Craniosynostosis syndromes

INTRODUCTION — Craniosynostosis, defined as premature fusion or growth arrest at one or more of the cranial sutures, most commonly occurs sporadically as an isolated defect. In contrast, syndromic craniosynostosis typically involves multiple sutures as part of a larger constellation of associated anomalies.

Syndromes most frequently associated with craniosynostosis include Apert, Crouzon, Pfeiffer, Carpenter, and Saethre-Chotzen [1]. Syndromic craniosynostoses are often sporadic and are the result of de novo autosomal dominant mutations involving fibroblast growth factor receptors (FGFRs) and TWIST genes. Common features of these conditions are skull-base abnormalities, midface hypoplasia, and limb anomalies. The etiology and clinical features of these disorders are reviewed here. The diagnosis and surgical management of nonsyndromic craniosynostosis are discussed separately. (See "Overview of craniosynostosis".)

APERT SYNDROME — Apert syndrome (acrocephalosyndactyly type I, MIM #101200) is an autosomal dominant disorder that occurs in 6 to 15.5 out of 1 million livebirths [2-6]. Most cases are sporadic. Mutations in the gene encoding fibroblast growth factor receptor 2 (FGFR2), located on chromosome 10, account for almost all known cases [7,8].

The fibroblast growth factor (FGF) family, which consists of 18 structurally related proteins, plays a central role in the growth and differentiation of mesenchymal and neuroectodermal cells. FGFRs consist of four tyrosine kinases that bind FGF and play a substantial role in signal transduction. FGFRs regulate cranial suture fusion on a macroscopic level. Animal studies suggest that defective FGF signal transduction due to receptor malfunction leads to growth arrest of the cranium as well as the midface [9].

Two common mutations in the exon IIIa of FGFR2 are associated with Apert syndrome [10]. In a mouse model, small hairpin RNA was used to suppress transcription of the mutant FGFR2 allele. This prevented the development of Apert-like syndrome in the treated mice [11]. Mutations in the FGFR also have been linked to Crouzon [12,13], Pfeiffer, Muenke [14], Jackson-Weiss [15], and Saethre-Chotzen [16] syndromes.

Clinical features — Apert syndrome manifests clinically as two noticeable craniofacial defects, bicoronal synostosis and maxillary hypoplasia, that cause a flat, recessed forehead and flat midface. In addition, affected patients typically present with protruding eyes (exorbitism), widely separated orbits (hypertelorism), and a laterally down-sloping slant [17]. Low-set ears are often accompanied by an abnormally small, flat nasal structure with a bulbous tip.

The palate is often highly arched and may be associated with clefting in up to one-third of patients. The maxillary dental arch is frequently V shaped. A class 3 malocclusion (underbite) is considered a nearly universal finding (picture 1).

Strabismus is a frequent finding in Apert syndrome, as is hearing loss resulting from persistent middle-ear effusion [18,19]. The small, malformed pharynx and hypoplastic midface may result in airway compromise. Severe acne vulgaris develops in 70 percent of patients with Apert syndrome and frequently involves the extremities.

Syndactyly is a characteristic feature of Apert syndrome that permits distinction from other similar syndromes (picture 2 and picture 3). Patients with Apert syndrome typically have a complex syndactyly known as mitten hand, in which the index, middle, ring, and fifth fingers share fused bone and soft tissue components with a common nail bed. The thumb is often relatively well formed and mobile. A similar syndactyly is frequently demonstrated in the feet [20].

Other features of Apert syndrome were described in a review of 136 cases [21]. The characteristic megalencephaly resulted in a mean birth weight and length >50^th percentile. Linear growth slowed during childhood, typically resulting in values between the 5^th and 50^th percentiles. This slowing became more pronounced from adolescence to adulthood. Some affected patients had associated central nervous system (CNS) abnormalities, including malformations of the corpus callosum and limbic structures, gyral abnormalities, hypoplastic white matter, and heterotopic gray matter. Most patients had ventriculomegaly, resulting from distortion imposed upon a large brain within a misshapen skull; however, progressive hydrocephalus occurred in only 10 percent of cases. Cardiovascular (atrial septal defect, ventricular septal defect, patent foramen ovale, overriding aorta) and genitourinary (hydronephrosis, cryptorchidism) anomalies occurred in 10 and 9.6 percent of cases, respectively. Intelligence varied from normal to mental deficiency. In another case series, intelligence quotient (IQ) was <70 in 67 percent of patients [22]. Three of nine patients (average age 30 years, range 22 to 41 years) followed long term in another series received college degrees, and two graduated from high school [23]. All reported good integration into society with normal social lives.

Surgery — Surgical correction is a three-staged process that parallels facial growth and psychosocial development [23]:

●Craniosynostosis release – Classically, craniosynostosis release with fronto-orbital advancement is completed at 6 to 12 months of age if intracranial pressure (ICP) is normal [24-26]. However, elevated ICP may occur in up to 43 percent of cases. In this event, prompt surgical advancement and potentially ventriculoperitoneal shunt placement is required [27].

Increasingly, surgeons are performing an initial procedure to distract the posterior skull in the first year of life. In addition to increasing intracranial volume, this reduces the appearance of a towering skull. The fronto-orbital advancement in these cases is deferred to a later date [28].

●Midface advancement – Despite early release of craniosynostosis, patients may require additional correction of cranial dysmorphism, such as brachycephaly, orbital dystopia, or midface hypoplasia, before entering school.

The timing of this corrective procedure, known as midface advancement, is controversial. Surgical correction at four to eight years of age provides the child with improved appearance during this psychologically formative period. However, the advanced midface has limited anteroposterior growth potential, and, therefore, relapse occurs in most cases as the mandible continues to develop normally. Most patients need readvancement in late adolescence [29,30]. An alternate approach is to perform midface advancement at 9 to 12 years of age, when growth is nearing completion and the rate of relapse is decreased. Although early coronal release and frontal advancement with reshaping reduces further dysmorphic changes, it is thought that such correction has little effect on mentation.

The two procedural options are the Le Fort III osteotomy or monobloc advancement by distraction osteogenesis [23,25,26]. Le Fort II is typically used if forehead retrusion is not present. Distraction osteogenesis involves methodical lengthening of bone by gradual mechanical displacement of a surgically created fracture. Application of this technique in the correction of midfacial structure deformity may produce a more durable result in the pediatric population and appears to improve the outcome of midface advancement compared with traditional techniques.

●Correction of hypertelorism – Hypertelorism may be corrected via resection of a wedge of interorbital bone. Upon removal of the interorbital bone, the orbits may be repositioned in a more medial location for improved cosmesis. If required, mandible surgery with maxillary advancement and orthodontics following maturation may enhance long-term cosmetic outcome.

CROUZON SYNDROME — Crouzon syndrome (craniofacial dysostosis type I, MIM #123500) is autosomal dominant and occurs at a frequency of 16 in 1 million livebirths [13,31,32]. Crouzon syndrome is predominantly caused by mutations in fibroblast growth factor receptor 2 (FGFR2) [12,13], although fibroblast growth factor receptor 3 (FGFR3) mutations have been identified in individuals with Crouzon syndrome and acanthosis nigricans [33]. A link between advanced paternal age and sporadic cases of Crouzon syndrome has also been demonstrated, as is often seen in autosomal dominant disorders caused by new mutations [34].

Crouzon syndrome is characterized by a tall, flattened forehead (secondary to bicoronal synostosis), proptosis, a beaked nose, and midface hypoplasia. The degree of facial deformity is milder than that of Apert syndrome [35], and cleft palate is rare. Also in contrast to Apert syndrome, patients with Crouzon syndrome typically have structurally normal hands and feet, as well as normal intelligence.

Cervical spine abnormalities occur in up to one-third of patients and must be thoroughly evaluated before surgical correction of craniosynostosis. The surgical treatment is similar in timing and technique to that used in Apert syndrome [36,37].

PFEIFFER SYNDROME — Pfeiffer syndrome (Pfeiffer-type acrocephalosyndactyly type V, MIM #101600) is the result of an autosomal dominant genetic defect. The majority of cases occur sporadically, although pedigrees are reported [38]. Pfeiffer syndrome is most commonly associated with mutations in fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor receptor 2 (FGFR2) [34,39,40]. Several patients have demonstrated a point mutation at the Ser351Cys locus (serine changed to cysteine at amino acid codon 351) of FGFR2, which appears to result in a more severe phenotype with decreased prognosis for survival [41,42].

The clinical features of Pfeiffer syndrome include variable degrees of craniosynostosis and midface hypoplasia. Broad thumbs and abnormally wide great toes are often paired with partial syndactyly of the second and third fingers, as well as second, third, and fourth toes [43,44]. The presence and extent of syndactyly are variable. Skeletal (eg, radiohumeral synostosis of the elbow), central nervous system (CNS; eg, hydrocephalus), and gastrointestinal abnormalities (eg, imperforate anus) also frequently occur [44].

Clinical subtypes — Pfeiffer syndrome is classified into three subtypes. The classification is helpful in predicting prognosis for mental impairment and survival.

Patients with type 1 Pfeiffer syndrome have the classic phenotype with symmetric bicoronal craniosynostosis, variable syndactyly, broad thumbs, and widened great toes. Intelligence is normal or near normal, and most patients survive to adulthood, although little follow-up data are available given the rarity of this syndrome [44]. Autosomal dominant inheritance is the rule, although sporadic cases occur.

Types 2 and 3 have a more severe phenotypic expression. In addition to the usual bicoronal craniosynostosis, multiple other sutures are frequently involved. Types 2 and 3 are similar in clinical features and outcome; however, they may be differentiated by the cloverleaf skull anomaly [45], which is only present in type 2.

Type 2 Pfeiffer syndrome is also characterized by severe ocular proptosis, ankylosis of the elbows, broad thumbs and great toes, as well as visceral anomalies [44]. There is severe CNS involvement, most often manifest as hydrocephalus, with poor prognosis and frequent early death [46]. To date, all documented cases of type 2 have been sporadic.

Type 3 Pfeiffer syndrome is similar to type 2; however, the cloverleaf skull deformity is absent. Severe ocular proptosis is present, and patients often have a markedly shorter anterior cranial base. Severe neurologic defects are common, and patients typically die early [46]. As with type 2 Pfeiffer syndrome, all documented cases have occurred sporadically.

Surgical management — Mild forms of Pfeiffer syndrome can be effectively managed via fronto-orbital and Le Fort III advancement. Severe cases often require extensive surgical release and ventriculoperitoneal shunting for hydrocephalus management.

CARPENTER SYNDROME — Carpenter syndrome, also known as acrocephalopolysyndactyly type II (MIM #201000), is a rare autosomal recessive disorder [47]. It is associated with mutations in RAB23 (RAS-associated protein), a guanosine triphosphate hydrolase (GTPase) involved in intracellular membrane trafficking regulation [48,49].

Patients affected by Carpenter syndrome have brachycephaly with concurrent coronal, sagittal, and lambdoid craniosynostosis [50]. The supraorbital ridges are shallow, the nasal bridge is flat, and the lateral canthi are displaced laterally with or without inner canthal folds. Other craniofacial features include a hypoplastic mandible and/or maxilla, low-set and malformed ears, and a narrow, high-arched palate.

Patients with Carpenter syndrome also are frequently affected by preaxial polydactyly (supernumerary digits of the medial ray). Common findings include brachydactyly (short digits) of the hands with clinodactyly (curved fingers), partial syndactyly, and camptodactyly (permanent flexion of the digit).

Cardiovascular anomalies are common in patients with Carpenter syndrome. Up to 50 percent demonstrate ventricular or atrial septal defect, patent ductus arteriosus, pulmonic stenosis, tetralogy of Fallot, or transposition of the great arteries [50]. Hypogonadism and omphalocele also have been linked to Carpenter syndrome. In addition, patients tend to be obese and moderately mentally impaired.

Surgical standard of care consists of early release of craniosynostoses with fronto-orbital advancement [51].

SAETHRE-CHOTZEN SYNDROME — Saethre-Chotzen syndrome, also known as acrocephalosyndactyly type III (MIM #101400), is an autosomal dominant disorder [52]. Mutations in the TWIST gene, which is located on chromosome 7p21.1 and encodes a basic helix-loop-helix transcriptional regulator, have been identified in many patients [53,54]. Mutations in fibroblast growth factor receptor 2 (FGFR2) also have been reported [16]. TWIST encodes for a basic transcription factor that is responsible for mesenchymal cell development during cranial neuralization [55,56]. In a study of calvaria osteoblastic cells with the TWIST mutation, osteocalcin gene expression was decreased and bone formation increased compared with controls [57].

Defects in the TWIST gene also have been linked to mutations in FGFR2, providing supportive evidence for an interaction between TWIST and FGFR genes during development. On a macroscopic level, these cellular alterations may contribute to premature cranial ossification.

Patients affected by Saethre-Chotzen syndrome typically have craniosynostosis of coronal, lambdoid, and/or metopic sutures (figure 1). The characteristic facial appearance includes a towering (turricephalic) forehead, low-set hairline, facial asymmetry with septal deviation, and ptosis of the upper eyelids [58,59]. Cutaneous syndactyly, usually partial, frequently occurs and involves the second and third fingers and/or the third and fourth toes [44]. Most patients have normal intelligence.

The underlying craniosynostosis frequently is mild and requires only a simple operative release. However, more severely affected patients may require cranial remodeling.

SUMMARY

●Overview – Craniosynostosis, defined as premature fusion or growth arrest at one or more of the cranial sutures, most commonly occurs sporadically as an isolated defect. In contrast, syndromic craniosynostosis typically involves multiple sutures as part of a larger constellation of associated anomalies. (See "Overview of craniosynostosis" and "Overview of craniosynostosis", section on 'Introduction'.)

●Apert syndrome – Craniofacial features of Apert syndrome (acrocephalosyndactyly type I) include bicoronal synostosis, maxillary hypoplasia, protruding eyes with a laterally down-sloping slant, hypertelorism, low-set ears, and high-arched palate. Additional features may include intellectual disability, strabismus, hearing loss, severe acne, and syndactyly of the hands and feet. (See 'Apert syndrome' above.)

●Crouzon syndrome – Craniofacial features of Crouzon syndrome (craniofacial dysostosis type I) include bicoronal synostosis, proptosis, and midface hypoplasia. The hands are typically normal, as is intelligence. (See 'Crouzon syndrome' above.)

●Pfeiffer syndrome – Craniofacial features of Pfeiffer syndrome (acrocephalosyndactyly type V) include variable degrees of craniosynostosis, midface hypoplasia, and proptosis. The presence and extent of syndactyly is variable. Additional manifestations may include broad thumbs and great toes, radiohumeral synostosis, hydrocephalus, and imperforate anus. Type 1 is mild. Types 2 and 3 are associated with severe neurologic defects that lead to early death. (See 'Pfeiffer syndrome' above.)

●Carpenter syndrome – Craniofacial features of Carpenter syndrome (acrocephalopolysyndactyly type II) include coronal, sagittal, and lambdoid craniosynostosis; shallow supraorbital ridges; flat nasal bridge; laterally displaced lateral canthi; hypoplastic mandible and/or maxilla; low-set and malformed ears; and narrow, high-arched palate. Additional features may include abnormalities of the digits (supernumerary, short, curved, permanent flexion), cardiovascular anomalies, hypogonadism, omphalocele, and obesity. (See 'Carpenter syndrome' above.)

●Saethre-Chotzen syndrome – Craniofacial features of Saethre-Chotzen syndrome (acrocephalosyndactyly type III) include craniosynostosis of coronal, lambdoid, and/or metopic sutures (figure 1), towering (turricephalic) forehead, low-set hairline, facial asymmetry with septal deviation, and ptosis. Many patients often have partial syndactyly. (See 'Saethre-Chotzen syndrome' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Patrick Cole, MD and Larry H Hollier, Jr, MD, who contributed to earlier versions of this topic review.