Craniosynostosis Syndromes

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Introduction

Craniosynostosis is a malformation that involves the early closure of a single or multiple sutures of the skull. An isolated craniosynostosis may occur or this condition may be associated with other abnormalities as part of a syndrome. Craniosynostosis syndromes are a set of genetic disorders that are characterized by the premature fusion of cranial sutures which can impair proper brain and craniofacial development from irregular bone formation [1-4]. There are close to 200 known syndromes of which craniosynostosis is associated. These syndromes are primarily differentiated by the type of suture and gene mutation involved [5].

Crouzon and Apert syndromes are two of the most common craniosynostosis syndromes, the latter being more relatively uncommon of the two as it only appears in 1 out of 100,000 to 160,000 live births [1-4]. Crouzon syndrome, in comparison, occurs in about 1 out of 25,000 live births [1-4]. The severity of the cranial bone deformations, associated systemic abnormalities and age of diagnosis may yield variable treatment outcomes and overall prognosis [6].

Signs and Symptoms

Generally, symptoms of craniosynostosis syndromes are specific to the suture involved and time of diagnosis. For instance, premature closure of the coronal suture would result in a short, broad skull, while premature closure of the sagittal suture would result in a long, narrow skull [5]. Infants with Crouzon or Apert syndromes face many similar potential clinical problems such as proptosis, shallow orbits, hypertelorism, strabismus, malocclusion, and hearing loss; many of these features are directly associated with bilateral coronal synostosis, which gives the appearance of a flat skull shape and the head appears tall and wide [7]. Hydrocephalus may be present in craniosynostosis as well.

Distinct deformations of the skull and extremities specific to Apert’s syndrome include a fused skull and an abnormally long or wide appearance to the skull. The hands and feet are comprised of soft tissue which, in many cases, leads to bone syndactyly [5], giving the extremities a webbed appearance [8]. Infants with Apert syndrome also face greater developmental impairments than those with Crouzon syndrome [9]. Crouzon syndrome manifests itself very similarly to Apert syndrome, but infants with this syndrome are more susceptible to keratitis, intranasal obstruction, and a v-shaped palate [3].

Cranial Deformities

Under normal conditions in the absence of structural anomalies caused by craniosynostosis or other conditions the infant head is normocephalic and symmetrical along the sagittal suture. Craniosynostosis presents itself in different forms; bilateral coronal synostosis is the most common type of deformity associated with Apert and Crouzon syndromes, in which the head appears short from front to back [7], hence the more common name, brachycephaly [4]. Another form is scaphocephaly, in which the sagittal suture fuses prematurely, thus fusing the parietal bones [6, 10].

Trigonocephaly is when the frontal or metopic suture fuses prematurely and the frontal bones become fused, as a result [6, 10]. The head also takes a slightly triangular shape, as indicated by the name. In anterior plagiocephaly, the coronal suture between the frontal and parietal bones fuse, leaving the occipital bone unaffected [11, 12]. In contrast, the occipital and parietal bones may fuse as a result of premature fusion of the lambdoid suture leaving the frontal bones unaffected [6, 10, 12].

Another cranial deformity is known as deformational plagiocephaly, which is not a result of premature fusion of a particular suture, but occurs when tissues press against an infant’s developing head in utero and give the appearance of a flattened head [4, 13]. This is typically of a lesser clinically significant in comparison, and the most common of the cranial deformities, occurring in about 5 to 45 percent of otherwise healthy infants [14]. This deformity can be treated non-surgically [10].

Inheritance Patterns

Craniosynostosis syndromes often occur spontaneously due to a de novo autosomal dominant mutation or they may be inherited by either an autosomal dominant (Figure 1) or autosomal recessive manner [5, 15]. Apert and Crouzon syndromes are autosomal dominant conditions, meaning that only one copy of the altered gene is necessary to cause the disorder [15]. A minority of the craniosynostosis syndromes have an autosomal recessive transmission, in which mutations in both copies of the gene in each cell must be present [15].

AA0 4501.jpg Figure 1. Example of an autosomal dominant inheritance pattern. Image courtesy of the American Academy of Ophthalmology (http://www.aao.org/clinical-education).

Genetics and Testing

Many of the craniosynostosis syndromes are caused by mutations in the FGFR1, FGFR2, and FGFR3 genes. FGFR2 mutations are present in Apert and Crouzon syndromes, as well as Pfeiffer syndrome (types 1-3), Jackson-Weiss syndrome, Beare-Stevenson syndrome and FGFR2-related isolated coronal synostosis [5]. Mutations in FGFR1 are associated with Pfeiffer syndrome (type 1) [5]. Mutations in FGFR3 are associated with Crouzon syndrome with acanthosis nigricans and also Muenke syndrome [5]. The FGFRs (fibroblast growth factor receptors) are normally responsible for suppressing excessive limb growth, therefore, a mutation in the FGFR gene is hypermorphic, as it excessively increases its gene’s product function [5, 16].

Craniosynostosis syndromes can be detected as early as in the prenatal period during ultrasound imaging, which may prompt the consideration of molecular genetic testing. Molecular genetic testing is only predictive if the disease causing mutation has already been identified in the family; furthermore the actual predictive value is generally considered to be poor [5]. If prenatal images indicate signs such as ventriculomegaly and increased biparietal diameter caused by hydrocephalus, or a cloverleaf shaped skull, preimplantation genetic diagnosis (PGD) can be offered (prior identification of mutation must be known) [17,18]. Otherwise, testing is generally rendered ineffectual in low risk cases and a definitive diagnosis is made after birth.

Test methods include deletion and duplication analyses, such as quantitative PCR, long-range PCR, multiplex ligation dependent probe amplification (MLPA), and chromosomal microarray [5]. Sequence analyses are typically not used as the initial diagnostic method since the mutations are not readily found using this technique. Instead, sequence analysis is generally used to confirm diagnosis in the infant [19].

Management and Treatment

There is no uniform treatment that encompasses all the potential manifestations of the craniosynostosis syndromes; treatment methods are multifaceted and dependent on factors such as the age, time of diagnosis, suture(s) involved, severity of the condition, and whether or not other systemic clinical features are present [5, 6]. Plastic surgeons, Neurosurgeons, Pediatricians, Otolaryngologists, Geneticists, and Ophthalmologists and other specialists are often needed to collaborate on a management and treatment plan [5].

The primary goal of treatment is generally to increase cranial volume to make space for an infant’s developing brain, and to minimize intracranial pressure, which left untreated could lead to hydrocephalus or more developmental defects [6]. For this reason, when indicated, treatment should begin as soon as possible and preferably before the end of an infant’s craniofacial growth period; treating craniosynostosis syndromes as early as possible may also potentially decrease the need for additional surgeries and may yield better functional as well as cosmetic results in certain cases [5, 20, 21]. Endoscopic surgery can be done in infants as young as 3 months of age; the surgeon creates small incisions in the scalp to view the anatomy of the skull, and then opens the affected suture to enable brain growth [22]. An early infant age may allow for an increased plasticity of the fontanelles and suture(s) involved [5]. A more traditional surgery known as calvarial vault remodeling is performed on infants older than 6 months of age, and involves moving affected areas and reshaping the skull [22]. A bilateral craniotomy with a fronto-orbital advancement can also be performed in older infants to create space for brain development [5].

Generally, non-syndromic cases of craniosynostosis require fewer surgeries than syndromic cases [5, 23]. For example infants with Apert’s syndrome, compared with non-syndromic cases, have a greater frequency of follow-up surgeries to correct their forehead shape, and may often experience minimal functional improvement after surgery to correct their bone syndactyly [24, 25].

Additional Resources

References

1. Corde Mason A, Bentz ML, Losken W. Craniofacial syndromes. In: Zitelli BJ, Davis HW, eds. Atlas of pediatric physical diagnosis. 4th ed. St. Louis: Mosby, 2002:803–17.

2. Haidar Kabbani, MD and Talkad S. Raghuveer, MD. Craniosynostosis. Am Fam Physician. 2004 Jun 15;69(12):2863-2870.

3. Craniosynostosis and Craniofacial Disorders. September, 2005. http://www.aans.org/Patient%20Information/Conditions%20and%20Treatments/Craniosynostosis%20and%20Craniofacial%20Disorders.aspx

4. Craniofacial/Skull. Retrieved July 1, 2015 from http://www.kidsplastsurg.com/craniofacial-anomalies/#apert

5. Nathaniel H Robin, MD, Marni J Falk, MD, and Chad R Haldeman-Englert, MD. FGFR-Related Craniosynostosis Syndromes. GeneReviews® [Internet]. Initial Posting: October 20, 1998; Last Update: June 7, 2011.

6. Craniosynostosis. Retrieved July 1, 2015 from http://www.chw.org/medical-care/neuroscience/conditions/craniosynostosis/

7. Bilateral Coronal Synostosis. Retrieved July 1, 2015 from https://www.childrens.com/specialties-services/specialty-centers-and-programs/plastic-craniofacial-surgery/programs-and-services/craniofacial-program/conditions-and-treatments/craniosynostosis/isolated-craniosynostosis/bilateral-coronal-synostosis

8. Andrew O. M. Wilkie. Craniosynostosis: Genes and Mechanisms. Hum. Mol. Genet. (1997) 6 (10): 1647-1656. doi: 10.1093/hmg/6.10.1647

9. Renier D, Arnaud E, Cinalli G, Sebag G, Zerah M, Marchac D. Prognosis for mental function in Apert's syndrome. J Neurosurg. 1996;85:66–72. [PubMed]

10. Common variation in craniosynostosis presentations. Retrieved July 1, 2015 from http://www.uptodate.com/contents/image?imageKey=ALLRG%2F52793&topicKey=ALLRG%2F2910&source=see_link&utdPopup=true

11. Lambdoidal Synostosis. Retrieved July 1, 2015 from http://www.ohsu.edu/xd/health/services/doernbecher/programs-services/lambdoidal.cfm

12. What are the different types of craniosynostosis? Retrieved July 1, 2015. http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/pediatric_neurosurgery/conditions/craniosynostosis/types.html

13. Plagiocephaly. Retrieved July 1, 2015 from http://smilesforkids.missouri.edu/common-conditions/plagiocephaly/

14. Deformational Plagiocephaly. Retrieved July 1, 2015 from http://www.facesofchildren.org/Deformational%20Plagiocephaly

15. What is Craniosynostosis? Retrieved July 1, 2015 from http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/pediatric_neurosurgery/conditions/craniosynostosis/

16. Hypermorphic Mutation. June 23, 2015. http://www.informatics.jax.org/glossary/hypermorphic

17. Chen CP, Su YN, Hsu CY, Ling PY, Tsai FJ, Chern SR, Wu PC, Chen HE, Wang W. Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome following sonographic findings of mild ventriculomegaly and clenched hands mimicking trisomy 18. Taiwan J Obstet Gynecol. 2010;49:129–32.[PubMed]

18. Weber B, Schwabegger AH, Vodopiutz J, Janecke AR, Forstner R, Steiner H. Prenatal diagnosis of apert syndrome with cloverleaf skull deformity using ultrasound, fetal magnetic resonance imaging and genetic analysis. Fetal Diagn Ther. 2010;27:51–6. [PubMed]

19. Bochukova EG, Roscioli T, Hedges DJ, Taylor IB, Johnson D, David DJ, Deininger PL, Wilkie AO. Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily. Hum Mutat. 2009;30:204–11. [PubMed]

20. Lajeunie E, Bonaventure J, El Ghouzzi V, Catala M, Renier D. Monozygotic twins with Crouzon syndrome: concordance for craniosynostosis and discordance for thumb duplication. Am J Med Genet. 2000;91:159–60.[PubMed]

21. Renier D, Lajeunie E, Arnaud E, Marchac D. Management of craniosynostoses. Childs Nerv Syst.2000b;16:645–58. [PubMed]

22. Surgical Options for Craniosynostosis. Retrieved July 1, 2015 from http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/pediatric_neurosurgery/conditions/craniosynostosis/surgery.html

23. Definition of Nonsyndromic. August 28, 2013. http://www.medicinenet.com/script/main/art.asp?articlekey=21328

24. American Cleft Palate-Craniofacial Association; Parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies. Cleft Palate Craniofac J. 1993;30:S1–16. [PubMed]

25. Thomas GP, Wilkie AO, Richards PG, Wall SA. FGFR3 P250R mutation increases the risk of reoperation in apparent 'nonsyndromic' coronal craniosynostosis. J Craniofac Surg. 2005;16:347–52. [PubMed]