Campomelic Dysplasia: Airway Management in Two ...

Annals of Otology. Rhinology & Laryngology 120(10):682-685. © 2011 Annals Publishing Company. All rights reserved.

Campomelic Dysplasia: Airway Management in Two Patients and an Update on Clinical-Molecular Correlations in the Head and Neck Marc E. Nelson, MD; Garrett R. Griffin, MD; Jeffrey W. Innis, MD, PhD; Glenn E. Green, MD Campomelic dysplasia is a rare and historically lethal skeletal dysplasia with a variable but recognizable phenotype; it affects the long bones and is associated with a variety of head and neck anomalies. Mutations in or around the S0X9 gene have been identified as the molecular origin in most patients. We briefly present 2 children who meet the diagnostic criteria for campomelic dysplasia to illustrate the various clinical manifestations. Many patients with campomelic dysplasia have airway obstruction at multiple levels. We describe our approach to managing the airway in these patients, and review recent advances in understanding how S0X9 mutations lead to the spectrum of abnormalities seen in the head and neck. Key Words: campomelic dysplasia, Pierre Robin syndrome, SOX9 gene, tracheobronchomalacia.

with campomelic dysplasia. A SOX9 gene mutation was identified in one of them. The otolaryngological findings, genetic workup, and treatment course of each patient are described, and suggestions for clinical management are provided.

INTRODUCTION Campomelic dysplasia (OMIM 114290) is a rare skeletal dysplasia with shortening and bowing of the long bones. Other typical findings include craniofacial abnormalities, club feet, hypotonia, ambiguous genitalia, and progressive cervicothoracic kyphoscoliosis leading to respiratory dysfunction. Intelligence is normal. The diagnosis is typically made by a combination of clinical and radiographie findings. Molecular genetic testing has identified mutations or chromosomal rearrangements affecting the SOX9 gene, a member of the SOX family of transcription factors, in nearly all patients with campomelic dysplasia.' Most probands have a de novo mutation, although familial reports have shown that campomelic dysplasia may be inherited in an autosomal dominant manner.

CLINICAL ASPECTS Patient 1 developed respiratory distress immediately after birth and was intubated after positioning maneuvers failed. The physical examination findings included micrognathia, cleft palate, and glossoptosis (Pierre Robin sequence); mild midface hypoplasia; a flattened nasal bridge; anteverted nares; and normal ears. Tbe skeletal findings included bilateral hypoplastic scapulae, multiple cervical spinal vertebral anomalies, 11 pairs of ribs with a bell-sbaped chest, lateral bowing of tbe bilateral tibiae, bilateral metatarsus adductus, and hypoplasia of the iliac bones.

Otolaryngological manifestations may include Pierre Robin sequence, distinctive facial anomalies, macrocepbaly, conductive and sensorineural hearing loss, laryngomalacia, and tracheobroncbomalacia. Historically, most newborns with campomelic dysplasia died of respiratory insufficiency in the neonatal period. Although the rib and thoracic abnormalities present in this syndrome limit respiration, death is thought to occur as a result of tracheobronchomalacia.^ A PubMed search for campomelic dysplasia returned only 2 reports from the otolaryngology literature, and none from the past 10 years. For illustrative purposes, we present 2 unrelated patients

After failed attempts at extubation, the patient was taken to the operating room, and airway evaluation showed an essentially normal larynx and trachea. There was dynamic collapse of the left main stem bronchus consistent with bronchomalacia (Fig 1). It was felt that the most significant cause of her respiratory failure was the relative macroglossia in the setting of Pierre Robin syndrome. She underwent mandibular distraction on day 8 of life. Repeat laryngoscopy revealed a grade I view ofthe larynx, and the patient had an air leak on the ventilator. Un-

From the Departments of Otolaryngology (Nelson, Griffin, Green), Pediatrics (Innis), and Human Genetics (Innis), University of Michigan Health System. Ann Arbor, Michigan. Correspondence: Marc E. Nelson, MD, PediaU-ic Ear Nose Throat Center, Akron Children's Hospital, 215 W Bowery St, Suite 3200, Akron, OH 44308.

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poplasia, frontal bossing, downslanting palpebral fissures, and mildly dysmorphic auricles with narrow external auditory canals bilaterally. The skeletal survey was significant for short and bowed tibiae and fibulae, mild bowing of the femurs, bilateral hip dislocation, multiple hypoplastic right ribs, and dextroconvex scoliosis of the lower thoracic spine (Fig 2). After multiple extubation attempts failed, the patient was taken the operating room, and airway evaluation revealed moderate distal tracheomalacia and severe left main stem bronchomalacia. The patient's glossoptosis was not considered severely obstructing, but because of the left main stem bronchial dynamic collapse, tracheotomy rather than mandibular distraction was performed as an initial intervention.

Fig 1. (Patient 1) Bronchoscopic view of carina demonstrates pronounced left main stem bronchomalacia (asterisk) that often accompanies campomelic dysplasia.

fortunately, extubation failed because of a combination of hypotonia with residual glossoptosis and distal bronchomalacia, and the patient subsequently underwent tracheotomy. Patient 2 was intubated for respiratory distress shortly after birth. The physical examination findings included Pierre Robin sequence, midface hy-

Fig 2. (Patient 2) Full-body radiograph demonstrates bowed tibiae and femora (single asterisks) and thoracic spine scoliosis. Note hypoplastic scapulae (double asterisks).

Karyotype (46,XX and 46,XY) and chromosomal microarray analyses (EmArray, 44K), which included 8 S0X9 intragenic probes, gave a normal result in both patients.-^ SOX9 gene sequencing gave a normal result in patient 1, whereas sequencing in patient 2 revealed a heterozygous mutation (c.l3121318del7ins5) resulting in a premature stop codon (p.Ser438ProfsX139). This specific mutation has not been reported before. DISCUSSION Campomelic (Greek for "bent limb") dysplasia is a rare skeletal disorder that historically has been lethal in most cases. The prevalence of this syn-

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drome is estimated to be in the range of 1:40,000 to 1:80,000. The patients described above presented to our neonatal intensive eare unit within a few weeks of each other, with several similar physical examination findings. Although both had features consistent with campomelic dysplasia, a mutation within the S0X9 gene was identified only in the second patient.

ing loss would be expected as a result of cochlear malformations. Takahashi et al'^ speculated that the abnormal area of cartilaginous and osseous tissues might be a remnant of an otic capsule that failed to ossify — a failure that might be explained by the loss of S0X9 function in the regulation of chondrocyte differentiation, particularly in the cartilaginous phase of endoehondral osteogenesis.

S0X9 is a 509-amino aeid protein of the SOX family of transeription faetors.^ There are at least 3 regulatory regions upstream of the 50X9 gene, and disruptions in these regions can lead to isolated Pierre Robin sequence in the absence of the full eampomelic dysplasia phenotype.^-^ One of the primary molecular functions of S0X9 is to regulate the chondrocyte differentiation pathway via interactions with C0L2A1, COLl 1A2, and ACAN.^ In terms of the head and neck, S0X9 is critical for the neural erest cell-derived endochondral bone formation seen within the first through fourth branchial arches. Tissue-specific, homozygous Sox9 knockout in the eranial neural crest in mice produced embryos with no evidence of the malleus, incus, stapes, body and lesser horns of the hyoid bone, or thyroid cartilage. The mandible was signifieantly reduced in size.^ This study did not comment on the cochlea, but tbis structure is formed by endoehondral ossification, as well. Nie** demonstrated murine Sox9 expression in the anterior and middle palate, partieularly in the midline of the fusing palatal shelves, whieh correlates well with the occurrence of cleft palate in eampomelic dysplasia.

Management of multilevel airway obstruction continues to be a challenge with patients with campomelic dysplasia. The literature consists mostly of anecdotal case reports, the interpretation of which is complicated by phenotypie variability. Often no molecular genetie workup is reported on these patients. Houston et al" reported a large series of 17 patients with eampomelic dysplasia. One patient underwent tracheotomy; only 5 of the 17 survived. Four were alive at an average follow-up of only 10 months, and a fifth patient was alive at 17 years. In eontrast, Mansour et al'^ deseribed 5 survivors who had an average follow-up of 13 years; only 1 had a tracheotomy (and was successfully decannulated at 6 years of age). Ruan et a l " described a successful single-stage laryngotracheal reconstruction in a 2-year-old patient with campomelic dysplasia, grade 2 subglottic stenosis, and laryngotracheomalacia. Ikonomidis et al''* recently reported their experience with partial cricotracheal resection, whieh allowed deeannulation in 95% of their patients with subglottie stenosis; the only patient in whom deeannulation failed had campomelic dysplasia.

Clinical manifestations of this syndrome have previously been described .^ A combination of several cbaracteristic physical or radiographie findings, or the presence of 46,XY sex reversal and bowed lower limbs, is suffieient for diagnosis. Our first patient, although not having an identifiable mutation in tbe SOX9 gene, fulfills the diagnosis for campomelic dysplasia based on the presence of bilateral hypoplastie scapulae, bowed tibia, micrognathia, cleft palate, and respiratory distress.

In our first patient, we felt that the main source of respiratory compromise was the Pierre Robin findings, and we pursued mandibular distraetion as firstline therapy. Despite an excellent distraction, the patient unfortunately was limited by the combination of pharyngeal and tongue hypotonia with distal bronchomalacia. She subsequently required tracheotomy and continues to require ventilatory support, showing that additional upper airway procedures would likely not be sufficient to allow deeannulation at this time.

The typical histopathologic findings of campomelie dysplasia in the temporal bone of a newborn infant were reported by Takahashi et al.'O The findings included abnormal eartilaginous and osseous tissue and abnormal globuli interossei in the otic capsule; hypoplastie or deformed cochlea, vestibule, and semieircular canals; hypoplastie and anomalous facial nerve and ossieles; and evidence of otitis media. Conductive hearing loss eould be explained by the high incidence of otitis media in these patients as a result of cleft palate as well as ossicular anomalies, whereas sensorineural hear-

Some patients with campomelic dysplasia will require tracheotomy, whereas others will not. In those who do require ventilatory support, surgical procedures designed for upper levels of obstruction will often be met with failure. Our findings were consistent with those in other cases in which anomalous cartilage development was identified at multiple airway levels."''^''^ Even with placement of a tracheotomy, some patients in these series had continued progression of respiratory failure due to the obstructive collapse of the distal airway in combination with the restrictive changes in the thoracic cage. If


patients survive through infancy, there may be some eventual maturation of the distal airway cartilage, in which case upper airway procedures may allow eventual decannulation. In summary, campomelic dysplasia is a rare skeletal malformation syndrome with several manifestations that likely require the intervention of a pediatric otolaryngologist. This condition arises from mutations, or disruption of regulation, of the S0X9 gene, which plays a role in chondrocyte differentiation. Medical genetics evaluation is important for diagnostic purposes, evaluation and management of S0X9 and chromosomal testing, and counseling with respect to recurrence risks. Management

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decisions for the otolaryngologist include when to address the Pierre Robin sequence with mandibular distraction and cleft palate repair, how to provide airway support, and how to approach testing and management of hearing loss. Whether these patients would be candidates for cochlear implantation would likely depend on the degree of cochlear hypoplasia observed. Hearing loss should be sought and addressed with amplification early in life. On the basis of our experience and the known mortality risk early in life, we would recommend early placement of a tracheotomy, to be followed sequentially by mandibular distraction and cleft palate repair. The expected decannulation rates for these patients are unknown.

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9. Nie X. Sox9 mRNA expression in the developing palate and craniofacial muscles and skeleton. Acta Odontol Scand 2006;64:97-103. 10. Takahashi H. Sando I, Masutani H. Temporal bone histopathological findings in campomelic dysplasia. J Laryngol Otol 1992;106:361-5. 11. Houston CS, Opitz JM, Spranger JW, et al. The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year-old boy first reported by Maroteaux et al in 1971. Am J Med Genet 1983;15:3-28. 12. Mansour S, Offiah AC, McDowall S, Sim P, Tolmie J, Hall C. The phenotype of survivors of campomelic dysplasia. J Med Genet 2002;39:597-602. 13. Ruan L, Mitchell RB, Pereira KD, Younis RT, Lazar RH. Campomelic syndrome — laryngotracheomalacia treated with single-stage laryngotracheal reconstruction. Int J Pediatr Otorhinolaryngol 1996;37:277-81. 14. Ikonomidis C, George M, Jaquet Y, Monnier P. Partial cricotracheal resection in children weighing less than 10 kilograms. Otolaryngol Head Neck Surg 2010;142:41-7. 15. Grad R, Sammut PH, Britton JR, Goodrich P, Hoy me HE, Dambro NN. Bronchoscopic evaluation of airway obstruction in campomelic dysplasia. Pediatr Pulmonol 1987;3:364-7. 16. Lee EA, Isaacs H Jr, Strauss J. The "campomelic" syndrome. Short life-span dwarfism with respiratory distress, hypotonia, peculiar faciès, and multiple skeletal and cartilaginous deformities. Am J Dis Child 1972; 124:485-96.

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