CLINICAL STUDY
Craniofrontonasal Dysplasia: Variability of the Frontonasal Suture and Implications for Treatment Erik Matthew Wolfswinkel, BS, William M. Weathers, MD, Bryan Correa, MD, Edward P. Buchanan, MD, and Larry H. Hollier Jr, MD, FACS Abstract: Craniofrontonasal dysplasia’s (CFND’s) phenotypic range includes hypertelorism, coronal craniosynostosis, frontonasal dysplasia, and digital anomalies. The variable expression is paradoxical for an X-linked syndrome because hemizygous males are less affected than heterozygous females. We describe a case of CFND due to a c.309T EFNB1 gene mutation. In place of the typical craniosynostosis found in CFND, she presented with a superiorly displaced nasion and an anomalously positioned frontonasal suture. This report reveals an unreported malformation in CFND and its surgical implications. Key Words: Craniofrontonasal dysplasia, craniofrontonasal syndrome, hypertelorism, frontonasal suture, EFNB1, Ephrin-B1 (J Craniofac Surg 2013;24: 1303Y1306)
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raniofrontonasal dysplasia (CFND) is an X-linked malformation syndrome characterized by variable phenotypes. The phenotypic range includes hypertelorism, coronal craniosynostosis, a broad or bifid nasal tip, dental anomalies, dry wiry hair, and several extremity anomalies.1 The variable expression is unusual for X-linked syndromes in that hemizygous males are less affected than heterozygous females.2 This paradoxical pattern is explained by random X inactivation in the heterozygote female patients resulting in mosaic loss of ephrin-B1 function. A mutation in the EFNB1 gene, which codes for ephrin-B1 transmembrane proteins, is found in the majority of both familial and sporadic CFND patients.3 Ephrin-B1 forms signaling complexes with Eph receptor tyrosine kinases that function in the formation of tissue boundaries by controlling cell migration, adhesion, sorting, midline fusion, neural guidance, and synaptogenesis.4Y6 Altered ephrin-mediated cell sorting leads to ectopic boundary expression.7,8 It is important clinically to be aware of the variation in phenotypes of CFND as it can have implications on treatment. This report evaluates a female patient with CFND due to a mutation in the EFNB1 gene with a high-riding frontonasal suture. This aberration of the frontonasal suture provided a stimulus for hypotheses as to her craniofacial dysmorphogenesis and must be considered when determining the surgical approach for correction of hypertelorism.
From the Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Received February 5, 2013. Accepted for publication March 25, 2013. Address correspondence and reprint requests to Erik Matthew Wolfswinkel, BS, Baylor College of Medicine, 6701 Fannin St, CC 610.00, Houston, TX 77030; E-mail:
[email protected] Mr Wolfswinkel is a medical student at Baylor College of Medicine. The authors report no conflicts of interest. Copyright * 2013 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0b013e3182942b5c
The Journal of Craniofacial Surgery
CLINICAL REPORT We present an 11-year-old girl diagnosed with CFND. The patient was born with multiple congenital anomalies consisting of severe ocular hypertelorism, frontal bossing, hypoplastic corpus callosum, a pulmonic valve abnormality, hiatal hernia, ectopically placed kidney, anteriorly placed anus, widely spaced and low-set nipples, bilateral fifth-finger clinodactyly, various clinodactyly of the toe digits, joint laxity, dental anomalies, and grooved nails. Her language and motor development were delayed. She is the product of the first pregnancy to a then 26-year-old mother. She was born 2 weeks postterm, weighing approximately 3.8 kg. The maternal health during pregnancy was unremarkable. Complications such as infections, vaginal bleeding, hypertension, excessive weight gain, and ingestion of teratogens were denied by the mother. While pregnant, she did not smoke or abuse alcohol. There is no history of consanguinity. There was no family history suggestive of a similar problem. At 2 years of age, the patient underwent a multidisciplinary evaluation and physical examination. A chromosome analysis was performed and was unremarkable. Several diagnoses were considered at this time including CFND, Smith-Lemli-Opitz syndrome, frontonasal dysplasia, and others. Computed tomography scans were performed showing dysmorphic facial development with relative reduction in overall anteroposterior dimensions, laterally oriented orbits, and hypertelorism. There was no evidence of craniosynostosis. There was, however, callosal dysgenesis and incomplete division of the striatum. The multidisciplinary team concluded that she would need surgical intervention to address her orbital hypertelorism. The option of utilizing a nasal bone graft was discussed; however, there was agreement that this would not be a good option to adequately camouflage her deformity. Instead, the consensus was that she would be a candidate for orbital repositioning when she reached 8 to 9 years of age. She was followed up yearly by the Craniofacial Multidisciplinary Clinic and Genetics. Genetics further investigated her diagnosis by testing for mutations of the EFNB1 gene by DNA sequencing. A polymerase chain reactionYamplified analysis of exons 1 to 5 of the EFNB1 gene and their flanking splice sites was performed. A bidirectional sequence was obtained, and DNA sequences were analyzed and compared with the published gene sequence. The patient was heterozygous for the C9T nucleotide substitution in exon 1 of the EFNB1 gene. This mutation results in a synonymous amino acid change at position 10, as the normal GGC codon is replaced with a GGT codon, both of which code for glycine. This mutation is denoted c.30 C9T at the cDNA level. The c.30 C9T mutation in the EFNB1 gene has been previously published in a female patient with sporadic CFND and developmental delay. RNA analysis indicates c.309T creates a cryptic splice donor site, causing abnormal gene splicing.3 Therefore, the presence of c.30 C9T is consistent with the diagnosis of CFND in this individual and altered EFNB1 function. The primary dysmorphic feature noticed is the patient’s hypertelorism (Fig. 1). The mother states she was constantly being teased at school and requested surgical intervention to correct her
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FIGURE 3. An arrow points to the high-riding frontonasal suture anomalously positioned above the low and dysplastic anterior cranial fossa. FIGURE 1. Ocular hypertelorism, referring to an increased distance between the orbits, is found in both affected male and females with CFND. Our patient had severe hypertelorism, presented here at ages 2 and 9 years. Also noted is her thick wiry hair. Photo used with permission from the patient’s guardian.
hypertelorism. The patient underwent preoperative workup and computed tomography as part of the surgical planning. During this study, the dysmorphic appearance of the orbits remained stable along with the hypoplastic corpus callosum compared with previous studies. Again there was no evidence of craniosynostosis. A dysplastic frontonasal suture was visualized on three-dimensional computed tomography reconstruction. The frontonasal suture remained continuous with the frontomaxillary suture, used for identification, but was comprised of an inverted-V shape, with the nasion displaced approximately 2 cm superiorly (Fig. 2). Her anterior cranial fossa was abnormal and located inferior to where expected (Fig. 3).
SURGICAL TECHNIQUES Box Osteotomies Paul Tessier9 performed the first treatment for orbital hypertelorism using box osteotomies. Various osteotomies separate the
FIGURE 2. A dysplastic frontonasal suture visualized on three-dimensional computed tomography reconstruction. The frontonasal suture normally runs across the top of the bridge of the nose but here is composed of an inverted-V shape, with the nasion displaced approximately 2 cm superiorly.
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entire bony orbit from the skull and surrounding facial bones. The central segment including the nasal bones and ethmoids is removed. The orbits are then mobilized and translocated toward the midline to an anatomically normal position. This approximates the eyebrows and eye corners and provides a pleasing aesthetic result.
Facial Bipartition Jacques van der Meulen10,11 modified the box osteotomies procedure, creating the facial bipartition. Facial bipartition involves separating the frontal bone from the supraorbital rim followed by monoblock osteotomies, releasing the orbits and midface from the skull base. Then, a triangular piece of bone, with the apex between the upper incisors, is removed from the midface. The bipartitioned midfaces are rotated toward each other, reducing the space between the orbits. This also results in widening of the maxilla and can be combined with distraction osteogenesis of the midface to normalize the relationship of the orbits, nose, and maxilla in relation to one another.12
Subcranial Approach The subcranial approach for the correction of hypertelorism was introduced by Vuillemin and Raveh13 in 1990. The technique includes complete ethmoid cell resection and osteotomies of the skull base and orbital roof with advancement of the fronto-orbital segments. This is advantageous over transfrontal approach because it avoids frontal lobe retraction. During transethmoidal resection of the ethmoid cells, the subcranial approach is performed caudally to the frontonasal suture. When considering the surgical approach, because of the severity of hypertelorism, only 2 of the aforementioned options were considered: box osteotomies and facial bipartition. Bipartition was deemed unnecessary as our patient had good occlusion and did not require maxillary widening. Therefore, we proceeded with box osteotomies and orbital repositioning. The postoperative interdacryon distance was reduced to 32 mm from 58 mm preoperatively. Bone grafts were placed laterally to prevent lateral migration of the box osteotomies. A bone graft was also fashioned to fill the central segment to give her good nasal projection. Following a successful surgery, the patient suffered from meningitis on postoperative day 8, which responded to a 2-week course of intravenous antibiotics. Since then, the patient has been doing well and is followed in the Craniofacial Multidisciplinary Clinic. She is noted to have significant improvement of her orbital hypertelorism postoperatively. * 2013 Mutaz B. Habal, MD
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CFND: Frontonasal Suture Variability
DISCUSSION Craniofrontonasal dysplasia is an X-linked condition resulting in diverse clinical phenotypes, primarily including coronal craniosynostosis, hypertelorism, bifid or absent nasal tip, and digital findings in heterozygous females and hypertelorism in hemizygous affected males.14,15 The shared and most common dysmorphic feature detected is hypertelorism. Craniosynostosis, usually unicoronal, is observed in 64% to 82% of affected females, but is rare in affected males.1,16 Our patient presented with a majority of these findings including hypertelorism, broad nasal tip, agenesis of the corpus callosum, developmental delay, clinodactyly of the fifth digit and several toes, joint laxity, thick wiry hair, and grooved nails. She also presented with additional congenital anomalies including pulmonic valve abnormality, an ectopically placed kidney, anteriorly placed anus, widely spaced and low-set nipples, and aberration of the frontonasal suture. In 87% of cases, CFND is the result of a loss-of-function mutations in EFNB1 gene.14,17Y19 The gene EFNB1, encoding ephrin-B1, is responsible for bidirectional cell signaling, tissue boundary formation, cell migration, and pattern formation during developmental morphogenesis.20 Ephrin-B1 forms signaling complexes with Eph receptor tyrosine kinases and is expressed in frontonasal neural crest. Mice with loss-of-function mutations of EFNB1 manifest similar CFND phenotypes.21 Murine models also demonstrated defects in neural crest migration and craniofacial morphogenesis with inactivation of the ephrin transduction system.4 In several tissues, ephrin ligand and receptors show complementary expression allowing for bidirectional cell signaling.1,17 Later studies have shown the complexity of this signaling system, demonstrating that ephrin-B1 PDZ domainYdependent reverse signaling controls corpus callosum neuronal axon guidance, whereas forward signaling aids in the development of craniofacial morphology.16,22 Alteration of the forward signal due to a loss-of-function mutation of EFBN1 gene therefore results in the dysplastic features of CFND. With coronal craniosynostosis observed in up to 82% of affected females, one would expect our patient to have synostosis of at least one of her coronal sutures.1 Without craniosynostosis, our patient’s dysplastic formation of sutures presented with abnormal positioning of the frontonasal suture. The frontonasal suture is continuous with the frontomaxillary suture normally running across the top of the bridge of the nose. It is a serrate suture between the superior border of the nasal bones and the nasal process of the frontal bone. An extension of this suture posteriorly would mark the height of the anterior cranial fossa. The loss of function of the ephrin-B1 ligand and Eph receptor tyrosine kinases, known to function in the formation of this suture, likely caused its anomalous positioning. The c.30 C9T mutation causes abnormal gene splicing resulting in alternative protein isoforms, altering neural crest migration and forward signaling, and ultimately altering craniofacial morphogenesis.3,14 These factors arresting migration plausibly contributed to a 2-cm anteriorly displaced nasion, inverted-V suture, relatively long but anteriorly placed nasal bones, failure of nasal capsule to properly form, and her most aesthetically prominent feature, hypertelorism.4 Behind the suture was highly congested dura, emphasizing the migration arrest. This aberration in suture position illustrates the variable impact of EFNB1 function loss in this congenital malformation syndrome. The EFNB1 function loss and superiorly displaced frontonasal suture also has implication for surgical treatment. Intraoperatively, the high anatomical location of the nasion was confirmed (Fig. 4). In our experience, a theoretical extension of the frontonasal suture usually serves as a boundary marker for the cranial floor. This was not the case in this patient, given the high position of her frontonasal suture and low anterior cranial fossa. We feel that the subcranial approach would not be the safest alternative for a patient with this aberration.
FIGURE 4. Intraoperative conformation of the anomalously placed frontonasal suture with superiorly displaced nasion. A bifrontal craniotomy was performed anteriorly to the superior orbital rims. Four bur holes were made including the one shown in the figure just above the nasion over the dysplastic frontonasal suture. The blood-tinged suture can be seen starting inferiorly to the bur hole and followed down into the orbits. The superior and medial portions of the box osteotomies are outlined.
The main advantage of the subcranial approach is avoiding fontal lobe retraction by subcranial resection of the ethmoid cells and frontonasal and ethmoid roofs.13 Provided a high-riding frontonasal suture, loss of cranial landmarks, and a low abnormal cranial floor, the subcranial approach would be a high-risk procedure. Without knowing the height of the anterior cranial fossa, it would be possible to resect through the cranial floor and into the cranial vault. In summary, we have described a patient with many classic CFND features due to a c.309T EFNB1 gene mutation. Although she did not have craniosynostosis typically found in CFND, she presented with superiorly displaced nasion and anomalously positioned frontonasal suture. This aberration in suture position illuminates the variable impact of EFNB1 function loss in this syndrome and should be considered when determining surgical treatment options.
REFERENCES 1. Wieacker P, Wieland I. Clinical and genetic aspects of craniofrontonasal syndrome: towards resolving a genetic paradox. Mol Genet Metab 2005;86:110Y116 2. Makarov R, Steiner B, Gucev Z, et al. The impact of CFNS-causing EFNB1 mutations on ephrin-B1 function. BMC Med Genet 2010;11:98Y107 3. Twigg SF, Matsumoto K, Kidd AJ, et al. The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males. Am J Hum Genet 2006;78:999Y1010 4. Poliakov A, Cotrina M, Wilkinson DG. Diverse roles of Eph receptors and ephrins in the regulation of cell migration and tissue assembly. Dev Cell 2004;7:465Y480 5. Klein R. Eph/ephrin signaling in morphogenesis, neural development and plasticity. Curr Opin Cell Biol 2004;16:580Y589 6. Pasquale EB. Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol 2005;6:462Y475 7. Compagni A, Logan M, Klein R, et al. Control of skeletal patterning by ephrin B1YEphB interactions. Dev Cell 2003;5:217Y230 8. Davy A, Soriano P. Ephrin signaling in vivo: look both ways. Dev Dyn 2005;232:1Y10 9. Tessier P, Guiot G, Derome P. Orbital hypertelorism. II. Definite treatment of orbital hypertelorism (OR.H.) by craniofacial or by extracranial osteotomies. Scand J Plast Recons 1973;7:39Y58 10. van der Meulen JC. The pursuit of symmetry in cranio-facial surgery. Brit J Plast Surg 1976;29:85Y91 11. van der Meulen JC. Medial faciotomy. Brit J Plast Surg 1979;32:339Y342
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12. Richardson D, Thiruchelvam JK. Craniofacial surgery for orbital malformations. Eye 2006;20:1224Y1227 13. Vuillemin T, Raveh J. Subcranial approach for the correction of hypertelorism. J Craniofac Surg 1990;1:91Y96 14. Twigg SF, Kan R, Babbs C, et al. Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc Natl Acad Sci U S A 2004;101:8652Y8657 15. Wieland I, Reardon W, Jakubiczka S, et al. Twenty-six novel EFNB1 mutations in familial and sporadic craniofrontonasal syndrome (CFNS). Hum Mutat 2005;26:113Y118 16. Zafeiriou DI, Pavlidou EL, Vargami E. Diverse clinical and genetic aspects of craniofrontonasal syndrome. Pediatr Neurol 2011;44:83Y87 17. Wieland I, Jakubiczka S, Muschke P, et al. Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. Am J Hum Genet 2004;74:1209Y1215
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18. Vasudevan PC, Twigg SF, Mulliken JB, et al. Expanding the phenotype of craniofrontonasal syndrome: two unrelated boys with EFNB1 mutations and congenital diaphragmatic hernia. Eur J Hum Genet 2006;14:884Y887 19. Wallis D, Lacbawan F, Jain M, et al. Additional EFNB1 mutations in craniofrontonasal syndrome. Am J Med Genet A 2008;146:2008Y2012 20. Bush JO, Soriano P. Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries. Gene Dev 2010;24:2068Y2080 21. Wieland I, Makarov R, Reardon W, et al. Dissecting the molecular mechanisms in craniofrontonasal syndrome: differential mRNA expression of mutant EFNB1 and the cellular mosaic. Eur J Hum Genet 2008;16:184Y191 22. Bush JO, Soriano P. Ephrin-B1 regulates axon guidance by reverse signaling through a PDZ-dependent mechanism. Gene Dev 2009;23:1586Y1599
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