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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])]

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 disease-causing       mutation in the FGFR2 gene. The diagnosis of the other six FGFR-related craniosynostosis syndromes is based on clinical findings; molecular genetic       testing of the FGFR1, FGFR2, and FGFR3 genes 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 is usually not possible owing to 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 to prevent exposure keratopathy in those with severe proptosis. Surveillance: for hydrocephalus in those at increased risk. Testing of relatives at risk: evaluation of at-risk relatives clinically and radiographically or with 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 available if the disease-causing mutation has been identified in the family; however, its use is limited by poor predictive value.

Diagnosis

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

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

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

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].

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 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 novo FGFR2 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.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

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 & Puczynsk 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 recent study found no pathologic mutations in FGFR1, CER1, or CDON in individuals with either syndromic or nonsyndromic metopic craniosynostosis, 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, El Ghouzzi et al 2000].

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 mental retardation 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 gene 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 (2004) 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 femora, 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 ,