FGFR-Related Craniosynostosis Syndromes

[Acrocephalosyndactyly. Includes: FGFR1-Related Craniosynostosis (includes: Pfeiffer Syndrome Types 1, 2, and 3), FGFR2-Related Craniosynostosis (includes: 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 (Crouzon Syndrome with Acanthosis Nigricans, FGFR3-Related Isolated Coronal Synostosis [includes: Muenke Syndrome])]

Clinical Diagnosis

The diagnosis of six of the eight "FGFR-related craniosynostosis" disorders is based primarily on the clinical findings of bilateral coronal craniosynostosis or cloverleaf skull, characteristic facial features, and variable hand and foot findings; molecular genetic testing for heterozygous mutations in FGFR1, FGFR2, or FGFR3 may be useful adjuncts in questionable cases and in cases in which prenatal detection in subsequent family members is desired.

Molecular testing is necessary to establish the diagnosis for two of the disorders, Muenke syndrome and FGFR2-related isolated coronal synostosis.

• Individuals with Muenke syndrome may have unilateral coronal synostosis or megalencephaly without craniosynostosis; diagnosis depends on identification of a disease-causing p.Pro250Arg mutation in FGFR3.

• FGFR2-related isolated coronal synostosis is characterized only by uni- or bicoronal craniosynostosis; diagnosis is based on identification of a disease-causing mutation in FGFR2.

The diagnosis of craniosynostosis and determination of the suture(s) involved are usually based on clinical findings and can be confirmed by a skull radiograph or head CT examination.

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).

Molecular Genetic Testing

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

Clinical testing

Sequence analysis. FGFR1, FGFR2, and FGFR3 sequence analysis has high sensitivity for Apert syndrome and the isolated FGFR-related craniosynostosis syndromes (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 cases of bilateral than unilateral coronal synostosis [Mulliken et al 2004].

Table 3 summarizes molecular genetic testing for this disorder.

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

Disorder	Test Method	Mutations Detected	Mutation Detection Frequency 1, 2	Test Availability
Pfeiffer syndrome (type 1)	Sequence analysis	FGFR1 sequence variants	67%	Clinical
Apert syndrome		FGFR2 sequence variants	>98%	Clinical
Beare-Stevenson syndrome
Crouzon syndrome			>50%
FGFR2-related isolated coronal synostosis			100%
Jackson-Weiss syndrome			Unknown
Pfeiffer syndrome (all types)			67%
Crouzon syndrome with acanthosis nigricans (AN)		FGFR3 sequence alterations 3	100%	Clinical
FGFR3-related isolated coronal synostosis		FGFR3 sequence variants
Muenke syndrome	Targeted mutation analysis	FGFR3 mutation 4

1. Proportion of affected individuals with a mutation(s) as classified by gene, disorder, and/or test method
2. Numbers reflect "sensitivity" (i.e., probability that an individual with the phenotype will have a positive result). No similar data exist for the positive predictive value of the test (i.e., probability that an individual with that test result would have the phenotype).
3. The mutation in Crouzon syndrome with AN is usually p.Ala391Glu.
4. Identification of the FGFR3 mutation p.Pro250Arg is an obligate and defining feature of this disorder [Muenke et al 1997].

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

Testing Strategy

To establish the diagnosis in a proband

• 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.

To confirm the diagnosis in a proband

• Crouzon syndrome with acanthosis nigricans (AN) is usually caused by the FGFR3 mutation p.Ala391Glu; therefore, the finding of AN in a young child with Crouzon syndrome should prompt testing for the p.Ala391Glu mutation in FGFR3 before testing for FGFR2 mutations. Choanal atresia, hydrocephalus, and the cranial features of Crouzon syndrome should suggest the diagnosis of Crouzon syndrome with AN even before AN appears. Subtle skeletal features such as 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 lend further support to this diagnosis [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.

  • An algorithm to increase efficiency and cost-effectiveness of molecular testing in craniosynostosis disorders involves initial performance of sequence analysis of recurrent mutations, followed by selective gene sequencing [Chun et al 2003].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies typically require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Mutations in FGFR1, FGFR2, and FGFR3 are responsible for a number of clinically distinct disorders.

FGFR1

• Osteoglophonic dysplasia is a skeletal dysplasia syndrome that shares characteristics with craniosynostosis syndromes and dwarfing syndromes. Features include craniosynostosis, prominent supraorbital ridge, depressed nasal root, rhizomelic dwarfism, and characteristic non-osseous bone lesions [White et al 2005]. The identification of pathogenic FGFR1 mutations demonstrates that FGFR1 may function as a negative regulator of long bone development rather than increasing skull bone growth [White et al 2005, Farrow et al 2006].

• An FGFR1 mutation (p.Pro252Arg) has now been reported in three kindreds with the classic hand and foot findings of Pfeiffer syndrome but without craniosynostosis or craniofacial features [Hackett & Rowe 2006].

FGFR2

• A familial scaphocephaly syndrome characterized by scaphocephaly, macrocephaly, midface flattening, and mild intellectual disabilities has been reported in a three-generation kindred with a p.Lys526Glu mutation in FGFR2. This mutation resides in the tyrosine kinase-1 domain, which is located outside the typical mutational hot spot of the gene seen in other craniosynostosis syndromes [McGillivray et al 2005].

• Saethre-Chotzen syndrome is typically caused by TWIST1 mutations, but a family with phenotypic features of Saethre-Chotzen syndrome and normal TWIST1 sequence analysis had the FGFR2 mutation p.Gln289Pro [Freitas et al 2006].

• Syndromic craniosynostosis with elbow contracture. The FGFR2 mutation p.Ser351Cys has been reported in approximately eight individuals with severe craniosynostosis, midface hypoplasia, elbow joint contracture, developmental delays, and often premature death [Akai et al 2006].

FGFR3

• Achondroplasia

• Hypochondroplasia

• Thanatophoric dysplasia

• Camptodactyly, tall stature, scoliosis, and hearing loss (CATSHL) syndrome is caused by a p.Arg621His mutation in the FGFR3 tyrosine kinase domain that leads to decreased protein function, indicating that mutations in FGFR3 can either hinder or promote bone growth [Toydemir et al 2006].

Note: FGFR3 mutations were reported in two individuals with both Muenke syndrome and hypochondroplasia. Both were cognitively normal but had early-onset temporal lobe seizures and bilateral dysgenesis of the medial temporal lobes [Grosso et al 2003].

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 proceed 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) finclude: ocular hypertelorism, proptosis, midface hypoplasia, small beaked nose, and prognathism. A high-arched palate is often present; more rarely, a cleft palate is present. 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, down-slanting palpebral fissures, and extreme proptosis; in addition, developmental delay and/or mental retardation, hydrocephalus, hearing loss, 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. In severe cases, these problems may present as life-threatening respiratory failure 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 [Renier, Lajeunie et al 2000]. Even if every medical complication is managed promptly, a proportion of affected children will develop mental retardation and neurologic problems. The greatest risk for mental retardation is found in Apert syndrome [Renier, 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.

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

• Intellect. Normal

• Craniofacial. Variable. Uni- or bilateral coronal craniosynostosis, or only megalencephaly; mild to significant midface hypoplasia; ocular hypertelorism

• Extremities. Variable. Carpal-tarsal fusion is diagnostic when present but is not always present; brachydactyly, carpal bone malsegregation, or coned epiphyses may occur.

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.

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

Apert syndrome

• Intellect. Varying degrees of developmental delay/mental retardation (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 [Cohen & Kreiborg 1993]

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/mental retardation 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; hydrocephalus; seizures; sacrococcygeal eversion [Oliveira et al 2006]; increased risk for early death

Pfeiffer syndrome type 3

• Intellect. Developmental delay/mental retardation 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

Beare-Stevenson cutis gyrata

• Intellect. All have mental retardation

• 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 the FGFR3 gene 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 mental impairment 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/Arg, p.Tyr340His) results exclusively in the Crouzon phenotype [Lajeunie et al 2006].

Pfeiffer syndrome-causing mutations p.Ser352Cys, p.Ser351Cys, p.Trp290Cys, p.Tyr342Arg, 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), 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].

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 novoFGFR2 mutation was associated with variable expressivity and reduced penetrance [de Ravel et al 2005].

Anticipation

There have been no reports of anticipation 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 gene 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.

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

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]. 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 [Renier, Lajeunie et al 2000].

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].

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

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].

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.

Testing 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.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Mode of Inheritance

FGFR-related craniosynostosis is 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 gene 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 de novo gene mutations.

• 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]. 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].

• FGFR3-related isolated coronal synostosis is usually inherited in an autosomal dominant manner with reduced penetrance.

Sibs of a proband

• The risk to sibs of the proband depends on the genetic status of the parents.

• If a parent is affected or has a disease-causing mutation, the risk is 50%.

• When the disease-causing mutation cannot be detected in the DNA of either parent, the risk to sibs of a proband is low, but greater than that of the general population because of the possibility of germline mosaicism.

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 upon the status of the proband's parents. If a parent is found to be affected or to have a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

See Testing of Relatives at Risk for information on testing 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. Nontheless, rare examples exist in which the phenotype of affected individuals in a given family has varied: 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 apparent de novo mutation. When the parents of a proband with an autosomal dominant condition are unaffected and/or do not have a disease-causing mutation, possible non-medical explanations including alternate paternity or undisclosed adoption could 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.

DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

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 15-18 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 the FGFR1, FGFR2, or FGFR3 genes 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). Three-dimensional ultrasound, 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]. Indeed, prenatal MRI is often used to accurately diagnosis suspected craniosynostosis syndromes such as Pfeiffer or Apert syndromes. Detectable MRI findings may include agenesis of the corpus callosum, hydrocephalus, or cloverleaf skull [Itoh et al 2006, Quintero-Rivera et al 2006].

Requests for prenatal testing for conditions such as FGFR-related craniosynostoses that 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, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

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].

Mutations in FGFR1, FGFR2, and FGFR3 have been associated with a variety of clinical phenotypes. 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 (reviewed in 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.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Readings

Revision History

• 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