Craniostenoses and craniofacial malformations

French national reference center for craniostenoses and craniofacial malformations (CRANIOST)

Craniofacial surgery unit at Necker-Enfants malades hospital is an internationally renowned reference center. The work of the founders of the center, professors Renier and Marchac, have allowed to build the bases of current clinical and surgical management of these pathologies and to develop the research to understand their genetic causes.

Since its certification in 2006, the team has paid particular attention to multidisciplinary craniofacial care, associating in particular the craniofacial plastic surgery and pediatric neurosurgery teams.

The craniofacial surgery activity of the Necker-Enfants malades hospital is located within the pediatric neurosurgery department. It is a reconstructive surgery activity for neurosurgical complications.

One of the largest cohorts in the world (4,500 craniostenoses operated on) is followed in the unit, with more than 200 operations per year on an active file of 1,270 patients, with approximately 370 new patients. Approximately 1,200 consultations for these patients are provided each year, with approximately 35% of patients from outside the region and 15% of foreign patients. The number of annual interventions is constantly increasing, due to recruitment and iterative interventions on certain patients.

This reference center is affiliated with the TETECOU rare diseases healthcare network and the CRANIO European reference network (ERN) on craniofacial anomalies and ENT disorders.

Medical
team

Michel Zérah

Medical leader
Michel Zérah
MD, PhD

Medical consultant
Giovanna Paternoster
MD

Medical consultant
Eric Arnaud
MD

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Phone: +33 (0)1 44 49 42 54

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The missions of the center are:

  • to establish a diagnosis with certainty thanks to a specialized team;
  • to offer personalized treatment based on multidisciplinary care;
  • to train the parents of patients and their families;
  • to prevent complications;
  • to ensure continuity of care until adulthood;
  • to develop clinical and fundamental research programs at national and international level;
  • to study the pathophysiological and etiological mechanisms underlying these malformations;
  • to develop new surgical techniques and tools;
  • to disseminate knowledge and good medical practices;
  • to develop a care network in collaboration with patient associations.

What is craniostenosis?

Craniostenosis is a primary growth defect in the cranial skeleton associated with the premature closure of one or more cranial sutures. There are various forms of craniostenoses without and with involvement of the facial mass or extremities (Crouzon, Pfeiffer, Saethre-Chotzen, Apert syndromes, etc.).

Craniostenoses pose a problem:

  • morphological: cranial and facial dysmorphia
  • functional: a growth conflict between skull and brain.

This can have mental, visual and psychological repercussions if the treatment is not early enough.

Sagittal craniostenosis (scaphocephaly)

Isolated scaphocephaly is a form of nonsyndromic craniosynostosis characterized by premature fusion of the sagittal suture.

Epidemiology

It is a relatively common malformation accounting for around 50% of all cases of nonsyndromic craniosynostosis and with an incidence of 1/5,000 live births. Males are more frequently affected than females (male/female ratio of 3.5:1) and the frequency of affected twins is unexpectedly high.

Clinical description

The premature fusion of the sagittal suture results in compensatory anteroposterior elongation of the skull. The mean cranial length is significantly increased and the sagittal suture is larger than normal. Frontal bossing and occipital bulging may occur depending on the extent of the premature fusion. Elevated intracranial pressure is rare and intelligence is usually normal.

Etiology

The underlying cause of isolated scaphocephaly remains to be determined: a mutation in the TWIST1 gene (7p21) has been reported in a single case. However, the concordance rate in monozygotic twins was found to be 30%, suggesting some cases might be genetically determined, whereas environmental determinants are involved in others.

Diagnostic methods

Diagnosis is based on clinical examination and radiological evaluation by X-rays, 3D CT scans and/or MRI of the skull.

Differential diagnosis

Sagittal synostosis can be isolated or occur as part of a syndrome (such as familial scaphocephaly with radioulnar synostosis or sagittal craniosynostosis with Dandy-Walker malformation and hydrocephalus; see these terms). The syndromic and nonsyndromic forms can be clearly distinguished due to the absence in isolated scaphocephaly of additional clinical features.

Genetic counseling

The majority of cases are sporadic but familial cases with autosomal dominant inheritance have been described (6% of all cases).

Management and treatment

Management may involve cranial vault reconstructive surgery to correct skull shape.

Prognosis

The clinical outcome of patients having undergone surgery is usually good with normal intelligence and psychomotor development.

Metopic craniostenosis (trigonocephaly)

Isolated trigonocephaly is a nonsyndromic form of craniosynostosis characterized by the premature fusion of the metopic suture.

Epidemiology

Incidence is estimated at 1/15,000 births. Males are more frequently affected than females (sex ratio of 2:1) and the frequency of trigonocephalic twins is unexpectedly high.

Clinical description

The premature closure of the metopic suture results in deformation of the anterior portion of the calvarium and a triangular-shaped forehead. In mild forms, only prominent ridging of the metopic suture is visible; while in more severe forms marked narrowing of the frontal and temporal regions affects the supraorbital rims leading to hypotelorism. The psychomotor development of patients is usually normal and the majority of cases are mild.

Etiology

The underlying genetic cause of isolated trigonocephaly remains to be delineated. However, the concordance rate of isolated trigonocephaly in monozygotic twins is 43%, suggesting that both genetic and environmental factors are involved in the etiology of this disorder.

Diagnostic methods

Diagnosis is based on clinical and ultrasound examination, radiological evaluation by X-rays, and 3D CT scans and/or MRI of the skull. Since fusion of the metopic suture normally occurs during early childhood, CT scans for metopic synostosis should be performed before 6 months of age to avoid misdiagnosis. Premature fusion of the metopic suture may occur both in syndromic and in nonsyndromic forms of synostosis.

Differential diagnosis

The differential diagnosis should include trisomy 13 and other chromosomal disorders (distal monosomy 9p and 11q), as well as C syndrome (see these terms), and is based on the presence of multiple anomalies (including facial dysmorphism, organ anomalies and intellectual deficit) in the syndromic forms. Fetal exposure to valproic acid during pregnancy usually leads to trigonocephaly, which in this case is often associated with intellectual deficit and dysmorphic features, and therefore fetal valproate syndrome (see this term) should also be included in the differential diagnosis.

Genetic counseling

Most cases are sporadic but familial forms with apparently autosomal dominant transmission have been reported (representing 7-8% of all cases).

Management and treatment

Surgery is the only treatment for correction of the skull deformation. Primary orbitocranioplasty is performed according to different techniques including reshaping with metallic fixation or use of primary bone grafting and resorbable fixation to expand the frontal region. Anterolateral expansion of the supraorbital bar and stabilization of the construct via bone grafting and resorbable fixation give the best esthetic outcome with a low incidence of reoperation.

Prognosis

The clinical outcome for patients having undergone surgery is usually satisfactory with a low requirement for additional interventions, especially in the mild forms. Recurrence of a prominent metopic ridge may occur in some rare cases.

Coronal craniostenosis (plagiocephaly)

Isolated synostotic plagiocephaly (SP) is a form of nonsyndromic craniosynostosis characterized by premature fusion of one coronal suture leading to skull deformity and facial asymmetry.

Epidemiology

Incidence is estimated at around 1 in 10,000 births.

Clinical description

Isolated SP is characterized by a rounded ipsilateral palpebral fissure, an ipsilaterally displaced nasal root, contralateral frontal bossing and skull asymmetry as a result of unilateral coronal synostosis. Mild facial hypoplasia and macrocephaly have been observed in some cases. Unilateral or bilateral hearing loss, and developmental delay or learning problems have also been reported in some patients. Frequent visual field abnormalities and defective eye movements were recently reported in 50% of infants with SP.

Etiology

A recurrent P250R mutation in fibroblast growth factor receptor 3 (encoded by the FGFR3 gene; 4p16.3) was found to be responsible for the majority of these familial cases and for some of the sporadic cases. Intrafamilial variability of the phenotype caused by the P250R mutation may result in patients presenting either plagiocephaly or brachycephaly within the same family. However, FGFR3 mutations have only been identified in a limited number of patients (7-10%); in most cases the etiology is unknown and is likely not to be genetically determined. Intrauterine deformational forces have been implicated but additional determinants such as maternal hematologic or metabolic disorders might be involved.

Diagnostic methods

Diagnosis is based on clinical examination and radiological evaluation by X-rays and 3D CT and/or MRI of the skull. Molecular screening for the FGFR3 mutation should be recommended as this mutation may be associated with additional anomalies (mild brachydactyly and fusion of carpal or tarsal bones) that are only detectable by radiographic analyses of the limbs.

Differential diagnosis

SP should be clearly distinguished from deformational plagiocephaly, a common form of plagiocephaly attributed to the supine sleep position that does not involve the sutures and does not usually require surgical treatment. The differential diagnosis should also include syndromes associated with premature fusion of one coronal suture (Crouzon, Pfeiffer and Saethre-Chotzen syndromes; see these terms), a distinction that mostly relies on the presence of limb anomalies in syndromic forms. Identification of the P250R mutation can be helpful for the differential diagnosis of synostotic plagiocephaly.

Genetic counseling

Most cases of SP are sporadic, but familial forms (2-3% of all cases) with autosomal dominant transmission have been reported.

Management and treatment

Surgical correction involving a bifrontal craniotomy is the most appropriate treatment for isolated SP. Hearing loss and visual defects need to be properly assessed before and after surgery.

Prognosis

Cranial expansion surgery at early stages during infancy usually results in normal intelligence in children and adolescents. However, the impact of reconstructive surgery on visual function has not yet been assessed.

Coronal craniostenosis (brachycephaly)

Isolated brachycephaly is a relatively frequent nonsyndromic craniosynostosis consisting of premature fusion of both coronal sutures leading to skull deformity with a broad flat forehead and palpable coronal ridges.

Epidemiology

Incidence at birth is in the range of 1/20,000.

Clinical description

The skull deformity is characterized by a short anteroposterior diameter with a compensatory increase in bitemporal width. Supraorbital recession and exorbitism may also be present. Brachycephaly may be associated with facial anomalies (midface hypoplasia, slight hypertelorism and bulging temporal fossae). Increased intracranial pressure (ICP) is frequent and may lead to intellectual deficit if left untreated. In adults, elevated ICP is associated with bony defects in the absence of treatment.

Etiology

The extent to which nonsyndromic brachycephaly is genetically determined is still uncertain. Although the majority of cases are sporadic, familial forms (accounting for 14% of all cases) have been reported, with dominant inheritance in around 10% of cases. In addition, recurrent (paternally inherited) P250R mutations in fibroblast growth factor receptor 3 (FGFR3; 4p16.3) were identified in 74% of familial cases, as well as in 17% of sporadic cases. Among patients carrying the P250R mutation, females are more severely and more frequently affected than males (female to male ratio of 2:1) and mild hearing impairment is common. Minor radiologic anomalies including brachydactyly or fusion of metacarpal bones may occur in some FGFR3 mutation carriers. A mutation in the TWIST 1 gene (7p21) has been reported recently in a single case of isolated bicoronal synostosis, but a genetic origin has not been confirmed for most remaining cases. Several other determinants might be involved including mechanical constraints during pregnancy and after birth.

Diagnostic methods

Diagnosis is based on clinical examination, radiologic studies, and 3D CT scans and/or MRI of the skull. Since postoperative morphological and functional outcomes appear to be better in non-carriers of the FGFR3 mutation, molecular screening is recommended for all families with nonsyndromic forms of brachycephaly.

Differential diagnosis

Clinical distinction between syndromic and nonsyndromic forms brachycephaly is often difficult owing to phenotypic variability in patients carrying the P250R mutation. Although the cranial appearance of some patients might be reminiscent of the Saethre-Chotzen or Pfeiffer syndromes (see these terms), the absence of obvious hand and/or feet anomalies is a hallmark of nonsyndromic brachycephalic patients. Marked bulging of temporal fossae, seen mainly in female carriers of the FGFR3 mutation, might be instructive for differential diagnosis.

Management and treatment

Cranial vault reconstructive surgery is the main treatment to improve skull shape and increase intracranial volume. This usually results in reduced ICP. Early identification of hearing loss allows timely intervention when required.

Prognosis

The intellectual outcome of patients after cranial expansion surgery is usually good. However, patients carrying the FGFR3 mutation are five times more likely to require a second operation and show a poorer post surgical outcome than non-carriers.

Saethre-Chotzen syndrome

A syndrome characterized by unilateral or bilateral coronal synostosis, facial asymmetry, ptosis, strabismus and small ears with prominent superior and/or inferior crus, among other less common manifestations.

Epidemiology

Saethre-Chotzen syndrome (SCS) prevalence ranges from 1/25,000 to 1/50,000 livebirths.

Clinical description

SCS has a variable spectrum of manifestations. Classic SCS presents at birth with synostosis of coronal (less commonly in conjunction with sagittal, metopic or lambdoid) sutures resulting in abnormal skull shape, facial asymmetry, low frontal hairline, ptosis, strabismus, tear duct stenosis and small ears with prominent crus. Brachydactyly, broad toes, partial cutaneous syndactyly of digits 2 and 3 of the hand, duplicated distal phalanx of the hallux are also often present. Intelligence is normal in most, but mild to severe developmental delay has been reported, primarily in cases with a large genomic deletion. Some may experience conductive and/or sensorineural hearing loss. Less common manifestations include short stature, hypertelorism, cleft palate, bifid uvula, maxillary hypoplasia, lacrimal duct stenosis, parietal foramina, vertebral anomalies, radioulnar synostosis, obstructive sleep apnea and congenital heart malformations. Mild phenotypes include patients with ptosis or blepharophimosis with or without craniosynostosis. Elevated intracranial pressure (ICP) associated with severe cases of synostosis may lead to headaches, visual loss, seizures and death if untreated.

Etiology

SCS is due to point mutations or deletions involving (or removing completely) the TWIST1 gene (7p21), which encodes a basic helix-loop-helix (bHLH) transcription factor responsible for cell lineage determination and differentiation. Loss of function mutations in this gene lead to the induction of premature cranial suture fusion. Gene deletions cause more severe phenotypes, usually associated with significant neurocognitive delays.

Diagnostic methods

Diagnosis is based mainly on the presence of characteristic clinical findings. CT of the head and radiographs are useful in characterizing abnormalities of the skull, spine and limbs. Molecular genetic testing can identify a TWIST1 mutation or deletion, confirming diagnosis.

Differential diagnosis

Although several features (such as 2-3 syndactyly of the hand) are unique to SCS, differential diagnoses include other syndromic forms of craniosynostosis such as Muenke, Baller-Gerold, Pfeiffer, and Crouzon syndromes as well as isolated unilateral coronal synostosis. Robinow_Sorauf syndrome is now considered within the spectrum of SCS, typically with milder features. Mutations in FGFR3FGFR2TCF12RECQL4, and EFNB1 have been reported to cause synostosis conditions that phenotypically overlap with SCS. This is not surprising, as there is evidence that FGFR and TWIST1 may be integrated into overlapping pathways, including in osteoblast differentiation. In addition, TWIST1 mutations have been noted in some cases of isolated single-suture craniosynostosis, including sagittal and unicoronal cases.

Antenatal diagnosis

Prenatal testing for a TWIST1 mutation is rare, but it can be performed in families with a known mutation or when an ultrasound shows craniosynostosis of unknown etiology.

Genetic counseling

SCS is inherited as an autosomal dominant trait. Genetic counseling is valuable. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.

Management and treatment

Treatment of SCS requires management by a multidisciplinary craniofacial team with follow-up until young adulthood. In general, patients must undergo cranioplasty in the first year of life to increase the intracranial volume and restore a more normal head shape. Recurrent increased ICP may necessitate further surgical expansion procedures. In childhood, orthodontic care and/or midfacial surgery may be necessary for treatment of airway obstruction and malocclusion. In those with cleft palate, surgical closure can be performed in the context of other malformations, with evaluation for velopharyngeal insufficiency and speech therapy offered as necessary. Routine evaluations of facial growth, hearing loss and psychomotor development are needed, as well as regular ophthalmologic examinations to monitor strabismus, amblyopia or chronic papilledema (that indicates increased ICP). Early intervention programs should be offered to children with developmental delay. Augmentation of hearing and supportive interventions related to deafness should be pursued when indicated.

Prognosis

In most cases, when treated and monitored from an early age, the prognosis is excellent. Developmental prognosis is worse for patients with a TWIST1 deletion, compared to those with point mutations.

Crouzon syndrome

Crouzon disease is characterized by craniosynostosis and facial hypoplasia.

Epidemiology

The estimated prevalence in the general population of Europe is 0.9/100,000 .

Clinical description

Craniosynostosis is variable but many sutures are usually involved. The facial dysmorphology is characterized by ocular hypertelorism, small beaked nose, proptosis, exophthalmos, hypoplastic maxilla and mandibular prognathism. The synostosis is evolutive and is usually either not visible or only slightly visible at birth. It usually manifests by the age of 2 years and becomes progressively more severe. However, precocious and congenital forms have been reported in which hypoplasia of the upper maxilla is pronounced and leads to respiratory difficulties, and the exophthalmia is severe resulting in palpebral malocclusion. Hydrocephaly, descent of the cerebellar tonsils and anomalies in jugular venous drainage are also frequently observed in Crouzon disease and may pose therapeutic problems. Two thirds of patients with Crouzon disease have intracranial hypertension, which may lead to blindness.

Etiology

Crouzon disease is caused by mutations of the fibroblast growth factor receptor FGFR2 (10q25.3-q26) with 80% being located to the immunoglobulin (Ig)-like domain III (IgIII domain) of the extracellular region and an additional 20% of mutations being located in the IgI-IgII domains, transmembrane and tyrosine kinase regions. A distinct form of Crouzon disease associated with acanthosis nigricans has been reported and is caused by a specific mutation (p.Ala391Glu) in the transmembrane domain of another protein from the same family, FGFR3 (Crouzon syndrome – acanthosisnigricans; see this term). Moreover, mutations in ERF (19q13.2) gene encoding the ETS2 repressor, resulting in anosteogenic stimulation, have been associated to a Crouzon-like syndrome.

Genetic counseling

The disease is transmitted in an autosomal dominant manner with variable penetrance.

Management and treatment

Surgical interventions are aimed at preventing cerebral, ophthalmological or respiratory complications and correcting the cranio-facial dysmorphy. The craniofacial surgical approach adopted needs to take into account both the cranial and facial synostosis and should be tailored to each patient.

Pfeiffer syndrome

An acrocephalosyndactyly associated with craniosynostosis, midfacial hypoplasia, hand and foot malformation with a wide range of clinical expression and severity. Most of the affected patients show various other associated manifestations.

Epidemiology

Pfeiffer syndrome (PS) birth prevalence is 1/100,000. The disorder affects males and females equally.

Clinical description

Abnormal skull shape is usually detected in the neonatal period (possibly on prenatal ultrasound). Characteristic cranial features include a wide cranial vault, a flat occiput, broad forehead, a small nose with depressed nasal bridge, orbital hypertelorism and proptosis. The clinical picture depends on the extent craniosynostosis (mostly bicoronal) and the associated functional disorders (respiratory, otological, ocular, neurological). Three forms of PS have been described (PS type 1, type 2, and type 3). Type 1 described as the « classic PD », is the less severe form of PS and is characterized by mild-to-moderate midface hypoplasia, minimal hand and foot abnormalities, little to no ocular proptosis and usually normal intellectual development. In contrast, types 2 and 3 are associated with more severe manifestations such as extreme proptosis and choanal stenosis or atresia, finger and toes abnormalities, elbow ankylosis or synostosis and complications (hydrocephalus and seizures) resulting in a poorer prognosis. Other complications include brain development disorders, exposure keratopathy, exorbitism, bilateral and symmetrical hearing loss, airway obstruction, and obstructive sleep apnea. Type 2, the most severe form, is distinguished form type 3 by the presence of kleeblattschädel, commonly referred to as trilobated or  »cloverleaf » skull. Types 2 and 3 have occurred only in sporadic cases and have increased risk of early death due to severe neurological compromise and respiratory problems.

Etiology

The majority of cases are caused by de novo mutations in the FGFR2 gene (10q25.3-q26), and very rarely in type 1 cases, by mutations in the FGFR1 (8p11.23-p11.22) gene. Patients meeting criteria for a clinical diagnosis of Pfeiffer syndrome without a mutation in FGFR1 or FGFR2 are estimated to be as high as 21%. Spontaneous mutations have been associated with advanced paternal age.

Diagnostic methods

The diagnosis is based on the presence of the characteristic clinical findings including craniosynostosis or cloverleaf skull, facial features, and variable hand and foot malformations. Diagnosis can be confirmed by molecular genetic testing.

Differential diagnosis

Differential diagnoses include other acrocephalosyndactyly syndromes (Apert, Crouzon, Carpenter, Saethre-Chotzen, Waardenburg) and other syndromic forms of craniosynostosis such as Jackson-Weiss, Muenke and Antley-Bixler syndromes and Cutis gyrata-acanthosis nigricans-craniosynostosis.

Antenatal diagnosis

Prenatal molecular genetic testing is possible. Results of genetic testing for low-risk pregnancies are of little prognostic value. Prenatal imaging may also be used for diagnosis if physical findings are apparent. Some ultrasound findings could pose the suspicion of the disease.

Genetic counseling

Genetic counseling should be provided to affected families. Inheritance from an affected parent in an autosomal dominant manner is reported in less severe cases of Pfeiffer syndrome. PS shows complete penetrance, although the expressivity is variable. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring. When prenatal features are evocative for PS, gene molecular testing for mutation, after standard and molecular karyotyping should be suggested.

Management and treatment

Treatment is symptomatic and corrective, depending on the extent of disease manifestations. A multidisciplinary approach should be adopted to plan multiple-stage surgical interventions and other treatments with the aim of improving cosmetics, function and quality of life. The psychosocial aspects of the disease should also be addressed.

Prognosis

The success of timely treatment is the main prognostic factor. Favorable outcomes can be achieved but the prognosis remains poor in severe cases with a high risk of early demise due to respiratory and neurological complications.

Apert syndrome

A frequent form of acrocephalosyndactyly, a group of inherited congenital malformation disorders, characterized by craniosynostosis, midface hypoplasia, and finger and toe anomalies and/or syndactyly.

Epidemiology

The estimated incidence of Apert syndrome is reported to be 1/100,000 to 1/160,000 live births.

Clinical description

Patients generally have extensive structural and functional impairments related to cranial and limb deformities. Craniosynostosis can lead to acrobrachycephaly or turribrachycephaly with delayed closure of fontanels and a possible impact on brain growth and neurological development. Macrocephaly is also found. Limb malformations mainly consist of soft tissue and bony syndactyly of fingers and toes (involving variable numbers of digits), occasional rhizomelic shortening, and elbow ankylosis, with functional impairments and restriction of mobility. Facial findings include midface hypoplasia that is generally moderate to severe with hypoplasia of the maxilla, shallow orbits, strabismus, hypertelorism, down-slanting palpebral fissures, and proptosis, as well as depressed nasal bridge and deviated nasal septum. Dental findings include delayed eruption, impaction, crowding, thick gingival swelling, and missing teeth, along with a high risk of caries. Unilateral and bilateral posterior crossbites are frequent. Common associated complications include chronic otitis media, hearing loss, and increased ocular pressure that can cause blindness. Moderate to severe intellectual disability and variable developmental delay are also common in AS (more than 50% of cases). Some patients are also reported to have agenesis of the corpus callosum, ventriculomegaly, hydrocephalus, fused cervical vertebrae (usually C5-C6), and occasionally, cardiac and gastrointestinal defects, radiohumeral synostosis, or cleft velum (see this term).

Etiology

A mutation in the FGFR2 gene (10q25.3-10q26) involved in cell signaling during embryonic development is causative in Apert syndrome. Advanced paternal age has been associated with de novo mutations, which are found in most cases.

Diagnostic methods

Diagnosis is based on the clinical findings at birth. Some cases may be identified prenatally. The diagnosis can be confirmed by molecular genetic testing.

Differential diagnosis

The differential diagnosis includes other syndromic craniosynostosis syndromes, such as Pfeiffer, Crouzon, Saethre-Chotzen, Muenke, and Jackson-Weiss syndromes (see these terms).

Antenatal diagnosis

Prenatal MRI or molecular genetic testing can be used to diagnose suspected cases.

Genetic counseling

A mutation in the FGFR2 gene (10q25.3-10q26) involved in cell signaling during embryonic development is causative in Apert syndrome. Advanced paternal age has been associated with de novo mutations, which are found in most cases.

Management and treatment

A multidisciplinary approach to care is necessary with life-long monitoring. Treatment primarily involves craniosynostosis release, followed by surgical advancement or distraction for midface hypoplasia, and reparative or cosmetic treatment of other malformations. Successful treatment can improve aesthetics and functional performance (breathing, mastication, oral and ocular health). In patients with mitten-glove syndactyly, surgical separation of the digits generally provides little functional improvement. The psychosocial aspects of the syndrome should also be taken into account.

Prognosis

The prognosis is guarded. Many individuals have life-threatening complications, including airway and central nervous system compromise. Others can do relatively well with proper medical and surgical management, but intellectual limitations are still very common. Life expectancy varies among patients with AS due to variable clinical severity and treatment success.

Multiple craniostenosis (Oxycephaly)

Isolated oxycephaly is a late-appearing form of nonsyndromic craniosynostosis characterized by premature fusion of both the coronal and sagittal sutures, and, in some cases, of the lambdoid sutures. Compensatory growth in the region of the anterior fontanel results in a pointed or cone-shaped skull.

Epidemiology

Prevalence is unknown.

Clinical description

The mean age at diagnosis is around six years. Elevated intracranial pressure is a common clinical feature (affecting more than 60% of the patients) leading to frequent ophthalmologic complications (papilledema) and moderate to severe intellectual deficit. Chiari type I malformation is commonly seen on MRI scans.

Etiology

Etiology is unknown.

Diagnostic methods

Diagnosis is based on clinical examination, X-rays and 3D CT scans of the skull. MRI exploration of the Chiari type I malformation and ophthalmologic examinations are also required for diagnosis.

Differential diagnosis

Oxycephaly may also be a feature of certain syndromes (Crouzon syndrome and Pfeiffer syndrome; see these terms). The syndromic and nonsyndromic forms can be distinguished by the absence of limb and/or facial anomalies in nonsyndromic forms.

Genetic counseling

Isolated oxycephaly is usually sporadic but familial cases have been reported.

Management and treatment

Cranial expansion surgery (fronto-orbital advancement) is essential for relieving intracranial pressure and stabilizing intellectual level. It should be performed during childhood, as soon as the clinical diagnosis has been established. In the absence of appropriate treatment, the intellectual deficit becomes significantly more profound. Papilledema, which is a consequence of increased intracranial pressure, usually disappears postoperatively. Following surgery, the intracranial pressure returns to normal and the intellectual deficit seems to stabilize in most cases. However, secondary surgery is more commonly required in oxycephaly patients than in those with single suture craniosynostosis.

Non-syndromic unclassifiable craniostenoses

Various associations can be observed: scaphocephaly for example can be associated with plagiocephaly, trigonocephaly or lambdoid synostosis. This is not frequent.

Cloverleaf skull syndrome

A form of craniosynostosis involving multiple sutures (coronal, lambdoidal, sagittal and metopic) characterized by a trilobular skull of varying severity (frontal towering and bossing, temporal bulging and a flat posterior skull), dysmorphic features (downslanting palpebral fissures, midface hypoplasia, and extreme proptosis) and that is complicated by hydrocephalus, cerebral venous hypertension, developmental delay/intellectual disability and hind brain herniation.

Craniofacial clefts with hypertelorism

Craniofacial fibrous dysplasia

Nasal encephalocele

Nasal encephalocele is an extracranial herniation of intracranial contents (that maintain a connection to the subarachnoid space) into the fonticulus frontalis, presenting with nasal broadening and/or as a compressible, blue, pulsatile mass near the nasal bridge (that enlarges on crying or with jugular vein compression) or as an intranasal mass originating in the cribiform plate and that can cause nasal obstruction or respiratory distress. Hydrocephalus and increased intracranial pressure are also reported in some cases.

Frontal encephalocele

Basal encephalocele

Dr Giovanna Paternoster
Pediatric neurosurgery

Dr Eric Arnaud
Plastic surgery

Dr Syril James
Pediatric neurosurgery

Dr Samer Haber
Plastic surgery

Dr Marie Bourgeois
Neuropediatrician

Dr Hossein Khonsari
Maxillofacial surgery

Karine André
Pediatric neuropsychology

Ludivine de Freitas
Nurse

Salima Madini
Secretary coordinator

Mireille Amona
Social worker

Sophie Leandri
Social worker

The team of the craniostenoses reference center is based in the pediatric neurosurgery department.
There is a close collaboration with the specialists of the Necker-Enfants malades hospital. You will find here a non-exhaustive list.

Pediatric ophthalmology

  • Dr Matthieu Robert
  • Dr Abdelkader Belahda

Pediatric otorhinolaryngology

  • Dr Marie-Paule Morrisseau-Durand
  • Pr Vincent Couloigner
  • Pr Nicolas Leboulanger
  • Dr Romain Luscan

Non-invasive ventilation and sleep unit for children

  • Pr Brigitte Fauroux
  • Dr Lucie Griffon

Maxillofacial surgery

  • Pr Arnaud Picard
  • Dr Eva Galliani

Stomatology

  • Dr Catherine Tomat
  • Dr Sophie Eche

Molecular genetics

  • Pr Valérie Cormier-Daire
  • Dr Geneviève Baujat
  • Dr Caroline Michot
  • Dr Pauline Marzin

Radiology

  • Pr Nathalie Boddaert
  • Dr Raphael Levy

Medical photography

  • Delphine Crépin
ETP CRANIOST

Faciocraniostenosis is a group of rare diseases corresponding to a growth disorder of the skull associated with a facial growth deficiency. The care is complex and must take into account different functional problems, essentially neurosurgical during the first years of life, then visual, orbital, respiratory, and occlusal-dental with growth. Neurosurgical treatment is done in several sequences, with several cranial expansions at different ages.

The pediatric neurosurgery team now wishes to develop a therapeutic patient education (TPE) program to complete the care offer for patients followed in its reference center for faciocraniostenosis. For this reason, it has responded to a national call for projects launched by the Direction Générale de l’Offre de Soins (DGOS) of the Ministry of solidarities and health in October 2019 to develop educational actions in rare diseases.

The leader of the project entitled « accompanying craniofacial distraction in faciocraniostenosis » is Dr Giovanna Paternoster, pediatric neurosurgeon and deputy coordinator of the CRANIOST reference center

This TPE program will :

  • improve patient and family knowledge about their disease and its care,
  • explain the different steps of the surgery, the complications, the hospitalization and the return home,
  • strengthen the autonomy of the patient and his family,
  • prepare the child and his or her family for the significant physical changes caused by the surgery,
  • reinforce concerted multidisciplinary support for the patient.

Workshop list

MDPH, AJPP, hospitalization, what should I do?

Taking care of the baby (Parents)

What is the Monobloc? (Parents)

Monobloc, what an ordeal? (Parents)

To explain is to reassure (Parents)

What about me? (Siblings-children)

What about me? (Siblings-teenagers)

What is the "Fort III"? (Parents)

The "Fort III", what an ordeal? (Parents)

What is the "Fort III"? (Children)

The "Fort III", what an adventure! (Children)

Everyone at home! (Parents)

Everyone at home! (Children)

  • Simple midline craniosynostosis PNDS (under validation)

Research

  • Creation in November 2019 of the « Skull shape and growth » laboratory, affiliated with the Imagine Institute, with 1 M2, 3 PhD and a post-doc.
    Modeling of craniofacial growth and evaluation of surgical results, thanks to a 350,000 euro grant from the Gueules Cassées foundation.
  • Launch of a 3D printing platform to produce anatomical models and medical devices for craniofacial surgery at Necker hospital, based on the same funding.
  • Coordination of the 3D printing policy for the AP-HP (mission led by C. Paugam), in conjunction with the agency for health equipment and products.
  • Medical directorate of the Health Data Hub (national centralized medical database).
  • « Emergence 2019 » obtained  funding (Paris City Hall), 350,000 euros for the « Skull shape and growth » laboratory.

Current projects

  • Industrial study
    • Evaluation of Kolibree (connected toothbrush) and Lunii (story box) on oral hygiene and perioperative anxiety in craniofacial malformation surgery – #2018A00758-47
  • 3 PhD thesis projects in progress (starting Nov. 2019)
    • Bone consolidation in FGFR mutants using mouse models, in collaboration with the Imagine Institute (A. Morice)
    • Optimization of the shape of the forehead in fronto-orbital advances, in collaboration with Arts et Métiers (M. Geoffroy)
    • Recognition of craniofacial syndromes by artificial intelligence, in collaboration with the Imagine Institute (Q. Hennocq)
  • 1 M2 project in progress (starting Nov. 2020)
    • Morphogenesis of the external ear and ear morphometry in craniofacial malformations, in collaboration with the Institut de la Vision (M. Cheval)
  • 1 M2 project completed
    • Modeling of frontal growth in trigonocephaly, in collaboration with Arts et Métiers (K. Bloch)

International collaborations

  • Visiting professor at University College London (mechanical engineering laboratory): projects on biomechanical modeling of craniofacial growth in simple craniostenosis (Pr Moazen)
  • Collaboration with Great Ormond St. Hospital (craniofacial surgery unit): projects on syndrome recognition by artificial intelligence
  • Funding from the International Relations Department for a collaboration with the craniofacial surgery team of the Burdenko Institute (Moscow): 4 stays planned, 2 in Paris and 2 in Moscow (project postponed to 2021 because of COVID)

Courses (2019/2020)

  • Course for interns in maxillofacial surgery and neurosurgery in Île-de-France: management of faciocraniostenosis
  • Courses at the IBODE School
  • Craniofacial anatomy course at the Estienne school (technical and scientific drawing school)
  • Participation in the teaching of the National Superior School of Beaux Arts: craniofacial malformations
  • Participation in the teaching of the medicine and society course of the Ecole Normale Supérieure (Paris): craniofacial malformations
  • Organization of the optional teaching unit « Representation of the body » (University of Paris) with a course on craniofacial malformations
  • Organization of the optional teaching unit « Experimental Embryology » (University of Paris) with two courses on craniofacial development and its anomalies
  • Organization of the optional teaching unit ‘Surgical Planning’ (University of Paris) with a course on 3D planning in craniofacial surgery
  • Organization of the UD ‘Surgical planning and personalized medicine’ with several courses on 3D planning in craniofacial surgery
  • Participation in the IUD of fetal medicine (University of Paris): midline abnormalities
  • Development of 3D printed models for teaching craniofacial surgery to medical students (University of Paris) and interns (Île-de-France and national level): project financed by the ARS Île de France (72,000 euros) in collaboration with iLumens (simulation platform, University of Paris) and BONE 3D (start-up specialized in 3D printing)
  • Development of an interface for teaching craniofacial anatomy and craniofacial surgery by virtual reality for medical students (University of Paris) and interns (Île-de-France and national level): in collaboration with iLumens (simulation platform, University of Paris) and Avatar Médical (start-up specialized in virtual reality)

2021

2020

2019

2018

2017

2016

  • The « Les p’tits courageux » association brings together parents and patients with monosutural and syndromic craniostenoses (Crouzon, Pfeiffer, Apert, Saethre-Chotzen …).
  • The « Epi Têtes » association supports families and children with non-syndromic craniostenoses (scaphocephaly, trigonocephaly, plagiocephaly, brachycephaly, oxycephaly …).
  • The « Tête en l’air » association is mobilizing for families whose children have been operated and followed in neurosurgery.

Contact information

Necker-Enfants malades university hospital
> Pediatric neurosurgery department

149 rue de Sèvres
75743 PARIS Cedex 15

> Pediatric welcome booklet

In Necker, the reference center for craniostenoses and craniofacial malformations in brief …

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patients followed at least once a year*
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medical consultations*
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fully hospitalized patients*
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current research projects*
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* data valid for 2019