Tracheal cartilaginous sleeve in patients with Beare‐Stevenson syndrome

Tracheal cartilaginous sleeve (TCS), a life-threatening malformation in patients with craniosynostosis syndromes, is a solid cartilaginous tube lacking the pars membranacea, caused by defective C-shaped tracheal rings. Without tracheostomy, it has a 90% mortality by 2 years. Beare-Stevenson syndrome (BSS) is a distinct craniosynostosis syndrome characterized by cutis gyrata. BSS is caused by one of two specific gain-of-function mutations of FGFR2, including p.Y375C and p.S372C (Supporting information Reference S1). Studies attribute the high mortality of BSS to respiratory distress, secondary to TCS, and other unexplained factors. However, in most BSS patients, the mechanism by which TCS causes sudden death remains unknown. To increase knowledge regarding TCS and Chiari malformation for respiratory distress in BSS, we report two cases with BSS and TCS. Patient 1 was the second child of healthy Japanese parents. After birth, she was intubated for severe respiratory failure caused by airway obstruction and choanal stenosis. Chest computed tomography (CT) and bronchoscopy showed dorsal recession of the tracheal internal wall, suggesting TCS (Figure 1A). She underwent ventriculoperitoneal (VP)-shunt placement; tracheostomy owing to choanal stenosis and glossoptosis; conventional cranioplasty with fronto-orbital advancement for anterior part expansion; and decompression for Chiari malformation, which had resulted in hydrocephaly, at 1, 2, 3, and 10 months, respectively. Thereafter, she was followed with oxygen therapy. At 5 years, she developed severe sleep apnea. A polysomnography (PSG) showed severe central sleep apnea with apnea hypoxia index (AHI) 140/h and SpO2 nadir 74%. Although bronchoscopy showed improvements in the tracheal wall abnormality, spinal magnetic resonance imaging revealed a hyper-intense signal at the C2 level (Figure 1B). She underwent additional decompression and required mechanical ventilation during sleep. Genetic analysis revealed a pathogenic FGFR2 variant c.1124A>G (p.Tyr375Cys). Currently, at 6 years of age, she can shuffle and requires mechanical ventilation during sleep. Patient 2 was the third child of healthy parents. His detailed clinical course in early childhood has been described previously. He underwent tracheostomy, owing to severe respiratory distress caused by choanal stenosis and epiglottis thickening; VP-shunt placement; conventional cranioplasty with fronto-orbital advancement for anterior part expansion; and decompression for Chiari malformation, which had resulted in hydrocephaly, at 16 days and at 2, 8, and 18 months, respectively. The tracheostomy tube was custom-made and designed to elongate and get over the portion of TCS. At age 10, he developed obstructive respiratory distress. Chest CT showed tracheostomy tube obstruction by a TCS-related dented deformity (Figure 1C). At 12 years of age, he died suddenly after respiratory distress caused by tracheostomy tube obstruction. The tip of the tracheostomy tube had caused tracheal wall injury resulting in the formation of a dented deformity. Stacking of the tracheostomy tip into the dented deformity was considered the likely cause for the respiratory distress. Autopsy revealed that the dented deformity resulted from the long-term injury from the tracheostomy tube, macroscopically and malformed cartilaginous islands and inflammation in the tracheal wall microscopically (Figure 1D-F). Genetic analysis identified a pathogenic FGFR2 variant c.1115C>G (p.Ser372Cys). TCS is widely observed in FGFR2-related craniosynostosis syndromes. Tiozzo et al demonstrated that the underlying mechanism of the TCS involved the dysregulated Fgf10 expression in the Received: 2 March 2019 Revised: 22 June 2019 Accepted: 21 July 2019 DOI: 10.1111/cga.12352