Patients with syndromic craniosynostosis have a molecularly identified genetic cause for the premature closure of their cranial sutures and associated facial and extra-cranial features. Their clinical complexity demands comprehensive management by an extensive multidisciplinary team. This review aims to marry genotypic and phenotypic knowledge with clinical presentation and management of the craniofacial syndromes presenting most frequently to the craniofacial unit at Great Ormond Street Hospital for Children NHS Foundation Trust.

Craniosynostosis is defined as the premature fusion of one or more cranial sutures. According to Virchow's concept, fusion of a cranial vault suture restricts growth perpendicular to it but “extra” growth parallel to produce an often typical skull deformity. More recent theories invoke the action of a “functional matrix” that comprises not only bone, but also the adjacent dura and other soft tissues [Moss, 1975].

The genetically determined syndromic craniosynostoses are a heterogeneous group of conditions usually associated with gain-of-function mutations, often including predominantly the fibroblast growth factor receptor (FGFR) family of genes involved in bone and cartilage development. Except for the X-linked inheritance of craniofrontonasal dysplasia (CFND) and the autosomal recessive inheritance of Carpenter syndrome, these syndromes most commonly have an autosomal dominant mode of inheritance [Cohen, 1979; Robin et al., 2011]. Approximately half of the causative mutations arise de novo, having an association with increased paternal age (for sporadic cases), perhaps indicating genetic fragility amplified by time [Forrest and Hopper, 2013]. In addition to craniofacial deformities, these syndromes are also responsible for complex visceral and skeletal anomalies affecting, in particular, the hands and feet (Table 1) [Britto et al., 2001; Rice, 2008].

Table 1

Clinical features associated with syndromic craniosynostosis

Clinical features associated with syndromic craniosynostosis
Clinical features associated with syndromic craniosynostosis

The overall incidence of craniosynostosis is estimated at between 1 in 2,100 and 1 in 2,500 live births [Johnson and Wilkie, 2011], but this varies greatly depending on the suture(s) involved. The most frequently diagnosed craniosynostosis-associated syndromes include Muenke (1 in 10,000-1 in 30,000), Crouzon (1 in 25,000), Pfeiffer (1 in 100,000), Apert (1 in 100,000), and Saethre-Chotzen (1 in 25,000-50,000) [Wilkie et al., 2017]. All but Saethre-Chotzen syndrome (SCS), which has a loss-of-function mutation in the TWIST gene [Cho et al., 2013], are associated with a gain-of-function mutation in the FGFR gene. Among less common syndromes included in this review are CFND and the more recently recognised syndromes caused by ERF and TCF12 mutations.

Because of the often extreme complexity of the various phenotypes produced by these mutations, a multidisciplinary approach to the affected children and their families is essential with meticulous attention to their initial assessment, the production of a management plan to ensure development to their greatest potential, and a follow-up schedule (that may stretch from infancy to adulthood) designed to detect and manage problems proactively.

Essential members of the treating team include Neurosurgeons, Plastic Surgeons, Clinical Geneticist, ENT Surgeon, Sleep Respiratory Physician, Paediatrician, Maxillofacial Surgeon, Orthodontist, Ophthamologist, Speech Therapist, Psychologist, Audiologist, and Clinical Nurse Specialists.

Syndromic patients in our centre complete a thorough 2-day multidisciplinary assessment with independent reviews by all members of the multidisciplinary team (MDT), comprising a craniofacial assessment (CFA). This assessment involves a sleep study; audiological testing; ophthalmology consultation with fundoscopic examination; electrodiagnostic tests (EDTs); optical coherence tomography (OCT), as indicated; psychological assessment, with questionnaires directed at their quality of life, expectations, and feelings about their treatment; developmental assessment (Ages and Stages Questionnaire); speech, language and feeding evaluation; orthodontic review; ear, nose and throat review; and finalising with a combined neurosurgical and plastic surgery assessment. The patient is scored across all parameters with a composite Great Ormond Street Craniofacial Outcome Score, demonstrating a score utilised as an indication of intervention or a measure of change related to surgery or treatment (Table 1).

Clinical review and summary discussion by all team members enable early detection and intervention if developmental changes or raised intracranial pressure (ICP) are detected through ophthalmological monitoring. Additionally, these comprehensive reviews gradually commence discussions of appearance difference and surgical possibilities addressing appearance difference.

For the older patients at lower functional risk, the craniofacial clinic (CRANF) is a conjoined clinic where all members of the MDT review the patient together. Additionally, the patient attends ophthalmological surveillance in parallel via the established protocol. This clinic acts to ensure functional stability, provide psychological, schooling, and social support as well as discuss surgery addressing appearance difference.

The frequency of CFA and CRANF assessment for syndromic patients was:

• From 0-2 years old: CFA 6 monthly

• From 2-6 years old: CFA yearly and consultant review yearly alternating 6 monthly

• From 6-10 years old: CRANF yearly

• At 10 years: CFA and CRANF together

• At 12 years: CRANF review

• At 14 years: CRANF transition review (transition clinic to start process)

• At 16 years: CRANF transition review and establishment in adult services

This review aims to address the clinical management of patients with Apert, Crouzon, Pfeiffer, Muenke, Saethre-Chotzen, ERF, TCF12, and CFND. These are the most frequently treated amongst the estimated 150 syndromes now associated with craniosynostosis [Forrest and Harper, 2013]. The greatest severity is associated with the mutations affecting FGFR2, requiring close surveillance and timely intervention to optimise airway, visual potential, and development. Our unit practises intervention in reaction to signs and investigations rather than a prescribed procedural protocol [Spruijt et al., 2016]. Figure 1 details the approach of the unit in caring for these syndromic patients and responding to results of their regular surveillance.

Fig. 1

Algorithm for the treatment of raised intracranial pressure.

Fig. 1

Algorithm for the treatment of raised intracranial pressure.

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This review addresses the incidence, genotype, phenotype, clinical concerns, and expected surgical course for each diagnosis with influences from our unit.

Clinical reports of Apert syndrome first appeared in the literature in 1906. The present incidence is estimated between 1:100,000 and 160,000 live births [Buchanan et al., 2014]. Apert syndrome results from a gain-of-function mutation Ser252Trp (66%) or Pro253Arg (33%) to the FGFR2 gene coding for a tyrosine kinase. This results in anomalies affecting bone and cartilage of the cranial vault, skull base, face, and joints - particularly apparent in the hands and feet. Apert is inherited in an autosomal dominant pattern but additionally presents with de novo mutations with an effect demonstrated with increasing paternal age [Wilkie et al., 2017].

These patients present with turribrachicephaly secondary to bicoronal synostosis but with a widely patent sagitto-metopic defect as an extended fontanelle [Hanieh and David, 1993]. This pathology results in a broad and tall head shape with a superior and anterior volume distribution with a prominent central upper forehead through the open fontanelle (Fig. 2). This pathognomonic head shape for Apert is likely a compensatory mechanism enabling brain growth. Apert is associated with structural brain anomalies, and ventriculomegaly is detected in 40-90% of the patients [Taylor et al., 2001; Collmann et al., 2005].The incidence of increased ICP is reported between 45% and our experience of 83% by the age of 5 years [Renier et al., 2000; Marucci et al., 2008; de Jong et al., 2010]. The contributing factors to this are, however, multifactorial and include obstructive sleep apnoea causing hypercarbia, anomalous venous drainage, ventriculomegaly and hydrocephalus as well as craniocerebral disproportion [Hayward 2004, 2005; Copeland et al., 2018]. Each of these causes has potential for surgical correction, but the elucidation of the cause by appropriate investigations and intervention is essential.

Fig. 2

Apert syndrome patient, unoperated, with plump ventricles, and a pre-shunt at age 10 weeks. Clinical images. A Front view. B Side view. C Hand. D Foot. Radiological images. E Front view. F Side view.

Fig. 2

Apert syndrome patient, unoperated, with plump ventricles, and a pre-shunt at age 10 weeks. Clinical images. A Front view. B Side view. C Hand. D Foot. Radiological images. E Front view. F Side view.

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The typical Apert face is characterised by a biconcave shape with a small beak nose from growth restriction of basal synsotosis [Crombag et al., 2014]. The exorbitism due to restricted frontal and maxillary growth creates shallow orbits and risk of corneal exposure. This is accentuated with down-slanting palpebral fissures due to the high position of the medial canthal ligaments and hypertelorism (Fig. 2, 3) [Lajeunie et al., 1999]. The midface demonstrates maxillary hypoplasia with a maxillary arch malpositioned with a superior cant creating an anterior open bite subtending a V-shaped high palate or cleft palate (Fig. 3) [Agochukwu et al., 2012a]. Palate anomalies include cleft, a submucous cleft, or bifid uvula with a frequency of 75% [Peterson and Pruzansky, 1974]. Airway compromise occurs at many levels from small nostrils, choanal stenosis and thickened secretions with the Class III occlusion, and anterior open bite creating difficulty with oral continence [Agochukwu et al., 2012a]. Cutaneous anomalies are a distinctive trait of the syndromic spectrum varying from severe acne to horizontal creases over the supraorbital rim [Cohen and Kreiborg, 1995].

Fig. 3

Apert syndrome patient before midface surgery with clinical features of hypertelorism, downslanting palpebral fissures, AOB, and midface hypoplasia at 10 years of age. A Front view. B Side view.

Fig. 3

Apert syndrome patient before midface surgery with clinical features of hypertelorism, downslanting palpebral fissures, AOB, and midface hypoplasia at 10 years of age. A Front view. B Side view.

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The complex symmetric syndactyly is a specific feature of Apert syndrome, and it involves both hands and feet, bilaterally. The classification is graded on syndactyly severity and ranges from I to III, where I is a partial defect, with thumb and little finger separated, II means the only finger separated is the thumb, and III all fingers are fused (Fig. 2) [Hanieh and David, 1993; Anderson et al., 1997b]. There is a predictable pattern to the hands with the different mutations affecting the severity of the syndactyly. The Pro253Arg mutation presents with more severe syndactyly and severe acne, whereas the Ser252Trp mutation confers milder hands and an increased incidence of cleft palate [Johnson and Wilkie, 2011]. The mutations therefore separate 2 groups in our unit, the former “bad hands, good airway and face” and the latter “good hands, bad airway and face.” Work is ongoing to demonstrate this statistically by classification.

Extra-cranial features include visceral anomalies, appendicular skeletal restrictions, and spinal anomalies in 63-68% of the patients (mainly C5 and C6 fusion) [Kreiborg et al., 1992; Thompson et al., 1996]. However, clinical implications from this appear to be minimal [Thompson et al., 1996]. Progressive stiffness and synostosis of joints including tarsals and carpals, radiohumeral synostosis, and generalised stiffness of large joints can make activities of daily living difficult [Agochukwu et al., 2012a]. Our cohort also describes patients with short stature and hearing impairment secondary to recurrent otitis media and glue ear. This is related to the high-arched palate or cleft with decreased ventilation due to poor eustachian tube opening by the palatine muscles. Developmental and learning difficulties are over-represented in children with Apert, and while many manage to meet the academic targets with assistance most of the time, some desist with mainstream education after primary school but report highly on quality of life [Patton et al., 1988; Tovetjärn et al., 2012; Raposo-Amaral et al., 2014].

The Apert patient group is clinically significant with respect to small obstructed airways frequently requiring intervention, the risk of raised ICP requiring vault expansion, and ocular surface protection secondary to the exorbitism.

Surgical Management

The management of a patient newly diagnosed with Apert syndrome involves ensuring an adequately patent airway, managing signs of increased ICP evident on palpation of the large fontanelle, EDTs, and protecting the ocular surface with tarsorrhaphy if required. These patients benefit from airway manoeuvres such as adenotonsillectomy and sometimes placement of a nasopharyngeal airway. If this is unsuccessful, an MDT must discuss the benefit of tracheostomy versus fronto-facial advancement, tending to the latter if all 3 critical concerns require addressing surgically.

Without critical concerns, these patients frequently undergo many co-ordinated procedures in their first few years of life addressing the syndactyly, the obstructed airway, and tympanostomy, with a potential posterior vault expansion (PVE) by springs in our unit on any early signs of EDT or fundoscopy changes of raised ICP.

The midface is generally treated later in life with patient involvement, aiming to wait until the patient is older than 8-10 years. Functional indications for this surgery include ocular surface protection, obstructive sleep apnoea, which would be treated with continuous positive airway pressure at this age, and occlusal issues. Additionally, a patient motivator for midface surgery is frequently their appearance difference creating unwanted attention through schooling. Surgically, the midface is managed with an osteotomy pattern designed to the individual face. The Apert face tends to gain the best results from a bipartition if the hypertelorism is significant or a Le Fort II/III with zygomatic repositioning if not too significant, both with distraction (Fig. 4) [Hopper et al., 2013]. Some patients require secondary procedures at skeletal maturity to correct nasal deformities and residual malocclusion, but in a recent review, our cohort found that midface surgeries with distraction achieve a good facial appearance with patients not electing for additional orthognathic surgery.

Fig. 4

Apert syndrome patient after Le Fort II/III osteotomies with zygomatic repositionings with Le Fort 2 segment distraction and dorsal bone graft. Ventriculoperitoneal shunting due to persistent symptomatic hydrocephalus; age 12 years. Clinical and radiological images, respectively. A, C Front view. B, D Side view.

Fig. 4

Apert syndrome patient after Le Fort II/III osteotomies with zygomatic repositionings with Le Fort 2 segment distraction and dorsal bone graft. Ventriculoperitoneal shunting due to persistent symptomatic hydrocephalus; age 12 years. Clinical and radiological images, respectively. A, C Front view. B, D Side view.

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A description of Crouzon syndrome first appeared in the literature in 1912 by Octave Crouzon. The many reported mutations of the FGFR2 gene are inherited in an autosomal dominant fashion, but it can also occur as a de novo mutation [Twigg and Wilkie, 2015]. Familial cases demonstrate great variability of expression. In sporadic cases, a correlation between paternal age and Crouzon and Apert syndrome has been described previously [Glaser et al., 2000]. Crouzon syndrome associated with the FGFR3 mutation Ala391Glu constitutes a different variation with acanthosis nigricans and a greater association with hydrocephalus [Schweitzer et al., 2001; Di Rocco et al., 2011; Johnson and Wilkie, 2011].

The phenotype is characterised by brachycephaly with or without turricephaly due mainly to bicoronal synostosis and frequently delayed synostosis of other sutures [Reddy et al., 1990]. The midface hypoplasia, Class III skeletal occlusal pattern relative to maxillary hypoplasia, short nose, shallow orbits with exorbitism, and an oval high-arched palate describe the facial phenotype (Fig. 5). They also present with a shortening of the anterior cranial base as a result of the growth arrest due to the synostosis [Kolar et al., 1988; Kreiborg et al., 1992]. Surprisingly, despite a molecular diagnosis, sutures are often patent at birth with later onset of synostosis ranging in severity of the head shape from almost normal to cloverleaf (Fig. 5) [Reddy et al., 1990; Connolly et al., 2004].

Fig. 5

A, B Unoperated Crouzon patient with exorbitism, midface hypoplasia, Class III occlusion pattern at age 27 weeks. C, D CT images demonstrating patent sutures. E, F Older unoperated patient with developing clinical features at age 75 weeks. G, H CT images showing the development of pansynostosis. I, J After posterior vault expansion at 2 years of age.

Fig. 5

A, B Unoperated Crouzon patient with exorbitism, midface hypoplasia, Class III occlusion pattern at age 27 weeks. C, D CT images demonstrating patent sutures. E, F Older unoperated patient with developing clinical features at age 75 weeks. G, H CT images showing the development of pansynostosis. I, J After posterior vault expansion at 2 years of age.

Close modal

Our published experience demonstrated a high incidence of 61% of increased ICP with therefore 39% not detected elevation on thorough 4 monthly ophthamological examination and EDTs [Taylor et al., 2001]. Therefore, despite many authors recommending an early intervention, we recommend a tailor-made evaluation with a close follow-up [Taylor et al., 2001; de Jong et al., 2010; Abu-Sittah et al., 2015]. This patient population additionally requires monitoring for Chiari malformation, which can present later in childhood [Taylor and Bartlett, 2017].

Extra-cranial manifestations are infrequently seen, reserved for severe cases and then most commonly cervical vertebral fusion [Anderson et al., 1997a]. No limb pathologies are described. Development and intelligence tends to be appropriate and consistent with the findings in the unaffected population, although cases with major intellectual impairment have been described in the literature [Kreiborg, 1981].

Clinical concerns are similar, in terms of preservation of airway patency, ocular surface protection, and detection of raised ICP. Crouzon syndrome management is targeted by age, with early issues of the triad above and similar maneuvers employed to manage the airway [Wang et al. 2016; Taylor and Bartlett, 2017].

Surgical Management

Crouzon syndrome is the milder of the Crouzon-Pfeiffer spectrum, but patients frequently require surgical management. Consistently, the syndromic craniosynostosis patients frequently undergo adenotonsillectomy and tympanostomy. Elevated ICP is managed by PVE with springs in the young and occasionally requires ventriculoperitoneal shunting for persistent ventriculomegaly in complex cases. Late-presenting Crouzon patients with raised ICP may require a bespoke vault expansion to address their cranio-cerebral disproportion (Fig. 5). Frequently, 1 vault expansion can protect through the early years with further surgery related to appearance difference. Similarly, these discussions begin around 8-10 years of age, with decision making in terms of fronto- facial versus midface surgery dependent on the forehead position and contour, as it is frequently unoperated in our unit. The operation of choice in our unit for the Crouzon face is most frequently the monobloc, with or without distraction dependent on the degree of advancement required. The degree of advancement is measured primarily at the peri-orbital region with secondary gain at the occlusal level. The occlusion may require further orthognathic balancing and orthodontics at an older age.

In 1964, Pfeiffer syndrome was first described and eponymously named [Pfeiffer, 1964]. The incidence is estimated at 1:100,000 live births [Cohen, 1993; Greig et al., 2013] but can present early with severe and life-threatening conditions. The underlying genetic mutations affect FGFR1 and FGFR2 and show genetic overlap; hence, Crouzon-Pfeiffer syndrome was classified. The mutations comprise substitutions with the most common involving cysteine and include Trp290Cys, Trp340Cys, Cys342Arg, and Ser351Cys. These are gain-of-function mutations coding for tyrosine kinase [Wilkie and Johnson, 2017].

In 1993, Cohen further categorised Pfeiffer syndrome with greater description of the phenotype, subdividing into Type I-III. Type I includes those with a better prognosis with cranial features of bicoronal synostosis and milder turribrachcephaly and midface hypoplasia. They are still distinguished by broad and deviated thumbs and toes and can present with spinal fusions and visceral anomalies but have normal intelligence. This subgroup may genotypically be subtended by the FGFR1 mutation of Pfeiffer syndrome. Type II is severely affected and difficult to treat with cloverleaf skull, hydrocephalus, severe midface hypoplasia, and exorbitism. This type frequently presents with airway obstruction, Chiari and later syrinx and possesses a poor prognosis with severe developmental delay. Type III often presents with severe midface hypoplasia resulting in a Class III occlusal pattern, significant airway obstruction, and ocular surface exposure. This type can additionally present with a Chiari, develop a syrinx, and suffer with developmental delay [Cohen, 1993].

An attempt at clinical re-categorization by Greig et al. [2013] stratified by clinical functional severity. This aids in clinical and surgical management and trajectory of patients. The emphasis from this time has been focussed on a genotypic classification with phenotypes and prognosis closely matched to the genotypes of patients [Greig et al., 2013].

A review of our cohort demonstrated a risk in more than 80% of patients with raised ICP with potential implications on visual and cognitive function [Hayward, 2005; Florisson et al., 2015]. Pfeiffer syndrome frequently presents some of the greatest clinical challenges and urgency of syndromic craniosynostoses. Visceral anomalies including intestinal malrotation and prune belly syndrome are reported [Greig et al., 2013].

Surgical Management

Type I cases tend to be quite mild if compared with type II and III variants; the mildness of the phenotype results from minor involvement of sutures, with bicoronal synostosis not affecting the skull base size. Type I may come to surgery or fronto-orbital remodelling (FOR) for appearance difference but undergo identical surveillance. Type II, also known as Kleeblattschädel, is the most difficult for management in craniofacial units [Thompson et al., 1995; Jarrahy et al., 2009; Johnson and Wilkie, 2011]. Types II and III due to the severity of the phenotype are usually associated with early intervention because of unstable airways with a nasopharyngeal airway or tracheostomy (Fig. 6). The affected airways frequently have multilevel disease with small nostrils, choanal stenosis, and a tracheal sleeve [Agochukwu et al., 2012a; Pickrell et al. 2017]. Additionally, early intervention due to hydrocephalus, cranio-cerebral disproportion, and raised ICP may require PVE or ventriculoperitoneal shunting (Fig. 6) [Gault et al., 1992; Derderian et al., 2015; Khonsari et al., 2016; Spruijt et al., 2016]. Rarely in the very young, this vault expansion accompanies a nasopharyngeal airway for OSA, ventriculoperitoneal shunt for hydrocephalus, protection tarsorrhaphy for globe subluxation, and a nasogastric tube for poor feeding and weight gain (Fig. 6). If the previous interventions are unsuccessful, a monobloc with distraction is planned to address multiple critical functional issues (Fig. 6) [Witherow et al., 2008; Ahmad et al., 2012; Khonsari et al., 2016].

Fig. 6

Pfeiffer syndrome. A-D Unoperated child with brachyturricephaly, exorbitism, midface hypoplasia, short nose, and broad thumbs and toes with deviation at age 54 days. E, F CT images showing pansynostosis. G, H Post-ventriculoperitoneal shunt and nasopharyngeal airway and globe subluxations (age 20 weeks). I, J CT images showing pansynostosis with ventriculoperitoneal shunt and turribrachycephaly. K, L Immediate post monobloc with rigid external distractor (RED) frame with resolution of exorbitism (age 46 weeks). M, N Post-monobloc CT images with RED frame in situ demonstrating osteotomies. O, P Changes after monobloc with resolution of exorbitism threatening ocular surface protection and improvement in midface hypoplasia (age 79 weeks). Q, R CT images showing post-monobloc bone consolidation and improvement in position. S, T After posterior vault expansion (PVE) due to signs of increased intracranial pressure, not decannulated because of multi-level airway obstruction and tracheal sleeve (age 4 years).

Fig. 6

Pfeiffer syndrome. A-D Unoperated child with brachyturricephaly, exorbitism, midface hypoplasia, short nose, and broad thumbs and toes with deviation at age 54 days. E, F CT images showing pansynostosis. G, H Post-ventriculoperitoneal shunt and nasopharyngeal airway and globe subluxations (age 20 weeks). I, J CT images showing pansynostosis with ventriculoperitoneal shunt and turribrachycephaly. K, L Immediate post monobloc with rigid external distractor (RED) frame with resolution of exorbitism (age 46 weeks). M, N Post-monobloc CT images with RED frame in situ demonstrating osteotomies. O, P Changes after monobloc with resolution of exorbitism threatening ocular surface protection and improvement in midface hypoplasia (age 79 weeks). Q, R CT images showing post-monobloc bone consolidation and improvement in position. S, T After posterior vault expansion (PVE) due to signs of increased intracranial pressure, not decannulated because of multi-level airway obstruction and tracheal sleeve (age 4 years).

Close modal

Especially for children with Pfeiffer syndrome, early diagnosis and proactive intervention as well as complex multidisciplinary care are essential with the critical period the first 6 months to a year.

Muenke syndrome was genetically described in 1997 [Muenke et al., 1997] and is now the most common syndromic presentation with a prevalence of 1 in 10,000-30,000 live births [Doherty et al., 2007; Wilkie et al., 2017]. This syndrome results from mutation c.749C>G in the FGFR3 gene, resulting in p.Pro250Arg [Muenke et al., 1997]. Interestingly, this is a homologous mutation in FGFR1 resulting in Pfeiffer syndrome, and in FGFR2 resulting in Apert syndrome. Similar to other syndromes, Muenke is of autosomal dominant inheritance, but 20% of the carriers do not express a phenotype with craniosynostosis [Agochukwu et al., 2012a; Kruszka et al., 2016].

This syndrome is frequently detected as a genetically related unicoronal or bicoronal synostosis [Johnson and Wilkie, 2011]. Muenke patients tend to present with coronal synostosis, bicoronal or unicoronal, with subtle other features with delayed genetic confirmation of their syndromic association. A recent review of our cohort accounts for 26 genetically confirmed patients. All patients presented with coronal synostosis, 18 out of 26 (69%) bicoronal, and 8 (31%) unicoronal. This finding is consistent with that described elsewhere in the literature [Kruszka et al., 2016]. The bicoronal synostosis results in brachycephaly with a recessed forehead. The patients with unicoronal synostosis have a head shape more consistent with a single-suture phenotype (Fig. 7). Muenke syndrome is additionally associated with strabismus, low-frequency hearing impairment (mostly sensorineural) with 20% requiring a hearing aid, carpal and tarsal synostosis, brachydactyly, thick straight hair, and neurodevelopmental delay [Doherty et al., 2007; de Jong et al., 2010; Johnson and Wilkie, 2011; Kruszka et al., 2016]. Seizures are identified as an association with Muenke syndrome, but not related to increased ICP, and a cause theorised as temporal anomalies [Grosso et al., 2003; Agochukwu et al., 2012b]. The existence of elevated ICP through ophthamological surveillance is detected indicating a need for vault expansion, but at a reduced rate to the previously described syndromes.

Fig. 7

Muenke syndrome. A-D Phenotype with right unicoronal synostosis demonstrating orbital and facial scoliosis (age 83 weeks). E, F Skull reconstruction image showing right unicoronal synostosis. G, H After fronto-orbital remodelling (age 2 years).

Fig. 7

Muenke syndrome. A-D Phenotype with right unicoronal synostosis demonstrating orbital and facial scoliosis (age 83 weeks). E, F Skull reconstruction image showing right unicoronal synostosis. G, H After fronto-orbital remodelling (age 2 years).

Close modal

Clinical concerns are addressed through CFA and include monitoring for raised ICP, developmental progress, and speech and language development with audiological surveillance essential for the patient's lifetime. Seizures are common in Muenke syndrome and are managed as any non-focal epilepsy.

Surgical Management

Muenke patients can present with raised ICP, treated equivalently as cranio-cerebral disproportion with PVE with springs in our unit. If there are concerns regarding forehead appearance or ongoing concerns of elevated ICP, then a second stage would involve an FOR coinciding with spring removal at 12 months after PVE. In the absence of increased ICP or severe brachycephaly, some parents elect for a single-stage FOR correction of the appearance difference (Fig. 7). Ophthamological surveillance is identical and surgery is common for strabismus, but airway surgery is less common.

Saethre-Chotzen syndrome (SCS) was first described by Haakon Saethre [1931] and Fritz Chotzen [1932] as a craniofacial anomaly [Johnson and Wilkie, 2011]. Presenting as one of the most frequent syndromes, SCS has a described incidence of 1 in 25,000-50,000 [Buchanan et al., 2014]. It results from the loss-of-function mutations in TWIST1, which are inherited in an autosomal dominant pattern [Howard et al., 1997; Johnson et al., 1998]. SCS typically presents with coronal synostosis - unilateral or bilateral, hypertelorism, facial asymmetry associated with a deviated nasal septum, strabismus, cleft palate, broad or bifid laterally deviating first digit, small external ear pinna with prominent crus, ptosis, low frontal hairline, incomplete simple syndactyly and brachydactyly as well as maxillary hypoplasia (Fig. 8) [Johnson and Wilkie, 2011; Agochukwu et al., 2012b; Cho et al., 2013]. Large deletions have been associated with learning disability [Johnson et al., 1998]. The patients can present to clinic with multiple generations affected demonstrating a strong penetrance (Fig. 8).

Fig. 8

Saethre-Chotzen syndrome. A, B Phenotypic features including brachycephaly and a tall flat forehead (age 75 weeks). C, D Bicoronal synostosis and typical orbital morphology. E, F After PVE with springs (age 83 weeks). G, H CT images showing PVE with springs demonstrating the expansion achieved. I Three generations of Saethre-Chotzen syndrome phenotype with a strong family history. J After fronto-orbital remodelling completing a 2-stage reconstruction (age 2.5 years).

Fig. 8

Saethre-Chotzen syndrome. A, B Phenotypic features including brachycephaly and a tall flat forehead (age 75 weeks). C, D Bicoronal synostosis and typical orbital morphology. E, F After PVE with springs (age 83 weeks). G, H CT images showing PVE with springs demonstrating the expansion achieved. I Three generations of Saethre-Chotzen syndrome phenotype with a strong family history. J After fronto-orbital remodelling completing a 2-stage reconstruction (age 2.5 years).

Close modal

Clinical concerns for these patients surround a risk of raised ICP, hearing loss, and obstruction of the visual axis due to ptosis which are monitored through CFAs.

Surgical Management

SCS patients, similar to those with other reported syndromes, sometimes require vault expansion due to increased ICP, which in our centre is indicated by changes in fundoscopy or EDTs. This is most frequently addressed in our unit with a PVE with springs. Considering the cranio-cerebral disproportion at the same time as addressing the appearance difference through FOR has been realised with good effects. Additionally, the 2-stage procedure of PVE followed by FOR results in functional and appearance gains (Fig. 8). The hypoplasia of the midface is generally milder [Johnson and Wilkie, 2011] than in Apert, Crouzon, or Pfeiffer, and therefore, less midface or fronto-facial surgery is undertaken but with the same assessment and approach. Surgery for cleft palate, airway, glue ear, ptosis, strabismus, or the associated congenital hand and foot anomalies is completed as recommended by the extended members of the MDT.

CFND was first described by Cohen [1979] and is caused by loss-of-function mutations in the EFNB1 (Ephrin B1) gene. EFNB1 encodes 1 of 8 known ephrin ligands with complex signalling effecting the grouping of cells (homophilic sorting) [Johnson and Wilkie, 2011; van den Elzen et al., 2014]. CFND is an X-linked disorder that intriguingly presents paradoxically with heterozygous females more severely affected than hemizygous males.

CFND is characterised by severe, often asymmetric hypertelorism, uni- or bicoronal synostosis, ridging and longitudinal splitting of the nails, wiry curly hair, down-slanting palpebral fissures, strabismus, shoulder and hip girdle abnormalities, soft-tissue syndactyly of the fingers and toes, and a broad thumb or great toe (Fig. 9) [Kawamoto et al., 2007; Johnson and Wilkie, 2011]. Features indicating a failure in midline formation include agenesis of the corpus callosum, cleft lip/palate, a high-arched palate, a broad nasal bridge and a broad or bifid nasal tip as well as a wide, late closing anterior fontanelle [van den Elzen et al., 2014]. The males often only display hypertelorism and occasionally cleft lip and/or palate [Johnson and Wilkie, 2011].

Fig. 9

Craniofrontonasal dysplasia. A-C Clinical images showing left unicoronal synostosis, asymmetric hypertelorism, and a broad nasal bridge and tip (age 65 weeks). D, E CT images showing left unicoronal synostosis, asymmetric hypertelorism, and an open metopic suture typical for craniofrontonasal dysplasia.

Fig. 9

Craniofrontonasal dysplasia. A-C Clinical images showing left unicoronal synostosis, asymmetric hypertelorism, and a broad nasal bridge and tip (age 65 weeks). D, E CT images showing left unicoronal synostosis, asymmetric hypertelorism, and an open metopic suture typical for craniofrontonasal dysplasia.

Close modal

Clinical concerns greatly relate to maintaining the visual axis [Tay et al., 2006] and detecting and treating increased ICP. If also affected by a cleft; feeding and airway concerns predominate. In difference to Kawamoto's and other units, our indication for surgical intervention is individually responsive to investigations rather than by algorithm [Kawamoto et al., 2007; Spruijt et al., 2016].

Surgical Management

Surgically, patients with CFND are an exercise in prevention of raised ICP and troublesome head shape, whilst awaiting dental development enabling surgery to correct the hypertelorism. Our patients are managed through our CFA surveillance with ophthamological changes or turricephalic head shape indicating the necessity for vault expansion. Patients with a unicoronal synostosis frequently undergo FOR, if possible only on the affected side, before 18 months of age, and then await further surgery if requested by the family at maxillary canine eruption. Bicoronal patients follow 1 of 3 paths, either early PVE with springs with a secondary effect to improve the bossing of the upper forehead, FOR under 18 months of age, or delaying all surgery until combined hypertelorism correction. If possible to delay forehead surgery for a single approach, the unoperated approach reduces the complication profile. Similar to other groups, our formal surgery relies on the tenets of facial bipartition and box osteotomies with the latter elected for the multidimensional hypertelorism. In concert with this surgery, a dorsal onlay bone graft rhinoplasty is undertaken as well as extensive soft tissue procedures. Later refinements in nasal tip and canthal structures may be required.

A new entity of genetically related craniosynostosis has recently been discovered by exome sequencing: TCF12-related synostosis [Sharma et al., 2013]. This syndrome, similar to Muenke syndrome or SCS, includes unilateral (plagiocephaly) or bilateral (brachycephaly) premature closure of the coronal sutures, hearing loss, broad toes, and carpal and tarsal fusions. Facial growth appears not greatly affected (Fig. 10) [Di Rocco et al., 2014; Goos et al., 2016]. The phenotype is variable, including non-penetrance of the TCF12 gene, which encodes a basic helix-loop-helix transcription factor [Sharma et al., 2013]. Due to its recent discovery, limited clinical descriptions exist in the literature; our unit reports 17 patients aged 1-20 years old, with no preference for gender with 9 female and 8 male.

Fig. 10

A child with a TCF12 mutation (c.1916del; p.Thr639Lysfs*16). A-C Brachycephaly with a tall, broad forehead. D, E CT images showing bicoronal synostosis. F-I Early post-PVE and CT images of PVE with springs demonstrating the expansion achieved. J, K Late after PVE. L Fronto-orbital remodelling results showing an acceptable appearance and function (age 3.5 years).

Fig. 10

A child with a TCF12 mutation (c.1916del; p.Thr639Lysfs*16). A-C Brachycephaly with a tall, broad forehead. D, E CT images showing bicoronal synostosis. F-I Early post-PVE and CT images of PVE with springs demonstrating the expansion achieved. J, K Late after PVE. L Fronto-orbital remodelling results showing an acceptable appearance and function (age 3.5 years).

Close modal

TCF12 is usually related to coronal synostosis and severe brachycephaly/turribrachycephaly; in our series, 14 children presented with bicoronal synostosis and 3 with unicoronal synostosis (2 right unicoronal and 1 left).

Our treatment protocol was applied to 16 patients; 6 required a 2-stage surgical protocol: PVE first and FOR as a secondary procedure in those cases severely brachicephalic and with increased suspicion of raised ICP as well as appearance concerns of the parents (Fig. 10).

The clinical concern with these patients primarily revolves around their significant brachycephaly tending towards turribrachicephaly. The associated risk of increased ICP in these patients cannot yet be delineated as these patients frequently choose to undergo vault surgery for shape change. As described, in the severe cases, this involves PVE with springs aiming to prevent the turricephaly with a secondary FOR addressing the recessed forehead (Fig. 10).

ERF mutation is a newly discovered craniosynostosis entity genetically identified by Twigg et al. [2013] and further phenotypically described by Chaudhry et al. [2015]. Mutations in the ERF gene, coding for ERF, a member of the ETS family of transcription factors, are implicated in a new single-gene cause of syndromic craniosynostosis. Autosomal dominant inheritance with variable expressivity and non-penetrance is described. There is an estimated contribution of up to 7% of ERF mutations to the craniosynostosis syndromes, either genetically undiagnosed or clinically misdiagnosed as Crouzon or Pfeiffer syndrome [Twigg et al., 2013]. Our recently reviewed cohort included 14 patients, expanding our understanding of the phenotypic and surgical course.

ERF syndrome presents with multisutural synostosis, frequently in a pattern of sagittal and bilambdoid synostosis (8 coronal affected), mild-moderate hypertelorism, hearing loss, maxillary hypoplasia with facial dysmorphism, Chiari 1 malformation, otitis media, motor skill deficits, poor concentration and/or hyperactivity, and language delay. Facial dysmorphism includes exorbitism, malar hypoplasia, often orbital hypertelorism, and unusually a Class I/II occlusal relationship (Fig. 11). Global language delay and dyspraxia are common, expressed through either fine or gross motor control [Twigg et al., 2013; Chaudhry et al., 2015].

Fig. 11

A boy with an ERF mutation (mutation c.247C>T; p.Arg83Trp) at 2 years of age. A, B Mild hypertelorism, mild scaphocephaly. The clinical features are within normal range. C, D Patent sutures. E, F Late closure of sagittal and bilambdoid sutures associated with increased intracranial pressure (ICP). G After PVE for raised ICP.

Fig. 11

A boy with an ERF mutation (mutation c.247C>T; p.Arg83Trp) at 2 years of age. A, B Mild hypertelorism, mild scaphocephaly. The clinical features are within normal range. C, D Patent sutures. E, F Late closure of sagittal and bilambdoid sutures associated with increased intracranial pressure (ICP). G After PVE for raised ICP.

Close modal

Of clinical concern is the undetectable nature of this syndrome with a high risk of increased ICP. These patients do not have a sufficiently abnormal head shape or facial appearance to raise suspicion of a craniofacial syndrome prompting referral to a craniofacial unit, potentially due to late and progressive synostosis. The clinical concern centres on delayed referral with development of elevated ICP and developmental delay as the facial dysmorphism is not associated with functional issues for the airway or ocular surface protection with a Class I/II occlusion.

Surgical Management

Multisutural craniosynostosis frequently resulted in early cranial vault surgery for raised ICP and/or Chiari 1 malformation. Ten of the 14 patients reviewed developed early increased ICP (identified by optic disc swelling and/or invasive monitoring) and/or a Chiari 1 malformation for which surgical intervention was required. The most common procedure, in keeping with raised ICP, was PVE.

The long-term outcome for these patients is not yet clear. Our recommendation is that all “at-risk” family members are offered molecular testing and those found to carry a mutation are followed up prospectively. Note that, similar to Crouzon syndrome, a normal CT scan in the neonatal period does not preclude the insidious development of craniosynostosis and raised ICP in later years; therefore, long-term surveillance is required (Fig. 11).

Patients with suspected syndromic craniosynostosis, familial craniosynostosis, and clinically non-syndromic coronal or multisuture craniosynostosis have lymphocyte DNA collected for genetic testing. Screening of the FGFR1, FGFR2, FGFR3, TWIST1, ERF, TCF12, IL11RA, and EFNB1 genes is carried out using next-generation sequencing (Agilent SureSelect and Illumina NextSeq). A minimum coverage of 30 reads is required to call a variant, and all variants are confirmed by Sanger sequence analysis. In-house validation attributes a minimum sensitivity of 99.9% to detect single nucleotide substitutions (with 95% confidence) and 77% for insertion/deletion variants (with 95% confidence) for regions with >30× coverage. Known benign polymorphisms and sequence variants that are assessed as unlikely to be pathogenic - or particularly for FGFR1 have not been associated with craniosynostosis previously - are not reported. In addition, all samples are screened for deletions and duplications in the EFNB1, TWIST, and TWISTNB genes using an MRC-Holland Multiplex Ligation-Dependent Probe Amplification kit which also includes probes for MSX2, ALX1, ALX3, ALX4, and RUNX2.

For patients with suspected syndromic or multisuture craniosynostosis in whom the panel testing has been normal, or those with metopic synostosis (in whom craniosynostosis panel testing is not routinely performed) with additional abnormalities, detailed screening for chromosomal imbalance is usually undertaken on lymphocyte DNA using an Affymetrix 750K (HG19) microarray (estimated average resolution 200 kb).

The worthy trend of a genotypic classification rather than an eponomous nomenclature, which has significant outliers and confusion, is hopefully years away with some reviews leading the movement [Forrest and Hopper, 2013]. The matching of genetics to clinical presentation and management may aid clinical expectation and multidisciplinary treatment by treating the phenotype with the knowledge projection of the genotype [Agochukwu et al., 2012a].

Care of the syndromic patient should lie in the hands of a specialised MDT with experience in the pattern recognition of the clinical presentations and the unusual cases to further investigate. This specialised knowledge expedites the greatly non-urgent treatment of the patients but prevents through expertise the life-threatening and functional losses of airway, feeding, vision, and cognition through timely intervention.

So many techniques are described in craniofacial surgery to achieve the same aim - that of normal growth of the brain and skull enabling optimal development. It is not possible in this review to describe the benefits of one technique over another, but it rather describes the influences of our unit. Surgical techniques continue with exponential innovation in a desire to make procedures less invasive with a reduced complication profile. The advent of promising results of endoscopic strip craniectomies and helmeting now applied to syndromic cases with very early intervention is an area to watch with some interest despite complications detailed in the literature [Cartwright et al., 2003; Kung et al., 2016]. The benefits of internal distraction applied to posterior vault procedures are appreciated for the specific patient, but our unit favours the benefits of spring expansion for most syndromic cases for the dynamic closure and volume difference without external prosthesis or parental investment [Nowinski et al., 2012; Taylor et al., 2012; de Jong et al., 2013; Goldstein et al., 2013; Derderian et al., 2015]. The syndromic patients drive the innovation and desire to continually improve what we can achieve. The algorithm for surveillance and management of raised ICP is detailed in Figure 1.

The influence of the genotype on the expected phenotype and clinical projection is now clearer for MDT treating syndromic patients. These often complex clinical cases can challenge multidisciplinary care with the emphasis of the entire treating team to achieve the greatest potential for these patients.

The authors have no conflicts of interest to disclose.

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