American Journal of Medical Genetics 4490-93 (1992)
Upper and Lower Airway Compromise .in the Apert Syndrome M. Michael Cohen, Jr. and Sven Kreiborg Department of Oral Biology, Faculty of Dentistry, and Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifajc, Nova Scotia, Canada (M.M.C. Jr.) and Department of Pediutric Dentistry, School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark (S.K.)
Both upper and lower airway compromise may be responsible for early death in some patients with the Apert syndrome. We report on two and review six cases with complete or partial cartilage sleeve abnormalities of the trachea. Possible mechanisms include tracheal stenosis andíor lack of tracheal distensibility which may result in respiratory inefficiency, inabiiity to clear secretions, andíor increased liability to surface injury from tracheal suctioning. Upper airway compromise, consisting of obstructive sleep apnea and cor pulmonale, may result from reduced nasopharyngeal and oropharyngeal dimensions in the Apert craniofacial configuration. 0 1992 Wiley-Lies, Inc.
KEY WORDS: Apert syndrome, acrocephalosyndactyly, cartilage sleeve abnormalities of the trachea, lower airway compromise, upper airway compromise, obstructive sleep apnea, cor pulmonale INTRODUCTION Elsewhere, we have reviewed our 119 cases of the Apert syndrome, given a case definition, and briefly mentioned early death [Cohen, 1986; Cohen and Kreiborg, 1990, 1991; Cohen et al., 19921. Although some patients with the Apert syndrome die early, others have a much longer, and sometimes normal, lifespan. The reasons for the former have not yet been attributed to specific abnormalities of the Apert syndrome. Here we suggest that specific types of upper and lower airway compromise may be responsible for early death in some Apert syndrome patients. We report on two cases with complete or partial cartilage sleeve abnormalities of the Received for publication November 6, 1991; revision received Eebruary 13, 1992. Address reprint requests to Dr. M. Michael Cohen, Jr., Dalhousie University, Halifax, Nova Scotia, Canada B3H 355.
0 1992 Wiley-Liss, Inc.
trachea, review six other cases in the literature, and discuss both lower and upper airway compromise in the Apert syndrome.
CLINICAL REPORTS Patient 1 A female infant with Apert syndrome, weighing 2.75 kg, the product of a 37 week gestation, was born to a 31year-old G,P, mother. The pregnancy was complicated by amniotic fluid leak 10 days prior to spontaneous rupture of membranes. Seimres occurred during the second day of life. Respiratory problems were evident early. During the first week, nasal stents were placed for choanal atresia. At 6 weeks, respiratory rate was increased with marked retraction and diaphragmatic breathing. At 8 weeks, the patient was admitted with a 10 day history of respiratory difficulty and possible apneic episodes. Periods of apnea lasting 5-8 seconds associated with bradycardia were documented. At 3 months, she was admitted for bifrontal craniotomy, orbital advancement, and removal of a cystic hemangioma of the occiput. She continued to have noisy breathing and an increase in nasal secretions. She was fussy and difficult to feed. She was admitted 9 days following her last discharge after pulling out her nasal stents. She had one episode of cyanosis in the hospital. The stents were not replaced since the right choana was patent. The left choana, which was obstructed, was repaired surgically. However, her airway remained problematic, the left choana becoming atretic within 4 weeks. At this time, CT showed an increase in subarachnoid fluid accumulation from the small amount noted earlier prior to the time of surgery. Also observed were abnormal ventricles. At 6V2 months, an apneic episode and possible seizure were experienced in association with feeding a t home. On admission, CT scan documented a subdural hematoma and unchanged ventricular size. Increased intracranial pressure (220 mm Hg) was evident together with papilledema, retina1 hemorrhage, sluggishly responsive pupils, abnormal deep tendon reflexes, and pulsatile bulging fontanelle. She was managed by intubation and infusions of mannitol and cryoprecipitate. She died 24 hours later. At postmortem examination, severe abnormalities were found in the tracheobronchial tree and the brain.
Apert Syndrome Airway Compromise The trachea and mainstem bronchi were composed of firm, hard cartilage without ring formation. The trachea and bronchi also had an abnormal course with slight deviation in the trachea and the right and left mainstem bronchi. The lumen was patent, but mildlyto-moderately stenotic. Brain malformations, which we have described in this case previously [Cohen and Kreiborg, 1990, Case E-21, consisted of gyral abnormalities, megalencephaly, ventriculomegaly, hypoplastic Corpus callosum, absent septum pellucidum, dorsally displaced hippocampi and hippocampal gyri, gray matter heterotopia, and hypoplastic white matter.
Patient 2 A female infant with Apert syndrome, weighing 2.68 kg at birth, the product of a 36-week gestation, was born to a 31-year-old G,P, mother by spontaneous vagina1 delivery. Apgar scores were 313 at the first and fifth minutes with apnea, absent muscle tone, absent reflexes, and poor color. Endotracheal tube placement and bagging were instituted and repeated frequently for poor or absent breath sounds and chest excursions. After 5 hours, the patient developed chest wall excursions with the ventilator, and both color and perfusion improved. Ten hours later, tonic-clonic seizures of the upper and lower limbs were observed which were treated with phenobarbital. She continued to deteriorate, failed to respond to reintubation, and died 6 hours later. At autopsy, the trachea and major bronchi were stenotic. Sections showed small, markedly thickened cartilage rings with some increase in the density of chondrocytes. The membranous portions between the cartilage rings were diminished. There was no histologic evidence of hyaline membrane disease. The only
other anomalies found were patent ductus arteriosus and a mucocutaneous tag at the entrance of the vagina.
DISCUSSION Congenital anomalies of the trachea are rare and those involving cartilage rings per se even rarer [Holinger et al., 19521.Greene [19761and Landing and Wells [19731 found that complete cartilaginous ring formation (instead of the normal incomplete U-shaped ring) is the most common of the cartilage ring abnormalities. Cartilage sleeve abnormalities in the acrocephalosyndactylies have recently been addressed by Davis et al. [1992]. The cartilage anomaly may vary in degree and in extent. For example, solid cartilaginous trachea was found in our first patient. Davis et al. [19921noted a case of solid cartilaginous trachea interrupted by abortive ring formation. Ring formation with small separations between them and marked thickening of the cartilage characterized our second patient. In some cases, only the trachea is involved. In others, such as our two cases and the one noted by Blank 119601, the cartilaginous anomaly extends into the bronchi. Table 1summarizes our two cases and six Apert cases from the literature known to have partial or complete tracheal cartilage sleeve abnormalities. No denominator is available. However, documentation of eight instances of a rarely encountered anomaly in one syndrome is striking. In each case, the abnormal trachea was not suspected during life but detected a t autopsy. Four of the eight Apert cases had tracheal stenosis; only two had areas of anglar deviation of the trachea; and none were apparently short (Table 1).Other mechanisms besides stenosis and/or angular deviation may be
TABLE 1. Cases With Complete or Partial Cartilage Sleeve Abnormalities of the Trachea Svndrome
Age at death
Apert
6% months
Cartilage sleeve Tracheal Sex abnormalitv stenosis
F
+
+
Aperi
1 day
F
+
+
Apert
15 months
?
?
Apert
4 months
?
+ +
+
Apert Apert Apert ?Apert
13 months 3 months 10 months Stillborn
F F F
+
Foca1
M
+ + +
Acrocephalospondylosyndactyly Pfeiffer Pfeiffer Pfeiffer Crouzon Crouzon Crouzon Cloverleaf
3 months
M
+
3 months 13 months 15 months
+ +
2 years 2 years 7 years 40 days
M M F F M M M
Cloverleaf
8 months
M
+
+ + +
+ I
Short Angulated trachea trachea
Other Involvement of larger bronchi Thick cartilage; involvement of larger bronchi Involvement of larger bronchi Thick cartilage; involvement of larger bronchi -
-
Thick cartilage
Namw lumen -
-
Subglottic Glottic
-
-
Cloverleaf -
Uniform -
Narrow lumen -
Cloverleaf -
-
91
-
-
Reference Cohen and Kreiborg, patient 1 Cohen and Kreiborg, patient 2 Blank, 1960 Trott, 1992 Schmid, 1971 Davis et al., 1992 Davis et al., 1992 Shimada and Misugi, 1979 Wells et al.. 1990 Stone et al., 1990 Davis et al., 1992 Ldge et al., 1992 Schmid, 1971 Devine et al., 1984 Davis et al., 1992 Shimada and Misugi, 1979; Sano et al.. 1982 Davis et al., 1992
Cohen and Kreiborg
92
responsible for compromise in the lower airway. Cartilage sleeve abnormalities may lack of disten- produce _ sibility of the normal trachea, resulting in respiratory inefficiency, inability to clear secretions, andlor increased liability to surface injury from tracheal suctioning [Davis et al., 19921. The trachea was almost certainly compromised by multiple intubations in our patient 2. Davis et al. [1992]found the immediate cause of death in one case to be extensive mucous plugging of the lower trachea and large bronchi. To date, the eight known cases of Apert syndrome with partial or complete cartilage sleeve abnormalities of the trachea have been observed during infancy. The average age at death was 6.8 months (range: stillborn15 months) (Table 1). At present, we are studying our Apert syndrome patients (119 cases) [Cohen and Kreiborg, 19911to determine whether such tracheal anomalies are found in older individuals. Certainly, partial or complete cartilage sleeve abnormalities of the trachea should be suspected in m~Apert syndrome infant with lower respiratory compromise. Careful study of the trachea in any Apert syndrome autopsy, infant or otherwise, is recommended. Table 1 shows that other conditions such as Crouzon syndrome, Pfeiffer syndrome, acrocephalospondylosyndactyly, and cloverleaf skull have been reported on occasion with partial or complete cartilage sleeve abnormalities of the trachea. Other types of tracheal anomalies reported with various syndromes and associations are summarized in Table 11. In the Apert syndrome, a three-way embryonic link in failure of cartilage segmentation may be perceived. First, cartilage rings of the trachea normally form as discontinuous aggregates of cartilage during the eighth-to-ninth weeks of embryonic development. Failure of segmentation results in partial or complete cartilaginous sleeve abnormalities in the trachea. Second, embryonic failure in separation of the cartilage models of the phalanges becomes evident in the Apert syndrome by progressive ossification observed radiographically [Cohen, 1986; Schauerte and St-Aubin, 19661. Finally, with variable degrees of embryonic cartilage undersegmentation of the cervical vertebrae, which characterized 68%of our Apert patients [Kreiborg et al., 19921, cervical fusions became evident with progressive ossification observed radiographically. Upper airway compromise in the Apert syndrome is more widely known and well-researched than lower airway compromise. Studies show that distortions and displacements of the craniofacial bones compromise the nasopharyngeal and oropharyngeal space. Particularly noteworthy are reduction in pharyngeal height, width, and depth; increased length and thickness of the velum; decreased length of the hard palate; marked reduction in the posterior cranial base with a lesser degree of reduction in the anterior cranial base; and a more acute cranial base angle. These changes are present during infancy and tend to become more pronounced with craniofacial growth [Peterson-Falzone et al., 19813. The extremely shallow oropharynx is recognized as an important factor in obligatory mouth breathing and forward placement of the tongue so frequently found in the Apert syndrome [Peterson and Pruzansky, 19741. The
TABLE 11. Other Reported Tracheal Anomalies in Syndromes and Associations
v
Anomaly (syndrome or association) nacheomalacia Atelosteogenesis 1" Campomelic dysplasia Cerebrocostomandibular syndrome
Diastrophic dysplasia Hallermann-Streiffsyndrome L~~~~~syndrome
nacheoesophagealfistula VATER, VACTERL associations CHARGE association TrisomY
l8 spdrome
Di,CUf,~$~~v~tebral spectrum
Asymmetric crying facies Tracheal agenesis VATER association Polyhydramnios, prematurity, growth retardation,laryngeal
Reference Whitley et al., 1986 Lee et al., 1972 Smith et al., 1966 Friedman et al., 1974 Salbert et al., 1991 Rock et al., 1988 Chen et al., 1982b Evans et al., 1985
Pagon et al., 1981 Evans et al., 1986 Evans et al., 1986 Bowen and Parry, 1980 Pape and Pickering, 1972 Milstein et al., 1985 Evans et al., 1986; Downing, 1992
~defects, ~ ~ ~duodenal ' $ " ~ ~ atresia, ~re,n;l"a'
diaphragmatic hernia Tracheal and bronchialstenosis Salonen et al., 1981 Hydrolethalus syndrome ~ac~eobronchomegaly Gay and Dee, 1984 Ascher syndrome ~ i f fabnormal ~ ~ ~ l ~
cmtilaginous patbming of trachea and bronchi Ellis-van Crevald syndrome Tracheal diverticulum and tracheal accessory bronchus Ivemark spdrome Complete cartilaginous rings
wndrome
Landing and Wells, 1973 Landing and Wells, 1973 Landing and Wells, 1973
"Atelosteogenesis 1 repiaces the earlier term "de la Chapelle syn-
~ent~ disorder, ~ ~ " " ~we~ think ~ t r ~they~ ~have , : SLarsen g Uthatgsyndrome, ptheir e s patients t e d had a differcombination of reduced nasopharyngeal dimensions and reduced patency of the posterior choanae poses a risk of respiratory embarrassment, obstructive sleep apnea, and cor pulmonale, particularly in infants and children with Apert syndrome. A case reported by Lauritzen et al. [1986] is instructive. A 37/12year old boy with Apert syndrome was observed to have long apneic periods with cyanosis while sleeping. Shortly thereafter, two episodes of cardiac arrest occurred during sleep and each time he was resuscitated successfully. A chest roentgenogram showed cor pulmonale. Tracheostomy stabilized the situation. Many other craniofacial syndromes such as Crouzon syndrome [Don and Siggers, 1971; Hess et al., 19861, Pfeiffer syndrome [Lauritzen et al., 19861, and Haller-
Apert Syndrome Airway Compromise
mann-Streiff syndrome [Cohen, 19911 may be associated with upper airway compromise, obstructive sleep apnea, and cor pulmonale. Since, on the average, children with obstructive sleep apnea experience a 2 year delay in referral for proper diagnosis, Apert syndrome patients in particular, or any other craniofacial syndrome patients for that matter, who are predisposed to upper airway compromise because of abnormal craniofacial configuration should be monitored carefully for snoring andlor an unusual amount of daytime somnolence. Such patients should be referred to a sleep center for proper diagnosis and treatment to prevent dangerous sequelae.
93
Hess CW, Sauter K, Bonfils P (1986):Severe adult hypersomnia: Sleep apnea syndrome in craniofacial dysostosis. Respiration 50:147152. Holinger P, Johnston K, Parchet V, Zimmermann A (1952):Congenital malformations of the trachea, bronchi and lungs. Ann Oto1 Rhinol Laryngol61:1159-1180. Kreiborg S, Barr M Jr, Cohen MM Jr (1992):The cervical spine in the Apert syndrome. Am J Med Genet, in press. Landing B, Wells T (1973):Tracheobronchialanomalies in children. In Rosenberg H, Boland R (eds): “Perspectives in Pediatric Pathology.” Chicago: YearBook Medical Publishers. Lauritzen C, Lilja J , Jarlstedt J (1986):Airway obstruction and sleep apnea in children with craniofacial anomalies. Plast Reconstr Surg 77:l-5. Lee FA, Isaacs H Jr, StraussJ (1972):The “campomelic” syndrome. Am J Dis Child 124:485-496. ACKNOWLEDGMENTS Lodge ML, Moore MH, Hanieh A, Trott JA, David DJ (1992):The cloverleaf skull anomaly: Managing extreme cranio-orbito-facioWe wish to thank Joe Siebert (Seattle), Cheng-Mei stenosis. Plast Reconstr Surg, in press. Shaw (Seattle), Ellsworth C. Alvord, Jr. (Seattle), Milstein JM, Lau M, Bickers RG (1985):Tracheal agenesis in infants Meinhard Robinow (Dayton), and Ruth MacLean (Haliwith VATER association. Am J Dis Child 139:77-80. fax) for their help with this project. Pagon RA, Graham J M Jr, Zonana J, Yong S-L (1981):Coloboma, congenital heart disease, and choanal atresia with multiple anomaREFERENCES lies: CHARGE association. J Pediatr 99:223-227. Blank CE (1960):Apert’s syndrome (a type of acrocephalosyndactyly): Pape KE, Pickering D (1972):Asymmetric crying facies: An index of other congenital anomalies. J Pediatr 81:21-30. Observations on a British series of thirty-nine cases. Ann Hum Genet 24151-163. Peterson SI,Pruzansky S (1974):Palatal anomalies in the syndrome of Apert and Crouzon. Cleft Palate J 11:394-403. Bowen AD, Parry WH (1980):Bronchopulmonary foregut malformation in the Goldenhar anomalad. Am J Roentgenol 134:186-188. Peterson-Falzone SJ, h z a n s k y S, Parris PJ, Laffer J L (1981):Nasopharyngeal dysmorphology in the syndromes of Apert and Chen H, Chang C, P e m n E, Perrin J (1982):A lethal Larsen-like Crouzon. Cleft Palate J 18:237-250. multiple joint dislocation syndrome. Am J Med Genet 13:149-161. Cohen MM Jr (1986):“Craniosynostosis: Diagnosis, Evaluation, and Rock MJ, Green CG, Pauli RM, Peters ME (1988):Tracheomalacia and bronchomalacia associated with Larsen syndrome. Pediatr PulManagement.” New York: Raven Press. mono1 5:55-59. Cohen MM Jr (1991):Hallermann-Streiff syndrome: A review. Am J Salbert BA, Stevens CA, Spence J E (1991): ‘kacheomalacia in HallerMed Genet 41:488-499. mann-Streiff syndrome. Am J Med Genet 41:521-523. Cohen MM Jr, Kreiborg S (1990):The central nervous system in the Salonen R, Howa R, Norio R (1981):The hydrolethalus syndrome: Apert syndrome. Am J Med Genet 35:36-45. Delineation of a “new,” lethal malformation syndrome based on 28 Cohen MM Jr, Kreiborg S (1991):Genetic and family study of the Apert patients. Clin Genet 19:321-330. syndrome. Cranio Genet Dev Biol 11:7-17. Sano J , Sasaki T, Shimada H, Misugi K, Kagyo H (1982):Cloverleaf Cohen MM Jr, Kreiborg S, Lammer EJ, Cordero J F , Mastroiacovo P, skull syndrome. Acta Path J p n 32:887-900. Erickson JD, Roeper P, Martinez-Frias ML (1992):Birth prevalence Schauerte EW, St-Aubin PM (1966):Progressive synostosis in Apert’s study of the Apert syndrome. Am J Med Genet 42:655-659. syndrome (acrocephalosyndactyly) with a description of roentDavis S, Bove KE, Wells T, Hartsell B, Weinberg A, Gilbert E (1992): genographic changes in the feet. Am J Roentgenol 97:67-73. Tracheal cartilaginous sleeve. Pediatr Pathol, in press. Schmid H (1971):Synchrondrosen des Laryngotrachrealskeletts und Devine P, Bhan 1, Feingold M, Leonidas JC, Wolpert SM (1984):ComTracheostenose beim Apert-Crouzon syndrome. Zentralbl Allg Paplete cartilaginous trachea in a child with Crouzon syndrome. Am J thol 114326-337. Dis Child 138:40-43. Shimada H, Misugi K (1979):Anomalies of the tracheal cartilage. Acta Don N, Siggers DC (1971):Cor pulmonale in Crouzon’s disease. Arch Pathol J p n 29:lOOl-1011. Dis Child 46:394-395. Smith DW, Theiler K, Schachenmann G (1966):Rib-gap defect with Downing GJ (1992):’ikacheal agenesis with diaphragmatic hernia. Am micrognathia, malformed tracheal cartilages, and redundant skin: J Med Genet 42:85-87. A new pattern of defective development. J Pediatr 69:799-803. EvanS JA, Reggin J, Greenberg c (1985):T ~ ~ c h eagenesis al and associ- Stone P, Trevenen CL, Mitchell 1, Rudd H (1990):Congenital tracheal ated malformations: A comparison with tracheoesophageal fistula stenosis in pfeiffer syndrome. Clin Genet 38:145-148. and the VACTERL association. Am J Med Genet 21:21-34. Trott JA, (1987):Tracheal stenosis, in Apert’s syndrome. In Marchac D. Friedman SE, Taber P, Hollister DW, Rimoin DL (1974):A lethal form (ed,): “Roceedings of First International Congres8 o f m e Internaof diastrophic dwarfism. In Bergsma D. (ed.): “Skeletal Dysplasias.” tional Society ofCranio-Maxillo-Facia1Surgery,” Berlin: SpringerNew York: Alan R. Liss, Inc., for the National Foundation-March verlag. of Dimes. BD:OAS V(10):43-49. Wells T, Falk R, Senac M, Vachon L (1990):AcrocephalospondylosynGay S, Dee P (1984):Tracheobronchomegaly: The Mounier-Kuhn syndactyly: A possible new syndrome. Pediatr Pathol 10:117-131. drome. Br J Radio1 57:640-644. Whitley CB, Burke BA, Granroth G, Gorlin R J (1986):de la Chapelle Gorlin RJ,Cohen MM Jr, h v i n L s (1990):“syndromes ofthe Head and J Med Genet 25:2gP3g, dysplasia, Neck.” New York Oxford University Press. Greene D (1976):Congenital complete tracheal rings. Arch Otolaryngol 102:241-243.
Upper and Lower Airway Compromise .in the Apert Syndrome M. Michael Cohen, Jr. and Sven Kreiborg Department of Oral Biology, Faculty of Dentistry, and Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifajc, Nova Scotia, Canada (M.M.C. Jr.) and Department of Pediutric Dentistry, School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark (S.K.)
Both upper and lower airway compromise may be responsible for early death in some patients with the Apert syndrome. We report on two and review six cases with complete or partial cartilage sleeve abnormalities of the trachea. Possible mechanisms include tracheal stenosis andíor lack of tracheal distensibility which may result in respiratory inefficiency, inabiiity to clear secretions, andíor increased liability to surface injury from tracheal suctioning. Upper airway compromise, consisting of obstructive sleep apnea and cor pulmonale, may result from reduced nasopharyngeal and oropharyngeal dimensions in the Apert craniofacial configuration. 0 1992 Wiley-Lies, Inc.
KEY WORDS: Apert syndrome, acrocephalosyndactyly, cartilage sleeve abnormalities of the trachea, lower airway compromise, upper airway compromise, obstructive sleep apnea, cor pulmonale INTRODUCTION Elsewhere, we have reviewed our 119 cases of the Apert syndrome, given a case definition, and briefly mentioned early death [Cohen, 1986; Cohen and Kreiborg, 1990, 1991; Cohen et al., 19921. Although some patients with the Apert syndrome die early, others have a much longer, and sometimes normal, lifespan. The reasons for the former have not yet been attributed to specific abnormalities of the Apert syndrome. Here we suggest that specific types of upper and lower airway compromise may be responsible for early death in some Apert syndrome patients. We report on two cases with complete or partial cartilage sleeve abnormalities of the Received for publication November 6, 1991; revision received Eebruary 13, 1992. Address reprint requests to Dr. M. Michael Cohen, Jr., Dalhousie University, Halifax, Nova Scotia, Canada B3H 355.
0 1992 Wiley-Liss, Inc.
trachea, review six other cases in the literature, and discuss both lower and upper airway compromise in the Apert syndrome.
CLINICAL REPORTS Patient 1 A female infant with Apert syndrome, weighing 2.75 kg, the product of a 37 week gestation, was born to a 31year-old G,P, mother. The pregnancy was complicated by amniotic fluid leak 10 days prior to spontaneous rupture of membranes. Seimres occurred during the second day of life. Respiratory problems were evident early. During the first week, nasal stents were placed for choanal atresia. At 6 weeks, respiratory rate was increased with marked retraction and diaphragmatic breathing. At 8 weeks, the patient was admitted with a 10 day history of respiratory difficulty and possible apneic episodes. Periods of apnea lasting 5-8 seconds associated with bradycardia were documented. At 3 months, she was admitted for bifrontal craniotomy, orbital advancement, and removal of a cystic hemangioma of the occiput. She continued to have noisy breathing and an increase in nasal secretions. She was fussy and difficult to feed. She was admitted 9 days following her last discharge after pulling out her nasal stents. She had one episode of cyanosis in the hospital. The stents were not replaced since the right choana was patent. The left choana, which was obstructed, was repaired surgically. However, her airway remained problematic, the left choana becoming atretic within 4 weeks. At this time, CT showed an increase in subarachnoid fluid accumulation from the small amount noted earlier prior to the time of surgery. Also observed were abnormal ventricles. At 6V2 months, an apneic episode and possible seizure were experienced in association with feeding a t home. On admission, CT scan documented a subdural hematoma and unchanged ventricular size. Increased intracranial pressure (220 mm Hg) was evident together with papilledema, retina1 hemorrhage, sluggishly responsive pupils, abnormal deep tendon reflexes, and pulsatile bulging fontanelle. She was managed by intubation and infusions of mannitol and cryoprecipitate. She died 24 hours later. At postmortem examination, severe abnormalities were found in the tracheobronchial tree and the brain.
Apert Syndrome Airway Compromise The trachea and mainstem bronchi were composed of firm, hard cartilage without ring formation. The trachea and bronchi also had an abnormal course with slight deviation in the trachea and the right and left mainstem bronchi. The lumen was patent, but mildlyto-moderately stenotic. Brain malformations, which we have described in this case previously [Cohen and Kreiborg, 1990, Case E-21, consisted of gyral abnormalities, megalencephaly, ventriculomegaly, hypoplastic Corpus callosum, absent septum pellucidum, dorsally displaced hippocampi and hippocampal gyri, gray matter heterotopia, and hypoplastic white matter.
Patient 2 A female infant with Apert syndrome, weighing 2.68 kg at birth, the product of a 36-week gestation, was born to a 31-year-old G,P, mother by spontaneous vagina1 delivery. Apgar scores were 313 at the first and fifth minutes with apnea, absent muscle tone, absent reflexes, and poor color. Endotracheal tube placement and bagging were instituted and repeated frequently for poor or absent breath sounds and chest excursions. After 5 hours, the patient developed chest wall excursions with the ventilator, and both color and perfusion improved. Ten hours later, tonic-clonic seizures of the upper and lower limbs were observed which were treated with phenobarbital. She continued to deteriorate, failed to respond to reintubation, and died 6 hours later. At autopsy, the trachea and major bronchi were stenotic. Sections showed small, markedly thickened cartilage rings with some increase in the density of chondrocytes. The membranous portions between the cartilage rings were diminished. There was no histologic evidence of hyaline membrane disease. The only
other anomalies found were patent ductus arteriosus and a mucocutaneous tag at the entrance of the vagina.
DISCUSSION Congenital anomalies of the trachea are rare and those involving cartilage rings per se even rarer [Holinger et al., 19521.Greene [19761and Landing and Wells [19731 found that complete cartilaginous ring formation (instead of the normal incomplete U-shaped ring) is the most common of the cartilage ring abnormalities. Cartilage sleeve abnormalities in the acrocephalosyndactylies have recently been addressed by Davis et al. [1992]. The cartilage anomaly may vary in degree and in extent. For example, solid cartilaginous trachea was found in our first patient. Davis et al. [19921noted a case of solid cartilaginous trachea interrupted by abortive ring formation. Ring formation with small separations between them and marked thickening of the cartilage characterized our second patient. In some cases, only the trachea is involved. In others, such as our two cases and the one noted by Blank 119601, the cartilaginous anomaly extends into the bronchi. Table 1summarizes our two cases and six Apert cases from the literature known to have partial or complete tracheal cartilage sleeve abnormalities. No denominator is available. However, documentation of eight instances of a rarely encountered anomaly in one syndrome is striking. In each case, the abnormal trachea was not suspected during life but detected a t autopsy. Four of the eight Apert cases had tracheal stenosis; only two had areas of anglar deviation of the trachea; and none were apparently short (Table 1).Other mechanisms besides stenosis and/or angular deviation may be
TABLE 1. Cases With Complete or Partial Cartilage Sleeve Abnormalities of the Trachea Svndrome
Age at death
Apert
6% months
Cartilage sleeve Tracheal Sex abnormalitv stenosis
F
+
+
Aperi
1 day
F
+
+
Apert
15 months
?
?
Apert
4 months
?
+ +
+
Apert Apert Apert ?Apert
13 months 3 months 10 months Stillborn
F F F
+
Foca1
M
+ + +
Acrocephalospondylosyndactyly Pfeiffer Pfeiffer Pfeiffer Crouzon Crouzon Crouzon Cloverleaf
3 months
M
+
3 months 13 months 15 months
+ +
2 years 2 years 7 years 40 days
M M F F M M M
Cloverleaf
8 months
M
+
+ + +
+ I
Short Angulated trachea trachea
Other Involvement of larger bronchi Thick cartilage; involvement of larger bronchi Involvement of larger bronchi Thick cartilage; involvement of larger bronchi -
-
Thick cartilage
Namw lumen -
-
Subglottic Glottic
-
-
Cloverleaf -
Uniform -
Narrow lumen -
Cloverleaf -
-
91
-
-
Reference Cohen and Kreiborg, patient 1 Cohen and Kreiborg, patient 2 Blank, 1960 Trott, 1992 Schmid, 1971 Davis et al., 1992 Davis et al., 1992 Shimada and Misugi, 1979 Wells et al.. 1990 Stone et al., 1990 Davis et al., 1992 Ldge et al., 1992 Schmid, 1971 Devine et al., 1984 Davis et al., 1992 Shimada and Misugi, 1979; Sano et al.. 1982 Davis et al., 1992
Cohen and Kreiborg
92
responsible for compromise in the lower airway. Cartilage sleeve abnormalities may lack of disten- produce _ sibility of the normal trachea, resulting in respiratory inefficiency, inability to clear secretions, andlor increased liability to surface injury from tracheal suctioning [Davis et al., 19921. The trachea was almost certainly compromised by multiple intubations in our patient 2. Davis et al. [1992]found the immediate cause of death in one case to be extensive mucous plugging of the lower trachea and large bronchi. To date, the eight known cases of Apert syndrome with partial or complete cartilage sleeve abnormalities of the trachea have been observed during infancy. The average age at death was 6.8 months (range: stillborn15 months) (Table 1). At present, we are studying our Apert syndrome patients (119 cases) [Cohen and Kreiborg, 19911to determine whether such tracheal anomalies are found in older individuals. Certainly, partial or complete cartilage sleeve abnormalities of the trachea should be suspected in m~Apert syndrome infant with lower respiratory compromise. Careful study of the trachea in any Apert syndrome autopsy, infant or otherwise, is recommended. Table 1 shows that other conditions such as Crouzon syndrome, Pfeiffer syndrome, acrocephalospondylosyndactyly, and cloverleaf skull have been reported on occasion with partial or complete cartilage sleeve abnormalities of the trachea. Other types of tracheal anomalies reported with various syndromes and associations are summarized in Table 11. In the Apert syndrome, a three-way embryonic link in failure of cartilage segmentation may be perceived. First, cartilage rings of the trachea normally form as discontinuous aggregates of cartilage during the eighth-to-ninth weeks of embryonic development. Failure of segmentation results in partial or complete cartilaginous sleeve abnormalities in the trachea. Second, embryonic failure in separation of the cartilage models of the phalanges becomes evident in the Apert syndrome by progressive ossification observed radiographically [Cohen, 1986; Schauerte and St-Aubin, 19661. Finally, with variable degrees of embryonic cartilage undersegmentation of the cervical vertebrae, which characterized 68%of our Apert patients [Kreiborg et al., 19921, cervical fusions became evident with progressive ossification observed radiographically. Upper airway compromise in the Apert syndrome is more widely known and well-researched than lower airway compromise. Studies show that distortions and displacements of the craniofacial bones compromise the nasopharyngeal and oropharyngeal space. Particularly noteworthy are reduction in pharyngeal height, width, and depth; increased length and thickness of the velum; decreased length of the hard palate; marked reduction in the posterior cranial base with a lesser degree of reduction in the anterior cranial base; and a more acute cranial base angle. These changes are present during infancy and tend to become more pronounced with craniofacial growth [Peterson-Falzone et al., 19813. The extremely shallow oropharynx is recognized as an important factor in obligatory mouth breathing and forward placement of the tongue so frequently found in the Apert syndrome [Peterson and Pruzansky, 19741. The
TABLE 11. Other Reported Tracheal Anomalies in Syndromes and Associations
v
Anomaly (syndrome or association) nacheomalacia Atelosteogenesis 1" Campomelic dysplasia Cerebrocostomandibular syndrome
Diastrophic dysplasia Hallermann-Streiffsyndrome L~~~~~syndrome
nacheoesophagealfistula VATER, VACTERL associations CHARGE association TrisomY
l8 spdrome
Di,CUf,~$~~v~tebral spectrum
Asymmetric crying facies Tracheal agenesis VATER association Polyhydramnios, prematurity, growth retardation,laryngeal
Reference Whitley et al., 1986 Lee et al., 1972 Smith et al., 1966 Friedman et al., 1974 Salbert et al., 1991 Rock et al., 1988 Chen et al., 1982b Evans et al., 1985
Pagon et al., 1981 Evans et al., 1986 Evans et al., 1986 Bowen and Parry, 1980 Pape and Pickering, 1972 Milstein et al., 1985 Evans et al., 1986; Downing, 1992
~defects, ~ ~ ~duodenal ' $ " ~ ~ atresia, ~re,n;l"a'
diaphragmatic hernia Tracheal and bronchialstenosis Salonen et al., 1981 Hydrolethalus syndrome ~ac~eobronchomegaly Gay and Dee, 1984 Ascher syndrome ~ i f fabnormal ~ ~ ~ l ~
cmtilaginous patbming of trachea and bronchi Ellis-van Crevald syndrome Tracheal diverticulum and tracheal accessory bronchus Ivemark spdrome Complete cartilaginous rings
wndrome
Landing and Wells, 1973 Landing and Wells, 1973 Landing and Wells, 1973
"Atelosteogenesis 1 repiaces the earlier term "de la Chapelle syn-
~ent~ disorder, ~ ~ " " ~we~ think ~ t r ~they~ ~have , : SLarsen g Uthatgsyndrome, ptheir e s patients t e d had a differcombination of reduced nasopharyngeal dimensions and reduced patency of the posterior choanae poses a risk of respiratory embarrassment, obstructive sleep apnea, and cor pulmonale, particularly in infants and children with Apert syndrome. A case reported by Lauritzen et al. [1986] is instructive. A 37/12year old boy with Apert syndrome was observed to have long apneic periods with cyanosis while sleeping. Shortly thereafter, two episodes of cardiac arrest occurred during sleep and each time he was resuscitated successfully. A chest roentgenogram showed cor pulmonale. Tracheostomy stabilized the situation. Many other craniofacial syndromes such as Crouzon syndrome [Don and Siggers, 1971; Hess et al., 19861, Pfeiffer syndrome [Lauritzen et al., 19861, and Haller-
Apert Syndrome Airway Compromise
mann-Streiff syndrome [Cohen, 19911 may be associated with upper airway compromise, obstructive sleep apnea, and cor pulmonale. Since, on the average, children with obstructive sleep apnea experience a 2 year delay in referral for proper diagnosis, Apert syndrome patients in particular, or any other craniofacial syndrome patients for that matter, who are predisposed to upper airway compromise because of abnormal craniofacial configuration should be monitored carefully for snoring andlor an unusual amount of daytime somnolence. Such patients should be referred to a sleep center for proper diagnosis and treatment to prevent dangerous sequelae.
93
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