Condition due to premature fusion of cranial sutures (sagittal, coronal, lambdoid, or metopic).
Incidence is 1 in 2000 livebirths. One of the most common human malformations.
Eighty to ninety percent of cases are isolated, 10%–20% are syndromic.
Women with fetuses suspected of having craniosynostosis should be referred for a detailed fetal anatomic survey. Sonographers should pay attention to the fetal hands, midface, heart, and central nervous system.
Differential diagnosis includes Muenke coronal craniosynostosis, Saethre–Chotzen syndrome, Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, and many others.
DNA diagnosis is available to detect mutations in the causative genes associated with craniosynostosis, including FGFR1, FGFR2, FGFR3, TWIST, and MSX2.
Newborns are at risk for difficulties with breathing, feeding, and vision. Consultation with genetics and neurosurgery is indicated.
Long-term outcome and recurrence risk depend on identification of a genetic basis through DNA analysis.
The term craniosynostosis refers to the process of premature bony fusion of the cranial sutures. The term is frequently used interchangeably with the word craniostenosis, which technically refers to the aberrant skull shape that results from the process of craniosynostosis (Graham, 1981). The weight of the brain doubles during the first year of life, and enlargement of the skull vault is distributed among the main cranial sutures—sagittal, coronal, lambdoid, and metopic. Premature fusion of a suture leads to reduced growth in the direction perpendicular to the fused suture (Thompson et al., 1994). Compensatory growth occurs in the remaining normal sutures. Normally, the cranial sutures are open at birth and become interdigitated by 7.5 months of age. Cranial sutures do not fuse completely until the fourth decade of life (Graham, 1981).
It is important to determine whether craniosynostosis is primary or secondary. In primary craniosynostosis, abnormal skull development is genetically determined and alteration in sutural growth is present from birth (Flores-Sarnat, 2002). In primary craniosynostosis, the head of the affected individual is frequently asymmetric. The brain grows at a normal rate but must adjust to the confined space. The brain continues to grow in areas where the sutures are open but not in areas where the sutures are closed (Lyons-Jones et al., 1980). Most children affected with primary craniosynostosis are normal neurologically and benefit from surgery. In secondary craniosynostosis, brain growth is impaired and most affected children are neurologically abnormal. In secondary craniosynostosis, a metabolic, storage, hematologic, or structural disorder results in microcephaly or otherwise abnormal brain growth (Table 10-1). In evaluating the fetus with craniosynostosis, it is important to determine whether the craniosynostosis is isolated (80–90% of cases) or syndromic (10–20% of cases). More than 150 syndromes have been described that include craniosynostosis as an associated feature (Lajeunie et al., 1995; Warren and Longaker, 2001).
Table 10-1Classification of Craniosynostosis ||Download (.pdf) Table 10-1 Classification of Craniosynostosis
| Primary ||Secondary |
|Single suture ||Multiple sutures || |
|Nonsyndromic (simple) ||Nonsyndromic ||Syndromic (complex) || |
|Scaphocephaly (sagittal) |
Plagiocephaly (coronal or lambdoid)
|Brachycephaly (bicoronal) ||Crouzon |
|Storage disorders |
Isolated craniosynostosis generally presents during the first year of life, and severe neuropsychologic sequelae are unusual (Meilstrup et al., 1995). In most studies, the sagittal suture is the most common site for isolated craniosynostosis (Figure 10-1). This is called “scaphocephaly,” and it results in a narrow, elongated head. Physical examination reveals a palpable ridge along the line of the fused suture. Bilateral coronal craniosynostosis (Figure 10-2) leads to “acrobrachycephaly” and a broad, short head (Flores-Sarnat, 2002). Unilateral coronal craniosynostosis, called “plagiocephaly,” results in asymmetric flattening of the forehead with loss of the supraorbital ridge. This condition is best appreciated when viewed from above the patient. In most reported studies, the least commonly involved suture is the metopic. This is called “trigonocephaly,” and produces a keel-shaped forehead and orbital hypotelorism (Thompson et al., 1994). The kleeblattschädel deformity, also described as a cloverleaf skull, has a more symmetric trilobar appearance, which results from premature synostosis of the coronal and lambdoidal sutures (Meilstrup et al., 1995).
Prenatal transaxial sonographic image of an isolated suture synostosis, which gives a lemon-like shape to the cranium.
Prenatal sonographic image of a fetus at 24 weeks with bilateral coronal craniosynostosis.
Craniosynostosis is one of the most common human malformations, with an incidence of approximately 1 in 2000 livebirths (Shuper et al., 1985; Lajeunie et al., 1995; Van der Ham et al., 1995). Craniosynostosis is associated with advanced paternal age (Lajeunie et al., 1995), maternal smoking, and higher altitudes (Alderman et al., 1994, 1995). In a study of 154 patients at Johns Hopkins Hospital followed over a 2-year period, Van der Kolk and Beatty (1994) found that 78% of affected patients had only one suture involved, whereas 16% of patients had multiple sutures involved. Of these 154 patients, 94% had isolated craniosynostosis and 6% had complex or syndromic craniosynostosis. In this study, secondary synostosis occurred in four patients as a result of microcephaly or following complications of ventriculoperitoneal shunt placement (Van der Kolk and Beatty, 1994). Craniosynostosis occurs in all ethnic and racial groups.
Of the syndromic craniosynostoses, the most common are Saethre–Chotzen syndrome (Lewanda et al., 1994) and Muenke coronal craniosynostosis (Muenke et al., 1997). The next most common is Crouzon syndrome, with an incidence of 1 per 25,000 livebirths (Leo et al., 1991). Apert syndrome, with its distinctive craniofacial and digital abnormalities, occurs in 1 per 65,000 to 160,000 livebirths (Chenowith-Mitchell and Cohen, 1994; Moloney et al., 1996). Apert syndrome is associated with advanced paternal age (Moloney et al., 1996).
Prenatal sonographic evaluation of the fetus in which craniosynostosis is suspected should include examination of
the symmetry of the calvarium contour (coronal views through temporal lobes and orbits);
the continuity of the calvarium to exclude encephalocele;
the size and shape of the orbits;
the cerebral ventricles;
the brain parenchyma;
the overall head size;
the remainder of fetal anatomy by detailed sonography (Meilstrup et al., 1995).
The most important consideration in the sonographic examination is the distinction between isolated and syndromic craniosynostosis. For most of the conditions associated with craniosynostosis, long-bone growth is within normal limits. It is particularly important to evaluate the fetal hands and feet, the central nervous system, and the heart.
In most published reports of prenatal diagnosis of craniosynostosis, the diagnosis was not made until the third trimester, unless a family history was present for one of the associated syndromes. In one report, 16 fetuses at risk for craniosynostosis were referred to a fetal medicine unit because of a positive family history (Delahaye et al., 2003). Serial sonographic examinations were performed at 12, 22, and 32 weeks of gestation. In all cases, postnatal diagnosis agreed with the third trimester (and, in a few cases, second trimester) diagnosis. Craniosynostosis was diagnosed when there was a loss of hypoechogenicity of the normal suture. Sutures were examined along their entire length. Dysmorphology and skull deformity preceded closure of the sutures by 4 to 16 weeks.
Fetuses at risk for Apert syndrome (Figure 10-3) should be evaluated for abnormalities of the hands (syndactyly), proptosis, congenital heart defects, agenesis of the corpus callosum, and abnormalities of the limbic structures of the brain (de León et al., 1987; Skidmore et al., 2003; Hansen et al., 2004). At least one case has been reported of Apert syndrome presenting as fetal hydrocephalus, although the presence of hydrocephalus is considered controversial (Kim et al., 1986). Some authors prefer to use the term distortion ventriculomegaly to indicate that the apparent abnormalities in fluid are the result of the misshapen brain (Cohen and Kreiborg, 1993b). One case of Apert syndrome presenting as nuchal-fold thickening as early as 12 weeks of gestation has been described (Chenowith-Mitchell and Cohen, 1994). This fetus did not demonstrate any additional sonographic abnormalities until after 26 weeks of gestation, when an abnormal head shape was first noted. By 29 weeks of gestation, the fetal skull was demonstrated to have prominent parietal lobes, and for the first time, lack of separate fetal finger movement was noted. This latter finding of the absence of distinct and separate movements of the fingers and toes is considered to be one of the hallmarks of Apert syndrome (Hill et al., 1987). Three-dimensional (3-D) sonographic imaging has been shown to be useful in the diagnosis of a sporadic case of Apert syndrome, specifically by demonstrating a widely open metopic suture and bilateral fusion of the coronal sutures (Esser et al., 2005).
Prenatal sonographic image of a fetus at 23 weeks’ gestation with Apert syndrome, demonstrating bilateral coronal suture synostosis and a tower-like shape of the skull (turricephaly).
Pfeiffer syndrome is characterized by coronal craniosynostosis, midface hypoplasia, and broad thumbs and great toes. There are three clinical subtypes: type I is the mildest presentation, type II is the most severe, and type III is intermediate. Type II is associated with a cloverleaf-shaped skull, severe ocular proptosis, midface hypoplasia, radially deviated digits, and occasional ventriculomegaly (Benacerraf et al., 2000). Several cases of the sonographic diagnosis of Pfeiffer syndrome, type II, with molecular confirmation, have been reported in the literature (Benacerraf et al., 2000; Blaumeiser et al., 2004; Gorincour et al., 2005).
Whenever craniosynostosis is considered in a fetus, an attempt should be made to rule out encephalocele (see Chapter 12) and the presence of an intracranial mass. Craniosynostosis is associated with abnormalities of chromosomes 5p, 7p, and 13q, single-gene disorders, and rare teratogens, such as aminopterin.
The most common conditions associated with syndromic craniosynostosis include Saethre–Chotzen syndrome, which includes craniosynostosis, facial asymmetry, low frontal hairline, ptosis, a deviated nasal septum, brachydactyly, and partial cutaneous syndactyly of the toes (Lewanda et al., 1994). Saethre–Chotzen syndrome is dominantly inherited, but in some families the features are so mild that they may go unrecognized.
A relatively recently identified syndrome, Muenke coronal craniosynostosis, has significant clinical overlap with Saethre–Chotzen syndrome (Vajo et al., 2000). It is also quite common. There is considerable phenotypic variability in this condition and mild cases may be missed. Affected individuals have coronal craniosynostosis, and mild abnormalities of the hands and feet, including carpal and tarsal fusion, brachydactyly, thimble-like middle phalanges, and cone-shaped epiphyses. Additional findings include sensorineural hearing loss and developmental delay (Muenke et al., 1997). This condition is also dominantly inherited.
The next most common syndrome associated with craniosynostosis is Crouzon syndrome, which includes coronal craniosynostosis, maxillary hypoplasia, shallow orbits, and ocular proptosis. This condition was first described in 1912 in an affected mother and daughter (Leo et al., 1991). Crouzon syndrome is distinguished from some of the other syndromes by the absence of abnormalities in the hands and feet. The essential features of this syndrome are limited to the skull and face, resulting in brachycephaly and orbital hypoplasia (Thompson et al., 1994).
Less common syndromes in the differential diagnosis include Jackson–Weiss, Pfeiffer (types I, II, III) and Carpenter. Jackson–Weiss syndrome was first described in an Amish kindred with more than 130 affected family members. The characteristic findings of Jackson–Weiss syndrome include craniosynostosis, maxillary retrusion, frontal prominence, hypotelorism, strabismus, and in general, anomalies of the feet but not the hands. The characteristic anomalies of the feet include medial deviation of the big toes and partial syndactyly of the first web space (Stankovic et al., 1994). Pfeiffer syndrome has three forms. There is a relatively benign form, known as the type I, which consists of an acrocephalic skull due to bicoronal synostoses. Affected patients have broad thumbs and great toes and soft tissue syndactyly. Like many of the other syndromes associated with craniosynostosis, affected patients have hypotelorism, maxillary hypoplasia, low-set ears, and normal intelligence (Hill and Grzybeck, 1994). Two other subgroups of patients with Pfeiffer syndrome had extreme proctosis and hydrocephalus. These patients have a uniformly poor outcome and are distinguished from each other as the type II form with the cloverleaf skull deformity and the type III form without the cloverleaf skull deformity (Moore et al., 1995). The kleeblattschädel, or cloverleaf, skull deformity is also associated with thanatophoric dysplasia (see Chapter 90). Of all patients with the cloverleaf skull deformity, 20% are due to Pfeiffer syndrome and 40% are due to thanatophoric dysplasia (Hill and Grzybeck, 1994). In Carpenter syndrome, affected patients have acrocephaly, soft-tissue syndactyly, radial/tibial polydactyly, congenital heart disease, and mental retardation. In Baller– Gerold syndrome, affected patients have craniosynostosis and radial/tibial upper-limb malformations (see Chapter 106) (Boudreaux et al., 1990).
Patients with the Apert syndrome, first described in 1906, have a shortened anterior–posterior diameter of the skull with a high, full forehead, flat occiput, flat facies, shallow orbits, hypotelorism, osseous and cutaneous syndactyly, and associated anomalies (Figures 10-3 and 10-4). Ten percent of patients have cardiovascular abnormalities, and approximately 10% have genitourinary anomalies, most commonly hydronephrosis and cryptorchidism (Cohen and Kreiborg, 1993b). One of the most characteristic findings of patients affected with Apert syndrome includes the complete digital fusion of the soft tissues of the digits 2, 3, and 4, which creates a mid-digital hand mass with a single common nail (see Figures 105-1 to 105-4).
Fetus from Figure 10-3 after termination, demonstrating turricephaly and a wide open metopic suture. Prenatal sonograms and post-termination photographs of this fetus’ extremities are shown in Figures 105-1 to 105-4
ANTENATAL NATURAL HISTORY
The cranium develops as islands of bone within a fibrous membrane called the “ectomenix.” The wedge-shaped proliferation of cells at the periphery is called the “osteogenic front.” When osteogenic fronts come in close proximity to each other, a suture develops. The suture allows spatial separation of cranial bones during growth. The suture includes fibrous tissue defined radiographically by lucency and by proliferating osteogenic tissue on the periphery of the bone. The cranial sutures consist of five layers including two cambial and two periosteal layers separated by a middle vascular layer. The suture allows bone growth at sutural margins secondary to distant forces separating sutures (Van der Kolk and Beatty, 1994).
The antenatal natural history for fetuses affected with craniosynostosis depends on whether the condition is isolated or syndromic. In general, fetuses with isolated craniosynostosis grow and develop normally. Fetuses with syndromic craniosynostosis are also generally normal, if not sometimes large for gestational age. There is no evidence that any of these syndromes are associated with increased lethality in utero.
One of the most important considerations in the management of pregnancy is to obtain a detailed family history. Both parents should be examined for the presence of facial asymmetry or for partial syndactyly of the fingers or toes. These findings are consistent with the mildest expression of some of the syndromic craniosynostoses. It is also important to remember that parents affected with one of the syndromic craniosynostoses may have had extensive plastic surgical repair and will therefore have a relatively normal appearance.
We recommend referral of the pregnant patient carrying a fetus with presumed craniosynostosis to a tertiary care center capable of targeted sonographic examination of the fetus. It is particularly important to rule out the presence of associated hand and foot abnormalities as well as the more serious cardiovascular abnormalities that can be present in some of these syndromes. If there is a positive family history of isolated craniosynostosis, no further work-up is necessary. If, however, the family history is negative, we recommend prenatal karyotyping to rule out chromosomal abnormalities associated with craniosynostosis (Fryburg and Golden, 1993). Furthermore, in the setting of a negative family history, if additional sonographic findings suggest a syndromic diagnosis, it is important that the parents meet with a medical geneticist to discuss the implications of the potential diagnoses and perform molecular diagnosis. Many of the syndromic craniosynostoses are associated with normal intelligence; however, Apert syndrome is associated with a significant chance of developmental delay.
Fetal magnetic resonance imaging (MRI) has been used to confirm cranial abnormalities in a case of Apert syndrome (Boog et al., 1999). If the diagnosis is made before 24 weeks of gestation, parents can be given the option of terminating the pregnancy. If the diagnosis is made in the third trimester, we recommend that the delivery occur in a tertiary care center because of the possibility of associated feeding and breathing difficulties in the neonate. In addition, it will be important for a medical geneticist to examine the infant after birth to confirm the presumed clinical diagnosis and perform confirmatory molecular diagnosis testing. Fetuses with skull abnormalities suggesting a head circumference larger than normal may need to be delivered by cesarean section.
In utero correction of craniosynostosis is not recommended (Warren and Longaker, 2001).
Infants with suspected craniosynostosis should have a detailed physical examination at birth. Some of the associated physical findings in the syndromic craniosynostosis are listed in Table 10-2. Anteroposterior and lateral views of the skull should be obtained. On radiography, the prematurely fused suture is either completely absent or represented by a line of increased density. In cases of coronal synostosis, the so-called harlequin appearance of the orbit is due to elevation of the ipsilateral sphenoid wing. Physical examination of the infant should be performed in consultation with a clinical geneticist to seek specific evidence of associated abnormalities. For example, 30% of infants affected with Apert syndrome have submucous cleft palate (Mulliken and Bruneteau, 1991). Furthermore, geneticists facilitate molecular testing to provide a definitive diagnosis. This is important even in the setting of isolated unilateral coronal craniosynostosis (Mulliken et al., 2004). In one study, mutations in FGFR2,3 or TWIST were found in 8 of 47 patients studied with unilateral coronal craniosynostosis. Detection of a mutation was shown to influence the type of surgical repair (Mulliken et al., 2004).
Table 10-2Differential Diagnosis of Craniosynostosis ||Download (.pdf) Table 10-2 Differential Diagnosis of Craniosynostosis
| Chromosome Abnormalities |
|Single-Gene Disorders ||Pattern of Inheritance |
|Apert syndrome ||Autosomal dominant |
|Crouzon syndrome ||Autosomal dominant |
|Pfeiffer syndrome ||Autosomal dominant |
|Saethre-Chotzen syndrome ||Autosomal dominant |
|Carpenter syndrome ||Autosomal dominant |
|Jackson-Weiss syndrome ||Autosomal dominant |
|Christian syndrome ||Autosomal recessive |
|Summitt syndrome ||Autosomal recessive |
|Baller-Gerold syndrome ||Autosomal recessive |
|Gorlin-Chaudhry-Moss syndrome ||Autosomal recessive |
| Teratogen |
For patients with suspected syndromic craniosynostosis, computed tomographic (CT) and MRI examinations are recommended to check for brain parenchymal abnormalities and for the presence of hydrocephalus.
Treatment of the affected newborn includes an assessment of four main functional areas: breathing, feeding, vision, and complications of increased intracranial pressure. In infants affected with syndromic craniosynostosis, the maxillary hypoplasia responsible for midface abnormalities reduces nasal and postnasal volume (Thompson et al., 1994). Foreshortening of the skull base, palatal arching, and choanal stenosis further compromise the upper airway. The hindbrain contents can herniate through the foramen magnum. Pediatricians should note the affected infant’s respiratory rate and work of breathing, monitor oxygen saturation, and consider nasal stents or nasal prongs, or even tracheostomy to prevent airway obstruction. The role of continuous positive airway pressure (CPAP) is being investigated for affected infants. MRI of the trachea can also be considered.
The anatomic abnormalities that affect breathing also can affect feeding. Infants should be evaluated for the presence of cleft palate. Oropharyngeal coordination during sucking and swallowing can be a major problem. A careful assessment should be made of feeding capabilities; feeding by gastrostomy tube can be considered.
One third of children with craniosynostosis have increased intracranial pressure. This is especially a problem in children who have multiple suture synostosis or syndromic synostosis (Thompson et al., 1994). Because intelligence quotient (IQ) and development can be affected, some authors recommend measurement of the intracranial pressure (Thompson et al., 1994). This helps to plan the timing of the surgical repair. Intracranial pressure can be measured by insertion of a subdural pressure transducer with pressure recordings made over a 24-hour period.
In patients with syndromic craniosynostosis who have proptosis, the globes are predisposed to infection, corneal ulceration, and recurrent prolapse of the orbital contacts. Excessive drying of the eyes may necessitate the use of artificial tears. Patients with severe proptosis are generally treated surgically.
The primary objective of surgery is to allow adequate brain growth within the first 12 months of life. The secondary objective is to improve the patient’s appearance. The optimal timing for surgical treatment of craniosynostosis is under debate. If evidence exists for symptomatic increased intracranial pressure (such as bulging fontanelles, or progressive optic atrophy), most surgeons would intervene as soon as possible (Warren and Longaker, 2001). In general, surgical repair consists of three phases: (1) suture release, cranial vault decompression, and upper orbital advancement at ages 6 to 12 months; (2) craniofacial surgery to correct midface abnormalities at ages 6 to 12 years; and (3) orthognathic surgery at ages 14 to 18 years (Warren and Longaker, 2001).
For patients who have isolated (simple) craniosynostosis, a single definitive operation performed during the first year of life produces excellent cosmetic results in 93% of affected patients (Whitaker et al., 1987; Thompson et al., 1994). For patients with scaphocephaly, a strip craniectomy is performed with a wide margin of excision. For patients with plagiocephaly and trigonocephaly, the frontal bones are removed and supraorbital ridges are adjusted via a bifrontal craniotomy (Thompson et al., 1994). Complications of surgery include bony infection, meningitis, aspiration pneumonia, and postoperative development of encephalocele (Whitaker et al., 1987).
For patients affected with syndromic craniosynostoses, a multidisciplinary assessment is recommended. The identification and control of elevated intracranial pressure is central to the planning of surgery. Most surgeons recommend an initial cranial vault expansion, followed by midface advancement to reduce maxillary hypoplasia. For patients affected with Apert syndrome, the surgery is typically staged. However, in Apert syndrome, only the coronal sutures are fused from the base upward; the sphenozygomatic, sphenotemporal, lambdoidal, and occipital mastoid sutures are all radiologically patent at birth. For individuals affected with Apert syndrome, the coronal sutures are released initially and frontal bone advancement occurs at 3 to 6 months of age (Mulliken and Bruneteau, 1991). The purpose of this initial surgery is to decompress the intracranial space, to protect proptotic globes, and to perform the initial construction of a normal-appearing supraorbital and frontal configuration. It is important for prospective parents to recognize that the syndromic craniosynostoses are more complicated than the isolated craniosynostoses. For most of the syndromes, initial decompression surgery is followed by plastic surgery in adolescence.
The long-term outcome depends on whether the craniosynostosis was simple or complex. In one study of 56 children with craniosynostosis, Noetzel et al. (1985) studied 27 patients with simple craniosynostosis. None of these patients had hydrocephalus on CT scan. Seventeen of 27 patients with simple craniosynostosis had average intelligence. An additional 6 had intelligence in the low average range, and 1 was developmentally delayed. This individual also had a history of perinatal depression. These authors noted that hydrocephalus occurred more frequently in complex craniosynostosis, specifically in affected patients with Pfeiffer and Crouzon syndromes. Of the 25 patients in the study who had complex or syndromic craniosynostosis, 19 had normal intelligence.
For most of the conditions associated with craniosynostosis, long-bone growth and pubertal development occur normally (Cohen and Kreiborg, 1993a). An additional complication of the complex craniosynostosis syndromes includes middle-ear infections (Kaplan et al., 1991). An unusual long-term complication of Apert syndrome is the presence of severe acne, which extends down to the forearm (Kaplan et al., 1991). This localized acne is now known to be due to a mutation in the fibroblast growth factor receptor 2 (FGFR2) gene (Munro and Wilkie, 1998). Patients with Apert syndrome also have excessive sweating.
GENETICS AND RECURRENCE RISK
All fetuses suspected of having craniosynostosis should have a detailed family history taken by a trained geneticist. Of 154 patients studied at John Hopkins Hospital, only 2.5% with isolated synostosis had a positive family history. In contrast, in patients affected with one of the syndromic craniosynostosis conditions, 50% had a positive family history (Van der Kolk and Beatty, 1994).
The first syndrome associated with craniosynostosis to be identified at the molecular level was a relatively rare form of craniosynostosis known as the “Boston type.” This condition is characterized by high penetrance and variable expression. Affected patients have a variety of phenotypes, including frontal orbital recession to pansynostosis to a cloverleaf skull deformity (Warman et al., 1993). Later that year Jabs et al. demonstrated that this condition was due to a substitution of histidine for a proline in the MSX2 homeobox, which created a gain-of-function mutation. Overexpression of MSX2 prevented osteoblast differentiation and mineralization of the extracellular matrix (Jabs et al., 1993).
The fibroblast growth factor receptor types 1, 2, and 3 genes are all involved in the molecular etiology of many of the conditions that cause craniosynostosis, specifically Apert, Crouzon, Jackson–Weiss, Pfeiffer, Muenke, and Beare– Stevenson syndromes (Li et al., 1994; Jabs et al., 1994; Gorry et al., 1995; Rutland et al., 1995; Wilkie, 2005). FGFRs are signal-transduction molecules that cross the cell membrane. All FGFRs share a similar structure in their molecular sequence, which consists of three extracellular immunoglobulin-like domains (IgI, IgII, and IgIII), a single-pass transmembrane segment, and a split tyrosine kinase domain (TK1/TK2) (Kan et al., 2002).
FGFR2 encodes a cell membrane receptor protein. Mutations in a single exon (IIIc) have been associated with three different phenotypes. The more severe phenotype associated with Apert syndrome has been mapped to exon IIIu. The mutation spectrum of Apert syndrome is suprisingly narrow. In a study of 118 unrelated patients with Apert syndrome, all had one of two specific cytosine-to-guanine transversions in the FGFR2 gene on chromosome 10. Furthermore, in every case the mutation arose from the father (Moloney et al., 1996).
The mutational spectrum of FGFR2 is relatively narrow, with distinct mutations occurring in a limited number of exons (Kan et al., 2002). In a prospective study of 259 patients with craniosynostosis, the IgIIIa/IIIc region of the gene was shown to be a genuine mutation hotspot (Kan et al., 2002). Investigators have also shown that Pfeiffer syndrome is genetically heterogenous. It is caused by mutations in two different genes, the FGFR1 gene, located on the short arm of chromosome 8, and FGFR2 gene located on the long arm of chromosome 10 (Muenke et al., 1994; Schell et al., 1995). Muenke coronal craniosynostosis and a specific subtype of Crouzon syndrome with acanthosis nigricans are both caused by mutations in FGFR3 (Vajo et al., 2000). In newly occurring cases in families, FGFR3 mutations exclusively occur on the paternal copy of chromosome 4 and are associated with advanced paternal age (Rannan-Eliya et al., 2004).
The gene for Saethre–Chotzen syndrome has been mapped to 7p21 (Rose et al., 1994; van Herwerden et al., 1994). Saethre–Chotzen syndrome is caused by mutations in TWIST, a basic helix-loop-helix transcription factor (Howard et al., 1997). Drosophila embryos that lack the TWIST protein have a “twisted” appearance. Haploinsufficiency for this gene is the pathogenetic mechanism for this condition (Johnson et al., 1998). More than 35 mutations in TWIST have been described in individuals with Saethre–Chotzen syndrome (Paznekas et al., 1998). TWIST mutations are also the underlying basis for Baller–Gerold syndrome, which manifests as craniosynostosis and radial aplasia.
The known genes identified in the syndromic craniosynostoses are listed in Table 10-3. A summary of the molecular mutations discovered to date in the craniosynostosis syndromes is given in Table 10-4.
Table 10-3Genes Involved in the Syndromic Craniosynostoses ||Download (.pdf) Table 10-3 Genes Involved in the Syndromic Craniosynostoses
|Gene ||Syndrome ||Mode of Inheritance ||Chromosomal Location |
|FGFR1 ||Pfeiffer (mild) ||AD ||8p11.2 |
|FGFR2 ||Apert |
|FGFR3 ||Muenke coronal craniosynostosis |
Crouzon with acanthosis nigricans
|MSX2 ||Boston-type craniosynostosis ||AD ||5q34-q35 |
|TWIST ||Saethre-Chotzen |
Table 10-4Molecular Basis of Syndromic Craniosynostosis ||Download (.pdf) Table 10-4 Molecular Basis of Syndromic Craniosynostosis
|Condition ||Gene ||Amino Acid Substitution |
|Craniosynostosis, Boston type ||MSX2 ||Pro7His |
|Greig cephalopolysyndactyly ||GLI3 ||— |
|Saethre-Chotzen syndrome ||TWIST ||Many |
|Crouzon syndrome ||FGFR2 Exon 9(B) |
Deletion His, lle, Glu 287-289
|Pfeiffer syndrome ||FGFR1 Exon 5 |
FGFR2 Exon 9(B)
Acceptor splice site
|Jackson-Weiss syndrome ||FGFR2 Exon 9(B) ||Ala344Gly |
|Apert syndrome ||FGFR2 Exon 7(u) ||Ser252Trp |
|Thanatophoric dysplasia, type II ||FGFR3 ||Lys650Glu |
Adult individuals affected with one of the craniosynostosis syndromes should have DNA analysis to determine their specific mutation prior to contemplating pregnancy. If the underlying mutation responsible for their disorder is identified, prenatal diagnosis is available for them on fetal tissue obtained by chorionic villus sampling (CVS) or amniocentesis. The advantage of DNA testing is that the diagnosis is available earlier in gestation than by sonographic examination and it is more definitive. Adult individuals affected with one of the syndromic craniosynostoses will have a 25% or 50% risk of recurrence, depending on the specific syndrome. In theory, unaffected individuals with a prior affected child do not have an increased incidence of recurrence above the underlying background risk, although gonadal mosaicism is a small possibility. For patients with a negative family history, prenatal sonographic diagnosis in subsequent pregnancies is warranted to provide reassurance.
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