor receptor 3. Novartis Found Symp. 2001;232:63–80, 272–282.
Johnson D, Wall SA, Mann S, Wilkie AOM. A novel mutation, Ala315Ser, in FGFR2: a gene-environment interaction leading to craniosynostosis? Eur J Hum Genet. 2000;8(8):571–7.
Kress W, Petersen B, Collmann H, Grimm T. An unusual FGFR1 mutation (fibroblast growth factor receptor 1 mutation) in a girl with non-syndromic trigonocephaly. Cytogenet Cell Genet. 2000;91(1-4):138–40.
Barroso E, Pérez-Carrizosa V, García-Recuero I, Glucksman MJ, Wilkie AO, García-Minaur S, Heath KE. Mild isolated craniosynostosis due to a novel FGFR3 mutation, p.Ala334Thr. Am J Med Genet. A. 2011;155(12):3050–3.
Wilkie AOM, Byren JC, Hurst JA, Jayamohan J, Johnson D, Knight SJL, Lester T, Richards PG, Twigg SRF, Wall SA. Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics. 2010;126(2):e391–400.
Levi B, Wan DC, Wong VW, Nelson E, Hyun J, Longaker MT. Cranial suture biology: from pathways to patient care. J Craniofac Surg. 2012;23(1):13–9. doi:10.1097/SCS.1090b1013e318240c318246c318240.
Wilkin DJ, Szabo JK, Cameron R, Henderson S, Bellus GA, Mack ML, Kaitila I, Loughlin J, Munnich A, Sykes B, Bonaventure J, Francomano CA. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet. 1998;63(3):711–6.
Glaser RL, Jiang W, Boyadjiev SA, Tran AK, Zachary AA, Van Maldergem L, Johnson D, Walsh S, Oldridge M, Wall SA, Wilkie AOM, Jabs EW. Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet. 2000;66(3):768–77.
Krakow D, Williams J, Poehl M, Rimoin DL, Platt LD. Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias. Ultrasound Obstet Gynecol. 2003;21(5):467–72.
1000 Genomes Consortium. A map of human genome variation from population scale sequencing. Nature. 2010;467(7319):1061–73.
Shendure J. Next-generation human genetics. Genome Biol. 2011;12(9):408.
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(8):1073–81.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9.
Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7(8):575–6.
Li X, Park WJ, Pyeritz RE, Jabs EW. Effect on splicing of a silent FGFR2 mutation in Crouzon syndrome. Nat Genet. 1995;9:232–3.
Cornejo-Roldan LR, Roessler E, Muenke M. Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome. Hum Genet. 1999;104(5):425–31.
Kan R, Twigg SRF, Berg J, Wang L, Jin F, Wilkie AOM. Expression analysis of an FGFR2 IIIc 5′ splice site mutation (1084+3A→G). J Med Genet. 2004;41(8):e108.
Traynis I, Bernstein JA, Gardner P, Schrijver I. Analysis of the alternative splicing of an FGFR2 transcript due to a novel 5′ splice site mutation (1084+1G>A): case report. Cleft Palate Craniofac J. 2011;49(1):104–8.
Lajeunie E, Ma HW, Bonaventure J, Munnich A, Le Merrer M, Renier D. FGFR2 mutations in Pfeiffer syndrome. Nat Genet. 1995;9:108.
Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucl Acids Res. 2009;37(9):e67.
Brunak S, Engelbrecht J, Knudsen S. Prediction of human mRNA donor and acceptor sites from the DNA sequence. J Mol Biol. 1991;220(1):49–65.
Cohen MM. Birth prevalence study of the Apert syndrome. Am J Med Genet. 1992;42:655–9.
Tolarova MM, Harris JA, Ordway DE, Vargervik K. Birth prevalence, mutation rate, sex ratio, parents’ age, and ethnicity in Apert syndrome. Am J Med Genet. 1997;72(4):394–8.
Moloney DM, Slaney SR, Oldridge M, Wall SA, Sahlin P, Stenman G, Wilkie AOM. Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet. 1996;13(1):48–53.
Wilkie AOM, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, Hayward RD, David DJ, Pulleyn LJ, Rutland P, Malcolm S, Winter RM, Reardon W. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;9(2):165–72.
Rohatgi M. Cloverleaf skull — a severe form of Crouzon’s syndrome: a new concept in aetiology. Acta Neurochir. 1991;108(1):45–52.
Murdoch-Kinch CA, Bixler D, Ward RE. Cephalometric analysis of families with dominantly inherited Crouzon syndrome: an aid to diagnosis in family studies. Am J Med Genet. 1998;77(5):405–11.
Cohen MM, Kreiborg S. Birth prevalence studies of the Crouzon syndrome: comparison of direct and indirect methods. Clin Genet. 1992;41(1):12–5.
Arnaud-López L, Fragoso R, Mantilla-Capacho J, Barros-Núñez P. Crouzon with acanthosis nigricans. Further delineation of the syndrome. Clin Genet. 2007;72(5):405–10.
Escobar LF, Hiett AK, Marnocha A. Significant phenotypic variability of Muenke syndrome in identical twins. Am J Med Genet A. 2009;149A(6):1273–6.
Bellus GA, Gaudenz K, Zackai EH, Clarke LA, Szabo J, Francomano CA, Muenke M. Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet. 1996;14(2):174–6.
Muenke M, Wilkie AOM. Craniosynostosis syndromes. In: Scriver C, Beaudet A, Sly W, et al., editors. The metabolic and molecular basis of inherited disease. New York, NY: McGraw-Hill; 2001.
Graham JM, Braddock SR, Mortier GR, Lachman R, Van Dop C, Jabs EW. Syndrome of coronal craniosynostosis with brachydactyly and carpal/tarsal coalition due to Pro250Arg mutation in FGFR3 gene. Am J Med Genet. 1998;77(4):322–9.
Lowry RB, Wang Jabs E, Graham GE, Gerritsen J, Fleming J. Syndrome of coronal craniosynostosis, Klippel-Feil anomaly, and sprengel shoulder with and without Pro250Arg mutation in the FGFR3 gene. Am J Med Genet. 2001;104(2):112–9.
Slavotinek A, Crawford H, Golabi M, Tao C, Perry H, Oberoi S, Vargervik K, Friez M. Novel FGFR2 deletion in a patient with Beare–Stevenson-like syndrome. Am J Med Genet A. 2009;149A(8):1814–7.
Cross HE, Opitz JM. Craniosynostosis in the Amish. J Pediatr. 1969;75:1037–44.
Jackson CE, Weiss L, Reynolds WA, Forman TF, Peterson JA. Craniosynostosis, midfacial hypoplasia and foot abnormalities: an autosomal dominant phenotype in a large Amish kindred. J Pediatr. 1976;88(6):963–8.
Jabs EW, Li X, Scott AF, Meyers G, Chen W, Eccles M, Mao J, Charnas LR, Jackson CE, Jaye M. Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2. Nat Genet. 1994;8:275–9.
Heike C, Seto M, Hing A, Palidin A, Hu FZ, Preston RA, Ehrlich GD, Cunningham M. Century of Jackson-Weiss syndrome: further definition of clinical and radiographic findings in “lost” descendants of the original kindred*. Am J Med Genet. 2001;100(4):315–24.
Cohen MM. Jackson-Weiss syndrome. Am J Med Genet. 2001;100(4):325–9.
Meyers GA, Day D, Goldberg R, Daentl DL, Przylepa KA, Abrams LJ, Graham JM, Feingold M, Moeschler JB, Rawnsley E, Scott AF, Jabs EW. FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing. Am J Hum Genet. 1996;58(3):491–8.
Roscioli T, Flanagan S, Kumar P, Masel J, Gattas M, Hyland VJ, Glass IA. Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature. Am J Med Genet. 2000;93(1):22–8.
Antley R, Bixler D. Trapezoidocephaly, midfacial hypoplasia and cartilage abnormalities with multiple synostoses and skeletal fractures. Birth Defects Orig Artic Ser. 1975;11(2):397–401.
McGlaughlin KL, Witherow H, Dunaway DJ, David DJ, Anderson PJ. Spectrum of Antley-Bixler syndrome. J Craniofac Surg. 2010;21(5):1560–4.
Chun K, Siegel-Bartelt J, Chitayat D, Phillips J, Ray PN. FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome. Am J Med Genet. 1998;77(3):219–24.
Schaefer F, Anderson C, Can B, Say B. Novel mutation in the FGFR2 gene at the same codon as the Crouzon syndrome mutations in a severe Pfeiffer syndrome type 2 case. Am J Med Genet. 1998;75(3):252–5.
White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, McKeown C, FitzPatrick D, Yu K, Ornitz DM, Econs MJ. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet. 2005;76(2):361–7.
Shiang R, Thompson LM, Zhu Y-Z, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 1994;78(2):335–42.
Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev. 2000;21(1):23–39.
Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet. 1995;10(3):357–9.
Nishimura G, Fukushima Y, Ohashi H, Ikegawa S. Atypical radiological findings in achondroplasia with uncommon mutation of the fibroblast growth factor receptor-3 (fgfr-3) gene (gly to cys transition at codon 375). Am J Med Genet. 1995;59(3):393–5.
Superti-Furga A, Unger S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet A. 2007;143A(1):1–18.
Foldynova-Trantirkova S, Wilcox WR, Krejci P. Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum Mutat. 2012;33(1):29–41.
Lanning RW, Brown CA. An improved methodology for the detection of the common mutation in the FGFR3 gene responsible for achondroplasia. Hum Mutat. 1997;10(6):496–9.
Etlik O, Koksal V, Tugba Arican-Baris S, Baris I. An improved tetra-primer PCR approach for the detection of the FGFR3 G380R mutation responsible for achondroplasia. Mol Cell Probes. 2008;22(2):71–5.
He X, Xie F, Ren Z-R (2012) Rapid detection of G1138A and G1138C mutations of FGFR3 gene in patients with achondroplasia using high-resolution melting analysis. Genet Test Mol Biomarkers (in press).
Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, Szabo J, Jiang W, Jabs EW, Wilcox WR, Wasmuth JJ, Donoghue DJ, Thompson LM, Francomano CA. A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am J Hum Genet. 1999;64(3):722–31.
Prinster C, Carrera P, Maschio MD, Weber G, Maghnie M, Vigone MC, Mora S, Tonini G, Rigon F, Beluffi G, Severi F, Chiumello G, Ferrari M. Comparison of clinical-radiological and molecular findings in hypochondroplasia. Am J Med Genet. 1998;75(1):109–12.
Langer LO, Yang SS, Hall JG, Sommer A, Kottamasu SR, Golabi M, Krassikoff N, Opitz JM, Bernstein J. Thanatophoric dysplasia and cloverleaf skull. Am J Med Genet. 1987;28(S3):167–79.
Chen C-P, Chern S-R, Shih J-C, Wang W, Yeh L-F, Chang T-Y, Tzen C-Y. Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenat Diag. 2001;21(2):89–95.
Tonni G, Azzoni D, Ventura A, Ferrari B, Felice CD, Baldi M. Thanatophoric dysplasia type I associated with increased nuchal translucency in the first trimester: early prenatal diagnosis using combined ultrasonography and molecular biology. Fetal Pediatr Pathol. 2010;29(5):314–22.
Naveen NS, Murlimanju BV, Kumar V, Pulakunta T, Jeeyar H. Thanatophoric dysplasia: a rare entity. Oman Med J. 2011;26(3):196–7.
Rousseau F, Saugier P, Merrer ML, Munnich A, Delezoide A-L, Maroteaux P, Bonaventure J, Narcy F, Sanak M. Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Nat Genet. 1995;10(1):11–2.
Rousseau F, El Ghouzzi V, Delezoide AL, Legeai-Mallet L, Le Merrer M, Munnich A, Bonaventure J. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet. 1996;5(4):509–12.
Tavormina PL, Shiang R, Thompson LM, Zhu Y-Z, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet. 1995;9(3):321–8.
Martínez-Frías ML, Egüés X, Puras A, Hualde J, de Frutos CA, Bermejo E, Nieto MA, Martínez S. Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: insights into its pathogenesis. Am J Med Genet A. 2011;155(1):197–202.
Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, Francomano CA. 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(6):1411–21.
Merrill AE, Sarukhanov A, Krejci P, Idoni B, Camacho N, Estrada KD, Lyons KM, Deixler H, Robinson H, Chitayat D, Curry CJ, Lachman RS, Wilcox WR, Krakow D. Bent bone dysplaisa-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. Am J Hum Genet. 2012;90:550–7.
Collet C, Alessandri JL, Arnaud E, Balu M, Daire V, Di Rocco F. Crouzon syndrome and bent bone dysplasia associated with mutatins at the same Tyr-381 residue in FGFR2 gene. Clin Genet. 2013. doi:10.1111/cge.12213. Epub ahead of print.
Toydemir RM, Brassington AE, Bayrak-Toydemir P, Krakowiak PA, Jorde LB, Whitby FG, Longo N, Viskochil DH, Carey JC, Bamshad MJ. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Hum Genet. 2006;79(5):935–41.
Makrythanasis P, Temtamy S, Aglan MS, Otaify GA, Hamamy H, Antonarakis SE. A Novel Homozygous Mutation in FGFR3 Causes Tall Stature, Severe Lateral Tibial Deviation, Scoliosis, Hearing Impairment, Camptodactyly, and Arachnodactyly. Hum Mutat. 2014;35(8):959–63.
Kaplan JD, Bernstein JA, Kwan A, Hudgins L. Clues to an early diagnosis of Kallmann syndrome. Am J Med Genet A. 2010;152A(11):2796–801.
Cadman SM, Kim SH, Hu Y, González-Martínez D, Bouloux PM. Molecular pathogenesis of Kallmann’s syndrome. Horm Res. 2007;67(5):231–42.
Kulkarni M, Balaji M, Kulkarni A, Sushanth S, Kulkarni B. Kallmann’s syndrome. Indian J Pediatr. 2007;74(12):1113–5.
Dode C, Levilliers J, Dupont J-M, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel J-C, Delemarre-van de Waal H, Goulet-Salmon B, Kottler M-L, Richard O, Sanchez- Franco F, Saura R, Young J, Petit C, Hardelin J-P. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. 2003;33(4):463–5.
Milunsky JM, Zhao G, Maher TA, Colby R, Everman DB. LADD syndrome is caused by FGF10 mutations. Clin Genet. 2006;69(4):349–54.
Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nurnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, Ulubil-Emeroglu M, Leroy JG, Li Y, Becker C, Lehnerdt K, Cremers CWRJ, Yuksel-Apak M, Nurnberg P, Kubisch C, Schlessinger J, van Bokhoven H, Wollnik B. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006;38(4):414–7.
Shams I, Rohmann E, Eswarakumar VP, Lew ED, Yuzawa S, Wollnik B, Schlessinger J, Lax I. Lacrimo-auriculo-dento-digital syndrome is caused by reduced activity of the fibroblast growth factor 10 (FGF10)-FGF receptor 2 signaling pathway. Mol Cell Biol. 2007;27(19):6903–12.
Lew ED, Bae JH, Rohmann E, Wollnik B, Schlessinger J. Structural basis for reduced FGFR2 activity in LADD syndrome: Implications for FGFR autoinhibition and activation. PNAS. 2007;104(50):19802–7.
Hollister DW, Klein SH, De Jager HJ, Lachman RS, Rimoin DL. The lacrimo-auriculo-dento-digital syndrome. J Pediatr. 1973;83(3):438–44.
Shiang EL, Holmes LB. The lacrimo-auriculo-dento-digital syndrome. Pediatrics. 1977;59(6):927–30.
Mathrawala N, Hegde R. Lacrimo-auriculo-dento-digital syndrome. J Indian Soc Pedod Prev Dent. 2011;29(2):168–70.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Sperber, S., Spector, E. (2016). Fibroblast Growth Factor Receptor and Related Skeletal Disorders. In: Leonard, D. (eds) Molecular Pathology in Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-19674-9_12
Download citation
DOI: https://doi.org/10.1007/978-3-319-19674-9_12
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-19673-2
Online ISBN: 978-3-319-19674-9
eBook Packages: MedicineMedicine (R0)