Clinical Review Laryngotracheal Anomalies in Children with Craniofacial Syndromes

Home , Arthrogryposis, Bronchomalacia, Fraser syndrome, Goldenhar syndrome, Pierre Robin sequence, Subglottic stenosis

Clinical Review Laryngotracheal Anomalies in Children With Craniofacial Syndromes

Frank A. Papay, MD, FACS* Vincent P. McCarthy, MD† Isaac Eliachar, MD‡ James Arnold, MD§

Cleveland, Ohio

INTRODUCTION sleep apnea. Recent literature reviews have ad- dressed the causes of sleep apnea in various cranio- he formation of the nasal oropharyngeal airway facial syndromes and will not be discussed in detail in conjunction with the laryngotracheal airway T herein.1,2 Craniofacial syndromes that involve an ab- and its related structures is a complex process de- normal anterior and middle cranial base in associa- pendent on the separate yet interrelated ontologic tion with mid-facial maxillary hypoplasia often have development of the mouth, nose, pharynx, larynx, narrow nasopharyngeal channels causing nasopha- and the tracheo-bronchial tree. These relationships ryngeal airway constriction. In neonates who are ob- are also influenced by the adjacent formation of the ligate nasal breathers, this may pose difficulties such posterior cranial base, anterior craniofacial skeleton, as a physiologic choanal atresia type of nasopharyn- neck, and adjacent thoracic structures. Not surpris- geal obstruction. In addition, the mid to lower cranial ingly, a vast array of airway anomalies can occur base in close association with the oropharyngeal cav- when each interrelated adjacent structure is abnor- ity, may cause respiratory comprise with the base of mal. Because of its vital nature, life-threatening air- the tongue and the glottic opening. Patients having way anomalies are apparent at birth or soon after. cranial base, maxillary midfacial hypoplasia with an Respiratory distress, cyanosis, difficulty feeding, and additional mandibular hypoplasia, will in essence visually observed abnormalities can lead to an early have partial obstruction in all zones of the upper diagnosis. However, less severe airway anomalies supraglottic airway. can be occult and take months or years to be diag- The etiologies of craniofacial syndromal upper nosed. These patients’ symptoms express only when airway obstruction and restriction are not based only the respiratory system is stressed during the de- on anatomic deformity. Ruckstein summarized the mands of increased respiratory function that can oc- impact of mucopolysaccharide infiltration into the cur with infection or postoperative. soft tissue of the upper airway in patients with the Of further note is the fact that while breathing mucopolysaccharidoses.3 Of interest is the fact that may be normal and asymptomatic while a patient is such infiltration and its consequent obstruction re- awake, significant difficulty may occur when the pa- solves with successful bone marrow transplantation. tient goes to sleep. Physicians and parents may be Solomon discussed a similar significance of muco- totally unaware of ongoing nocturnal symptoms. Of polysaccharide soft tissue infiltration in Apert’s syn- those patients with craniofacial syndromes, the ma- drome.4 Recently, mutations in human growth factor jority of respiratory difficulties are due to obstructive receptors (FGFR1, FGFR2, and FGFR3) have been associated with the phenotypic expression of the Ap- *Head, Section of Craniofacial Surgery, Department of Plastic ert, Crouzon, Pfeiffer, and Jackson-Weiss syndromes and Reconstructive Surgery, Cleveland Clinic Foundation, Cleve- as well as thanatophoric dysplasia, with or without a land, Ohio, USA; †Fellow, Section of Sleep Medicine, Department cloverleaf deformity.5 of Neurology, Cleveland Clinic Foundation, Cleveland, Ohio, USA; ‡Head, Section of Laryngotracheal Reconstruction, Depart- Neither craniofacial syndromes nor congenital ment of Otolaryngology and Communicative Disorders, Cleve- anomalies of the pediatric airway are common. Mal- land Clinic Foundation, Cleveland, Ohio, USA; §Head Section of formations in general occur in 0.47% of live births Pediatric Otolaryngology, Department of Otolaryngology, Univer- and respiratory tract malformations account for 0.3% sity Hospitals, Cleveland, Ohio, USA. of these.6 Significant craniofacial syndromes with Correspondence to Frank A. Papay, MD, FACS, Cleveland Clinic Foundation, 9500 Euclid Avenue—Desk A60, Cleveland, craniosynostosis have an occurrence of 0.4 in 1,000 OH 44195, USA births.7 Case reports have documented marked

351 THE JOURNAL OF CRANIOFACIAL SURGERY / VOLUME 13, NUMBER 2 March 2002 lower airway pathology in craniofacial syndromes Laryngeal Atresia with mid-facial maxillary hypoplasia, i.e. Apert’s Severe laryngeal atresia was reported in a case report and Crouzons’s syndromes, but such reports have of a term infant with 47XXX Syndrome (hypertelor- been sporadic and based primarily on autopsy find- 8 ism, short philtrum, beaked nasal tip, rudimentary ings. There have been no comprehensive attempts to helices) who died at birth. The vocal cords were hy- broadly define the coincidental occurrence of airway poplastic and the larynx was totally occluded with a anomalies in craniofacial syndromes and their im- band of cartilage and connective tissue (Table 1) (Fig pact on one another. 1).9 Below the occlusion was a patent trachea. De- This presentation attempts to provide an over- spite visualization of the vocal cords, an endotrache- view of congenital anomalies of the pediatric airway al tube could not be passed and the patient failed proximal to the bronchioles that are likely to confront tracheostomy. Schimke et al reported a 35-week-old the craniofacial surgeon, otolaryngologist, anesthesi- infant with hypomandibular cranial dysostosis (max- ologist, and pediatric pulmonologist in patients with illary and zygomatic hypoplasia, coronal synostosis craniofacial anomalies. The advent of the pediatric and absent mandible). The patient had bilateral choa- flexible fiberoptic bronchoscope, and standards for nal stenosis and optic nerve hypoplasia, in addition pediatric polysomnography allow direct evaluation to a rudimentary epiglottis, a slit-like larynx with of infants and children with preoperative symptoms. absence of laryngeal cartilage, and an atretic trachea, The pediatric flexible bronchoscope allows both a which ended blindly 1 cm below the larynx. No tra- static and dynamic evaluation of the upper and cheal cartilage was present in the trachea or primary lower airways. Preoperatively, all symptomatic pa- bronchi.10 In such instances where it is apparent that tients with craniofacial anomalies should be exam- ventilation can be maintained despite inability to in- ined for obstructive sleep apnea and the possibility tubate the trachea by the laryngeal route, a tracheo- of occult airway anomalies that may affect the peri esophageal fistula must exist, and the esophago- and/or postoperative course of these patients. Indi- tracheal communication needs to be cannulated and vidual patients with any given craniofacial syn- isolated from the gastrointestinal tract. A cervical dromes may have single or multiple anomalies. At esophagostomy also needs to be established to con- the same time more than one anomaly may be asso- trol oral secretions. These emergent measures will ciated with a specific syndrome. Thirty-six syn- allow time to better assess the overall viability of the dromes with craniofacial anomalies were found that patient and make the correct individual ethical deci- were associated with one or more of 14 airway mal- sions pertinent to the situation.11 Two patients with formations or anomalies. To simplify this issue, in- Fraser’s Syndrome (cryptophalmos, dyscephaly, syn- dividual anomalies will be presented with the syndactyly, and urogenital anomalies) have been de- dromes that have been described to have an scribed with laryngeal atresia, having a poorly de- association. Appendix 1, however, will alphabeti- veloped larynx, small vocal cords, and an anterior cally list all syndromes and their associated anoma- membranous fusion.12,13 lies. Laryngeal Hypoplasia

LARYNGEAL ANOMALIES Small, malformed larynxes with laryngeal stenosis have also been described in several craniofacial syn- he larynx begins development from the laryn- dromes (Fig 2) (Table 2). In some instances, the dif- Tgotracheal groove in the fourth week and is a ference between hypoplasia and atresia is arbitrary, well-formed organ by the eighth week. A wide spec- and the degree site of stenosis often creates a con- trum of laryngeal anomalies has been described in tinuum rather than a well-defined anatomical diag- association with craniofacial syndromes. The symp- nosis. Two infants with Marshall-Smith Syndrome toms of a laryngeal abnormality are usually stridor, (accelerated skeletal maturation, failure to thrive, respiratory distress, or abnormal phonation. Emer- and dysmorphic features), ages 3 to 16 months re- gent laryngoscopy is indicated when life-threatening laryngeal anomaly is suspected. In the face of a se- Table 1. Craniofacial Anomalies Associated with vere craniofacial anomaly however, laryngoscopy Laryngeal Atresia may be difficult to perform, even with a flexible fi- 1. Fraser syndrome beroptic laryngoscope. Antecedent radiologic or 2. Hypomandibular fasciocranial dysostosis computed tomographic evaluation of the airway 3. 47 XXX syndrome may help localize the pathology in these instances.

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external compression due to an aberrant innominate artery.15 Camera et al described a 2-year-old female with Toriello-Carey Syndrome (craniofacial defects, congenital heart defects, agenesis of the corpus callosum, hypotonia, and growth retardation) who at laryngoscopy demonstrated moderate laryngeal hypoplasia, a Robin sequence, and a submucous cleft.16 Toriello’s original description of the syndrome also included 2 children with laryngeal hypoplasia, the Robin sequence, and a cleft palate.17 Krauss et al reported a term infant with Nager Syndrome (mandibular-facial dysostosis and thumb anomalies) who had respiratory distress at birth. At autopsy, there was hypoplasia of the epiglottis and the larynx with the laryngeal orifice being only 0.5 cm in the greatest diameter. Early respiratory distress and death had been commonly reported in this rare syndrome but this report was the first to describe the critical airway anatomy.18 Shpinntzen and Goldberg reported a pedigree of a father and two daughters with dysmorphic facies, omphalocele, spinal anomalies, learning disabilities, and laryngeal hypoplasia. The father’s speech had a very high pitch and laryngoscopy demonstrated an omega-shaped epiglottis and a short larynx that had a glottic area two-thirds normal size. Similar laryngeal findings were shared in common with both daughters who had histories of prolonged respiratory difficulties in the neonatal period necessitating prolonged stays in the intensive care unit.19

Laryngomalacia

Laryngomalacia is a congenital flaccid larynx with associated inspiratory collapse (Fig 2) (Table 3). La- ryngomalacia accounts for 75% of all laryngeal anomalies. It has been associated with both obstructive apnea and sudden death in infants. There is a 20% reported prevalence of additional endoscopic findings with laryngomalacia, the most common of which is tracheomalacia. Laryngomalacia has been Fig 1 Hypoplasia. reported as a solitary lesion or in association with either tracheomalacia, bronchomalacia or both. O’Herlhy described a neonate with Larsen’s syn- spectively, were described at autopsy to have rudi- drome (abnormal facies, multiple joint dislocations, mentary epiglottis and hypoplastic larynx. The first and hand abnormalities) who had stridor in the de- patient also had micrognathia and choanal atresia, livery room. Laryngoscopy demonstrated laryngo- while the second patient had an anterior chest wall malacia and lateral neck films showed a deficiency of deformity composed of cartilage and bone. Both pa- hyoid cartilage.20 Latta et al described another term tients died of respiratory failure.14 Huot et al de- infant with neonatal respiratory distress and sternal scribed a 19-week-old with intrauterine exposure to retractions who also had laryngomalacia on laryn- valproic acid who had cyanosis, crying following goscopy.21 In both cases, symptoms were short-lived. bottle feedings, with nasal flaring and intercostal re- There are cases of infants with Larsen’s syndrome, tractions. Laryngoscopy demonstrated severe laryn- however with symptomatic laryngomalacia who geal hypoplasia and tracheomalacia associated with have died suddenly.22,23 In one instance this oc-

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Fig 2 Laryngomalacia. (A) Ant. Collapse (B) Airway obstruct. curred in spite of a tracheostomy. Microscopy in one hypercarbia, and hypoxia. Laryngomalacia has also of these cases revealed a significant reduction in the been described with an increased incidence in Ap- number of elastic fibers in the larynx, trachea, and ert’s Marshall-Smith’s, and Pfeiffer’s syndromes and bronchi. Gallini and Matt described a 2-month-old the Pierre-Robin sequence. with Freeman-Sheldon syndrome (mask-like ‘whis- tling face’, hypoplastic alae nasi, and flexion contrac- Vocal Cord Paralysis tures) who presented with stridor, apnea, and oxy- gen desaturations. Laryngomalacia was diagnosed at The larynx develops as a differentiation of the me- laryngoscopy and the excision of loose arytenoid tis- soderm of the pulmonary diverticulum, while the sue resulted in resolution of symptoms.24 The aryte- vocal cords take their origin from the mucous mem- noid submucosa unexpectedly contained peripheral branes of the lateral wall of the laryngeal cavity. Vo- nerve trunks infiltrated with striated muscle. Epi- cal cord paralysis (Fig 3) (Table 4) accounts for 10% glottoplasty has proven safe and effective for se- of congenital laryngeal anomalies in general and is lected patients with severe laryngomalacia and ob- the second most common cause of such anomalies. In structive apnea documented on polysomnography.25 patients with craniofacial syndromes it has not un- Continuous positive airway pressure may be neces- commonly been associated with additional laryngeal sary, in addition in these patients with coincidental anomalies. Cohen and Isaacs described two patients tracheomalacia, with or without a tracheostomy. with severe arthrogryposis multiplex congenital or Polysomnography can be used as a guide to the ef- the Guerin-Stern syndrome (non progressive flexion ficacy of both of these modalities in reducing apnea, and extension fractures, and absence of normal flex-

Table 2. Craniofacial Anomalies Associated with Table 3. Craniofacial Anomalies Associated Laryngeal Hypoplasia with Laryngomalacia

1. Dysmorphic facies, omphalocele, spinal anomalies, learning 1. Apert syndrome disabilities and laryngeal hypoplasia 2. Freeman-Sheldon syndrome 2. Fetal Valproate syndrome 3. Larsen’s syndrome 3. Marshall-Smith syndrome 4. Marshall-Smith syndrome 4. Nager syndrome 5. Pfeiffer syndrome 5. Toriello-Carey syndrome 6. Pierre-Robin syndrome

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Fig 3 Laryngomalacia. (A) View of airway obstruct. (B) Uni abduct. (C) Bi abduct.

ion creases over involved joints) with mid-line vocal cord paralysis, laryngomalacia, absent gag reflexes, pharyngeal paralysis, and expressionless faces.26 Mehta and Schon described a 5-month-old with Gor- lin-Cohen syndrome or frontometaphyseal dysplasia Table 4. Craniofacial Anomalies Associated with (overgrowth of the supraorbital ridges, muscular un- Vocal Cord Paralysis derdevelopment, restricted joint movement) with persistent stridor who was found to have laryngo- 1. Arthrogryposis multiplex congenita malacia, left vocal cord paralysis, and subglottic ste- 2. Cri du Chat 3. Frontometaphyseal dysplasia nosis. Because of a combination of a short neck, man- 4. Klippel-Feil syndrome dibular hypoplasia, and limited motion of the neck and jaw, both a difficult intubation and postopera-

355 THE JOURNAL OF CRANIOFACIAL SURGERY / VOLUME 13, NUMBER 2 March 2002 tive obstructive apnea should be anticipated. Cau- 5). The subglottic lumen of a newborn is 4.5 to 5.0 tion should also be exercised with the use of relax- mm and a lumen less than 4.0 mm indicates stenosis. ants before intubation. Since these patients may also Kobel and Steward reviewed the records of 100 con- have thoracic scoliosis and consequent restrictive secutive patients with Trisomy 21 who underwent lung disease, continuous positive airway pressure general anesthesia and surgery. These children should again be considered as a postoperative adju- ranged in age from 1 day to 18 years of age with a vant to protect and maintain functional residual ca- mean age of 5.8 years. Twenty-three percent of these pacity. Clarke described a patient with Klippel-Feil patients required an endotracheal tube 1 or 2 sizes syndrome (short neck, block vertebrae of the cervical smaller than predicted by age.30 Subglottic stenosis spine) with subglottic stenosis complete immobility with complete tracheal rings from the cricoid to the of the right vocal cord and partial fixed adduction of carina was discovered in an infant with Trisomy 21 the left vocal cord.27,28 Patients with the Cri-du-Chat undergoing repair of the tracheal stenosis.31 An al- syndrome (moon facies, micrognathia, and narrow, ready compromised airway in these patients can be diamond-shaped larynx on inspiration and a charac- further compromised in Trisomy 21 patients postop- teristic failure of vocal cord approximation in the eratively by upper airway obstruction due to pha- posterior commissure with phonation) can present ryngeal hypotonia, lymphoid hyperplasia, and mac- with laryngeal inspiratory distress (Fig 4).29 The roglossia. characteristic mewing cry matures with age but re- Continuous positive airway pressure can be a mains abnormal. useful postoperative adjunct in this patient population in this scenario. Karas and Respler reported that Laryngeal Stenosis laryngeal stenosis was the single most common oto- Congenital subglottic stenosis is reportedly the third laryngeal finding in patients with Fraser’s syn- 32 most common cause of laryngeal anomalies (Table drome. In this patient population, subglottic stenosis may be a distinct finding or it may more commonly be a part of a continuum of the general- ized laryngeal hypoplasia previously discussed. Min et al described a 2-month-old with respiratory distress at birth without a cleft or choanal atresia who at laryngoscopy had a normal supraglottis but demonstrated fusion of the true cords except in the posterior commissure; laryngeal tomograms showed severe laryngeal stenosis extending through the entire subglottic space. At tracheotomy, the subglottic space was found to be filled with a mass consisting of fibrous tissue and skeletal muscle. No mention is made of the lower airway, however the child was found dead one morning, with autopsy evidence of pulmonary edema. This would suggest that there had been an episode of struggling with a resultant increase in intrathoracic pressure. In retrospect, a trial of continuous positive airway pressure at night may have been beneficial in stinting open the airway while asleep.33 Ford described four cases of children with Fraser syndrome, two of whom also had choanal atresia. In each of these instances, the subglottic stenosis was discovered on intubation for a recon-

Table 5. Craniofacial Anomalies Associated with Laryngeal Stenosis

1. Fraser syndrome 2. Frontometaphyseal dysplasia 3. Klippel-Feil syndrome 4. Trisomy 21 Fig 4 Cri-du-Chat. (Top) Phonation. (Bottom) Inspir.

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Fig 5 Infant larynx. structive procedure.34 Fitzsimmons et al described four patients in a pedigree of three generations with frontometaphyseal dysplasia. There were two infants with stridor at birth and a history of pallor and ap- Fig 6 Laryngeal cleft. nea.35 Both infants were found to have subglottic stenosis with an anterior web occurring as an additional finding in one instance. sions of the glottic chink have been described with The above discussion lends credence to two laryngeal atresia in Fraser’s syndrome, and has been mentioned as occurring with subglottic stenosis in points. First, the presence of one laryngeal anomaly 35 should necessitate the need to totally eliminate the frontometaphyseal dysplasia. possibility of a second or even third coexisting anomaly. Second, the presence of a known anomaly Laryngeal Cleft in one family member with syndromal findings This laryngeal anomaly (Fig 6) (Table 7) has been again necessitates the need to rule occult lesions in rarely described in craniofacial syndromes, but has subsequent members with the same syndrome. been specifically associated with two particular syndromes. Approximately 143 cases of the G syndrome Laryngeal Web (dysphagia, ocular hypertelorism, and hypospadias) Laryngeal webs (Fig 5) (Table 6) have been described have been described in the literature with a 30% in- in craniofacial syndromes as an isolated finding and cidence of laryngotracheal clefting. Associated in association with other laryngeal anomalies. An anomalies include, laryngotracheomalacia, cleft pal- isolated laryngeal web was described by Shprintzen ates, absence of tracheal rings, and high tracheal bi- et al as an incidental finding in a patient with velo- furcations. Patients present clinically with stridor, re- cardialfacial syndrome (hypernasality, submucous spiratory distress, choking, difficulty with increased cleft, cardiac anomalies, learning disability).36 Fu- Table 7. Craniofacial Anomalies Associated with Table 6. Craniofacial Anomalies Associated with Laryngeal Cleft Laryngeal Web 1. G syndrome 1. Velo-Cardio-Facial syndrome 2. Pallister-Hall syndrome

357 THE JOURNAL OF CRANIOFACIAL SURGERY / VOLUME 13, NUMBER 2 March 2002 secretions, and cyanosis with feedings.37 A high level the carrot shaped trachea with tapering of the tra- of suspicion must exist in dealing with this clinical cheal caliber from the cricoid to the carinal bifurca- situation since an existing cleft has been missed with tion(Table 8). A specific association of this anomaly fluoroscopy, and even with laryngoscopy and bron- with Trisomy 21 has been described in the literature. choscopy. In some instances a diagnosis should be Shimada, Devine, and Hansen each described single suspected at surgery when there is either difficulty in cases of infants with Trisomy 21 who died of respi- establishing or maintaining tracheal intubation. Of ratory insufficiency and had complete rings from note is the fact that a significant cleft may go unde- the cricoid to the carina with only a small triangular tected until autopsy in patients succumbing to recur- area of pars membranacea in the supra-carinal area rent aspiration.37 In the original description of the (Fig 7).39–41 The inner diameter of the trachea de- Pallister-Hall syndrome (hypothalamic hamarblas- scribed by Shimade was only 3 mm. Eight cases of toma, hypopituitarism, imperforate anus, postaxial mid-tracheal stenosis in patients with Trisomy 21 polydactyly), the first three patients were found to have also been described with an unusual widening have laryngeal clefts at the time of autopsy.38 of the supra carinal pars membranacea (Fig 8). In In patients with a suspected or confirmed cleft, three cases, complete ring formation occurred from an airway must be secured and protected from oral the fourth to the eleventh, fifth to the eleventh, and aspiration until corrective surgery can be done. This sixth to the twelfth rings respectively.42 Cartilagi- may necessitate a tracheostomy and a double gas- nous rings were arranged in a helical pattern rather trostomy with a high gastric division to allow con- than the classic napkin ring pattern. Tracheal ring tinued enteral feedings. defects occurred in patients with and without cardiac defects. TRACHEAL ANOMALIES Net-Like Deformity he laryngotracheal outgrowth arises from the Tcaudal portion of the pharynx during the fourth Landing and Wells described a 3-week-old with El- week of gestation. By the eighth week, cartilage is lis-van Creveld syndrome (short limbed dwarfism, histologically discernable and tracheal rings are hexadactyly, dysplastic nails, dysodontiasis, and car- noted by the ninth week. Tracheal and bronchial cardiac defects) with a diffusely abnormal pattern of tilage is complete by 24 weeks gestation. The normal tracheal and bronchial cartilages arranged in a net- trachea contains 16 to 18 rings from the cricoid to the like design (Table 9).43 Schwyzer et al44 described a carina, with three to five rings in the right mainstem newborn with multiple congenital anomalies who bronchus, two in the right upper lobe bronchus, died shortly after birth. A diagnosis of Fryn’s syn- three to four in the intermediate bronchus, and 9 drome (dysmorphic facies, lung hypoplasia, dia- rings in the left mainstem bronchus. Any defect in phragmatic defects, hypoplastic phalanges) was the number, shape, or consistency of these rings can made at autopsy; again the tracheal and bronchial give rise to a wide spectrum of anatomic anomalies cartilages showed a net-like arrangement.44 capable of occult as well as overt respiratory distress. The majority of these anomalies are discernable only Cartilage Plate Defects on flexible fiber optic bronchoscopy and therefore go Malformed rings with an abnormal shape may result undiagnosed until unexplained respiratory distress in inadequate support and partial collapse of air- occurs. The spectrum of tracheal anomalies seen in ways, causing respiratory distress. Herring et al de- patients with craniofacial anomalies is the same as scribed a 7-month-old with Treacher-Collins man- that seen in the general population, however certain dibulofacial dysostosis (anti-mongoloid slant, anomalies have demonstrated a predilection for spe- coloboma, nasal beaking, malformed ears, hearing cific syndromes. loss) with repeated infections and respiratory dis- Congenital Tracheal Stenosis tress despite a tracheostomy. At autopsy, the tracheal rings were small and partially collapsed (Table 10).44 Tracheal stenosis with absence of the pars mem- Smith et al reported a newborn with respiratory in- branacea and resultant complete ring formation has been divided into three categories: the stovepipe deformity where complete rings are seen the length of Table 8. Craniofacial Anomalies Associated with the trachea and the carinal bifurcation, the hourglass Congenital Tracheal Stenosis deformity with mid-tracheal ring formation and di- 1. Trisomy 21 latation of the pars above and below the rings, and

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Fig 7 Supra-carinal area. sufficiency who died at 8 hours of age. The patient had micrognathia, an absence of rib tissue between the posterior ossified rib, and the ventral cartilaginous ribs. The tracheal cartilages were partially col- Fig 8 Solid tracheal rings. lapsed resulting in significant reduction of the anterior-posterior diameter of the trachea.45 Whitley et al described two infants with de la Chapelle Dysplasia Table 9. Craniofacial Anomalies Associated with (micromelia, small thorax, equino varus, cleft palate, Net-Like Deformity small hands) who died at birth. The cartilage rings of the trachea and bronchi were incomplete resulting in 1. Ellis-van Creveld syndrome 2. Fryn’s syndrome collapsed lumens in these structures.46

Abnormal Cartilage Ring Size and Number Table 10. Craniofacial Anomalies Associated with Landing and Wells described a 1-month-old with Tracheal Cartilage Plate Defects Langer type mesomelic dwarfism who had a cleft palate and recurrent aspiration. At autopsy there 1. de la Chapelle dwarfism was more slender rings in the trachea and right 2. Rib-Gap defect mainstem bronchus (Table 11).43 3. Treacher-Collins syndrome

Tracheal Cartilaginous Sleeve A cartilaginous trachea with complete vertical fusion Table 11. Craniofacial Anomalies Associated with of the tracheal rings (Fig 9) (Table 12) can occur with Abnormal Cartilage Ring Size or Number or without an intact pars membranacea. The trachea 1. Langer type mesomelic dwarfism is rigid and non-distensible resulting in an ineffective

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Fig 9 Various states of tracheal rings. cough and poor mucociliary clearance. Often a dys- Mixter has cautioned against a predisposition to tra- morphic carins is present. Findings may go undiag- cheal injury in this instance with the risks of signifi- nosed until autopsy or occur as an unexpected post- cant granulomatous reaction resulting in obstruction operative finding. Bronchoscopy demonstrates a and hemorrhage.8 smooth anterior tracheal wall without ring segmen- tation. The pars membranacea may be normal or a Tracheomalacia completely cartilaginous wall may exist. A review of the literature revealed 25 cases, the majority occur- The term tracheomalacia infers a softness of the tra- ring in patients with congenital craniosynostosis. cheal cartilage resulting in an excessive collapsibility There were 12 cases of Apert’s syndrome (acroceph- causing complete or partial intermittent airway ob- aly, dysmorphic facies, syndactyly), four cloverleaf struction. On flexible fiber optic bronchoscopy, the anomalies, four cases of Crouzon’s (acrocephaly, trachea is often anatomically normal, however there syndactyly, dysmorphic facies, broad stocky thumbs, is dynamic collapse with expiration (Fig 10) (Table halluces), one case of Saethre-Chotzen syndrome (ac- 13). This finding is often absent with rigid broncho- rocephaly, dysmorphic facies, syndactyly), and one scopy under general anesthesia and forced ventila- case of Goldenhar’s syndrome (facial asymmetry, tion. The abnormality may be isolated or associated epibulbar dermoid, preauricular tags, unilateral mac- with either laryngomalacia, bronchomalacia, or both. rostomia).46–57 Associated anomalies in selected Tracheomalacia may also occur as a result of extrin- cases included laryngomalacia and subglottic steno- sic compression due to an aberrant vessel. Clinically, sis. Cartilaginous cylinders may extend past the ca- stridor, retractions, feeding difficulties, ineffective rina into mainstem bronchi. Sudden death was not cough, and recurrent lower respiratory infections an uncommon occurrence in this patient population. may occur. With severe extrinsic compression, ‘dy- ing spells’ have been described. Sudden death has also been associated with tracheomalacia in Larsen’s Table 12. Craniofacial Anomalies Associated with syndrome; at autopsy, there was a significant reduc- Cartilagineous Tracheal Sleeve tion in normal elastic fibers, and a thinning of the hyaline cartilage in the tracheal rings.58 Kuwashima 1. Apert syndrome et al described a term infant with atelosteogenesis 2. Cloverleaf anomaly type 3 (dysmorphic facies, cleft palate, rhizomelic 3. Crouzon’s syndrome dwarfism, multiple dislocations, S shaped cervical 4. Goldenhar’s syndrome 5. Pfeiffer syndrome spine curvature) with recurrent apnea and severe 6. Saethre-Chotzen syndrome persistent tracheomalacia necessitating tracheostomy and mechanical ventilation.59 Salbert et al reported

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an infant with Hallerman-Streif syndrome (short stature, ‘bird like’ facies, congenital cataracts, micrognathia, hypotrichosis, frontal bossing) with severe apnea and bradycardia. Tracheomalacia was documented by fluoroscopic examination. Despite tracheostomy, the patient developed biventricular heart failure, and died.60 Nocturnal continuous positive airway pressure or mechanical ventilation may be helpful in these instances, again in maintaining functional residual capacity and resultant oxygenation. Tracheomalacia has also been described in Fetal Val- proate syndrome, Fryn’s syndrome, Kniest syndrome, and metatropic dwarfism.61–63

BRONCHIAL ANOMALIES

Bronchomalacia

an Benthm described three siblings, two of Vwhom died with recurrent pneumonias and demonstrated thinning, hypoplasia, and collapsibility of the left mainstem bronchus (Table 14). These patients also demonstrated kyphoscoliosis, flattening of the left chest, cryptorchidism, dysmorphic facies, hypoplastic musculature, and mental retardation.64 Bronchomalacia due to absence of bronchial cartilage in the left upper lobe bronchus resulting in diffuse emphysematous distention of the left upper lobe was described in an infant with Ellis-van Creveld syndrome.65 Bilateral absence of bronchial cartilage in the distal bronchi resulting in respiratory distress necessitating mechanical ventilation in the neonatal period has been described in the hyperphalangism, hallux valgus, facial anomaly, and bronchomalacia association.66 Isolated bronchomalacia was also described in a patient with hypomandibular fasciocranial dysostosis. Bronchomalacia would appear to be Fig 10 Tracheomalacia. a more benign phenotypic expression of this syndrome as her sibling presented at birth with laryngotracheal atresia with absence of cartilage in the trachea and primary bronchi.10 In addition, bron-

Table 14. Craniofacial Anomalies Associated Table 13. Craniofacial Anomalies Associated with Bronchomalacia with Tracheomalacia 1. Apert’s syndrome 1. Atelosteogenesis types 1 and 3 2. Ellis-van Creveld syndrome 2. Fetal Valproate syndrome 3. Fryn’s syndrome 3. Fryn’s syndrome 4. Hyperphalangism-facial anomaly-hallus valgus-bronchomalacia 4. Kneist syndrome 5. Hypomandibular fasciocranial dysostosis 5. Hallerman-Streif syndrome 6. Larsen’s syndrome 6. Larsen’s syndrome 7. Pfeiffer’s syndrome 7. Metatropic dwarfism 8. Pierre-Robin sequence

361 THE JOURNAL OF CRANIOFACIAL SURGERY / VOLUME 13, NUMBER 2 March 2002 chomalacia has been described as a component of 9. Hood OJ, Hartwell EA, Shattuck KE, et al. Multiple congenital laryngotracheomalacia in patients with Larsen’s syn- anomalies associated with a 47XXX chromosome constitution. Am J Med Genet 1990;36:73–5 drome, Apert’s syndrome, Pfeiffer’s syndrome, 10. Schimke RN, Clafin KS, Seguin JH, et al. Hypomandibular 8,67 Fryn’s syndrome, and the Pierre-Robin sequence. faciocranial dysostosis: Report of an affected sib and follow- up. Am J Med Genet 1991;41:102–4 11. Altman RP, Randolph JG, Shearin RB. Tracheal agenesis: Rec- CONCLUSION ognition and management. J Ped Surg 1972;7:112–18 any of the airway anomalies presented were 12. Kapoor S. Otolaryngologic features of malformation syndrome with cryptophthalmos. J Laryngol Otol 1979;93:519–25 Mdiscovered either at the time of intubation, or 13. Waring GO, Shields JA. Partial unilateral cryptophthalmos postoperatively. In many situations, surgery was with syndactyly, brachycephaly and renal anomalies, Am J done urgently because of existing distress, in other Ophthalmol 1975;79:437–40 situations it was done electively. In either situation, 14. Johnson JP, Carey JC, Glassey FJ, et al. Marshall-Smith syndrome: Two case reports and a review of pulmonary symp- unexpected or unanticipated perioperative airway toms. Pediatrics 1983;71:219–23 compromise can result in increased morbidity. Only 15. Huot C, Gauthier M, Lebel M, et al. Congenital malformations awareness and anticipation can prevent this. In the associated with maternal use of valporic acid. Can J Neuro Sci era of the team approach to patient management, 1987;14:290–93 16. Camera G, Right E, Romagnoli G. Toriello-Carey syndrome: rare airway-syndromal associations can be easily Report of a new case. Clin Dysmorphology 1993;2:260–63 overlooked. The instances, subclinical symptoms 17. Toriello HV, Carey JC. Corpus callosum agenesis, facial may not be uncovered unless systemically sought. anomalies, Robin sequence, and other anomalies: A new au- Because several anomalies can occur concurrently in tosomal recessive syndrome? Am J Med Genet 1988;31:17–23 18. Krauss CM, Hassel LA, Gang DL. Brief clinical report: Anoma- more than one syndrome, the presence of one lies in an infant with Nager acrofacial dysostosis. Am J Med anomaly should automatically necessitate the need Genet 1985;21:761–64 to specifically rule out the presence of coexisting 19. Shprintzen RJ, Goldberg RD. Dysmorphic facies, omphalocele, anomalies. Lateral neck films, fluoroscopy, and com- laryngeal and pharyngeal hypoplasia, spinal anomalies, and learning disabilities in a new dominant malformation syn- puted tomography can be helpful when trying to iso- drome. Birth Defects: Original Article Series, 1979;15:347–53 late a finding. Aggressive use of airway endoscopy 20. O’Herlihy C, O’Brien N. 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Appendix 1. Craniofacial Syndromes and Associated Airway Anomalies*

1. Apert syndrome 2. Arthrogryposis Multiplex Congenita laryngomalacia vocal cord paralysis cartilaginous tracheal sleeve bronchomalacia 3. Atelosteogenesis 4. Cloverleaf Anomaly tracheomalacia cartilagineous tracheal sleeve 5. Cri-du-Chat 6. Crouzon syndrome vocal cord paresis cartilagineous tracheal sleeve 7. de la Chapelle Dysplasia tracheal cartilage plate defects 8. Dysmorphic facies, omphalocele, spinal anomalies, learning disabilities, laryngeal hypoplasia laryngeal hypoplasia 9. Ellis van Creveld syndrome 10. Fetal Valproate syndrome bronchomalacia laryngeal hypoplasia tracheal cartilage net-like deformity tracheomalacia 11. Fraser syndrome 12. Freeman-Sheldon syndrome laryngeal atresia laryngomalacia laryngeal stenosis 13. Frontometaphyseal Dysplasia 14. Fryn’s syndrome laryngeal stenosis bronchomalacia vocal cord paralysis tracheomalacia Tracheal cartilage net-like defect 15. G syndrome 16. Goldenhar’s syndrome laryngeal cleft cartilaginous tracheal sleeve 17. Hallerman-Streif syndrome tracheomalacia 18. Hyperphalangism, facial anomaly, hallux valgus, bronchomalacia association bronchomalacia 19. Hypomandibular fasciocranial dysostosis bronchomalacia laryngeal atresia 20. Klippel-Feil syndrome 21. Kneist syndrome laryngeal stenosis Tracheomalacia vocal cord stenosis 22. Langer type mesomelic dwarfism 23. Larsen’s syndrome abnormal cartilage ring size or number bronchomalacia laryngomalacia tracheomalacia 24. Marshall-Smith syndrome 25. Metatropic Dwarfism laryngomalacia tracheomalacia laryngeal hypoplasia 26. Nager syndrome 27. Pallister-Hall syndrome laryngeal hypoplasia laryngeal cleft 28. Pfeiffer syndrome 29. Pierre-Robin sequence bronchomalacia bronchomalacia cartilaginous tracheal sleeve laryngomalacia laryngomalacia 30. Rib-Gap Defect 31. Saethre-Chotzen syndrome tracheal cartilage plate defect cartilaginous tracheal sleeve 32. Treacher-Collins syndrome 33. Trisomy 21 tracheal cartilage plate defect congenital tracheal stenosis Laryngeal stenosis 34. Toriello-Carey syndrome 35. Velo-Cardial-Facial syndrome laryngeal hypoplasia laryngeal web 36. 47 XXX syndrome laryngeal atresia

*Craniofacial syndromes are listed first, followed by the associated airway anomaly.

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