Abstract
Objectives
Myhre-LAPS syndrome is a recently recognized disease caused by a mutation in the SMAD4 gene. This results in a range of pathology including laryngotracheal stenosis, arthropathy, prognathism and short stature, or LAPS syndrome. We aim to delineate the role of intubation in development of airway stenosis in these patients as well as provide insight into diagnosis and management of this syndrome. Herein we present four patients with Myhre-LAPS syndrome complicated by airway stenosis and perform a systematic review of all cases of Myhre-LAPS syndrome with reported airway pathology.
Study design
Retrospective review
Methods
All patients diagnosed with Myhre-LAPS syndrome and airway stenosis at a single institution from 1981 to 2014 were reviewed.
Results
Four patients (4F, median age 42) were identified that met inclusion criteria. Initial presenting signs included progressive shortness of breath, dyspnea on exertion and respiratory distress. All four (100%) patients had multi-level airway stenosis most commonly in the subglottic and glottic regions and all patients had undergone at least one endotracheal intubation prior to presentation. One patient with a history of nasal tracheal intubation presented with nasal obstruction and was found to have choanal as well as subglottic stenosis. Two of the four (50%) patients are tracheostomy tube dependent, 1/4 (25%) died of a fatal cardiac arrhythmia and 1/4 (25%) has had 6 endoscopic treatments for subglottic stenosis in 4 years with rapid symptom recurrence.
Conclusions
Myhre-LAPS syndrome is characterized by progressive systemic fibrosis and patients are diagnosed by characteristic findings of prognathism, short stature, abnormal facies, and thick skin among other abnormalities. Airway management is complicated by recurrent, refractory subglottic stenosis often preceded by elective intubation as well as maxillary hypoplasia, trismus, and limited neck extension. Endotracheal intubation and surgical intervention should be approached with caution in these patients and multidisciplinary care teams are necessary to address all manifestations of this syndrome.
1
Introduction
Myhre syndrome is a rare genetic condition first described in 1981 by Myhre et al. which is characterized by short stature, brachydactyly, facial dysmorphism, thick skin, a generalized muscular appearance and restricted joint mobility, among other abnormalities . More recently, a syndrome characterized by laryngotracheal stenosis, arthropathy, prognathism and short stature, or LAPS syndrome, was described as a unique clinical entity . However, mutation screens of patients affected with Myhre and LAPS syndromes have revealed that they are both phenotypic variants caused by de novo mutations in the SMAD4 gene which affect the function of the TGF-β/Bone Morphogenic Protein (BMP) pathway . Patients with this syndrome, which herein we will call Myhre-LAPS Syndrome (MLS), develop a host of systemic manifestations thought to be related to extracellular matrix (ECM) dysregulation . Though these patients exhibit a myriad of signs and symptoms, their cardiopulmonary and airway issues account for the majority of morbidity and mortality. Regarding airway stenosis, these patients develop refractory laryngotracheal stenosis, often resulting in multiple re-operations and long-term tracheostomy . We hypothesize that these airway manifestations are a result of repeated airway trauma together with dysregulation of the ECM and resulting scar formation. The primary goals of this study are to provide otolaryngologists/head and neck surgeons with key features of the disease to facilitate identification of MLS and to further expand the critical airway and cardiopulmonary features of this syndrome. Herein we describe four cases of airway manifestations associated with MLS and perform a systematic literature review of all MLS cases with reported airway pathology.
2
Materials and methods
After institutional review board approval (IRB No 14-002555), a retrospective review was performed on all patients diagnosed with either Myhre or LAPS syndrome from 1981 to 2014 at a single tertiary care center. Patients were assessed for subglottic stenosis with flexible tracheoscopy and direct laryngoscopy. Surgical intervention, when indicated, was performed by a single staff surgeon. No statistical analysis was performed in this series due to small case numbers. Systematic literature review was performed for all patients with MLS and airway pathology.
2
Materials and methods
After institutional review board approval (IRB No 14-002555), a retrospective review was performed on all patients diagnosed with either Myhre or LAPS syndrome from 1981 to 2014 at a single tertiary care center. Patients were assessed for subglottic stenosis with flexible tracheoscopy and direct laryngoscopy. Surgical intervention, when indicated, was performed by a single staff surgeon. No statistical analysis was performed in this series due to small case numbers. Systematic literature review was performed for all patients with MLS and airway pathology.
3
Results
Four patients (4F, median age 42) with MLS and airway stenosis were identified between 1981 and 2014 at the authoring institution. Two patients (case 1 and case 2) have been described previously at the authoring institution and been reviewed by others . In addition, we present two new adult cases of MLS (case 3 and case 4) that have never previously been reported in the literature.
3.1
Case 1
Patient 1 is a 40-year-old female originally evaluated at our institution at the age of 18 for three months of progressive dyspnea on exertion. She underwent endoscopic evaluation and was diagnosed with, and subsequently treated for, subglottic stenosis (SGS) ( Table 1 ). Prior airway trauma included a single intubation for adenotonsillectomy at age 5. She required several additional endoscopic interventions, ultimately leading to the placement of a permanent tracheostomy at age 20 ( Table 2 ). Her tracheostomy T-tube was routinely changed twice per year, at which time she would also undergo endoscopic treatment of SGS consisting of CO2 laser division of subglottic scar. In total she has had over twenty endoscopic interventions for SGS.
| Patient | Nasopharynx | Oropharynx | Glottis | Subglottis | Trachea |
|---|---|---|---|---|---|
| 1 | X | X | |||
| 2 | X | X | X | ||
| 3 | X | X | X (posterior) | X | X |
| 4 | X | X (posterior) | X |
| Patient | Nasal | Pharyngeal | Laryngeal | Subglottis |
|---|---|---|---|---|
| 1 | None | None | X (intubation > 1) | X (> 20) |
| 2 | None | None | X (> 12) | X (> 12) |
| 3 | X (intubation X 1) | None | X (intubation X 2) | X (intubation X 2) |
| 4 | None | Pharyngeal flap | X (intubation X 2) | X (intubation X 2, endoscopic procedures X 6) |
The patient was evaluated by several departments at our multidisciplinary institution and found to have short stature, rounded-facies, flattening of the midface, prognathism, arthropathy, and very taut skin. At age 29 she was diagnosed with the same condition as described by Hopkin et al. and genetic testing eventually confirmed a mutation in the SMAD4 gene ( Table 3 ) . She underwent pulmonary function testing (PFT) and an echocardiogram, which revealed obstructive pulmonary disease and fibrinous constrictive pericarditis, respectively ( Table 3 ).
| Patient | Pulmonary Function Testing | Echocardiogram | Cardiopulmonary procedures | Genetic testing | Tracheostomy dependence? |
|---|---|---|---|---|---|
| 1 | Age: 38 FEV1: 11% FVC: 11% FEV1/FVC:98% a | Constrictive pericarditis with effusion. Valvular disease | Emergent pericardiocentesis age 32 | SMAD4 gene: c.1498A>G p.I500V | Yes |
| Pericardectomy age 33 | |||||
| 2 | Age: 52 FEV1: 22% FVC: 26% FEV1/FVC:74.5% | Constrictive pericarditis with pericardial calcifications. Mild right-sided heart failure. Pulmonary edema. | Surgical window age 13 for pericarditis | SMAD4 gene : c.1499T>C p.I500T | Yes |
| 3 | Age: 43 FEV1: 36% FVC: 42% FEV1/FVC: 76% | No constrictive pericarditis. Normal ejection fraction | None | SMAD4 gene: c.1498A>G p.I500V | No |
| 4 | Age: 24 FEV1: 21% FVC: 20% FEV1/FVC:96% a | Not performed | None | Not performed | No |
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