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REVIEW ARTICLE |
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| Year : 2022 | Volume
: 17
| Issue : 5 | Page : 54-60 |
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Craniosynostosis: A pediatric neurologist’s perspective
Shruthi N M1, Sheffali Gulati2
1 Division of Pediatric Neurology, First Neuro Brain and Spine Superspeciality Hospital, Mangalore, Karnataka, India
2 Department of Pediatrics, Child Neurology Division, Centre of Excellence and Advanced Research for Childhood Neurodevelopmental Disorders, AIIMS, New Delhi, India
| Date of Submission | 05-Feb-2022 |
| Date of Acceptance | 12-Mar-2022 |
| Date of Web Publication | 19-Sep-2022 |
Correspondence Address:
Dr. Sheffali Gulati
DM Pediatric Neurology, Child Neurology Division, Coordinator of DM Pediatric Neurology Program, Centre of Excellence and Advanced Research for Childhood Neurodevelopmental Disorders, Department of Pediatrics, AIIMS, New Delhi
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jpn.JPN_25_22
 Abstract | | |
Craniosynostosis is premature fusion of sutures of the cranium, resulting in an abnormal skull shape and restriction of brain growth. It may affect either a single suture or multiple sutures. In most cases, craniosynostosis is secondary to an underlying abnormality of the growing brain; however, syndromic craniosynostosis is not uncommon. It might lead to several complications such as raised intracranial pressure, neurological deficits, and neurodevelopmental disabilities. Pediatric neurologists do play a significant role in early identification and treatment, and thereby ensure a better clinical and neurodevelopmental outcome in such children.
Keywords: Approach, craniosynostosis, nonsyndromic, pediatric
How to cite this article:
N M S, Gulati S. Craniosynostosis: A pediatric neurologist’s perspective. J Pediatr Neurosci 2022;17, Suppl S1:54-60 |
| Introduction | |  |
Craniosynostosis is an intricate heterogenous condition resulting in an abnormal skull shape due to aberrant premature fusion of one or more sutures of the cranium. It affects three to five individuals per 10000 live births.[1] It may be primary, or secondary, resulting from an associated abnormality in underlying brain growth. Primary craniosynostosis constitutes only 2–8% of the affected population.[1] Also, craniosynostosis may be an isolated entity (nonsyndromic craniosynostosis) or may be associated with other malformations (syndromic craniosynostosis). It is called simple craniosynostosis when only one suture fuses prematurely and compound craniosynostosis when multiple cranial sutures are affected. Primary syndromic craniosynostosis manifests early in infancy compared with the other entities. The prognosis depends on the number of sutures affected, type of craniosynostosis, associated conditions, and the underlying etiology.
| Etiopathogenesis | | |
In the embryonic period, the cranial sutures correspond to the sites of approximation of membranous bones. These sites represent the major zones of skull bone expansion in a growing child. Ossification of each cranial bone occurs in a centrifugal fashion extending outward to the periphery from the center of the bone. The growing brain keeps the sutures open, and the skull grows perpendicular to the axis of each suture. The dura mater at the suture site interacts with the overlying cranial vault and the surrounding tissues and regulates the sutural fusion. There exist numerous complex mechanisms (genetic/acquired) that can disrupt this natural process and result in aberrant premature sutural fusion.[2] The metopic suture fusion is the earliest to occur between nine months and two years of age, and the sagittal suture fusion is the last to occur. When there is premature fusion of the sutures, the brain growth in that direction will be restricted, and continued growth will be directed perpendicular to the other sutures that are open, resulting in a deformed skull. As the Monro-Kellie doctrine states, the intracranial volume is constant and is the sum of the volumes of brain, cerebrospinal fluid, and blood; thus continued brain growth in a closed cavity leads to rise in intracranial pressure.
Craniosynostosis is caused by a complex interaction between genetic, epigenetic, and environmental factors. Several external mechanical factors such as restricted intrauterine space, oligohydramnios, maternal smoking, or other teratogenic exposure (such as antiepileptic medications), infections during pregnancy, and internal factors such as the genetic makeup of the individual may contribute to the pathogenesis.[1],[3-6] Genetics contribute to approximately 20% of the cases, are mostly inherited in an autosomal dominant pattern, and may be chromosomal/single gene or polygenic disorders.[1] About 50% of the cases are caused by de novo mutations.[7] Among the genetic causes, single gene disorders contribute to 80% of the cases and chromosomal disorders to about 15%.[6] Complex and syndromic craniosynostosis mostly has a genetic basis and is more likely to be associated with complications. FGFR2 (32% of all the genetic cases), FGFR3 (25%), TWIST1 (19%), and EFNB1(7%) are the common genetic mutations associated with craniosynostosis.[7] Nonsyndromic single suture craniosynostosis (SSC) is also known to occur due to some single gene mutations involving FGFR3 genes.[7]
| Classification of Craniosynostosis | | |
Craniosynostosis can be classified based on various aspects. It is called primary when the deficit is related to the ossification process of the sutures and secondary when it is related to the hampering of brain growth due to multiple genetic/acquired/neurological/systemic causes. It is called syndromic when a syndrome is identified with craniosynostosis as in Apert syndrome and nonsyndromic if otherwise. It is called simple craniosynostosis / SSC if one suture is involved and complex if multiple sutures are involved.
| Primary Craniosynostosis | | |
Primary craniosynostosis results from a primary deficit in the sutural ossification process. A normal skull has a metopic suture separating two frontal bones, a coronal suture separating the frontal and parietal bones, a sagittal suture between two parietal bones, lambdoid sutures between parietal and occipital bones, and an anterior and posterior fontanelle. [Figure 1] is a pictorial representation of the sutures of the skull. Sagittal craniosynostosis is the most common entity (50–58%), and lambdoid fusion is the least common (2–4%).[1] Coronal sutural involvement is the second most common type and is more common among females, unlike sagittal craniosynostosis, which is more common among males. In 80–90% of the cases, only one or two sutures are involved, and, in such cases, cosmetic morbidity is the primary concern. Complications such as raised intracranial pressure are encountered only when multiple sutures are involved. [Figure 2] is a pictorial representation of various skull malformations resulting from SSC. The following are the different types of craniosynostosis based on the suture involved:  | Figure 2: A pictorial representation of various cranial vault malformations resulting from single suture craniosynostosis. A: Scaphocephaly; B: Brachycephaly; C: Trigonocephaly; D: Uni-coronal plagiocephaly; E: Unilateral lambdoid plagiocephaly; F: Deformational plagiocephaly (Dotted lines represent the prematurely fused sutures, and arrows suggest the direction of compensatory skull growth)
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Scaphocephaly: sagittal suture fusion resulting in a long narrow head, bossing of the forehead and/or occiput; it is the most common isolated form of craniosynostosis and has a male preponderance.
Brachycephaly: bilateral coronal suture fusion and it is mostly seen in syndromic forms, resulting in a short wide skull
Trigonocephaly: metopic suture fusion resulting in a ridge on the forehead and triangular skull (ridging without triangular skull is a normal variant); there is reduced distance between the orbits.
Oxycephaly(turricephaly): multiple suture fusion (tower-shaped head)
Plagiocephaly: unilateral suture fusion with subsequent facial asymmetry; anterior-coronal suture fusion (leads to a rotated facial appearance, flattened on the ipsilateral side, pushed forward on the contralateral side and displacement of the orbit and nose; raised ipsilateral supraorbital margins and characteristic Harlequin sign on the radiograph of the skull) and posterior-lambdoid suture fusion (leads to displacement of the ear backward and downward with frontal and occipital bossing on the contralateral side).
Positional(deformational) plagiocephaly: It is a common condition in neonates. There is ipsilateral flattening of the head and displacement of the ear anteriorly with contralateral bossing of the occiput. Positional plagiocephaly results from continued pressure to the same area due to preferential positioning. Over the recent years, the prevalence has increased due to the changed practice of putting babies to sleep on the back to prevent sudden infant death syndrome. It is seen in about 46.6% healthy infants and is known to peak at around three months of age.[8] It can also be seen increasingly in firstborn males, lack of active head rotation, children with developmental delay, prematurity, torticollis, floppy babies and in those with restricted ability of movement.[8],[9]
| Syndromic Craniosynostosis | | |
This is a less common (25%) entity and is usually associated with conditions such as Apert syndrome [Figure 2], Crouzon syndrome, Carpenter syndrome, Pfeiffer syndrome, and many more. More than 180 syndromes of syndromic craniosynostosis have been identified till date.[6] These children will have dysmorphism and additional characteristic manifestations related to the syndrome. They may have other system involvement (cardiac/musculoskeletal/genitourinary). Children with syndromic craniosynostosis have a genetic basis, and most of them result from a gain-of-function mutation in fibroblast growth factor receptor (FGFR) genes, leading to a premature sutural fusion. Most of these syndromes are dominantly inherited, except the autosomal recessive Carpenter syndrome and the X-linked cranio-fronto-nasal dysplasia, with approximately half of them being de novo in origin.
| Secondary Craniosynostosis | | |
Secondary craniosynostosis is more common, and it results from the underlying abnormalities of brain growth resulting from varied etiologies or from systemic causes such as hypothyroidism, rickets, mucopolysaccharidosis, hematologic conditions such as sickle cell anemia, and shunted hydrocephalus. Since the brain is not growing, it is unlikely to cause a secondary rise in intracranial pressure but leads to microcephaly. Neurodevelopmental deficits are commonly seen and are related to the underlying etiology (genetic/acquired causes). Management primarily aims at the underlying condition leading to abnormalities in brain growth, and it does not need surgical correction.
| Neurodevelopmental Glitches in Craniosynostosis | | |
Both syndromic and nonsyndromic craniosynostosis in a child bear significant impact on neurodevelopment. These issues are more common in syndromic craniosynostosis than nonsyndromic/ isolated SSC. Emerging evidence has suggested that when compared with typically developing children, a higher proportion of children with SSC have lower neurodevelopmental scores, language and cognitive problems, academic difficulties, behavioral issues, and learning disabilities as they grow.[10],[11] Children with sagittal craniosynostosis fare better than those with metopic, lambdoid, or unilateral coronal involvement.[2] However, the evidence also suggests that there is no significant difference between those operated early and those left unoperated (among children with SSC), suggesting a possibility that these cognitive-behavioural issues being unrelated to the skull distortion and subsequent negative effects on the brain, but per se may be an inherent deficit.[12],[13] There is also considerable debate on whether raised intracranial tension or underlying associated structural alterations (Chiari I malformation, ventriculomegaly, corpus callosal alterations, widened frontal spaces) are causing neurocognitive changes due to altered connectivity and neural plasticity.[12] In children with unilateral coronal suture involvement, those with left-sided affection predominantly showed deficits in language and reading skills and those with right-sided affection showed deficits in nonverbal learning and social perception.[12] The age at surgery has also been found to be inversely associated with poor developmental and neurocognitive outcomes.[10] Nevertheless, early identification and intervention may particularly help in improving the overall development of the child; hence, it is important to regularly screen and follow these children for any such issues. In addition, children might be facing psychosocial stress due to their physical appearance, developmental and cognitive limitations and may have impaired family functioning due to the various associated factors. These issues also need to be addressed in a growing child during rehabilitation.
| Approach to a Child With Craniosynostosis | | |
The primary aim in the evaluation of a child with craniosynostosis is to confirm the diagnosis, to look for additional findings pointing to a syndrome, to establish the causation, and to identify the complications early, for early intervention, leading to a healthier neurological, cognitive, and developmental outcome.
Clinical history
Detailed history has an important role to play while evaluating a child with craniosynostosis. History taking includes the age of onset, progression (acquired secondary craniosynostosis), the associated neurological symptoms (headache, vomiting, blurred vision, cranial nerve deficits, seizures and altered sensorium, paresis, abnormal movements, ataxia, or nystagmus), and symptoms related to other system affection (musculoskeletal, cardiac, or pulmonary). A detailed perinatal (probing into antenatal complications such as abnormal intrauterine life, intrauterine growth restriction, oligohydramnios in the mother, twin pregnancy, exposure to teratogens such as antiepileptic drug intake, radiation etc.), developmental and family history will help in etiological diagnosis.
Clinical features
The clinical manifestations can be apparent early in infancy or may appear later. Most commonly, parents are concerned about an abnormal shape of the skull or a hard ridge that can be felt on the skull and poor skull growth. Poor head growth may be incidentally picked up during routine pediatric clinic visits for vaccination. Rarely, when multiple sutures are involved, with resulting raised intracranial pressure, the child may also present with headache, vomiting, irritability or lethargy, failure to thrive, gaze palsies, vision problems, developmental issues, and learning disabilities. Overall, 35–50% of children with SSC have persistent neuropsychological deficits when they reach the school age.[12] Literature suggests that these differences persist despite surgery, especially in metopic sutural synostosis. Raised intracranial pressure is seen in one-third of children with syndromic craniosynostosis and in 15–20% of children with SSC.[14]
Examination
A meticulous clinical examination focusing on the following important aspects should be done:
Head circumference: micro/macrocephaly to differentiate between primary and secondary craniosynostosis
Anterior fontanelle (may be open or closed) and posterior fontanelle: size and shape, bulging fontanelle as evidence of raised intracranial pressure
Neurocutaneous markers
Dysmorphism (facial asymmetry, midfacial hypoplasia, hyper/hypotelorism, low set ears, displaced ears or orbits, syndactyly in Apert syndrome; big toe and broad thumb in Pfeiffer syndrome, abnormal skull shape, ridging over the skull, cleft palate, etc.) [Figure 3] represents the facial profile and dysmorphic features in a child with Apert syndrome.
Detailed neurological examination (cranial nerve deficits, fundus examination for papilledema/optic atrophy, focal neurological deficits)
Developmental examination | Figure 3: Child with Apert syndrome with the typical facies (A) and oxycephaly (B), with syndactyly of the toes in lower limbs (C)
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Investigations
A child with craniosynostosis is evaluated with computed tomography (CT) of the head (additional three-dimensional reconstruction is more beneficial) to determine the sutures affected, which, to a certain extent, will also help in evaluating underlying neuro-parenchymal abnormalities.[15] Magnetic resonance imaging (MRI) is a superior choice for brain parenchymal evaluation but it is less accurate in evaluation of the sutures.[16] CT head is more cost effective and less time consuming when compared with MRI, but it is associated with the risk of radiation exposure to the young brains. With the ongoing advancements in imaging practices, newer MRI sequencing techniques such as gradient and spin echo imaging can be used in diagnosing craniosynostosis.[17] Various studies have failed to identify increased incidence of structural brain abnormalities in SSC compared to the control population, with the overall prevalence of such abnormalities being very low.[18],[19] Among the abnormalities detected, Chiari I malformation was the most common finding, mostly incidental and was not associated with any particular sutural involvement.[19] At times, there might also be ventriculomegaly or thinning of the corpus callosum.[18] However, a routine MRI brain evaluation is unwarranted in the evaluation of nonsyndromic SSC.
Plain radiography (X-ray) skull has a limited value in comparison with either of these two modalities. Another cost-effective radiation-free alternative is ultrasound of the head, which can be used in young children with an open fontanelle. It is also effective in identifying craniosynostosis as early as in the fetus in utero.[20] In milder cases, wherein repeated follow-up imaging is required, sonography is a reliable choice and when performed by experienced radiologists, yield is comparable to the CT head.[21]
Developmental, cognitive, and psychological evaluation is usually performed in all children at regular intervals. Hearing assessment and speech and language evaluation is also routinely performed. When a syndromic diagnosis is suspected, additional investigations such as X-ray, echocardiography, or others may be needed to determine other system affection. Electroencephalography and visual evoked potentials are performed only when indicated. In recent times, with advanced genetic tests being available at an affordable price, a genetic evaluation plays a very important role in determining the etiology and predicting the recurrence risk that would aid in genetic counseling.[1] A chromosomal microarray/gene panels or exome sequencing may be offered when indicated. At the least, FGFR2/FGFR3 mutation testing is to be offered to all children with coronal/multisutural synostosis.[7]
Treatment
A multidisciplinary team consisting of developmental pediatricians, pediatric neurologists, child psychologists, neurosurgeons, plastic and reconstructive surgeons, ophthalmologists, otorhinolaryngologists, audiologists, dentists and orthodontists, geneticists, genetic counselors, and rehabilitation experts are involved in caring for a child with craniosynostosis.
The goal of treating a child with craniosynostosis is to provide adequate space within the skull for the growing brain and to improve the cosmetic appeal. When only a few sutures are involved in craniosynostosis and when the child is fairly maintained, a conservative approach is best considered. Surgery is indicated only when multiple sutures are affected and there are features of raised intracranial pressure, to prevent complications. The optimum age of intervention is controversial, and surgery is usually considered between 6 and 12 months of age when done electively.[22] However, earlier surgery has been proven to improve the neurocognitive development and morphological outcomes.[23],[24]
Surgery can be performed either endoscopically (minimally invasive, when only few sutures are affected) or as a traditional open procedure, where the sutures are reopened. Minimally invasive surgery is done with the help of an endoscope and is effective if performed early in infancy (<6 months) when the skull bones are easily moldable. It is less invasive with a shorter recovery period postoperatively and causes less blood loss. However, postsurgery, there is a need of reshaping the skull with a cranial molding helmet. Cranial molding helmets are worn for approximately 20–22 h a day till one year of age and have an outer hard shell and a foam mold on the inside, directing the skull growth to a more normal shape and require frequent adjustments by an orthotist. These helmets are also beneficial in some children with significant positional plagiocephaly, although most of them do not need any intervention.
Traditional open surgeries are usually performed in older children with firmer bones (>6 months) or where complex involvement is seen. Open surgeries provide a better access, but they have significant concerns related to blood loss, a higher rate of postoperative complications, and longer recovery time.[2] The postoperative mortality is around 2.6% and morbidity is about 12%.[2] A cranial expander spring is also sometimes used after surgery to keep the sutures separated, and a second surgery is needed later to remove them. When multiple sutures are involved, cranial distractors are also used to separate the sutures slowly and steadily with the help of screws that can be adjusted; also, a second surgery is needed for the removal of distractors. If not monitored or followed up regularly after surgery, there is a risk of refusion of the sutures.[2] Multiple-staged coordinated surgeries are often essential in children with syndromic craniosynostosis to rectify various accompanying deformities.
| Genetic Counseling | | |
When a genetic cause has not been identified and in families with no positive history, a sibling recurrence risk of 10% for bicoronal and multisutural synostosis, 5% for unicoronal synostosis, and 2% for sagittal and metopic synostosis is predicted.[7] In case of identified single gene disorders with normal parental genetic evaluation, the recurrence risk is predicted to be <1%.[7] In the remaining cases, most genes are inherited in an autosomal dominant fashion and have variable penetration and expressivity. A cautious approach is to be considered for counseling the family, and the assistance of a genetic counselor should be sought.
| Conclusions | | |
Current goals in treating children with craniosynostosis do not just aim at the correction of morphological deformity, but they aim at a comprehensive approach targeting neurodevelopment and cognition as well. With advancements in the medical turf, there are increasing opportunities to identify a child with craniosynostosis early and to intervene, thereby improving the overall outcomes and reducing the morbidity and mortality. Genetic evaluation and counseling are an essential part of evaluation, contributing to clinical management, prognostication, and family planning. Pediatric neurologists are an integral part of the multidisciplinary team and share an enormous responsibility in caring for such children. With advanced surgical interventions, the outcome is generally good with relatively normal developmental and cognitive-language abilities.
Financial support and sponsorship
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflicts of interest
The authors have no conflict of interest to disclose regarding this article.
Author contribution
SNM contributed to the writing of the initial draft of the article and the literature search.
SG contributed to the critical review and revision of the article.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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[Figure 1], [Figure 2], [Figure 3]
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