CHAPTER 181 Genetics of Craniosynostosis
Craniosynostosis, or the premature fusion of calvarial sutures, occurs in approximately 1 in 2500 live births1 and has traditionally been classified as being either nonsyndromic or syndromic based on phenotypic descriptions. The children considered nonsyndromic often had single-suture synostosis without other abnormalities, whereas those with syndromic disorders were more likely to have multiple sutures fused, harbor other skeletal anomalies, and have a strong family history. Although phenotypic classification has been the “gold standard” for some time, there has been a recent movement toward genotypic classification as the genetic basis of craniosynostosis has slowly been revealed. This movement toward defining the genetic basis of the disease started in 1993 with discovery of the first mutation identified in synostosis, an MSX2 gene mutation in Boston-type synostosis.
As the genetic story unfolds, it is likely that all forms of synostosis will be revealed to have a genetic origin, and therefore the traditional “syndromic” cases will probably be the ones in which the affected gene has more protean manifestations. Investigations have revealed that craniosynostosis can be caused by mutations in multiple genes, including those for fibroblast growth factor receptors (FGFR1 to FGFR3), transcription factors (TWIST, MSX2, RUNX2), transmembrane ligands for Eph receptor tyrosine kinases (EFNB1), structural proteins (FBN1), cell regulatory proteins (TGFBR1 and TGFBR2), proteins involved in electron transfer from the reduced form of nicotinamide adenine dinucleotide phosphate (POR), small guanosine triphosphatases (RAB23), and a RecQ helicase family protein (RECQL4).2–15 Some genes (RBP4, GPC3, C1QTNF3, IL11RA, PTN, POSTN, WIF1, ANXA3, CYFIP2) have also been identified as potentially playing a role in premature calvarial fusion, but these genes must still be studied in more detail.16 The objective of this review is to outline the different types of syndromic and nonsyndromic craniosynostosis and summarize the major genetic mechanisms behind their pathogenesis.
Syndromic Craniosynostosis
Homology in Genetic Mutation
Muenke’s Syndrome
Muenke’s syndrome has been one of the most instructive genetic conditions in the field of synostosis because of its variable clinical features and its seemingly high genetic prevalence in patients with craniosynostosis. From a cranial perspective, it is often associated with unicoronal or bicoronal craniosynostosis and may be associated with a range of other abnormalities, including brachydactyly, thimble-like middle phalanges, coned epiphyses, carpal and tarsal fusions, sensorineural hearing loss, and developmental delay,17 although perhaps the most striking finding is the phenotypic variability of the syndrome. It is believed that many cases of “nonsyndromic” synostosis, including many previously thought to be isolated unilateral coronal synostosis, are actually variants of Muenke’s syndrome. It is inherited in an autosomal dominant fashion and is caused by a point mutation in Pro250Arg in the Ig II-III linker region of the FGFR3 gene on chromosome 4p16.3.17 This mutation is highly associated with familial cases of Muenke’s syndrome, and affected females have a more severe phenotype.18,19 In patients with sporadic Muenke’s syndrome, it has been suggested that advanced paternal age might result in de novo Pro250Arg mutations.20 Numerous studies of patients with Muenke’s syndrome and the Pro250Arg mutation have shown that the clinical findings are highly variable.18,21–26 In fact, some patients with this mutation have been found to have congenital bilateral sensorineural deafness without symptomatic craniosynostosis.27 Because of the high variability in phenotype and the association of coronal synostosis with other craniosynostosis syndromes, genetic testing for the Pro250Arg mutation in FGFR3 is necessary to establish the diagnosis of Muenke’s syndrome.17
Apert’s Syndrome
Apert’s syndrome is characterized by coronal synostosis, severe syndactyly in the fingers and toes, symphalangism, radiohumeral fusion, and mental retardation.28,29 Other clinical features include midface hypoplasia, a short nose with a depressed nasal bridge, hypertelorism, proptosis, a trapezoidal-shaped mouth, and a variety of dermatologic manifestations, including severe acne.30–32 As with the other craniosynostosis syndromes, there is a wide range of severity of deformities.33 The syndrome follows autosomal dominant inheritance and is caused by a number of different mutations in FGFR2 on chromosome 10q26, including two missense mutations (Ser252Trp, Pro253Arg) and two Alu insertions.34–36 Interestingly, the Pro253Arg mutation in Apert’s syndrome is in the homologous Ig II-III linker region of FGFR2, similar to the Pro250Arg mutation in FGFR3 in Muenke’s syndrome. Patients with Ser252Trp tend to have a high frequency of cranial and cleft palate anomalies, but less syndactyly than in those with the Pro253Arg genotype. Sporadic cases have been associated with advanced paternal age.37,38
Pfeiffer’s Syndrome
Pfeiffer’s syndrome is characterized by coronal synostosis with or without premature fusion of other calvarial sutures, broad fingers and toes, and partial syndactyly of the fingers and toes.39 Patients may also have maxillary hypoplasia, a small nose with a low nasal bridge, hypertelorism, shallow orbits, proptosis, strabismus, limb malformation, and radiohumeral synostosis.39,40 In 1993, Cohen suggested categorizing Pfeiffer’s syndrome into three different types based on the severity of deformities, ranging from type I (classic Pfeiffer’s syndrome, a mild entity with autosomal dominant inheritance) to types II and III (more severe, with early death and sporadic inheritance).41 Similar to Muenke’s and Apert’s syndromes, mutation of Pro252Arg in the Ig II-III linker region of FGFR1 on chromosome 8p11.2-p11 has been identified,42 thus suggesting that all three genes for FGFR play a similar role in suture development and lead to distinct craniosynostosis syndromes.43 In fact, each syndrome is associated with altered ligand-binding specificity for the FGFs. Genetic analysis has revealed that FGFR1 mutations cause type I Pfeiffer’s syndrome whereas FGFR2 mutations have been associated with all three types of Pfeiffer’s syndrome.36,39 Clearly, those associated with FGFR2 mutations have a much more extreme phenotypic expression. As a result, it has recently been proposed that Pfeiffer’s syndrome caused by FGFR2 mutations should not be classified as Pfeiffer’s syndrome but rather as Crouzon’s syndrome.43 This is obviously at odds with traditional nomenclature inasmuch as limb deformities have generally been considered pathognomonic of Pfeiffer’s syndrome.39,44
Crouzon’s Syndrome
Crouzon’s syndrome is an autosomal dominant disorder characterized by the classic triad of coronal synostosis, midfacial hypoplasia, and exopthalmos.45,46 Other manifestations may include involvement of other calvarial sutures, brachycephaly, hypertelorism, Chiari I malformation, hydrocephalus, and mental retardation.43 Numerous missense mutations in the Ig III domain of the FGFR2 gene have been implicated, many of which involve the gain or loss of a cysteine residue.4,47–53 The effect of the mutation is constitutive activation of FGFR2, which is believed to be due to the unpaired cysteine residues forming intermolecular disulfide bonds.54,55 In cases in which the mutation does not involve a cysteine residue but still results in constitutive activation of FGFR2, it is believed that the mutation also plays an important role in increasing the amount of intermolecular disulfide bonding by disrupting the normal intramolecular disulfide bonds.56 In addition to the missense mutations, one study reported a patient suffering from Crouzon’s syndrome with an in-frame insertion.57 Sporadic cases of Crouzon’s syndrome have been associated with germinal mosaicism and advanced paternal age.46,58–61 Chang and coworkers thus suggest that genetic testing for Crouzon’s syndrome should include sequencing of the Ig III region of FGFR2.51 In another article, Preston and associates suggested that mutations in PAX2 (on chromosome 10q25) might also be involved in Crouzon’s syndrome.53 It is important to note that Crouzon’s syndrome with acanthosis nigricans is a different disorder; it is caused by an A391E mutation in FGFR3.62,63
Jackson-Weiss Syndrome
Jackson-Weiss syndrome is characterized by a highly variable range of phenotypes, including craniosynostosis (ranging from brachycephaly to acrocephaly), broad toes with a medially deviated great toe, second and third toe syndactyly, tarsal-metatarsal fusion, broad and short metatarsals and proximal phalanges, midfacial hypoplasia, hypertelorism, proptosis, and normal intelligence.52,64,65 Interestingly, it has been described in only a single large Amish kindred and ancestors of that group.64 It is an autosomal dominant disorder. Mutations that have been implicated in causing Jackson-Weiss syndrome include A344G in the highly conserved Ig IIIc domain of FGFR2, as well as two nucleotide missense mutations that result in Cys342Ser and Cys342Arg.52,66 Importantly, these mutations have also been found in patients classified as having Crouzon’s and Pfeiffer’s syndrome, which suggests a genetic relationship between these three phenotypically different syndromes.
Saethre-Chotzen Syndrome
Patients with Saethre-Chotzen syndrome have coronal craniosynostosis with highly variable clinical findings; the most distinguishing features include limb abnormalities (syndactyly of the second and third digits, bifid hallux) and facial abnormalities (facial asymmetry, low frontal hairline, ptosis, small ears with prominent ear crura).67–72 It is inherited in an autosomal dominant fashion with complete penetrance and variable expressivity.67,68,73 Numerous loss-of-function mutations in TWIST have been implicated in playing a role in the pathogenesis of Saethre-Chotzen syndrome; such mutations range from missense and nonsense mutations to deletions, insertions, and duplications.69,74–78 Although deletions in TWIST have been suggested to cause Saethre-Chotzen syndrome with developmental delay, this finding has been inconsistent.70,79
The TWIST gene, located on chromosome 7p21.1, encodes a phylogenetically highly conserved basic helix-loop-helix transcription factor that plays an important role in calvarial osteoblast proliferation and differentiation.13,80,81 Rice and colleagues have shown that Twist regulates FGFR genes in the mouse.82 Reductions in the amount of RUNX2 have also been found in patients with Saethre-Chotzen syndrome.13 As discussed previously, it is therefore believed that TWIST may play a role in the cascade of events that regulate expression of the FGFR and RUNX2 genes in human calvarial suture formation.13,83 Not surprisingly, mutations in FGFR2 have also been implicated in patients with Saethre-Chotzen syndrome.84 A recent report has even identified a specific Q289P mutation in FGFR2 in a family with Saethre-Chotzen syndrome.85 Therefore, in patients with suspected Saethre-Chotzen syndrome, genetic analysis of TWIST1, FGFR2, and RUNX2 could be helpful in verifying the diagnosis.
The common types of synostosis and their phenotypic and genetic features are listed in Table 181-1. Other less common types of synostosis and their genetic basis are listed in Table 181-2.
| TYPE | PHENOTYPIC FEATURES | GENETIC MUTATION |
|---|---|---|
| Muenke’s | Unicoronal or bicoronal craniosynostosis with brachydactyly, thimble-like middle phalanges, coned epiphyses, carpal and tarsal fusions, sensorineural hearing loss, and developmental delay | Autosomal dominant. Caused by a point mutation in Pro250Arg in the Ig II-III linker region of the FGFR3 gene on chromosome 4p16.3 |
| Saethre-Chotzen | Coronal craniosynostosis with limb abnormalities (syndactyly of the second and third digits, bifid hallux) and facial abnormalities (facial asymmetry, low frontal hairline, ptosis, and small ears with prominent ear crura) | Autosomal dominant with complete penetrance and variable expressivity. Caused by loss-of-function mutations in TWIST (missense, nonsense, deletions, insertions, and duplications) |
| Crouzon’s | Classic triad: coronal synostosis, midfacial hypoplasia, and exophthalmos; may also include involvement of other calvarial sutures, brachycephaly, hypertelorism, Chiari I malformation, hydrocephalus, and mental retardation | Autosomal dominant. Caused by numerous missense mutations in the Ig III domain of the FGFR2 gene (many involve the gain or loss of a cysteine residue) |
| Pfeiffer’s | Type I: classic Pfeiffer’s syndrome is a mild entity Types II and III: more severe, with early death Features include coronal synostosis with or without premature fusion of other calvarial sutures, broad fingers and toes, and partial syndactyly of the fingers and toes; may also include maxillary hypoplasia, small nose with a low nasal bridge, hypertelorism, shallow orbits, proptosis, strabismus, limb malformation, and radiohumeral synostosis |
Type I: autosomal dominant inheritance. Caused by FGFR1 mutations, including Pro252Arg in the Ig II-III linker region on chromosome 8p11.2-p11. Can also be caused by mutations in FGFR2 and be associated with more severe phenotypic expression Types II and III: sporadic inheritance. Caused by FGFR2 mutations |
| Apert’s | Coronal synostosis with severe syndactyly in the fingers and toes, symphalangism, radiohumeral fusion, and mental retardation | Autosomal dominant. Caused by a number of different mutations in FGFR2 on chromosome 10q26, including two missense mutations (Ser252Trp, Pro253Arg) and two Alu insertions |
| Jackson-Weiss | Craniosynostosis (ranging from brachycephaly to acrocephaly), with broad toes and a medially deviated great toe, second and third toe syndactyly, tarsal-metatarsal fusion, broad and short metatarsals and proximal phalanges, midfacial hypoplasia, hypertelorism, proptosis, and normal intelligence | Autosomal dominant. Caused by mutation A344G in the highly conserved Ig IIIc domain of FGFR2, as well as two nucleotide missense mutations that result in Cys342Ser and Cys342Arg |
TABLE 181-2 Less Common Types of Synostosis and Their Genetic Bases
| TYPE | GENETIC MUTATION |
|---|---|
| Boston-type craniosynostosis | Caused by gain-of-function mutations (P148H) in the MSX2 gene, which encodes a transcription factor that maps to 5q34-q352 |
| Craniofrontonasal syndrome | Caused by mutations in the EFNB1 gene on chromosome Xq12. Paradoxically, affected females show significantly more severe abnormalities than do males7,8 |
| Shprintzen-Goldberg syndrome | Caused by mutations in the FBN1 gene on chromosome 15q21.1, as well as a missense mutation in TGFBR29,10 |
| Antley-Bixler syndrome | Caused by mutations in the POR gene on chromosome 7q11.211,12 |
| Baller-Gerold syndrome | Caused by mutations in the RECQL4 gene on chromosome 8q24.315 |
| Carpenter’s syndrome | Caused by mutations in the RAB23 gene on chromosome 6p12.1-q1214 |
| Beare-Stevenson cutis gyrata syndrome | Caused by mutations in the FGFR2 gene86 |
Nonsyndromic Craniosynostosis
Nonsyndromic craniosynostosis accounts for approximately 85% of cases of craniosynostosis and is phenotypically classified on the basis of suture involvement.87,88 Each single suture fusion (sagittal, coronal, metopic, lambdoid) is believed to be controlled by a different molecular mechanism, which suggests that certain genes are more likely to cause craniosynostosis of different sutures.88 It is also thought that environmental factors in combination with genetic factors may play a role in premature calvarial fusion.89 Many authors discourage the designation “nonsyndromic craniosynostosis” because they believe that these cases could actually be variants of syndromic craniosynostosis90 and that we simply do not have all the genetic tools to fully identify the conditions. Nevertheless, we will describe the two most common types of “nonsyndromic” craniosynostosis.
Sagittal
Sagittal craniosynostosis (also known as scaphocephaly or dolichocephaly) is the most common form of craniosynostosis and occurs at a rate of 1 in 5000 children, with a male-to-female ratio of 3.5 : 1.91–93 Missense mutations (S188L and S201Y) in the TWIST box have been identified in patients with isolated sagittal craniosynostosis.70,94,95 In addition, a K526E mutation in the tyrosine kinase domain of the FGFR2 gene in a large familial case has been reported.96 Otherwise, our understanding of the genetic basis of this disease has been limited.
Coronal
Coronal craniosynostosis is the second most common form and occurs at a rate of 1 in 10,000 children, with a male-to-female ratio of 1 : 2.97,98 Because many cases of “syndromic” craniosynostosis, especially Muenke’s syndrome, may be associated with unicoronal synostosis, it is highly recommended that one should test for these mutations before diagnosing nonsyndromic coronal synostosis.99 In our clinical practice, we have found a high genetic association of Muenke’s syndrome in children with unilateral coronal synostosis whose contralateral side does not exhibit significant compensatory bossing, thus establishing an association of the phenotype with the genotype.
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