CLINICAL STUDY
Achondroplasia and Multiple-Suture Craniosynostosis Frank P. Albino, MD,* Benjamin C. Wood, MD,* Chima O. Oluigbo, MD,† Angela C. Lee, MD,‡ Albert K. Oh, MD,* and Gary F. Rogers, MD, MPH*
Abstract: Genetic mutations in the fibroblast growth factor receptor 3 gene may lead to achondroplasia or syndromic forms of craniosynostosis. Despite sharing a common genetic basis, craniosynostosis has rarely been described in cases of confirmed achondroplasia. We report an infant with achondroplasia who developed progressive multiple-suture craniosynostosis to discuss the genetic link between these clinical entities and to describe the technical challenges associated with the operative management. Key Words: Multiple-suture craniosynostosis, achondroplasia, FGFR (J Craniofac Surg 2015;26: 222–225)
C
raniosynostosis, the premature fusion of 1 or more cranial sutures, is rare, with an overall incidence between 1:2000 and 1:2500 live births.1,2 Syndromic forms of craniosynostosis generally have an identifiable causative genetic mutation, whereas nonsyndromic cases typically do not. Mutations in fibroblast growth factor receptors (FGFR1–3) are responsible for most craniosynostosis syndromes (eg, Pfeiffer, Apert, Crouzon, and Jackson-Weiss syndromes); however, other genetic causes have been identified, such as TWIST (Saethre-Chotzen syndrome), MSX-2 (Boston-type craniosynostosis), and EFNB-1 (craniofrontonasal malformation).1–4 Nearly 25% of all identified mutations that cause craniosynostosis involve the FGFR3 gene.1 Specifically, FGFR3 gain-of-function mutations are responsible for Muenke syndrome, a common cause of syndromic coronal suture fusion, and the less common Crouzon syndrome with acanthosis nigricans.5–7 In addition to these syndromic forms of craniosynostosis, FGFR3 activating mutations may also result in achondroplasia.3,4,8 As the most common cause of short-limb dwarfism, achondroplasia affects 5 to 15:100,000 live births and is characterized by macrocephaly, frontal bossing, midface hypoplasia, short stature, rhizomelic limb shortening, and trident hands.2,4 Although achondroplasia or craniosynostosis may result from point
From the *Divisions of Plastic Surgery, †Neurosurgery, and ‡Anesthesiology, Sedation and Perioperative Medicine, Children's National Medical Center, Washington, DC. Received June 11, 2014. Accepted for publication July 31, 2014. Address correspondence and reprint requests to Gary F. Rogers, MD, JD, MBA, MPH, Division of Plastic Surgery, Children's National Medical Center, 111 Michigan Ave NW, West Wing, 4th Floor, Suite 100, Washington, DC 20010; E-mail: [email protected] The authors report no conflicts of interest. Copyright © 2014 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000001267
222
mutations in the transmembrane domain of FGFR3, premature cranial suture fusion is rarely described in cases of achondroplasia. We report on an infant with multisutural craniosynostosis and achondroplasia to offer a genetic link between these clinical entities and to discuss the operative challenges faced in managing his fused sutures.
CLINICAL REPORT A male infant born at 25 weeks of gestation to a G4P1 mother was transferred to our institution after an abdominal delivery complicated by prolonged, premature rupture of amniotic membranes. He was initially treated for respiratory distress as well as sepsis and ultimately required tracheostomy for refractory apnea and respiratory failure. Physical findings included subtle frontal bossing and midface hypoplasia, exophthalmos, rhizomelic limb shortening, trident hands, as well as narrowing of the spinal pedicles (Figs. 1, 2). There was radiographic evidence of generalized skeletal dysplasia; subsequent genetic testing confirmed the diagnosis of achondroplasia with a causative Gly380Arg FGFR3 mutation. Computed tomographic (CT) scans of the head and neck demonstrated bilateral coronal synostosis and severe stenosis of the foramen magnum. At 5 months corrected age, he underwent decompression of the foramen magnum and a C1 laminectomy. A subsequent CT scan taken to evaluate the decompression demonstrated progression of the craniosynostosis with additional involvement of both squamosal sutures, bulging in the region of the anterior fontanel, and jugular venous stenosis (Fig. 3). Review of his cranial growth revealed a gradual decline in percentile head circumference, dropping from the 50th percentile to less than the 5th percentile on the adjusted achondroplasia-male head circumference growth chart during this 5-month period7 (Fig. 4). These findings were strongly suggestive of imminent intracranial hypertension, and a cranial vault expansion was planned. Because of the severe jugular venous stenosis, a preoperative magnetic resonance imaging/magnetic resonance angiography was ordered to assess the cerebral vascularity. The scan demonstrated significant transosseous venous collaterals in the mastoid and posterior temporal regions that appeared to be the primary outflow of the brain. To reduce the risk for disrupting all cerebral outflow and causing cerebral herniation, the decision was made to avoid a posterior dissection and to focus the expansion in the anterior and lateral regions. At 9 months corrected age, the patient underwent bilateral frontal orbital advancement with biparietal outfracturing for lateral expansion. Multiple large anterior and apical emissary veins were encountered intraoperatively, and each was carefully dissected and cauterized with minimal blood loss. Nevertheless, numerous intraosseous blood vessels were encountered during the subsequent craniotomy and approximately 1500 mL of blood was lost during the removal of the frontal segment alone. The dura was very thin and immediately bulged upon opening of the cranial vault. The procedure was stopped until the patient was sufficiently resuscitated. The remaining osteotomies and cranial reconstruction were easily completed with only an additional 200 mL of bleeding. The cranial
The Journal of Craniofacial Surgery • Volume 26, Number 1, January 2015
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
The Journal of Craniofacial Surgery • Volume 26, Number 1, January 2015
Achondroplasia
FIGURE 1. A to D, Preoperative photographs demonstrating brachycephaly, hypertelorism, midface hypoplasia, and flattened nasal bridge.
FIGURE 2. Anteroposterior x-ray of the infant's left hand taken during a skeletal survey at 5 months of age demonstrating trident hand.
© 2014 Mutaz B. Habal, MD
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
223
The Journal of Craniofacial Surgery • Volume 26, Number 1, January 2015
Albino et al
FIGURE 3. A to D, Three-dimensional reconstruction of preoperative head CT notable for bilateral coronal and squamous suture synostosis at 6 months old.
expansion included a 1.5-cm frontal advancement and expansion of both parietal segments. The moved osseous structures were affixed with absorbable plates and screws. Generous scoring of the galea was required to close the scalp. The patient recovered uneventfully and was discharged home in 3 weeks with routine tracheostomy care. The combined expansion results in a 2.5-cm increase in head circumference.
DISCUSSION Craniosynostosis is a rare finding in patients with achondroplasia. If the incidence of each condition is considered as an independent variable, the probability of these events occurring simultaneously approaches 1:40,000,000 live births. There have only been 5 publications reporting 7 cases of multiple-suture craniosynostosis in the setting of confirmed skeletal dysplasias, and although it is possible, other cases of affected patients have not been reported. The apparent rarity of this association suggests that a concurrence is random.2–4,9,10 Nevertheless, the possibility of an association warrants further consideration for 2 reasons: first, FGFR3 signaling is instrumental in regulating both membranous (cranial) and endochondral (axial or appendicular) ossification; and second, mutations affecting the FGFR3 transmembrane domain are causative in both achondroplasia and certain forms of syndromic craniosynostosis.6 There are 4 fibroblast growth factor receptors (1–4) mapped to p16.3 of chromosome 4. Each serves as a tyrosine kinase receptor to inhibit bone growth and chondrocyte proliferation.6 Once activated, FGFR3 is responsible for the patterning, proliferation, differentiation, and migration of tissue of osteogenic fate as demonstrated by both human sampling and animal studies.7,11–13 Fibroblast growth factor receptor 3 negatively regulates bone growth with
224
gain-of-function mutations leading to constitutive FGFR3 activation, upregulation of STAT to propagate downstream signaling, transcription of chondrocyte proliferation inhibitors, and cell cycle arrest.7,11–13 Gain-of-function FGFR3 mutations activate STAT signaling pathways, inhibit chondrocyte development, and lead to arrested bone growth by both membranous and endochondral ossification as seen in craniosynostosis and skeletal dysplasia, respectively.7,11–13 Fibroblast growth factor receptor 3–related skeletal dysplasias represent a spectrum of disorders ranging from the mild hypochondroplasia, to a more severe achondroplasia, to lethal thanatophoric dysplasia. Hypochondroplasia, characterized by short stature, micromelia, and lumbar lordosis, most commonly results from an Asn540Lys FGFR3 mutation, whereas achondroplasia and thanatophoric dysplasia are commonly caused by Gly380Arg and Lys650Glu FGFR3 mutations, respectively. The Gly380Arg FGFR3 mutation observed in our patient is the most common genetic point mutation found in patients with achondroplasia. The skeletal effects of FGFR3 mutations may extend beyond impaired endochondral ossification for patients with achondroplasia and evidence of craniosynostosis. A recent animal study using FGFR3knockout mice as a model of achondroplasia demonstrated premature coronal suture fusion, abnormal foramen magnum architecture, and nonossified frontal bone gaps.8 Fibroblast growth factor receptor 3 mutations are also responsible for at least 2 forms of syndromic craniosynostosis: Muenke syndrome and Crouzon syndrome with acanthosis nigricans.6 Muenke syndrome develops from a Pro250Arg FGFR3 mutation and is characterized by coronal synostosis and variable macrocephaly and hearing loss. Crouzon syndrome with acanthosis nigricans develops from an Ala391Glu FGFR3 mutation and is characterized by widespread acanthosis nigricans associated with melanocytic nevi, choanal atresia, hydrocephalus, Chiari malformations, and vertebral abnormalities.7 In these conditions, FGFR3 mutations not only inhibit membranous ossification leading to suture fusion prematurely but also inhibit endochondral ossification during skeletal development. Patients with Crouzon syndrome with acanthosis nigricans may demonstrate radiographic narrowing of the sacrosciatic notches, short vertebral bodies, as well as broad, short metacarpals and phalanges.10 Muenke syndrome can be associated with lower extremity osseous aberrancies including talocalcaneal and calcaneocuboid coalition.5 These extracranial manifestations emphasize that the causative FGFR3 mutations can affect both endochondral and membranous ossification. One significant challenge related to the treatment of our patient was the massive intraoperative blood loss; the blood loss occurred primarily during the craniotomy portions of the patient and was calculated at 280% of his total blood volume.14,15 The formulas and values used for the calculation are as follows:
FIGURE 4. A and B, Intraoperative photographs demonstrating bicoronal synostosis and bulging at the anterior fontanelle.
© 2014 Mutaz B. Habal, MD
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
The Journal of Craniofacial Surgery • Volume 26, Number 1, January 2015 ERCV lost ¼ ERCV preop þ ERCV transfused −ERCV postop
Achondroplasia
circulation should serve as a warning against excessive cranial exposure, which could result in rapid cerebral swelling, herniation, and death.
¼ ð616 mLÞ ð36:2=100Þ þ ð1011 mLÞ ð60=100Þ − ð616 mLÞ ð33:1=100Þ
¼ 625:696 mL
REFERENCES
ERCV ¼ EBV HCT EBV ¼ 80 mL=kg 7:7 kg ¼ 616 mL
ERCV transfused ¼ PRBCtransfused HCT transfusedPRBC =100 EBV lost ðmL=kgÞ ¼ ERCV lost ðmLÞ= wtðkgÞ HCT preop =100
¼ 625:696 mL=ð7:7 kg 36:2=100Þ
¼ 224:472 mL=kg
The calculated blood loss is as follows: 224:472 mL=kg 7:7 kg ¼ 1728 mL
where ERCV is the estimated red cell volume; EBV, estimated blood volume; HCT, hematocrit; and PRBC, packed red blood cell (in milliliters). The blood loss was likely caused by a combination of physiologic and anatomic causes. First, although our patient did not undergo intracerebral monitoring to document intracranial hypertension, there were numerous signs to suggest that it was present (ie, bulging at the anterior fontanelle, the ominous steady decline in percentile head circumference, and the intraoperative findings). Probable intracranial hypertension, coupled with the severe jugular venous stenosis and enlarged emissary veins, was a major factor contributing to the robust intraoperative bleeding. In addition, our patient had severe bronchopulmonary dysplasia and required a positive end expiratory pressure setting of 8 cmH2O; high levels of positive end expiratory pressure have been associated with elevations in intracranial pressure, although this effect is modest in children.16 The patient also had multiple intraoperative bronchospastic episodes that raised intracranial pressure: 1 of these episodes resulted in the PaCO2 peaking at 76.8 mm Hg for which he received albuterol, sevoflurane, as well as mannitol and was hyperventilated. In conclusion, it is possible that the Gly380Arg gain-offunction FGFR3 mutation observed in our patient not only resulted in the development of achondroplasia but also may have played some part in the premature fusion of his cranial sutures. Operative correction of the latter condition was complicated by the presence of jugular foraminal stenosis, which is common in patients with achondroplasia. It is prudent to obtain a preoperative magnetic resonance imaging/magnetic resonance angiography of the brain to evaluate the venous collateral system; significant transcranial
1. Johnson D, Wilke AO. Craniosynostosis. Eur J Hum Genet 2011;19:369–376 2. Georgoulis G, Alexiou G, Prodromou N. Achondroplasia with synostosis of multiple sutures. Am J Med Genet 2011;155: 1969–1971 3. Bessenyei B, Nagy A, Balogh E, et al. Achondroplasia with multiple-suture craniosynostosis: a report of a new case of this rare association. Am J Med Genet 2013;161:2641–2644 4. Karadimas C, Trouvas D, Haritatos G, et al. Prenatal diagnosis of achondroplasia presenting with multiple-suture syonostosis: a novel association. Prenat Diagn 2006;26:258–261 5. Agochukwu NB, Solomon BD, Benson LJ, et al. Talocalcaneal coalition in Muenke syndrome: report of a patient, review of the literature in FGFR-related craniosynostoses, and consideration of mechanism. Am J Med Genet 2013;161: 453–460 6. Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev 2000;21:23–39 7. Norgaard P, Hagan CP, Hove H, et al. Crouzon syndrome associated with acanthosis nigricans: prenatal 2D and 3D ultrasound findings and postnatal 3D CT findings. Acta Radiol Short Rep 2012;4 doi: 10.1258/arsr.2012.110017. 8. Di Rocco F, Biosse Duplan M, Heuze Y, et al. FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Hum Mol Genet 2014;23:2914–2925 9. Hubbard BA, Gorski JL, Muzaffar AR. Unilateral frontosphenoidal craniosynostosis with achondroplasia: a case report. Cleft Palate Craniofac J 2011;5:631–635 10. Schweitzer DN, Graham JM, Lachman RS, et al. Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substation in FGFR3. Am J Med Genet 2001;1:75–91 11. Connolly JP, Gruss JD, Seto ML, et al. Progressive postnatal craniosynostosis and increased intracranial pressure. Plast Reconstr Surg 2004;113:1313–1323 12. Martinex-Abadias N, Motch SM, Pankra TL, et al. Tissue specific responses to aberrant FGF signaling in complex head phenotypes. Dev Dyn 2013;242:80–94 13. Schibler L, Gibbs L, Benoist-Lasselin C, et al. New insight on FGFR3-related chondrodysplasias molecular physiopathology revealed by human chondrocyte gene expression profiling. PLoS One 2009;4:e7633 14. Kearney RA, Rosales JK, Howes WJ. Craniosynostosis: an assessment of blood loss and transfusion practices. Can J Anaesth 1989;36: 473–477 15. Goobie SM, Meier PM, Pereira LM, et al. Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial. Anesthesiology 2011;114:862–871 16. Pulitano S, Mancino A, Pietrini D, et al. Effects of positive end expiratory pressure (PEEP) on intracranial and cerebral perfusion pressure in pediatric neurosurgical patients. J Neurosurg Anesthesiol 2013;25:330–334 17. Horton WA, Rotter JI, Rimoin DL, et al. Standard growth curves for achondroplasia. J Pediatr 1978;93:435–438
© 2014 Mutaz B. Habal, MD
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
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Achondroplasia and Multiple-Suture Craniosynostosis Frank P. Albino, MD,* Benjamin C. Wood, MD,* Chima O. Oluigbo, MD,† Angela C. Lee, MD,‡ Albert K. Oh, MD,* and Gary F. Rogers, MD, MPH*
Abstract: Genetic mutations in the fibroblast growth factor receptor 3 gene may lead to achondroplasia or syndromic forms of craniosynostosis. Despite sharing a common genetic basis, craniosynostosis has rarely been described in cases of confirmed achondroplasia. We report an infant with achondroplasia who developed progressive multiple-suture craniosynostosis to discuss the genetic link between these clinical entities and to describe the technical challenges associated with the operative management. Key Words: Multiple-suture craniosynostosis, achondroplasia, FGFR (J Craniofac Surg 2015;26: 222–225)
C
raniosynostosis, the premature fusion of 1 or more cranial sutures, is rare, with an overall incidence between 1:2000 and 1:2500 live births.1,2 Syndromic forms of craniosynostosis generally have an identifiable causative genetic mutation, whereas nonsyndromic cases typically do not. Mutations in fibroblast growth factor receptors (FGFR1–3) are responsible for most craniosynostosis syndromes (eg, Pfeiffer, Apert, Crouzon, and Jackson-Weiss syndromes); however, other genetic causes have been identified, such as TWIST (Saethre-Chotzen syndrome), MSX-2 (Boston-type craniosynostosis), and EFNB-1 (craniofrontonasal malformation).1–4 Nearly 25% of all identified mutations that cause craniosynostosis involve the FGFR3 gene.1 Specifically, FGFR3 gain-of-function mutations are responsible for Muenke syndrome, a common cause of syndromic coronal suture fusion, and the less common Crouzon syndrome with acanthosis nigricans.5–7 In addition to these syndromic forms of craniosynostosis, FGFR3 activating mutations may also result in achondroplasia.3,4,8 As the most common cause of short-limb dwarfism, achondroplasia affects 5 to 15:100,000 live births and is characterized by macrocephaly, frontal bossing, midface hypoplasia, short stature, rhizomelic limb shortening, and trident hands.2,4 Although achondroplasia or craniosynostosis may result from point
From the *Divisions of Plastic Surgery, †Neurosurgery, and ‡Anesthesiology, Sedation and Perioperative Medicine, Children's National Medical Center, Washington, DC. Received June 11, 2014. Accepted for publication July 31, 2014. Address correspondence and reprint requests to Gary F. Rogers, MD, JD, MBA, MPH, Division of Plastic Surgery, Children's National Medical Center, 111 Michigan Ave NW, West Wing, 4th Floor, Suite 100, Washington, DC 20010; E-mail: [email protected] The authors report no conflicts of interest. Copyright © 2014 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000001267
222
mutations in the transmembrane domain of FGFR3, premature cranial suture fusion is rarely described in cases of achondroplasia. We report on an infant with multisutural craniosynostosis and achondroplasia to offer a genetic link between these clinical entities and to discuss the operative challenges faced in managing his fused sutures.
CLINICAL REPORT A male infant born at 25 weeks of gestation to a G4P1 mother was transferred to our institution after an abdominal delivery complicated by prolonged, premature rupture of amniotic membranes. He was initially treated for respiratory distress as well as sepsis and ultimately required tracheostomy for refractory apnea and respiratory failure. Physical findings included subtle frontal bossing and midface hypoplasia, exophthalmos, rhizomelic limb shortening, trident hands, as well as narrowing of the spinal pedicles (Figs. 1, 2). There was radiographic evidence of generalized skeletal dysplasia; subsequent genetic testing confirmed the diagnosis of achondroplasia with a causative Gly380Arg FGFR3 mutation. Computed tomographic (CT) scans of the head and neck demonstrated bilateral coronal synostosis and severe stenosis of the foramen magnum. At 5 months corrected age, he underwent decompression of the foramen magnum and a C1 laminectomy. A subsequent CT scan taken to evaluate the decompression demonstrated progression of the craniosynostosis with additional involvement of both squamosal sutures, bulging in the region of the anterior fontanel, and jugular venous stenosis (Fig. 3). Review of his cranial growth revealed a gradual decline in percentile head circumference, dropping from the 50th percentile to less than the 5th percentile on the adjusted achondroplasia-male head circumference growth chart during this 5-month period7 (Fig. 4). These findings were strongly suggestive of imminent intracranial hypertension, and a cranial vault expansion was planned. Because of the severe jugular venous stenosis, a preoperative magnetic resonance imaging/magnetic resonance angiography was ordered to assess the cerebral vascularity. The scan demonstrated significant transosseous venous collaterals in the mastoid and posterior temporal regions that appeared to be the primary outflow of the brain. To reduce the risk for disrupting all cerebral outflow and causing cerebral herniation, the decision was made to avoid a posterior dissection and to focus the expansion in the anterior and lateral regions. At 9 months corrected age, the patient underwent bilateral frontal orbital advancement with biparietal outfracturing for lateral expansion. Multiple large anterior and apical emissary veins were encountered intraoperatively, and each was carefully dissected and cauterized with minimal blood loss. Nevertheless, numerous intraosseous blood vessels were encountered during the subsequent craniotomy and approximately 1500 mL of blood was lost during the removal of the frontal segment alone. The dura was very thin and immediately bulged upon opening of the cranial vault. The procedure was stopped until the patient was sufficiently resuscitated. The remaining osteotomies and cranial reconstruction were easily completed with only an additional 200 mL of bleeding. The cranial
The Journal of Craniofacial Surgery • Volume 26, Number 1, January 2015
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
The Journal of Craniofacial Surgery • Volume 26, Number 1, January 2015
Achondroplasia
FIGURE 1. A to D, Preoperative photographs demonstrating brachycephaly, hypertelorism, midface hypoplasia, and flattened nasal bridge.
FIGURE 2. Anteroposterior x-ray of the infant's left hand taken during a skeletal survey at 5 months of age demonstrating trident hand.
© 2014 Mutaz B. Habal, MD
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
223
The Journal of Craniofacial Surgery • Volume 26, Number 1, January 2015
Albino et al
FIGURE 3. A to D, Three-dimensional reconstruction of preoperative head CT notable for bilateral coronal and squamous suture synostosis at 6 months old.
expansion included a 1.5-cm frontal advancement and expansion of both parietal segments. The moved osseous structures were affixed with absorbable plates and screws. Generous scoring of the galea was required to close the scalp. The patient recovered uneventfully and was discharged home in 3 weeks with routine tracheostomy care. The combined expansion results in a 2.5-cm increase in head circumference.
DISCUSSION Craniosynostosis is a rare finding in patients with achondroplasia. If the incidence of each condition is considered as an independent variable, the probability of these events occurring simultaneously approaches 1:40,000,000 live births. There have only been 5 publications reporting 7 cases of multiple-suture craniosynostosis in the setting of confirmed skeletal dysplasias, and although it is possible, other cases of affected patients have not been reported. The apparent rarity of this association suggests that a concurrence is random.2–4,9,10 Nevertheless, the possibility of an association warrants further consideration for 2 reasons: first, FGFR3 signaling is instrumental in regulating both membranous (cranial) and endochondral (axial or appendicular) ossification; and second, mutations affecting the FGFR3 transmembrane domain are causative in both achondroplasia and certain forms of syndromic craniosynostosis.6 There are 4 fibroblast growth factor receptors (1–4) mapped to p16.3 of chromosome 4. Each serves as a tyrosine kinase receptor to inhibit bone growth and chondrocyte proliferation.6 Once activated, FGFR3 is responsible for the patterning, proliferation, differentiation, and migration of tissue of osteogenic fate as demonstrated by both human sampling and animal studies.7,11–13 Fibroblast growth factor receptor 3 negatively regulates bone growth with
224
gain-of-function mutations leading to constitutive FGFR3 activation, upregulation of STAT to propagate downstream signaling, transcription of chondrocyte proliferation inhibitors, and cell cycle arrest.7,11–13 Gain-of-function FGFR3 mutations activate STAT signaling pathways, inhibit chondrocyte development, and lead to arrested bone growth by both membranous and endochondral ossification as seen in craniosynostosis and skeletal dysplasia, respectively.7,11–13 Fibroblast growth factor receptor 3–related skeletal dysplasias represent a spectrum of disorders ranging from the mild hypochondroplasia, to a more severe achondroplasia, to lethal thanatophoric dysplasia. Hypochondroplasia, characterized by short stature, micromelia, and lumbar lordosis, most commonly results from an Asn540Lys FGFR3 mutation, whereas achondroplasia and thanatophoric dysplasia are commonly caused by Gly380Arg and Lys650Glu FGFR3 mutations, respectively. The Gly380Arg FGFR3 mutation observed in our patient is the most common genetic point mutation found in patients with achondroplasia. The skeletal effects of FGFR3 mutations may extend beyond impaired endochondral ossification for patients with achondroplasia and evidence of craniosynostosis. A recent animal study using FGFR3knockout mice as a model of achondroplasia demonstrated premature coronal suture fusion, abnormal foramen magnum architecture, and nonossified frontal bone gaps.8 Fibroblast growth factor receptor 3 mutations are also responsible for at least 2 forms of syndromic craniosynostosis: Muenke syndrome and Crouzon syndrome with acanthosis nigricans.6 Muenke syndrome develops from a Pro250Arg FGFR3 mutation and is characterized by coronal synostosis and variable macrocephaly and hearing loss. Crouzon syndrome with acanthosis nigricans develops from an Ala391Glu FGFR3 mutation and is characterized by widespread acanthosis nigricans associated with melanocytic nevi, choanal atresia, hydrocephalus, Chiari malformations, and vertebral abnormalities.7 In these conditions, FGFR3 mutations not only inhibit membranous ossification leading to suture fusion prematurely but also inhibit endochondral ossification during skeletal development. Patients with Crouzon syndrome with acanthosis nigricans may demonstrate radiographic narrowing of the sacrosciatic notches, short vertebral bodies, as well as broad, short metacarpals and phalanges.10 Muenke syndrome can be associated with lower extremity osseous aberrancies including talocalcaneal and calcaneocuboid coalition.5 These extracranial manifestations emphasize that the causative FGFR3 mutations can affect both endochondral and membranous ossification. One significant challenge related to the treatment of our patient was the massive intraoperative blood loss; the blood loss occurred primarily during the craniotomy portions of the patient and was calculated at 280% of his total blood volume.14,15 The formulas and values used for the calculation are as follows:
FIGURE 4. A and B, Intraoperative photographs demonstrating bicoronal synostosis and bulging at the anterior fontanelle.
© 2014 Mutaz B. Habal, MD
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
The Journal of Craniofacial Surgery • Volume 26, Number 1, January 2015 ERCV lost ¼ ERCV preop þ ERCV transfused −ERCV postop
Achondroplasia
circulation should serve as a warning against excessive cranial exposure, which could result in rapid cerebral swelling, herniation, and death.
¼ ð616 mLÞ ð36:2=100Þ þ ð1011 mLÞ ð60=100Þ − ð616 mLÞ ð33:1=100Þ
¼ 625:696 mL
REFERENCES
ERCV ¼ EBV HCT EBV ¼ 80 mL=kg 7:7 kg ¼ 616 mL
ERCV transfused ¼ PRBCtransfused HCT transfusedPRBC =100 EBV lost ðmL=kgÞ ¼ ERCV lost ðmLÞ= wtðkgÞ HCT preop =100
¼ 625:696 mL=ð7:7 kg 36:2=100Þ
¼ 224:472 mL=kg
The calculated blood loss is as follows: 224:472 mL=kg 7:7 kg ¼ 1728 mL
where ERCV is the estimated red cell volume; EBV, estimated blood volume; HCT, hematocrit; and PRBC, packed red blood cell (in milliliters). The blood loss was likely caused by a combination of physiologic and anatomic causes. First, although our patient did not undergo intracerebral monitoring to document intracranial hypertension, there were numerous signs to suggest that it was present (ie, bulging at the anterior fontanelle, the ominous steady decline in percentile head circumference, and the intraoperative findings). Probable intracranial hypertension, coupled with the severe jugular venous stenosis and enlarged emissary veins, was a major factor contributing to the robust intraoperative bleeding. In addition, our patient had severe bronchopulmonary dysplasia and required a positive end expiratory pressure setting of 8 cmH2O; high levels of positive end expiratory pressure have been associated with elevations in intracranial pressure, although this effect is modest in children.16 The patient also had multiple intraoperative bronchospastic episodes that raised intracranial pressure: 1 of these episodes resulted in the PaCO2 peaking at 76.8 mm Hg for which he received albuterol, sevoflurane, as well as mannitol and was hyperventilated. In conclusion, it is possible that the Gly380Arg gain-offunction FGFR3 mutation observed in our patient not only resulted in the development of achondroplasia but also may have played some part in the premature fusion of his cranial sutures. Operative correction of the latter condition was complicated by the presence of jugular foraminal stenosis, which is common in patients with achondroplasia. It is prudent to obtain a preoperative magnetic resonance imaging/magnetic resonance angiography of the brain to evaluate the venous collateral system; significant transcranial
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© 2014 Mutaz B. Habal, MD
Copyright © 2014 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
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