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FGFR-Related Craniosynostosis Syndromes

Synonym: Acrocephalosyndactyly. Includes: FGFR1-Related Craniosynostosis (including: Pfeiffer Syndrome Types 1, 2, and 3), FGFR2-Related Craniosynostosis (including: Apert Syndrome, Beare-Stevenson Syndrome, Crouzon Syndrome, FGFR2-Related Isolated Coronal Synostosis, Jackson-Weiss Syndrome, Pfeiffer Syndrome Types 1, 2, and 3), FGFR3-Related Craniosynostosis (including: Crouzon Syndrome with Acanthosis Nigricans, FGFR3-Related Isolated Coronal Synostosis [including: Muenke Syndrome])

, MD, , MD, and , MD.

Author Information
, MD
Departments of Genetics and Pediatrics
University of Alabama at Birmingham
Birmingham, Alabama
, MD
Division of Human Genetics
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
, MD
Department of Pediatrics
Section on Medical Genetics
Wake Forest University School of Medicine
Winston-Salem, North Carolina

Initial Posting: ; Last Update: June 7, 2011.

Summary

Disease characteristics. The eight disorders comprising the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome (isolated coronal synostosis caused by the p.Pro250Arg mutation in FGFR3). Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis; the remainder are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings.

Diagnosis/testing. The diagnosis of Muenke syndrome is based on identification of the p.Pro250Arg mutation in FGFR3; the diagnosis of FGFR2-related isolated coronal synostosis is based on identification of a FGFR2 disease-causing mutation. The diagnosis of the other six FGFR-related craniosynostosis syndromes is based on clinical findings; molecular genetic testing of FGFR1, FGFR2, and FGFR3 may be helpful in establishing the specific diagnosis in questionable cases.

Management. Treatment of manifestations: Management by a multidisciplinary craniofacial clinic affiliated with a major pediatric medical center when possible; syndromic craniosynostosis usually requires a series of staged surgical procedures (craniotomy and fronto-orbital advancement) tailored to individual needs; for syndromic craniosynostosis, the first surgery is often as early as age three months, for nonsyndromic craniosynostosis the first surgery is often between ages six months and one year; congenital spine anomalies need immediate attention; surgical correction of limb defects depends on the nature of the skeletal anomalies.

Prevention of secondary complications: Early treatment of craniofacial anomalies may reduce the risk for secondary complications such as hydrocephalus and cognitive impairment; ophthalmologic lubrication can prevent exposure keratopathy in those with severe proptosis.

Surveillance: For hydrocephalus in those at increased risk.

Evaluation of relatives at risk: Clinical and radiographic evaluation, or molecular genetic testing if the disease-causing mutation in the family is known, so that mildly affected relatives can benefit from early intervention.

Genetic counseling. The FGFR-related craniosynostosis syndromes are inherited in an autosomal dominant manner. Affected individuals have a 50% chance of passing the disease-causing mutation to each child. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family; however, its use is limited by poor predictive value.

Diagnosis

Clinical Diagnosis

The phenotypes associated with FGFR-related craniosynostosis were clinically defined long before the molecular basis of this group of disorders was discovered (see Table 1).

Six of the eight FGFR-related craniosynostosis disorders can be diagnosed primarily on the clinical findings of:

  • Unicoronal or bicoronal craniosynostosis (rather than sagittal or metopic craniosynostosis) or cloverleaf skull, usually based on clinical findings that can be confirmed by skull radiograph or head CT examination;
  • Characteristic facial features;
  • Variable hand and foot findings.

Two of the eight FGFR-related craniosynostosis disorders require molecular genetic testing:

  • Muenke syndrome may have unilateral coronal synostosis or megalencephaly without craniosynostosis; diagnosis is based on identification of the p.Pro250Arg mutation in FGFR3.
  • FGFR2-related isolated coronal synostosis is characterized by uni- or bicoronal craniosynostosis only; diagnosis is based on identification of a disease-causing mutation in FGFR2.

Table 1. Distinguishing Clinical Features in the FGFR-Related Craniosynostosis Syndromes

DisorderThumbsHandsGreat ToesFeet
Crouzon syndromeNormal Normal Normal Normal
Crouzon syndrome with acanthosis nigricans (AN)Normal Normal Normal Normal
Apert syndromeOccasionally fused to fingers Soft tissue ± Bone syndactyly Occasionally fused to toes Soft tissue ± Bone syndactyly
Pfeiffer syndromeBroad, medially deviated Variable brachydactyly Broad, medially deviated Variable brachydactyly
Muenke syndrome Normal ± Carpal fusion ± Broad ± Tarsal fusion
Jackson-Weiss syndromeNormal Variable Broad, medially deviated Abnormal tarsals
Beare-Stevenson syndromeNormal Normal Normal Normal
FGFR2-related isolated coronal synostosisNormalNormal NormalNormal

Molecular Genetic Testing

Genes. Mutations in FGFR1, FGFR2, and FGFR3 cause FGFR-related craniosynostosis (Table 2).

Table 2. Molecular Basis of FGFR-Related Craniosynostosis Syndromes

PhenotypeProportion of FGFR-Related Craniosynostosis Phenotypes Attributed to Mutations in This Gene
FGFR1FGFR2 FGFR3
Crouzon syndrome100%
Crouzon syndrome with acanthosis nigricans (AN)100%
Apert syndrome100%
Pfeiffer syndrome type 15%95%
Pfeiffer syndrome type 2100%
Pfeiffer syndrome type 3100%
Muenke syndrome 100%
Jackson-Weiss syndrome100%
Beare-Stevenson syndrome<100%
FGFR2-related isolated coronal synostosis100%

Table 3. Summary of Molecular Genetic Testing Used in FGFR-Related Craniosynostosis Syndromes

Gene SymbolTest MethodMutations Detected
FGFR1Sequence analysisSequence variants 1
Targeted mutation analysisp.Pro252Arg 2
FGFR2Sequence analysis (sequence analysis of select exons 3 and targeted mutation analysis 4)Sequence variants 1
Deletion/duplication analysis 5Exonic or whole-gene deletions 6
FGFR3Sequence analysisSequence variants 1
See footnote 7
Targeted mutation analysisp.Pro250Arg 8

1. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected.

2. The FGFR1 mutation p.Pro252Arg is associated with Pfeiffer syndrome type 1.

3. Select exons most often include exons 8 and 10 and also 3, 5, 7, 9, 11, 14-17.

4. p.Pro253Arg, p.Ser252Trp, p.Ser252Leu, p.Gln289Pro, and p.Ala344Gly (see Table 5)

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. For example, the FGFR2 exonic deletion in Apert syndrome described by Bouchukova et al [2009]

7. The causative FGFR3 mutation in Crouzon syndrome with AN is usually p.Ala391Glu in exon 10.

8. The FGFR3 mutation p.Pro250Arg is a defining feature of Muenke syndrome [Muenke et al 1997].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

Note: FGFR1, FGFR2, and FGFR3 sequence analysis has high sensitivity for Apert syndrome and the FGFR-related craniosynostosis syndromes in which craniosynostosis is an isolated finding (i.e., FGFR2-related isolated coronal synostosis and Muenke syndrome). The sensitivity of molecular testing is lower for the other disorders; its primary utility is in confirming questionable clinical diagnoses. The yield of molecular genetic testing is higher in bilateral than unilateral coronal synostosis [Mulliken et al 2004].

  • Most FGFR-related craniosynostosis syndromes. An algorithm to increase efficiency and cost-effectiveness of molecular testing in craniosynostosis disorders involves initial performance of targeted mutation analysis for recurrent mutations as listed below, followed by selective gene sequencing [Chun et al 2003; see full text].
  • Apert syndrome. Targeted mutation analysis of FGFR2 for the mutations p.Ser252Trp and p.Pro253Arg. If normal, sequence analysis for rare FGFR2 mutations or partial-gene insertions/deletions [Bochukova et al 2009].
  • Crouzon syndrome or Pfeiffer syndrome. Sequence analysis of exons 8 and 10 (in which approximately 80% of FGFR2 mutations are located) [Kan et al 2002, Passos-Bueno et al 2008]. If normal, sequence analysis of FGFR2 exons 3, 5, 11, 14, 15, 16, and 17 (in which an additional 10% of mutations are located) and targeted mutation analysis for the FGFR3 mutation p.Pro250Arg. Consider FGFR1 testing for Pfeiffer syndrome if a mutation in FGFR2 is not identified and/or the patient has a milder phenotype.
  • Crouzon syndrome with acanthosis nigricans (AN) is usually caused by the FGFR3 mutation p.Ala391Glu; therefore, such testing is warranted before testing for FGFR2 mutations in a young child with Crouzon syndrome and either AN or other characteristic findings that include: choanal atresia; hydrocephalus; cranial features of Crouzon syndrome; and subtle skeletal features (narrow sacrosciatic notches; short vertebral bodies; lack of the normal increase in interpediculate distance from the upper lumbar vertebrae caudally; and broad, short metacarpals and phalanges) [Schweitzer et al 2001].
  • If testing is performed on a child with features of Crouzon syndrome during the first year of life (before the usual onset of AN), it is reasonable to test for FGFR2 and FGFR3 mutations concurrently.
  • Testing for the FGFR3 mutation p.Ala391Glu in a child older than age two years with Crouzon syndrome features without AN is likely to have a low yield.
  • Muenke syndrome requires the combination of unilateral coronal synostosis or megalencephaly without craniosynostosis and identification of the p.Pro250Arg mutation in FGFR3.
  • FGFR2-related isolated coronal synostosis requires the combination of uni- or bicoronal craniosynostosis and a disease-causing mutation in FGFR2.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Note: Prenatal diagnosis of various craniosynostosis syndromes may be possible if physical findings are apparent on prenatal imaging (see Prenatal Testing).

Clinical Description

Natural History

The abnormal skull shape in the FGFR-related craniosynostosis syndromes is usually noted in the newborn period; occasionally, it may be detected either prenatally by ultrasound examination or not until later in infancy. Because the skull grows in planes perpendicular to the cranial sutures, premature suture closure causes skull growth to cease in the plane perpendicular to the closed suture and to precede parallel to the suture. The skull shape becomes asymmetric, with the shape depending on which suture(s) is (are) closed. Coronal craniosynostosis causes the skull to be turribrachycephalic, or "tower shaped." Occasionally, cloverleaf skull (called Kleeblatschadel) is seen. Cloverleaf skull involves a trilobar skull deformity usually caused by synostosis of coronal, lambdoidal, metopic, and sagittal sutures. The brain protrudes through open anterior and parietal fontanels.

The characteristic facial features shared by all of the FGFR-related craniosynostosis syndromes (except Muenke and FGFR2-related isolated coronal synostosis) include: ocular hypertelorism, proptosis, midface hypoplasia, small beaked nose, and prognathism. A high-arched palate is often present; more rarely, a cleft palate is present [Stoler et al 2009]. Choanal stenosis or atresia can be seen, as well as sensorineural hearing loss and visual problems including strabismus. Cloverleaf skull is accompanied by midface hypoplasia, downslanting palpebral fissures, and extreme proptosis; in addition, developmental delay and/or intellectual disability, hydrocephalus, Chiari type 1 malformation [Ranger et al 2010], hearing loss [Honnebier et al 2008], and visual impairment are common.

Breathing problems can occur in the first few months of life because of upper-airway obstruction related to the midface hypoplasia and associated choanal atresia or stenosis [Chen et al 2008]. In severe cases, these problems may present as life-threatening respiratory failure [Freeman et al 2008] or as failure to thrive resulting from poor feeding. In either case, tracheostomy is often needed.

Non-communicating hydrocephalus is another complication that can result in neurologic impairment or death if not diagnosed and treated at an early stage. The risk of intracranial hypertension is greatest in Crouzon syndrome [Lajeunie et al 2000, Renier et al 2000b].

Chiari malformation may either be congenital or acquired as a consequence of the skull deformities and other associated intracranial factors in individuals with craniosynostosis [Ranger et al 2010].

Even if every medical complication is managed promptly, a proportion of affected children develop intellectual disability and neurologic problems. The greatest risk for intellectual disability is found in individuals with Apert syndrome [Renier et al 1996, Lajeunie et al 2000].

Overall, the risk for significant problems depends on the associated anomalies in the individual rather than on the specific syndrome.

Specific clinical features of each of the FGFR-related craniosynostosis syndromes are summarized below.

Crouzon syndrome

  • Intellect. Normal
  • Craniofacial. Significant proptosis, external strabismus, mandibular prognathism
  • Extremities. Normal (although radiographic metacarpal-phalangeal profile may reveal shortening) [Murdoch-Kinch & Ward 1997]
  • Other. Progressive hydrocephalus (30%), often with tonsillar herniation. Sacrococcygeal tail has also been described [Lapunzina et al 2005].

Crouzon syndrome with acanthosis nigricans (AN)

  • Intellect. Normal
  • Craniofacial. Significant proptosis, external strabismus, mandibular prognathism
  • Extremities. Normal (although radiographic metacarpal-phalangeal profile may reveal shortening) [Murdoch-Kinch & Ward 1997]
  • Cutaneous. The 5% of individuals with Crouzon syndrome who have AN (pigmentary changes in the skin fold regions) are said to have Crouzon syndrome with AN. AN can be present in the neonatal period or appear later.

Apert syndrome

  • Intellect. Varying degrees of developmental delay/intellectual disability (50%), possibly related to the timing of craniofacial surgery [Renier et al 1996]
  • Craniofacial. Turribrachycephalic skull shape; moderate-to-severe midface hypoplasia
  • Extremities. Soft tissue and bony ('mitten glove') syndactyly of fingers and toes involving variable number of digits; occasional rhizomelic shortening, elbow ankylosis
  • Other. Fused cervical vertebrae (68%), usually C5-C6; hydrocephalus (2%); occasional internal organ anomalies such as cardiac and gastrointestinal defects [Cohen & Kreiborg 1993, Zarate et al 2010]; ovarian dysgerminoma [Rouzier et al 2008]

Pfeiffer syndrome. Pfeiffer syndrome has been subdivided into three clinical types [Cohen 1993]; types 2 and 3 are more common and more severe than type 1.

Pfeiffer syndrome type 1

  • Intellect. Usually normal
  • Craniofacial. Moderate-to-severe midface hypoplasia
  • Extremities. Broad and medially deviated thumbs and great toes; variable degree of brachydactyly. In one family, reported involvement of the feet was the only abnormality [Rossi et al 2003].
  • Other. Hearing loss and hydrocephalus can be seen. Overall prognosis is more favorable than in Pfeiffer syndrome types 2 and 3.

Pfeiffer syndrome type 2

  • Intellect. Developmental delay/intellectual disability common
  • Craniofacial. Cloverleaf skull, extreme proptosis (often unable to close eyelids)
  • Extremities. Broad and medially deviated thumbs and great toes; ankylosis of elbows, knees; variable degree of brachydactyly
  • Other. Choanal stenosis/atresia, laryngotracheal abnormalities, cleft palate [Stoler et al 2009]; hydrocephalus; seizures; sacrococcygeal eversion/appendage [Oliveira et al 2006, Lai et al 2008]; increased risk for early death

Pfeiffer syndrome type 3

  • Intellect. Developmental delay/intellectual disability common
  • Craniofacial. Turribrachycephalic skull shape, extreme proptosis (often unable to close eyelids)
  • Extremities. Broad and medially deviated thumbs and great toes; ankylosis of elbows, knees; variable degree of brachydactyly
  • Other. Choanal stenosis/atresia, laryngotracheal abnormalities; hydrocephalus; seizures, increased risk for early death

Muenke syndrome. Phenotypic overlap occurs with Pfeiffer, Jackson-Weiss, and Saethre-Chotzen syndromes. Some individuals with a disease-causing mutation have no clinically apparent abnormalities and are identified only on clinical, radiographic, or molecular genetic evaluation after they give birth to an affected child.

  • Intellect. Normal to mild intellectual disability
  • Craniofacial. Variable. Uni- or bilateral coronal craniosynostosis, or only megalencephaly; mild to significant midface hypoplasia; ocular hypertelorism. Unicoronal synostosis is more frequently seen in males [Honnebier et al 2008].
  • Extremities. Variable. Carpal-tarsal fusion is diagnostic when present but is not always present; brachydactyly, carpal bone malsegregation, or coned epiphyses may occur.
  • Other. Bilateral, symmetric, low- to mid-frequency sensorineural hearing loss [Honnebier et al 2008]; osteochondroma [Barbosa et al 2009]

Jackson-Weiss syndrome

  • Intellect. Normal
  • Craniofacial. Mandibular prognathism
  • Extremities. Broad and medially deviated great toes, with normal hands; short first metatarsal, calcaneocuboid fusion, abnormally formed tarsals

Beare-Stevenson cutis gyrata

Intellect. Intellectual disability present in all affected individuals

Craniofacial. Moderate-to-severe midface hypoplasia; abnormal ears, natal teeth

  • Extremities. Normal; furrowed palms and soles
  • Cutaneous. Widespread cutis gyrata and AN, which are usually evident at birth; skin tags, prominent umbilical stump, accessory nipples
  • Genital. Bifid scrotum, prominent labial raphe, rugated labia majora
  • Other. Pyloric stenosis; anterior anus

FGFR2-related isolated coronal synostosis

  • Intellect. Normal
  • Craniofacial. Unilateral coronal synostosis
  • Extremities. Normal

Genotype-Phenotype Correlations

A wide phenotypic range has been described among individuals with identical mutations in FGFR2 [Mulliken et al 1999, Ito et al 2005]. Mutations in FGFR2 or FGFR3 can give rise to either bilateral or unilateral coronal synostosis, even in the same family [Mulliken et al 2004]. In a study of 47 individuals with unilateral coronal synostosis (also known as synostotic frontal plagiocephaly), asymmetric brachycephaly and orbital hypertelorism were strongly correlated with identification of a mutation in FGFR2, FGFR3, or TWIST1 (formerly TWIST) [Mulliken et al 2004].

One specific genotype-phenotype correlation is the association of the p.Ala391Glu mutation in FGFR3 in individuals with Crouzon syndrome and AN. Individuals with Crouzon syndrome who do not have AN are unlikely to have a mutation in FGFR3.

Cleft palate, severe ocular problems (strabismus, ptosis, astigmatism, and amblyopia), nasolacrimal stenosis, and possibly humeroradial synostosis are more common in individuals with the p.Ser252Trp mutation in FGFR2 [Akai et al 2006], whereas the degree of syndactyly and intellectual disability is more prominent in individuals with the p.Pro253Arg mutation in FGFR2 [Slaney et al 1996, Lajeunie et al 1999, Kanauchi et al 2003, Jadico et al 2006]. Individuals with Apert syndrome and the p.Pro253Arg mutation have a more improved craniofacial appearance following craniofacial surgery [von Gernet et al 2000].

Mutations seen in individuals with Crouzon, Pfeiffer, and Jackson-Weiss syndromes occur in and around the B exon of the third immunoglobulin-like domain in FGFR2.

Identical mutations have been seen in individuals with Crouzon, Pfeiffer, and Jackson-Weiss syndromes [Hollway et al 1997, Oldridge et al 1997], suggesting that unlinked modifier genes or epigenetic factors play a role in determining the final phenotype. Interestingly, two FGFR2 mutations creating cysteine residues (p.Trp290Cys and p.Tyr340Cys) cause severe forms of Pfeiffer syndrome whereas conversion of the same residues into another amino acid (p.Trp290Gly, p.Trp290Arg, p.Tyr340His) results exclusively in the Crouzon syndrome phenotype [Lajeunie et al 2006].

Pfeiffer syndrome-causing mutations p.Ser351Cys, p.Trp290Cys, and p.Cys342Arg in FGFR2 have been associated with severe phenotypes including cloverleaf skull, severe exophthalmia, midface flattening, hydrocephalus requiring ventriculoperitoneal shunt, radio-ulnar-humeral synostosis, fusion of the cartilaginous tracheal rings (tracheal sleeve), congenital or acquired Chiari malformation, and frequently premature death [Zackai et al 2003, Hockstein et al 2004, Gonzales et al 2005, Akai et al 2006, Lajeunie et al 2006, Oliveira et al 2006, Stevens & Roeder 2006, Chen et al 2008, Ranger et al 2010].

Three individuals were reported to have clinical features of Crouzon, Pfeiffer, or Apert syndromes, but had mutations in both FGFR2 and TWIST1 [Anderson et al 2006].

Penetrance

FGFR-related coronal synostosis is usually autosomal dominant with reduced penetrance.

Jackson-Weiss, Apert, and Pfeiffer syndromes show complete penetrance.

Crouzon syndrome typically implies complete penetrance; however, in one family a de novo FGFR2 mutation was associated with variable expressivity and reduced penetrance [de Ravel et al 2005].

Anticipation

Anticipation has not been reported in the FGFR-related craniosynostosis syndromes.

Nomenclature

Adelaide-type craniosynostosis, a term to describe Muenke syndrome, is no longer used.

Prevalence

The overall incidence for all forms of craniosynostosis is 1:2000-1:2500 live births.

The incidence of coronal synostosis is 1:16,000 in males and 1:8000 in females; the overall contribution of FGFR mutations to the incidence of craniosynostosis is unknown.

The incidence of Crouzon syndrome is 1.6:100,000; that of Apert syndrome is 1:100,000; the combined incidence of the Pfeiffer syndromes is 1:100,000.

Differential Diagnosis

Primary craniosynostosis needs to be distinguished from secondary craniosynostosis. In primary craniosynostosis, abnormal biology of the suture causes premature suture closure, as in the FGFR-related craniosynostoses; in secondary craniosynostosis, the suture biology is normal, but abnormal external forces result in premature suture closure. In children with deficient brain growth, all cranial sutures fuse and the head is symmetric and microcephalic. Abnormal head positioning in utero or in infancy may produce an abnormal skull shape (plagiocephaly); the abnormality often resolves with appropriate head positioning but occasionally results in craniosynostosis [Hunt & Puczynski 1996, Kane et al 1996].

In individuals with primary craniosynostosis it is important to determine which cranial sutures are involved and whether the craniosynostosis is an isolated finding or part of a syndrome.

  • Lambdoidal or sagittal synostosis suggests a diagnosis other than FGFR-related craniosynostoses, even in the presence of hand and foot anomalies (e.g., sagittal synostosis and cutaneous hand and foot syndactyly in Philadelphia-type craniosynostosis [Robin et al 1996]).
  • Metopic synostosis, which causes trigonocephaly, is usually an isolated finding, but may be part of a more complex disorder in which progressive involvement of other sutures occurs [Tartaglia et al 1999]. Therefore, FGFR molecular genetic testing is not warranted in individuals with isolated trigonocephaly, but is a consideration in individuals with trigonocephaly in whom other craniofacial anomalies are seen. A study in individuals with either syndromic or nonsyndromic metopic craniosynostosis found no pathologic mutations in FGFR1, CER1, or CDON, suggesting that analysis of these genes is not warranted in persons with these findings [Jehee et al 2006].

Isolated craniosynostosis (i.e., craniosynostosis occurring without other anomalies) accounts for the vast majority of craniosynostosis. Only rarely is isolated craniosynostosis familial, but in such cases it is usually autosomal dominant with reduced penetrance, with the recurrence risk dependent on which suture is involved [Cohen 1996, Lajeunie et al 1996].

The incidence of FGFR3 disease-causing mutations in individuals with apparently isolated coronal craniosynostosis is not known.

  • One study found an FGFR3 mutation in four of 37 individuals with nonsyndromic coronal craniosynostosis; in three of the four individuals, the father had the FGFR3 mutation [Gripp et al 1998].
  • In another study, 29 of 76 individuals with isolated coronal synostosis had the FGFR3 mutation p.Pro250Arg.
  • In another study, eight of 47 individuals with unilateral coronal synostosis had identifiable mutations, including two in FGFR2, three in FGFR3, and three in TWIST1 [Mulliken et al 2004]. Therefore, testing of all individuals with either unilateral or bilateral coronal craniosynostosis for FGFR2 or FGFR3 mutations is probably warranted, particularly if asymmetric brachycephaly and/or orbital hypertelorism are present [Renier et al 2000a].

Syndromic craniosynostosis. Craniosynostosis is a finding in more than 150 genetic disorders. Additional syndromes that should be considered:

  • Saethre-Chotzen syndrome. Classic Saethre-Chotzen syndrome is characterized by coronal synostosis (unilateral or bilateral), facial asymmetry (particularly in individuals with unicoronal synostosis), ptosis, and characteristic appearance of the ear (small pinna with a prominent crus). Syndactyly of digits two and three of the hand is variably present. Although mild to moderate developmental delay and intellectual disability have been reported, normal intelligence is more common. Less common manifestations of Saethre-Chotzen syndrome include short stature, parietal foramina, radioulnar synostosis, cleft palate, maxillary hypoplasia, ocular hypertelorism, hallux valgus, and congenital heart malformations. The diagnosis of Saethre-Chotzen syndrome is made primarily on clinical findings. Mutations in TWIST1 are causative. Inheritance is autosomal dominant.

    Several features are shared by Saethre-Chotzen syndrome and Muenke syndrome. However, persons with Saethre-Chotzen syndrome with a TWIST1 mutation typically have a lower frontal hairline, worsening ptosis, soft-tissue syndactyly, hallux valgus, and increased cranial pressure resulting from early suture fusion. Persons with Muenke syndrome have an increased frequency of hearing loss and mental disabilities [Kress et al 2006]. The clinical diagnosis of Saethre-Chotzen syndrome has also been reported in a family with an FGFR2 mutation (p.Gln289Pro), suggesting that the TWIST1 and FGFR products may interact during development [Freitas et al 2006]. Testing for suspected Saethre-Chotzen syndrome should include analysis of FGFR2, FGFR3, and TWIST1.
  • Boston-type craniosynostosis. From the 19 affected individuals in the one family reported to date [Warman et al 1993], four general phenotypes emerged:
  • Type 1. Fronto-orbital recession (8 individuals)
  • Type 2. Frontal bossing (2)
  • Type 3. Turribrachycephaly as a result of coronal craniosynostosis (7)
  • Type 4. Cloverleaf skull (2)

Short first metatarsals are present. Headaches, seizures, myopia, and visual deficits may occur. Of note, some individuals who have a disease-causing mutation are asymptomatic. Mutations in MSX2 are causative [Ignelzi et al 2003]. Inheritance is autosomal dominant, with complete penetrance and variable expression. This disorder is apparently rare; Wilkie & Mavrogiannis [2012] found no MSX2 mutation in 211 individuals with craniosynostosis of unknown cause who had no mutations identified in other major genes.

  • Antley-Bixler syndrome (trapezoidocephaly-multiple synostosis syndrome) is caused by a sterol biosynthesis defect and involves premature closure of the coronal and lambdoidal sutures, brachycephaly with frontal bossing, proptosis, downslanting palpebral fissures, severe depression of the nasal bridge (with or without choanal stenosis or atresia), and low-set, protruding ears. The main limb features are radiohumeral synostosis, medial bowing of the ulnae, bowing of the femurs, slender hands and feet, contractures at the proximal IP joints, fractures, and advanced bone age. Some individuals have congenital heart disease, renal anomalies, abnormalities of the female genitalia, and signs of congenital adrenal hyperplasia [Bottero et al 1997, Williamson et al 2006]. Mutations in the gene encoding cytochrome P450 reductase (POR) are causative [Adachi et al 2006, Marohnic et al 2006]. Inheritance is autosomal recessive.
  • Baller-Gerold syndrome is a craniosynostosis syndrome with radial aplasia. The craniosynostosis usually involves the coronal sutures but may affect multiple sutures. The radial defect may be asymmetric, resulting in aplasia on one side and hypoplasia on the other. The thumb can be absent and the ulna is usually short and curved. Carpal and metacarpal bones may be absent. Occasional findings include ocular hypertelorism, epicanthal folds, a prominent nasal bridge, midline capillary hemangiomas, genitourinary malformations, and intellectual disability. Identification of RECQL4 mutations in two unrelated families supports the notion that Baller-Gerold syndrome is allelic to Rothmund-Thomson syndrome and RAPADILINO syndrome, and that mutations in RECQL4 cause a subset of Baller-Gerold syndrome [Van Maldergem et al 2006]. Inheritance is autosomal recessive.
  • Carpenter syndrome (acrocephalopolysyndactyly type II) is a craniosynostosis syndrome with preaxial polydactyly of the feet. Brachydactyly, syndactyly, and aplasia or hypoplasia of the middle phalanges is present in the hands. Intellectual disability is variable. The gene in which mutation is causative is RAB23 [Jenkins et al 2007]. Inheritance is autosomal recessive.
  • Craniofrontonasal syndrome is characterized by premature closure of the coronal suture and frontonasal dysplasia. Features include severe ocular hypertelorism, a broad bifid nose, asymmetric frontal bossing, a low posterior hairline, anterior widow's peak, and occasionally a cleft lip and palate, neck webbing, rounded shoulders, abnormal clavicles, and raised scapulae. Longitudinal splitting of the nails occurs often, skin syndactyly is occasionally present, and the fingers and toes may be deviated distally or occasionally hypoplastic. Most children have normal intelligence. More females have been reported than males, with more severe manifestations in females [Saavedra et al 1996]. Mutations in EFNB1 are causative. Inheritance is X-linked dominant.
  • Greig cephalopolysyndactyly features include high forehead with frontal bossing, macrocephaly, hypertelorism, broad nasal base, polydactyly of the hands (often postaxial), and feet with syndactyly of toes 1, 2, and 3 and often a duplicated hallux [Biesecker 1997]. Mutations in GLI3 are causative. Standard Giemsa-banding cytogenetic studies may detect translocations or gross cytogenetic deletions involving 7p13. FISH analysis detects deletions in the estimated 5%-10% of individuals with large deletions. Inheritance is autosomal dominant.
  • Opitz trigonencephaly C syndrome is a multiple malformation syndrome with trigonocephaly. The gene in which mutation is causative is not known, but one person has been reported to have a de novo balanced reciprocal translocation t(3;18)(q13.13;q12.1) [Chinen et al 2006]. Inheritance is autosomal recessive.
  • Philadelphia-type craniosynostosis, featuring sagittal suture craniosynostosis with cutaneous hand and foot syndactyly, was identified in a single large kindred [Robin et al 1996]. Duplications within and around IHH have been found in three families [Klopocki et al 2011]. Inheritance is autosomal dominant.
  • Shprintzen-Goldberg syndrome (marfanoid-craniosynostosis syndrome) is characterized by craniosynostosis (involving the coronal, sagittal, or lambdoid sutures), distinctive craniofacial features, skeletal changes (dolichostenomelia, arachnodactyly, camptodactyly, pes planus, pectus excavatum or carinatum, scoliosis, joint hypermobility, or contractures), neurologic abnormalities, mild to moderate intellectual disability, and brain anomalies (hydrocephalus, dilatation of the lateral ventricles, and Chiari 1 malformation). Cardiovascular anomalies (mitral valve prolapse, mitral regurgitation, and aortic regurgitation) may occur. Minimal subcutaneous fat, abdominal wall defects, cryptorchidism in males, and myopia are also characteristic findings. The diagnosis is suspected in individuals with characteristic clinical findings and radiographic findings showing C1-C2 abnormality, wide anterior fontanel, thin ribs, 13 pairs of ribs, square-shaped vertebral bodies, and osteopenia. The gene in which mutation is causative and the mode of inheritance are unknown.
  • Mutations of TGFBR1 and TGFBR2 (see Loeys-Dietz Syndrome) can also be associated with craniosynostosis, but this feature is not one of the major clinical characteristics of the corresponding syndromes, or occurs with low frequency [Passos-Bueno et al 2008].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with FGFR-related craniosynostosis, the following evaluations are recommended:

  • Assessment for hydrocephalus by brain CT or MRI in all cases of syndromic craniosynostosis, with close observation in those with mutations known to have a more severe phenotype
  • Assessment for upper-airway obstruction or tracheal sleeve (in FGFR2-related Pfeiffer syndrome)
  • Assessment for exposure keratopathy
  • Spinal x-rays to evaluate for vertebral anomalies
  • Imaging of the gastrointestinal system in individuals with Pfeiffer or Apert syndrome for intestinal malrotation or esophageal atresia

Treatment of Manifestations

Craniofacial. Children with any of the FGFR-related craniosynostosis syndromes benefit from the multidisciplinary team approach practiced in most craniofacial clinics affiliated with major pediatric medical centers. The specialists usually include plastic surgeons, neurosurgeons, otolaryngologists, and dentists as well as audiologists, speech pathologists, developmental pediatricians, social workers, and medical geneticists. The team can usually identify and address physical and developmental problems as well as psychosocial and other issues.

Individuals with syndromic craniosynostosis usually require a series of staged surgical procedures; the number and type are tailored to the individual's needs [Posnick & Ruiz 2000, Honnebier et al 2008]. Three-dimensional skull CT can be used for morphologic mapping to help plan surgical treatment [Binaghi et al 2000]. Some individuals with syndromic craniosynostosis require a dozen or more surgeries over a lifetime. Seldom is the correction perfect, but significant cosmetic improvement is often possible. Evidence suggests that the calvarial bone needed for these surgeries is often more brittle, thinner, and less robust than cranial bone from unaffected donors [Tholpady et al 2004].

In contrast to children with nonsyndromic craniosynostosis, in whom the first surgery is usually performed between ages six months and one year, children with syndromic craniosynostosis often have their first surgery as early as age three months. The procedure is a bilateral craniotomy with a fronto-orbital advancement to expand the cranial vault. Because the procedure leaves uncovered areas of dura that fill in by age 15-18 months, it must be performed before the child is 18 months old. In a series of 2,317 individuals who underwent surgery for craniosynostosis, improved cosmetic and functional results followed early surgery; no increased operative risk was seen in infants [Lajeunie et al 2000, Renier et al 2000b].

Distraction osteogenesis of the craniofacial skeleton and long bones of the extremities may be a less invasive alternative approach to bone grafting in some individuals. In addition, the distraction procedures can expand the overlying soft tissues simultaneously. The devices used for distraction of the mandible, midface, and cranium tend to be the buried type and made of absorbable materials; cytokine administration may shorten the consolidation period. The usefulness and appropriateness of the distraction procedure must be assessed for each disorder [Matsumoto et al 2003].

In some cases, other complications including hydrocephalus, upper-airway obstruction, and exposure keratopathy of the cornea may prompt even earlier craniotomy or fronto-orbital advancement, or other interventions including ventriculo-peritoneal stunting, tracheostomy, or surgical eyelid closure.

Timing of subsequent craniofacial surgeries influences their success. Procedures done prior to the cessation of growth in the particular facial region usually have poor long-term results and require additional operations.

Individuals with Apert syndrome have the highest incidence of repeat surgery to correct forehead contour [Wong et al 2000, Thomas et al 2005].

Wilkie et al [2012] noted that children with craniosynostosis resulting from single gene mutations were more likely to require repeat surgery compared to individuals whose craniosynostosis was caused by a chromosomal abnormality.

Spine. Congenital spine anomalies can cause scoliosis and spinal injury and thus need immediate attention.

Limbs. Surgical correction of limb defects is usually not possible because the skeletal anomalies are developmental and the structures have never formed normally.

  • In the mitten-glove syndactyly seen in Apert syndrome, surgical separation of the digits often provides relatively little functional improvement.
  • With the elbow ankylosis seen in Pfeiffer syndrome types 2 and 3, some functional improvement can be gained by altering the angle at which the elbows are fixed. For example, in most affected individuals, elbow contractures are at approximately the same angle, often so that an individual cannot reach the mouth easily with the hands or clean appropriately following toileting; functional improvement can be achieved if the angle of each arm is altered so that one arm is positioned for eating and the other for toileting.

Prevention of Secondary Complications

The primary treatment of craniofacial abnormalities associated with craniosynostosis is surgical reconstruction. Early treatment may reduce the risk for secondary complications (e.g., hydrocephalus, cognitive impairment).

Patients with severe proptosis often require ophthalmologic lubrication to prevent exposure keratopathy.

Surveillance

Persons with a known risk for significant complications, including hydrocephalus, should be monitored from birth throughout life at intervals and by methods appropriate for the severity of the clinical findings.

Six of 29 persons with the FGFR3 mutation p.Pro250Arg required reoperation for increased intracranial pressure, emphasizing the need for continued long-term monitoring [Thomas et al 2005].

Evaluation of Relatives at Risk

At-risk relatives should be evaluated by clinical and radiographic criteria given that manifestations may not be readily evident in all affected individuals. When the disease-causing mutation is known in the family, molecular genetic testing can be used to evaluate relatives for the disorder. Early diagnosis may allow mildly affected relatives to benefit from early surveillance and intervention.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The FGFR-related craniosynostosis syndromes are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • An individual with FGFR-related craniosynostosis may have an affected parent or may have the disease as the result of a de novo mutation.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical, radiographic, and molecular genetic evaluation.

With a milder phenotype, as can be seen in Muenke syndrome, Crouzon syndrome, Pfeiffer syndrome, and Jackson-Weiss syndrome, inheritance of the disease-causing mutation from an affected parent is common; whereas in the most severe forms, de novo gene mutations are common.

  • All cases of Pfeiffer syndrome 3 and Beare-Stevenson syndrome and all but one case of Pfeiffer syndrome 2 have resulted from a de novo mutation.

Advanced paternal age has been shown clinically to be associated with de novo mutations for Crouzon syndrome, Apert syndrome, Pfeiffer syndrome [Glaser et al 2000], Beare-Stevenson syndrome, and Muenke syndrome [Rannan-Eliya et al 2004]. Paternal age effect in de novo mutations has been conclusively demonstrated at the molecular level in Apert syndrome [Moloney et al 1996, Yoon et al 2009]. It has been proposed that FGFR mutations are paradoxically enriched in the male germline because they confer a selective advantage to the spermatagonial cells in which they arise [Goriely et al 2003, Choi et al 2008, Bochukova et al 2009, Yoon et al 2009].

Sibs of a proband

Offspring of a proband. Affected individuals have a 50% chance of passing the disease-causing mutation to each child.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Each syndrome is usually consistent within an individual family; for example, if a parent has the clinical findings of Pfeiffer syndrome, he or she has a 50% chance of having a child with Pfeiffer syndrome rather than Crouzon, Jackson-Weiss, or Apert syndrome. Nonetheless, rare examples in which the phenotype of affected individuals in a given family has varied have been reported: some family members had findings suggestive of Pfeiffer syndrome, whereas others had findings suggestive of Jackson-Weiss or Crouzon syndromes [Meyers et al 1996, Steinberger et al 1996, Hollway et al 1997, Steinberger et al 1997].

Considerations in families with an apparently de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder and/or the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancies. Prenatal diagnosis for pregnancies at 50% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancies. In a pregnancy not previously identified to be at risk for craniosynostosis in which an abnormal skull shape is detected on prenatal ultrasound examination, prenatal testing is more difficult. While testing for mutations in FGFR1, FGFR2, or FGFR3 is possible, the yield is likely to be low. Furthermore, identification of a mutation in one of these genes would not clarify the prognosis, which is determined by clinical findings (e.g., the prognosis for cloverleaf skull is generally poor regardless of the molecular defect or nature of hand and foot findings).

Prenatal diagnosis of various craniosynostosis syndromes may be possible if physical findings including abnormal biparietal diameter and ventriculomegaly are apparent on prenatal imaging [Chen et al 2010, Weber et al 2010].

Three-dimensional ultrasound examination, three-dimensional CT scan, or MRI has proven useful in some cases to further delineate suspicious ultrasound findings and assess for underlying brain abnormalities [Benacerraf et al 2000, Mahieu-Caputo et al 2001, Hansen et al 2004, Itoh et al 2006]. Prenatal MRI is often used to accurately diagnosis suspected craniosynostosis syndromes such as Pfeiffer or Apert syndromes. Findings detectable by MRI may include agenesis of the corpus callosum, hydrocephalus causing increased biparietal diameter, or cloverleaf skull [Itoh et al 2006, Quintero-Rivera et al 2006, Weber et al 2010].

Requests for prenatal testing for conditions which (like FGFR-related craniosynostosis) have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • Cleft Palate Foundation (CPF)
    1504 East Franklin Street
    Suite 102
    Chapel Hill NC 27514-2820
    Phone: 800-242-5338 (toll-free); 919-933-9044
    Fax: 919-933-9604
    Email: info@cleftline.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. FGFR-Related Craniosynostosis Syndromes: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for FGFR-Related Craniosynostosis Syndromes (View All in OMIM)

101200APERT SYNDROME
101600PFEIFFER SYNDROME
123150JACKSON-WEISS SYNDROME; JWS
123500CROUZON SYNDROME
123790BEARE-STEVENSON CUTIS GYRATA SYNDROME; BSTVS
134934FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3
136350FIBROBLAST GROWTH FACTOR RECEPTOR 1; FGFR1
176943FIBROBLAST GROWTH FACTOR RECEPTOR 2; FGFR2
602849MUENKE SYNDROME; MNKES
612247CROUZON SYNDROME WITH ACANTHOSIS NIGRICANS; CAN

Molecular Genetic Pathogenesis

The fibroblast growth factors (FGFs) are a family of at least 22 known signaling molecules that function to regulate cell proliferation, differentiation, and migration through a variety of complex pathways [Wilkie 1997, Coumoul & Deng 2003]. They are important in angiogenesis, wound healing, limb development, mesoderm induction and patterning neuronal differentiation, and malignant transformation. They act through the fibroblast growth factor receptors (FGFRs), a family of four tyrosine kinase receptors that bind the FGFs in a nonspecific manner (any FGF can bind to any FGFR).

The FGFRs share the general structure of a split cytoplasmic tyrosine kinase domain, a transmembrane domain, and an extracellular domain that contains three immunoglobulin (Ig)-like domains. Ligand binding occurs at the second and third Ig-like domains. After binding an FGF, an FGFR dimerizes with another FGFR through a series of cysteine residues in these Ig-like domains. Dimerization promotes activation of the tyrosine kinase, which initiates a complex cascade of intracellular signals including activation of Runx2, a key transcription factor in osteoblast differentiation [Baroni et al 2005, Kim et al 2006]. Both ligand binding and dimerization are nonspecific, with any type of FGFR binding to any FGF and then dimerizing with any FGFR.

The FGF/FGFR system achieves its specificity through temporal and spatial variations in expression patterns. Additional diversity is created by alternative splicing of exons of the FGFRs, exemplified by exon 7 of FGFR2 [Ornitz 2005]. A p.Cys278Phe mutation in FGFR2 decreases protein glycosylation while increasing degradation, demonstrating that FGFR2 localization and autoactivation is glycosylation dependent [Hatch et al 2006].

Although mutations in FGFR1, FGFR2, and FGFR3 have been associated with a variety of clinical phenotypes (and, in those with craniosynostosis, affected sutures) [Wilkie et al 2010], they have not been associated with nonsynostotic plagiocephaly [Dhamcharee & Boles 2008]. To date, no evidence linking FGFR4 to craniofacial or skeletal disorders exists [Gaudenz et al 1998].

Interestingly, the same mutation in either FGFR1, FGFR2, or FGFR3 results in different clinical craniosynostosis syndromes, thus implicating a common pathologic mechanism with FGFR gain of function in Pfeiffer, Apert, Muenke, and Beare-Stevenson syndromes [Wilkie et al 2001]. FGF9 binding is enhanced in the FGFR1 Pfeiffer-related mutation p.Pro252Arg and the FGFR3 Muenke-related mutation p.Pro250Arg; thus, FGF9 may be a potential pathophysiologic ligand for mutant FGFRs in mediating craniosynostosis [Ibrahimi et al 2004]. Differences in the primary sequence among FGFRs result in varying effects on ligand binding specificity [Ibrahimi et al 2004].

The normal function of the FGFRs appears to be to restrain limb growth, as FGFR3 knockout mice have elongated tails and hindlimbs [Colvin et al 1996, Deng et al 1996]. This phenomenon suggests that FGFR mutations are hypermorphic, causing the gene product to perform its normal function excessively. The exact mechanism of the hypermorphic effect is different for different types of mutations that have been reported in the FGFR-related craniosynostosis syndromes [Wilkie 1997].

It appears that the diseases caused by FGFR2 mutations in these clinically distinct syndromes may be points along a continuum of a phenotypic spectrum. Evidence to support this concept comes from reports of clinically unique phenotypes caused by FGFR2 mutations. An example is the phenotype of the family reported by Steinberger et al [1996] with an FGFR2 mutation previously associated with Crouzon syndrome but not consistent with any of the FGFR2-related craniosynostosis syndromes (i.e., Apert, Crouzon, Pfeiffer, and Jackson-Weiss). Affected family members lacked the broad and medially deviated thumbs of Pfeiffer syndrome. Only one of nine had broad great toes, but they were not medially deviated as one would expect with Jackson-Weiss syndrome. In addition, significant midfacial hypoplasia and ocular proptosis were not present, as would be expected with Crouzon syndrome.

FGFR1

Normal allelic variants. FGFR1 has a genomic size of approximately 58 kb. Several mRNA splice variants produce seven isoforms. Isoform 1 contains 18 total exons (17 coding exons) and has the largest mRNA product.

Pathologic allelic variants. A single common mutation, p.Pro252Arg, in the linker region between the second and third Ig-like domains of FGFR1 has been associated in five unrelated families with a relatively mild form of Pfeiffer syndrome type 1. FGFR1 mutations have also been associated with Jackson-Weiss syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome. See Table A.

Table 4. Selected FGFR1 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.755C>Gp.Pro252ArgNM_023110​.2
NP_075598​.2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Basic fibroblast growth factor receptor 1 (FGFR1) has three extracellular Ig-like domains (only two of which are active), a transmembrane domain, and a split tyrosine kinase intracellular domain. The Ig-like domains function in promiscuous ligand binding: any FGFR binds any FGF. With ligand binding, two FGFRs dimerize and activate the tyrosine kinase, initiating an intracellular cascade. Basic FGFR1 and FGFR2 mRNA is found during embryogenesis in cartilage and bone precursors that will form the craniofacial and apical skeleton [Muenke & Schell 1995]. In the apical skeleton, basic FGFR1 is expressed throughout the entire developing limb bud, whereas FGFR2 is primarily expressed in the outer ectodermal layer.

Abnormal gene product. No functional studies have been done on the FGFR1 receptor mutation p.Pro252Arg, but studies have been done on the analogous mutations seen in both FGFR2 and FGFR3. Like the mutations seen in FGFR2 and FGFR3, the FGFR1 mutation is dominant, so that the altered protein's effect is seen even in the presence of the normal second allele. Based on a number of studies on fibroblasts and animal models containing FGFR mutations, the effect seems to be one of excess activity; i.e., the mutant receptors work better than the wild type. The p.Pro252Arg mutation occurs in the region between the second and third Ig-like loops, a site that is thought to be important in ligand binding. The substitution of the bulkier residue is thought to change the configuration of the site, thereby altering ligand binding. The increased affinity of the receptor for ligand causes excessive activity, which may then promote excessive receptor down-regulation (summarized in Wilkie [2005]).

FGFR2

Normal allelic variants. FGFR2 contains approximately 120 kb of genomic DNA with 18 total exons (17 coding exons). Alternative splicing produces two isoforms, where isoform 2 is one amino acid longer than isoform 1.

Pathologic allelic variants. Most FGFR2 mutations are missense mutations, although small insertions, deletions, and splice site mutations have also been reported. No nonsense or frameshift mutations have been reported [Wilkie 1997]. Mutations in FGFR2 have been associated with a variety of phenotypes including Apert, Crouzon, Pfeiffer, Jackson-Weiss, and Beare-Stevenson [Przylepa et al 1996] syndromes. In addition, a novel heterozygous mutation was found in a family in which the proband, who displayed intrauterine constraint, had nonsyndromic unicoronal synostosis and other family members had only mild facial asymmetry without synostosis; this represents an example of interaction of environment and a genetic predisposition to cause craniosynostosis. See Table A.

Two common mutations account for 98% of Apert syndrome: p.Pro253Arg and p.Ser252Trp [Ferreira et al 1999]. These mutations occur in the identical location as the FGFR1 mutation in Pfeiffer syndrome and the FGFR3 mutation in Muenke syndrome. This is the linker region between Ig-like loops II and III, the area thought to be critical in ligand binding; the replacement of a proline for a bulkier arginine may alter the orientation of the IgII and IgIII loops [Wilkie 1997]. The p.Ser252Trp mutation is more common than the p.Pro253Arg mutation, seen in 71% and 26% of individuals with Apert syndrome, respectively. Both mutations augment receptor binding affinity; however, indiscriminate increased affinity of fibroblast growth factor receptor 2 (FGFR2) for any FGF is seen in p.Pro253Arg mutations, whereas p.Ser252Trp mutations convey a selective FGFR2 affinity for a limited subset of FGFs [Ferreira et al 1999].

Rare unique mutations involving Alu element de novo insertions have provided evidence that syndactyly in Apert syndrome is caused by signaling through keratinocyte growth factor receptors (KGFRs) [Oldridge et al 1999].

Six FGFR2 mutations have been identified in individuals with Jackson-Weiss syndrome [Heike et al 2001]. Mutations seen in individuals with Crouzon, Pfeiffer, and Jackson-Weiss syndromes occur in and around the B exon of the third Ig-like domain in FGFR2. The exon is subjected to alternative splicing; it is included in the bone FGFR2 isoform that is expressed in the cranial sutures and limbs, and is spliced out in making the KGFR. Mutations in and around the splice sites cause aberrant splicing [Meyers et al 1996]. Other mutations cause a loss or gain of a cysteine residue, while others alter splice sites [Wilkie 1997]. Identical mutations have been seen in individuals with Crouzon, Pfeiffer, and Jackson-Weiss syndromes [Hollway et al 1997, Oldridge et al 1997], suggesting that unlinked modifier genes or epigenetic factors play a role in determining the final phenotype. A study of individuals with Crouzon and Pfeiffer syndromes found that 60% of mutations are caused by two mutation hot spots at the critical cysteine residues 278 and 342 [Kress et al 2000]. Mutations in residues 372 and 375 were identified in individuals with Beare-Stevenson syndrome [Fonseca et al 2008].

It is noteworthy that the FGFR2 mutation appears to arise exclusively from the male chromosome [Moloney et al 1996]. The mutation may convey an advantage in sperm, as the FGF/FGFR pathway is known to be important in maintaining and initiating spermatogenesis [Van Dissel-Emiliani et al 1996]. The de novo mutation rate is high, with 11 of 21 cases of Crouzon syndrome and Pfeiffer syndrome found to arise from de novo FGFR2 mutations [Kress et al 2000].

A mouse model of a gain-of-function mutation in Fgfr2c orthologous to the human FGFR2 mutation (p.Cys342Tyr) in Crouzon and Pfeiffer syndromes was shown to recapitulate the phenotype of these disorders. Specific features seen in heterozygotes included shortened face, protruding eyes, and premature fusion of cranial sutures, while homozygotes displayed multiple joint fusions, cleft palate, and defects of the trachea and lung, and died shortly after birth. The study suggests that the long-term aspects of the mutant phenotype, including craniosynostosis, are related to the FGFR2 regulation of the osteoblast lineage [Eswarakumar et al 2004].

Table 5. Selected FGFR2 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.755C>Tp.Ser252Leu
c.755C>Gp.Ser252TrpNM_000141​.4
NP_000132​.3
c.758C>Gp.Pro253Arg
c.833G>Tp.Cys278Phe
c.866A>Cp.Gln289Pro
c.870G>Tp.Trp290Cys
c.870G>Cp.Trp290Cys
c.868T>Gp.Trp290Gly
c.868T>Gp.Trp290Arg
c.1019A>Gp.Tyr340Cys
c.1018T>Cp.Tyr340His
c.1024T>Cp.Cys342Arg
c.1025G>Ap.Cys342Tyr
c.1031C>Gp.Ala344Gly
c.1052C>Gp.Ser351Cys
c.1576A>Gp.Lys526Glu

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Basic FGFR1 has three extracellular Ig-like domains, a transmembrane domain, and a split tyrosine kinase intracellular domain. The Ig-like domains function in promiscuous ligand binding: any FGFR binds any FGF. With ligand binding, two FGFRs dimerize and activate the tyrosine kinase, initiating an intracellular cascade. Basic FGFR1 and FGFR2 mRNA is found during embryogenesis in cartilage and bone precursors that will form the craniofacial and apical skeleton [Yin et al 2008]. In the apical skeleton, basic FGFR1 is expressed throughout the entire developing limb bud, while FGFR2 is primarily expressed in the outer ectodermal layer.

Abnormal gene product. Like the mutations seen in FGFR1 and FGFR3, FGFR2 mutations are dominant, so that the effect of the altered protein is seen even in the presence of the normal second allele. Based on a number of studies on fibroblasts and animal models containing FGFR mutations, the effect seems to be one of excess activity; i.e., the mutant receptors work better than the wild-type receptors [Wilkie 1997]. For example, one study suggested that mutations causing Apert syndrome increase ligand affinity [Anderson et al 1998] .The increased affinity of the receptor for the ligand causes excessive activity, which may then promote excessive receptor down-regulation (summarized in Wilkie [2005]).

Mutations of exons IIIa and IIIc, the exons in FGFR2 that are most commonly associated with Pfeiffer syndrome, frequently involve cysteine codons [Cornejo-Roldan et al 1999]. The loss or gain of the cysteine residues around the IgIII loop, as is commonly seen in Crouzon syndrome, may alter the configuration of the IgIII loop (cysteine-cysteine disulfide bonding is thought to stabilize the IgIII loop). A free unpaired cysteine may enable ligand-free dimerization and activation of the receptor. Similarly, other mutations that alter splice sites may alter ligand binding affinity or allow for ligand-free activation [Wilkie 2005].

FGFR3

Normal allelic variants. FGFR3 has a genomic size of approximately 15 kb. There are two mRNA splice variants, of which the full nature is unknown. Isoform 1 contains 17 exons and has the largest mRNA product.

Pathologic allelic variants. Mutations in FGFR3 cause achondroplasia, hypochondroplasia, and thanatophoric dysplasia. An alanine-to-glutamic acid change at amino acid 391 (p.Ala391Glu) was identified in individuals with Crouzon syndrome with acanthosis nigricans (AN) [Mulliken et al 1999]. In addition, a single mutation, p.Pro250Arg, was identified in a series of individuals and families with craniosynostosis (including some who had been previously diagnosed as having Pfeiffer, Jackson-Weiss, and Saethre-Chotzen syndromes) as well as in the original family with Adelaide-type craniosynostosis (now called Muenke syndrome). A p.Pro250Arg mutation in FGFR3 was reported in an individual with a mild presentation of Beare-Stevenson syndrome and epidermal hyperplasia [Roscioli et al 2001]. The same mutation had been described in FGFR2 (Apert syndrome) and FGFR1 (Pfeiffer syndrome) [Bellus et al 1996, Muenke et al 1997]. See Table A.

Table 6. Selected FGFR3 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.749C>Gp.Pro250ArgNM_000142​.4
NP_000133​.1
c.1138G>Ap.Gly380Arg
c.1138G>Cp.Gly380Arg 1
c.1172C>Ap.Ala391Glu
c.1862G>Ap.Arg621His

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Associated with achondroplasia

Normal gene product. Fibroblast growth factor receptor 3 (FGFR3) mRNA is found in highest amounts in the developing central nervous system, but is also present in resting cartilage and the skeletal precursors for all bones during the period of endochondral ossification, but not in hypertrophic cartilage. Normal FGFR3 product has two isoforms as a result of alternative splicing of the third FGFR2-like loop; FGFR3 IIIa is found in the brain; FGFR3 IIIb is not.

Abnormal gene product. Like the mutations seen in FGFR1 and FGFR2, FGFR3 mutations are dominant, so that the effect of the altered protein is seen even in the presence of the normal second allele. Based on a number of studies on fibroblasts and animal models containing FGFR mutations, the effect seems to be one of excess activity; i.e., the mutant receptors work better than the wild type (summarized in Wilkie [2005]).

The p.Pro250Arg mutation seen in Muenke syndrome occurs in the region between the second and third Ig-like loops, a site that is thought to be important in ligand binding. The substitution of the bulkier residue is thought to change the configuration of the site, thereby altering ligand binding. The increased affinity of the receptor for ligand causes excessive activity, which may then promote excessive receptor down-regulation [Wilkie 2005].

No studies have been done on the p.Ala391Glu mutation seen in Crouzon syndrome with AN, but much work has been done on the nearby p.Gly380Arg mutation seen in achondroplasia. The mutation demonstrates weak ligand-free activation. While it seems plausible that the p.Ala391Glu mutation works in the same way, the widely different phenotypes produced by the two mutations suggest that other mechanisms of action may be at work [Chen & Deng 2005, Wilkie 2005].

References

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Suggested Reading

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Chapter Notes

Revision History

  • 7 June 2011 (me) Comprehensive update posted live
  • 27 September 2007 (me) Comprehensive update posted to live Web site
  • 9 January 2006 (nr) Revision: Table 3, Pfeiffer syndrome
  • 18 April 2005 (me) Comprehensive update posted to live Web site
  • 13 February 2003 (me) Comprehensive update posted to live Web site
  • 20 October 1998 (pb) Review posted to live Web site
  • March 1998 (nr) Original submission
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