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Congenital stridor with feeding difficulty as a presenting symptom of Dok7 congenital myasthenic syndrome
International Journal of Pediatric Otorhinolaryngology 74 (2010) 991–994
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Congenital stridor with feeding difficulty as a presenting symptom of Dok7 congenital myasthenic syndrome Chris G. Jephson a,*, Nikki A. Mills a, Matthew C. Pitt b, David Beeson c, Annie Aloysius d, Francesco Muntoni e, Stephanie A. Robb e, C. Martin Bailey a a
Department of Otolaryngology, Great Ormond Street Hospital for Children and Institute of Child Health, Great Ormond Street, London, WC1N 3JH, UK Department of Neurophysiology, Great Ormond Street Hospital for Children and Institute of Child Health, London, UK Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK d Department of Speech and Language Therapy, Hammersmith Hospital, London, UK e Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children and Institute of Child Health, London, UK b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 March 2010 Received in revised form 17 May 2010 Accepted 18 May 2010 Available online 15 June 2010
Objective: The congenital myasthenic syndromes (CMS) are a group of genetic disorders of neuromuscular transmission causing fatigable weakness. Symptoms may be present from birth, but diagnosis is often delayed for several years, notably in post-synaptic CMS due to mutations in the DOK7 gene. Recently, we noted a subgroup of children with CMS in whom congenital stridor and bilateral vocal cord palsy predated other symptoms. All had mutations in the DOK7 gene. The purpose of this study was to review our population of DOK7 CMS patients with congenital stridor and assess whether there were other phenotypic features which might raise suspicion of a diagnosis of CMS in the neonatal period, in the absence of limb weakness and ptosis and prompt earlier referral for neurophysiological investigation, genetic diagnosis and appropriate treatment. Methods: A retrospective case review of 11 DOK7 CMS patients at a tertiary referral centre. Results: Six patients were identified with DOK7 mutations and congenital stridor, four requiring intubation soon after birth. Four patients had a diagnosis of bilateral vocal cord palsy and three required tracheostomy, successfully decannulated in one after 3 years. All six patients had difficulty with feeding, with weak suck and swallow necessitating nasogastric feeding in five, two of whom required gastrostomy. Despite all six children having had neonatal symptoms, the mean age at CMS diagnosis was 5 years and 9 months. Conclusion: CMS, particularly caused by mutations in the DOK7 gene, is a rare but treatable cause of congenital stridor in the neonate. A combination of congenital stridor, especially with an apparently idiopathic bilateral vocal cord palsy and weak suck and swallow should alert the clinician to the possibility of CMS and prompt early referral for neurophysiology and genetic investigations. Confirmation of a CMS diagnosis enables treatment to be initiated, informed management of the VCP and anticipation of myasthenic symptoms, particularly life-threatening respiratory decompensation. Treatment may allow early decannulation or possible avoidance of tracheostomy. At least 12 genes are known to cause CMS; the presence of congenital stridor may help target genetic diagnosis. ß 2010 Elsevier Ireland Ltd. All rights reserved.
Keywords: Congenital myasthenic syndrome Stridor Feeding difficulty Vocal cord palsy DOK7
1. Introduction The congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders of neuromuscular transmission. Mutations in at least 12 genes have been recognised to date, many associated with distinctive phenotypes and with variable response to treatment [1]. Most mutations cause fatigable weakness, which may be manifest from birth. Once the clinical diagnosis is
* Corresponding author. Tel.: +44 20 7813 8220. E-mail address: [email protected] (C.G. Jephson). 0165-5876/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2010.05.022
considered, it may be rapidly supported by finding increased jitter on stimulation single fibre EMG (stimSFEMG), successfully carried out in most children with topical analgesia [2,3] and confirmed by genetic mutation analysis. However, diagnosis is frequently delayed [4], notably in the recently described postsynaptic CMS caused by mutations in DOK7, in which early motor milestones are often normal with later onset of weakness in a predominantly limb girdle pattern, which responds poorly to treatment with acetylcholinesterase inhibitors [5–9]. In a recent review of 46 childhood CMS cases [4] we noted stridor in 6 children, congenital in 5, with bilateral vocal cord palsy (VCP) in 3, with few other neonatal symptoms suggesting an
Poor feeding: ng feeding 6 weeks 3 years 9 months (stimSFEMG) Tracheostomy in situ aged 5 years Tracheostomy 3 weeks Bilateral vocal cord palsy
Birth
Birth (intubated)
Patient 5
Patient 6
MLB 1 day
Poor breast feeding; bottle fed 4 years 4 months (stimSFEMG) Satisfactory – –
Glottic oedema MLB 4 days Birth (intubated)
–
Poor feeding: ng feeding + gastrostomy 1 years 5 years 6 months (mutation analysis- sib stimSFEMG) Satisfactory
Poor feeding: ng feeding for 9 months 5 years 5 months (stimSFEMG) Decannulated aged 3 years MLB 7 days
Interarytenoid scarring; bilateral vocal cord palsy Bilateral vocal cord palsy; laryngomalacia
Laser cordotomy + aryepiglottoplasty 6 weeks; tracheostomy 13 weeks Laryngeal rest
5 years 10 months (stimSFEMG) Satisfactory Serial MLBs
10 years (stimSFEMG)
Poor feeding: ng feeding, gastrostomy in situ aged 11 years Poor breast feeding: bottle fed MLB 7 days
Airway intervention Airway diagnosis
Tracheostomy in situ aged 11 years
Patient 4
All children presented at birth with stridor and some degree of respiratory difficulty. Four of the children required intubation soon after birth. Two of the children had persisting stridor, one associated with desaturations and bradycardias but neither required intubation.
Birth (intubated)
3.1. Age at presentation of stridor
Patient 3
Six children with CMS were identified as having congenital stridor. All had mutations in the DOK7 gene. (Table 1)
Birth
3. Results
Patient 2
Exons within the gene encoding Dok-7 were screened by bidirectional sequencing of PCR amplicons. The pathogenicity of DOK7 mutations c.325G>T, c.415G>C, C.496G>A was established by assays measuring the ability of mutant Dok-7 to induce the clustering of acetylcholine receptors in C2C12 myotubes [8] and will be reported elsewhere.
Airway investigation
2.2. Genetic testing
Age of presentation of stridor
The details of the technique of stimSFEMG and how the normative data were determined have been described [2]. The upper limit of the mean consecutive difference (MCD) was 32 ms with no more that 10% of the individual MCD measurements being greater than 44 ms. The MCD was determined by the proprietary programme present on the computer. Post-collection manual processing was performed and only those MCD were accepted where the recording was stable. In all cases the interference pattern of orbicularis oculi and its motor unit potentials were assessed for evidence of denervation and reinnervation (neurogenic change).
Table 1 Summary of clinical features and mutation analysis in 6 CMS children with congenital stridor.
2.1. EMG
Tracheostomy 10 weeks
Age of presentation of stridor Airway investigation Airway diagnosis Airway intervention Airway outcome Other symptoms present at birth Age at CMS diagnosis Genetic mutation
Airway outcome
Bilateral vocal cord palsy
We carried out a retrospective review of patients with DOK7 mutation CMS and congenital stridor. Data from the medical records were collected under the following headings:
MLB 9 days
Age of CMS diagnosis
2. Methods
Birth (intubated)
Other symptoms present at birth
Genetic mutation
underlying neurological disorder apart from feeding difficulties. Mutations in DOK7 have now been identified in all five congenital cases. The sixth case, with mutations in gene encoding cholineacetyltransferase (CHAT), had stridor from early childhood, and was diagnosed with laryngomalacia. Bilateral VCP is an uncommon cause of neonatal stridor [10]. VCP has been previously reported as an early presenting feature in three previous neuromuscular cases [11]. One of these had a clinical diagnosis of CMS, but the paper antedated the recognition of the DOK7 genotype [8]. We reviewed the clinical and ENT features of our DOK7 cases who presented with congenital stridor, with the aim of identifying any additional phenotypic features which might serve as a diagnostic clue for CMS and prompt early referral for neurological and neurophysiological assessment and subsequently for genetic screening.
DOK7 c.1378C>T c.1339_1342dupCTGG DOK7 c.415G>C c.415G>C DOK7 c.1378insC c.1124_1127dupTGCC DOK7 c.(101-24_141del; 176_206delinsAG) c.1124_1127dupTGCC DOK7 c.325G>T c.596delT DOK7 c.496G>A c.1124_1127dupTGCC
C.G. Jephson et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 991–994
Patient 1
992
C.G. Jephson et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 991–994
3.2. Airway investigation, diagnosis, intervention and outcome In one patient, the stridor resolved spontaneously and was not further investigated. Five patients were investigated by at least one microlaryngoscopy and bronchoscopy (MLB) under general anaesthesia, ranging from age 1 to 9 days. Three children were diagnosed as having bilateral VCP at initial MLB. One of these children, who also had laryngomalacia, underwent laser cordotomy and aryepiglottoplasty (aged 6 weeks). All three underwent tracheostomy (aged 3, 10 and 12 weeks). One child was found to have no abnormality at initial MLB, but was subsequently diagnosed with interarytenoid scarring which resolved and bilateral VCP which persisted on repeated MLBs. One child was diagnosed with glottic and subglottic oedema and was treated with a period of undisturbed intubation (laryngeal rest). Of the three children requiring tracheostomy, one was decannulated aged 3 years and two still have the tracheostomy in situ aged 5 and 11 years. One of the children with a tracheostomy also requires nocturnal BiPAP. 3.3. Age at CMS diagnosis The mean age of initial CMS diagnosis (by stimSFEMG in patients 1–4 and 6 and primary genetic analysis in patient 5, whose sibling had an abnormal stimSFEMG and confirmed DOK7 genetic mutations) was 5 years and 9 months, with a range of 3 years and 9 months to 10 years. 3.4. Neurophysiology investigation Four children underwent EMG testing at Great Ormond Street Hospital (Table 2). EMG was performed at a mean age of 6 years, with a range of 3 years and 9 months to 10 years. One child underwent EMG testing at another centre. 3.5. Other symptoms presenting at birth All six children had some degree of feeding difficulty from birth requiring speech and language therapist input. The neonatal feeding problems included weak sucking, leading to the failure of breastfeeding or the need for supplemental nasogastric tube (NGT) feeding. Where there were significant respiratory difficulties in the neonatal period associated with congenital stridor, further difficulties with poor swallow and breathing co-ordination and the risk of aspiration of liquids during swallowing were also noted. Neonatal videofluoroscopy in one such infant demonstrated silent aspiration during the swallow, potentially linked to poor airway closure secondary to impaired vocal cord mobility. Five children required NGT feeding in the first few weeks/months of life. Three were weaned off tube feeding as their swallowing improved, associated with management of their underlying respiratory difficulties. Two went on to have gastrostomy tube placement for longer term supplemental tube feeding. The early placement of gastrostomy was also prompted by the acute need for Nissen Table 2 Summary of stimulation single fibre EMG (stimSFEMG) data in the four patients examined at GOSH. Patient number
Age StimSFEMG performed (years)
Mean MCD (ms)
% of individual MCD > 44 ms
1 2 5 6
10.0 5.8 4.3 3.75
107 47 47 81
72 55 53 69
MCD: mean consecutive difference, a measure of ‘jitter’, normal values < 32 ms, with no more than 10% > 44 ms.
993
fundoplication in one case due to significant gastro-oesophageal reflux which was contributing to recurrent chest infections and life threatening apnoeic episodes. Once the acute neonatal feeding difficulties resolved, all the children went on to have some oral intake requiring texture modification, although mealtimes were often prolonged with fatigue. One child had the gastrostomy removed at 4 years of age; the other continues to use it for supplemental feeds. No additional myasthenic symptoms were elicited at birth in any of the children. 4. Discussion We report six children who presented with congenital stridor (four with documented bilateral vocal cord palsy) and feeding difficulty as the only manifestations of their congenital myasthenic syndrome, which remained undiagnosed for up to 10 years. Congenital stridor has several causes that can be sub-divided according to the site of obstruction. Laryngomalacia is the most common cause [10]. Other congenital anomalies of the larynx include webs, cysts, laryngocele, laryngeal cleft, subglottic stenosis, neoplasia and vocal cord palsy; and in the trachea, vascular anomalies, webs, cysts, stenosis and tracheomalacia can also produce stridor [10,12]. Four of the five children who underwent MLB were found to have bilateral vocal cord palsy. Bilateral vocal cord paralysis is a rare cause of congenital stridor accounting for less than 10% of cases [10,13]. Congenital VCP has been recognised to originate from conditions affecting the central or peripheral nervous systems and in association with cardiovascular anomalies and malformations of the oesophagus, trachea and larynx. However, each of these causes is individually rare and an underlying aetiology may not be identified in up to 50% of cases [13–15]. Although CMS is a rare cause of congenital VCP, early diagnosis is important to ensure appropriate treatment, which may significantly improve muscle strength and ameliorate life-threatening respiratory crises, particularly during infancy [16]. The possibility of reduced respiratory muscle strength in addition to bilateral vocal cord palsy and impaired swallow, with the risk of aspiration, is of particular concern in these infants, many of whom have required early tracheostomy. In these circumstances, CPAP or BiPAP may be helpful in children with bilateral VCP and a marginal airway, enabling tracheostomy to be delayed while investigations are carried out. In the absence of obvious fatigable weakness and ptosis, feeding difficulties with a weak suck and swallow, leading to failure of breastfeeding or the need for NG feeds, are an important clue to the CMS diagnosis. StimSFEMG carried out by an experienced operator provides rapid confirmation, particularly in infants with DOK7 mutations who are unlikely to respond to therapeutic trials of anticholinesterases. Treatment with ephedrine or salbutamol (Albuterol) appears to be of benefit in older infants and children with DOK7 CMS [9,17]. Gastro-oesophageal reflux disease is also common in many neuromuscular conditions; although not specific to CMS it was present in one patient and should be considered and investigated in any child with feeding problems or recurrent chest infections. In our experience stridor and VCP without classical CMS symptoms, appear to be an early indicator of CMS and DOK7 in particular and may help target molecular diagnosis. Of 11 children with DOK7 mutations reviewed in our unit, 6 had presented in this way, but the CMS diagnosis was delayed by a mean of almost 6 years. There are two other studies in the literature reporting congenital stridor with DOK7: the first reports a 10-year old boy who required tracheostomy for congenital stridor, attributed to tracheomalacia [7]; the second reports two patients with congenital stridor, one of which had a tracheostomy aged 4
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C.G. Jephson et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 991–994
months, although no cause for the stridor is mentioned [18]. In addition, several DOK7 cases in the literature have been reported to require respiratory support at birth for respiratory distress [5] or ventilatory failure [9]. Congenital stridor and VCP are not exclusive to DOK7 CMS. Since reviewing these cases we have seen another infant with congenital stridor, bilateral VCP and feeding difficulties, in whom stimSFEMG was abnormal, but a screen for DOK7 mutations was negative. Homozygous c.P121L mutations in the AChR epsilon subunit gene (CHRNE) that underlie a fast channel syndrome were identified. The infant developed ptosis, fatigable weakness and recurrent, life-threatening respiratory crises by 3 months of age. However, infants with fast channel syndrome mutations respond to pyridostigmine and, interestingly, following pyridostigmine treatment in this infant, there was documented improvement in vocal cord mobility. Although bulbar dysfunction with stridor were recently reported as early presenting features in two cases with RAPSN and CHRNE mutations [19], the RAPSN infant also had hypotonia and recurrent apnoeic episodes and ptosis was present in the CHRNE infant, additional features suggestive of CMS, which were not present in our DOK7 cases. The possibility exists that the laryngeal musculature is also fatigable, resulting in intermittent stridor. This may explain why patient 2 presented with congenital stridor but had a normal MLB aged 7 days and subsequent MLB established a diagnosis of VCP. This patient was also diagnosed with interarytenoid scarring following a possible 48 h intubation at another institution (incomplete history). This might have contributed to reduce vocal cord mobility, although the most recent MLBs report complete resolution of the interarytenoid scarring with no cricoarytenoid joint fixation but with persistent bilateral VCP. Patient 4 was diagnosed with laryngeal oedema at MLB and patient 5 had stridor at birth which resolved spontaneously, though mild stridor recurs with intercurrent chest infections. It is possible that both cases had an underlying transient VCP. Three of our patients required tracheostomy, which was successfully decannulated in one and is now undergoing review in the other two, following improvement in strength with ephedrine. 5. Conclusion It appears that congenital myasthenic syndromes (CMS) are a rare cause of congenital stridor due to bilateral vocal cord palsy. In particular there seems to be a connection with DOK7 CMS. In a patient with bilateral VCP at MLB, which appears to be idiopathic, a diagnosis of CMS should be considered and excluded. Suspicion should increase greatly if there is a concurrent feeding difficulty. A careful neurological examination should look for subtle signs such as ptosis and limb weakness. Recognition of the significance of bilateral VCP in relatively asymptomatic neonates should lead to referral to a neurologist for further investigation. StimSFEMG in the hands of an experienced neurophysiologist is diagnostic of NMJ disorders. Molecular analysis provides the definitive diagnosis of CMS. Early diagnosis of CMS enables more informed management
of the VCP and anticipation of later symptoms. Appropriate treatment may ameliorate weakness, feeding difficulties and the life-threatening respiratory complications of CMS. Pharmacological treatment may allow earlier decannulation and might even avoid the need for tracheostomy altogether. Acknowledgements We are grateful to the National Commissioning Group and the Muscular Dystrophy Campaign for funding to the Dubowitz Neuromuscular Centre and the Oxford Myasthenia Centre. References [1] J. Palace, D. Beeson, The congenital myasthenic syndromes, J. Neuroimmunol. 201–202 (2008) 2–5. [2] M. Pitt, Neurophysiological strategies for the diagnosis of disorders of the neuromuscular junction in children, Dev. Med. Child Neurol. 50 (2008) 328–333. [3] M. Pitt, Workshop on the use of stimulation single fibre electromyography for the diagnosis of myasthenic syndromes in children held in the Institute of Child Health and Great Ormond Street Hospital for Children in London on April 24th, 2009, Neuromuscul. Disord. 19 (2009) 730–732. [4] M. Kinali, D. Beeson, M.C. Pitt, H. Jungbluth, A.K. Simonds, A. Aloysius, et al., Congenital myasthenic syndromes in childhood: diagnostic and management challenges, J. Neuroimmunol. 201–202 (2008) 6–12. [5] J.S. Muller, A. Herczegfalvi, J.J. Vilchez, J. Colomer, L.L. Bachinski, V. Mihaylova, et al., Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes, Brain 130 (2007) 1497–1506. [6] J. Palace, D. Lashley, J. Newsom-Davis, J. Cossins, S. Maxwell, R. Kennett, et al., Clinical features of the DOK7 neuromuscular junction synaptopathy, Brain 130 (2007) 1507–1515. [7] J.A. Anderson, J.J. Ng, C. Bowe, C. McDonald, D.P. Richman, R.L. Wollmann, et al., Variable phenotypes associated with mutations in DOK7, Muscle Nerve 37 (2008) 448–456. [8] D. Beeson, O. Higuchi, J. Palace, J. Cossins, H. Spearman, S. Maxwell, et al., Dok-7 mutations underlie a neuromuscular junction synaptopathy, Science 313 (2006) 1975–1978. [9] D. Selcen, M. Milone, X.M. Shen, C.M. Harper, A.A. Stans, E.D. Wieben, et al., Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients, Ann. Neurol. 64 (2008) 71–87. [10] R. Zoumalan, J. Maddalozzo, L.D. Holinger, Etiology of stridor in infants, Ann. Otol. Rhinol. Laryngol. 116 (2007) 329–334. [11] J.F. Lapena Jr., R.G. Berkowitz, Neuromuscular disorders presenting as congenital bilateral vocal cord paralysis, Ann. Otol. Rhinol. Laryngol. 110 (2001) 952–955. [12] K.W. Altman, R.F. Wetmore, R.R. Marsh, Congenital airway abnormalities requiring tracheotomy: a profile of 56 patients and their diagnoses over a 9 year period, Int. J. Pediatr. Otorhinolaryngol. 41 (1997) 199–206. [13] B. Fearon, D. Ellis, The management of long term airway problems in infants and children, Ann. Otol. Rhinol. Laryngol. 80 (1971) 669–677. [14] P.J. Emery, B. Fearon, Vocal cord palsy in pediatric practice: a review of 71 cases, Int. J. Pediatr. Otorhinolaryngol. 8 (1984) 147–154. [15] H. Daya, A. Hosni, I. Bejar-Solar, J.N. Evans, C.M. Bailey, Pediatric vocal fold paralysis: a long-term retrospective study, Arch. Otolaryngol. Head Neck Surg. 126 (2000) 21–25. [16] A.G. Engel, The therapy of congenital myasthenic syndromes, Neurotherapeutics 4 (2007) 252–257. [17] D. Lashley, J. Palace, S. Jayawant, S. Robb, D. Beeson, Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7, Neurology 74 (2010) 1517–1523. [18] A.A. Ben, F. Petit, N. Alexandri, K. Gaudon, S. Bauche, A. Rouche, et al., Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7, J. Neurol. 257 (2010) 754–766. [19] S. Beri, N. Hussain, A.P. Balky, R. Alzoubidi, J.A. Gosalakkal, S. Kanhere, Bulbar dysfunction: an early presentation of congenital myasthenic syndrome, Eur. J. Paediatr. Neurol. 13 (2009) S1–S46.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Congenital stridor with feeding difficulty as a presenting symptom of Dok7 congenital myasthenic syndrome Chris G. Jephson a,*, Nikki A. Mills a, Matthew C. Pitt b, David Beeson c, Annie Aloysius d, Francesco Muntoni e, Stephanie A. Robb e, C. Martin Bailey a a
Department of Otolaryngology, Great Ormond Street Hospital for Children and Institute of Child Health, Great Ormond Street, London, WC1N 3JH, UK Department of Neurophysiology, Great Ormond Street Hospital for Children and Institute of Child Health, London, UK Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK d Department of Speech and Language Therapy, Hammersmith Hospital, London, UK e Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children and Institute of Child Health, London, UK b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 March 2010 Received in revised form 17 May 2010 Accepted 18 May 2010 Available online 15 June 2010
Objective: The congenital myasthenic syndromes (CMS) are a group of genetic disorders of neuromuscular transmission causing fatigable weakness. Symptoms may be present from birth, but diagnosis is often delayed for several years, notably in post-synaptic CMS due to mutations in the DOK7 gene. Recently, we noted a subgroup of children with CMS in whom congenital stridor and bilateral vocal cord palsy predated other symptoms. All had mutations in the DOK7 gene. The purpose of this study was to review our population of DOK7 CMS patients with congenital stridor and assess whether there were other phenotypic features which might raise suspicion of a diagnosis of CMS in the neonatal period, in the absence of limb weakness and ptosis and prompt earlier referral for neurophysiological investigation, genetic diagnosis and appropriate treatment. Methods: A retrospective case review of 11 DOK7 CMS patients at a tertiary referral centre. Results: Six patients were identified with DOK7 mutations and congenital stridor, four requiring intubation soon after birth. Four patients had a diagnosis of bilateral vocal cord palsy and three required tracheostomy, successfully decannulated in one after 3 years. All six patients had difficulty with feeding, with weak suck and swallow necessitating nasogastric feeding in five, two of whom required gastrostomy. Despite all six children having had neonatal symptoms, the mean age at CMS diagnosis was 5 years and 9 months. Conclusion: CMS, particularly caused by mutations in the DOK7 gene, is a rare but treatable cause of congenital stridor in the neonate. A combination of congenital stridor, especially with an apparently idiopathic bilateral vocal cord palsy and weak suck and swallow should alert the clinician to the possibility of CMS and prompt early referral for neurophysiology and genetic investigations. Confirmation of a CMS diagnosis enables treatment to be initiated, informed management of the VCP and anticipation of myasthenic symptoms, particularly life-threatening respiratory decompensation. Treatment may allow early decannulation or possible avoidance of tracheostomy. At least 12 genes are known to cause CMS; the presence of congenital stridor may help target genetic diagnosis. ß 2010 Elsevier Ireland Ltd. All rights reserved.
Keywords: Congenital myasthenic syndrome Stridor Feeding difficulty Vocal cord palsy DOK7
1. Introduction The congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders of neuromuscular transmission. Mutations in at least 12 genes have been recognised to date, many associated with distinctive phenotypes and with variable response to treatment [1]. Most mutations cause fatigable weakness, which may be manifest from birth. Once the clinical diagnosis is
* Corresponding author. Tel.: +44 20 7813 8220. E-mail address: [email protected] (C.G. Jephson). 0165-5876/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2010.05.022
considered, it may be rapidly supported by finding increased jitter on stimulation single fibre EMG (stimSFEMG), successfully carried out in most children with topical analgesia [2,3] and confirmed by genetic mutation analysis. However, diagnosis is frequently delayed [4], notably in the recently described postsynaptic CMS caused by mutations in DOK7, in which early motor milestones are often normal with later onset of weakness in a predominantly limb girdle pattern, which responds poorly to treatment with acetylcholinesterase inhibitors [5–9]. In a recent review of 46 childhood CMS cases [4] we noted stridor in 6 children, congenital in 5, with bilateral vocal cord palsy (VCP) in 3, with few other neonatal symptoms suggesting an
Poor feeding: ng feeding 6 weeks 3 years 9 months (stimSFEMG) Tracheostomy in situ aged 5 years Tracheostomy 3 weeks Bilateral vocal cord palsy
Birth
Birth (intubated)
Patient 5
Patient 6
MLB 1 day
Poor breast feeding; bottle fed 4 years 4 months (stimSFEMG) Satisfactory – –
Glottic oedema MLB 4 days Birth (intubated)
–
Poor feeding: ng feeding + gastrostomy 1 years 5 years 6 months (mutation analysis- sib stimSFEMG) Satisfactory
Poor feeding: ng feeding for 9 months 5 years 5 months (stimSFEMG) Decannulated aged 3 years MLB 7 days
Interarytenoid scarring; bilateral vocal cord palsy Bilateral vocal cord palsy; laryngomalacia
Laser cordotomy + aryepiglottoplasty 6 weeks; tracheostomy 13 weeks Laryngeal rest
5 years 10 months (stimSFEMG) Satisfactory Serial MLBs
10 years (stimSFEMG)
Poor feeding: ng feeding, gastrostomy in situ aged 11 years Poor breast feeding: bottle fed MLB 7 days
Airway intervention Airway diagnosis
Tracheostomy in situ aged 11 years
Patient 4
All children presented at birth with stridor and some degree of respiratory difficulty. Four of the children required intubation soon after birth. Two of the children had persisting stridor, one associated with desaturations and bradycardias but neither required intubation.
Birth (intubated)
3.1. Age at presentation of stridor
Patient 3
Six children with CMS were identified as having congenital stridor. All had mutations in the DOK7 gene. (Table 1)
Birth
3. Results
Patient 2
Exons within the gene encoding Dok-7 were screened by bidirectional sequencing of PCR amplicons. The pathogenicity of DOK7 mutations c.325G>T, c.415G>C, C.496G>A was established by assays measuring the ability of mutant Dok-7 to induce the clustering of acetylcholine receptors in C2C12 myotubes [8] and will be reported elsewhere.
Airway investigation
2.2. Genetic testing
Age of presentation of stridor
The details of the technique of stimSFEMG and how the normative data were determined have been described [2]. The upper limit of the mean consecutive difference (MCD) was 32 ms with no more that 10% of the individual MCD measurements being greater than 44 ms. The MCD was determined by the proprietary programme present on the computer. Post-collection manual processing was performed and only those MCD were accepted where the recording was stable. In all cases the interference pattern of orbicularis oculi and its motor unit potentials were assessed for evidence of denervation and reinnervation (neurogenic change).
Table 1 Summary of clinical features and mutation analysis in 6 CMS children with congenital stridor.
2.1. EMG
Tracheostomy 10 weeks
Age of presentation of stridor Airway investigation Airway diagnosis Airway intervention Airway outcome Other symptoms present at birth Age at CMS diagnosis Genetic mutation
Airway outcome
Bilateral vocal cord palsy
We carried out a retrospective review of patients with DOK7 mutation CMS and congenital stridor. Data from the medical records were collected under the following headings:
MLB 9 days
Age of CMS diagnosis
2. Methods
Birth (intubated)
Other symptoms present at birth
Genetic mutation
underlying neurological disorder apart from feeding difficulties. Mutations in DOK7 have now been identified in all five congenital cases. The sixth case, with mutations in gene encoding cholineacetyltransferase (CHAT), had stridor from early childhood, and was diagnosed with laryngomalacia. Bilateral VCP is an uncommon cause of neonatal stridor [10]. VCP has been previously reported as an early presenting feature in three previous neuromuscular cases [11]. One of these had a clinical diagnosis of CMS, but the paper antedated the recognition of the DOK7 genotype [8]. We reviewed the clinical and ENT features of our DOK7 cases who presented with congenital stridor, with the aim of identifying any additional phenotypic features which might serve as a diagnostic clue for CMS and prompt early referral for neurological and neurophysiological assessment and subsequently for genetic screening.
DOK7 c.1378C>T c.1339_1342dupCTGG DOK7 c.415G>C c.415G>C DOK7 c.1378insC c.1124_1127dupTGCC DOK7 c.(101-24_141del; 176_206delinsAG) c.1124_1127dupTGCC DOK7 c.325G>T c.596delT DOK7 c.496G>A c.1124_1127dupTGCC
C.G. Jephson et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 991–994
Patient 1
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3.2. Airway investigation, diagnosis, intervention and outcome In one patient, the stridor resolved spontaneously and was not further investigated. Five patients were investigated by at least one microlaryngoscopy and bronchoscopy (MLB) under general anaesthesia, ranging from age 1 to 9 days. Three children were diagnosed as having bilateral VCP at initial MLB. One of these children, who also had laryngomalacia, underwent laser cordotomy and aryepiglottoplasty (aged 6 weeks). All three underwent tracheostomy (aged 3, 10 and 12 weeks). One child was found to have no abnormality at initial MLB, but was subsequently diagnosed with interarytenoid scarring which resolved and bilateral VCP which persisted on repeated MLBs. One child was diagnosed with glottic and subglottic oedema and was treated with a period of undisturbed intubation (laryngeal rest). Of the three children requiring tracheostomy, one was decannulated aged 3 years and two still have the tracheostomy in situ aged 5 and 11 years. One of the children with a tracheostomy also requires nocturnal BiPAP. 3.3. Age at CMS diagnosis The mean age of initial CMS diagnosis (by stimSFEMG in patients 1–4 and 6 and primary genetic analysis in patient 5, whose sibling had an abnormal stimSFEMG and confirmed DOK7 genetic mutations) was 5 years and 9 months, with a range of 3 years and 9 months to 10 years. 3.4. Neurophysiology investigation Four children underwent EMG testing at Great Ormond Street Hospital (Table 2). EMG was performed at a mean age of 6 years, with a range of 3 years and 9 months to 10 years. One child underwent EMG testing at another centre. 3.5. Other symptoms presenting at birth All six children had some degree of feeding difficulty from birth requiring speech and language therapist input. The neonatal feeding problems included weak sucking, leading to the failure of breastfeeding or the need for supplemental nasogastric tube (NGT) feeding. Where there were significant respiratory difficulties in the neonatal period associated with congenital stridor, further difficulties with poor swallow and breathing co-ordination and the risk of aspiration of liquids during swallowing were also noted. Neonatal videofluoroscopy in one such infant demonstrated silent aspiration during the swallow, potentially linked to poor airway closure secondary to impaired vocal cord mobility. Five children required NGT feeding in the first few weeks/months of life. Three were weaned off tube feeding as their swallowing improved, associated with management of their underlying respiratory difficulties. Two went on to have gastrostomy tube placement for longer term supplemental tube feeding. The early placement of gastrostomy was also prompted by the acute need for Nissen Table 2 Summary of stimulation single fibre EMG (stimSFEMG) data in the four patients examined at GOSH. Patient number
Age StimSFEMG performed (years)
Mean MCD (ms)
% of individual MCD > 44 ms
1 2 5 6
10.0 5.8 4.3 3.75
107 47 47 81
72 55 53 69
MCD: mean consecutive difference, a measure of ‘jitter’, normal values < 32 ms, with no more than 10% > 44 ms.
993
fundoplication in one case due to significant gastro-oesophageal reflux which was contributing to recurrent chest infections and life threatening apnoeic episodes. Once the acute neonatal feeding difficulties resolved, all the children went on to have some oral intake requiring texture modification, although mealtimes were often prolonged with fatigue. One child had the gastrostomy removed at 4 years of age; the other continues to use it for supplemental feeds. No additional myasthenic symptoms were elicited at birth in any of the children. 4. Discussion We report six children who presented with congenital stridor (four with documented bilateral vocal cord palsy) and feeding difficulty as the only manifestations of their congenital myasthenic syndrome, which remained undiagnosed for up to 10 years. Congenital stridor has several causes that can be sub-divided according to the site of obstruction. Laryngomalacia is the most common cause [10]. Other congenital anomalies of the larynx include webs, cysts, laryngocele, laryngeal cleft, subglottic stenosis, neoplasia and vocal cord palsy; and in the trachea, vascular anomalies, webs, cysts, stenosis and tracheomalacia can also produce stridor [10,12]. Four of the five children who underwent MLB were found to have bilateral vocal cord palsy. Bilateral vocal cord paralysis is a rare cause of congenital stridor accounting for less than 10% of cases [10,13]. Congenital VCP has been recognised to originate from conditions affecting the central or peripheral nervous systems and in association with cardiovascular anomalies and malformations of the oesophagus, trachea and larynx. However, each of these causes is individually rare and an underlying aetiology may not be identified in up to 50% of cases [13–15]. Although CMS is a rare cause of congenital VCP, early diagnosis is important to ensure appropriate treatment, which may significantly improve muscle strength and ameliorate life-threatening respiratory crises, particularly during infancy [16]. The possibility of reduced respiratory muscle strength in addition to bilateral vocal cord palsy and impaired swallow, with the risk of aspiration, is of particular concern in these infants, many of whom have required early tracheostomy. In these circumstances, CPAP or BiPAP may be helpful in children with bilateral VCP and a marginal airway, enabling tracheostomy to be delayed while investigations are carried out. In the absence of obvious fatigable weakness and ptosis, feeding difficulties with a weak suck and swallow, leading to failure of breastfeeding or the need for NG feeds, are an important clue to the CMS diagnosis. StimSFEMG carried out by an experienced operator provides rapid confirmation, particularly in infants with DOK7 mutations who are unlikely to respond to therapeutic trials of anticholinesterases. Treatment with ephedrine or salbutamol (Albuterol) appears to be of benefit in older infants and children with DOK7 CMS [9,17]. Gastro-oesophageal reflux disease is also common in many neuromuscular conditions; although not specific to CMS it was present in one patient and should be considered and investigated in any child with feeding problems or recurrent chest infections. In our experience stridor and VCP without classical CMS symptoms, appear to be an early indicator of CMS and DOK7 in particular and may help target molecular diagnosis. Of 11 children with DOK7 mutations reviewed in our unit, 6 had presented in this way, but the CMS diagnosis was delayed by a mean of almost 6 years. There are two other studies in the literature reporting congenital stridor with DOK7: the first reports a 10-year old boy who required tracheostomy for congenital stridor, attributed to tracheomalacia [7]; the second reports two patients with congenital stridor, one of which had a tracheostomy aged 4
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months, although no cause for the stridor is mentioned [18]. In addition, several DOK7 cases in the literature have been reported to require respiratory support at birth for respiratory distress [5] or ventilatory failure [9]. Congenital stridor and VCP are not exclusive to DOK7 CMS. Since reviewing these cases we have seen another infant with congenital stridor, bilateral VCP and feeding difficulties, in whom stimSFEMG was abnormal, but a screen for DOK7 mutations was negative. Homozygous c.P121L mutations in the AChR epsilon subunit gene (CHRNE) that underlie a fast channel syndrome were identified. The infant developed ptosis, fatigable weakness and recurrent, life-threatening respiratory crises by 3 months of age. However, infants with fast channel syndrome mutations respond to pyridostigmine and, interestingly, following pyridostigmine treatment in this infant, there was documented improvement in vocal cord mobility. Although bulbar dysfunction with stridor were recently reported as early presenting features in two cases with RAPSN and CHRNE mutations [19], the RAPSN infant also had hypotonia and recurrent apnoeic episodes and ptosis was present in the CHRNE infant, additional features suggestive of CMS, which were not present in our DOK7 cases. The possibility exists that the laryngeal musculature is also fatigable, resulting in intermittent stridor. This may explain why patient 2 presented with congenital stridor but had a normal MLB aged 7 days and subsequent MLB established a diagnosis of VCP. This patient was also diagnosed with interarytenoid scarring following a possible 48 h intubation at another institution (incomplete history). This might have contributed to reduce vocal cord mobility, although the most recent MLBs report complete resolution of the interarytenoid scarring with no cricoarytenoid joint fixation but with persistent bilateral VCP. Patient 4 was diagnosed with laryngeal oedema at MLB and patient 5 had stridor at birth which resolved spontaneously, though mild stridor recurs with intercurrent chest infections. It is possible that both cases had an underlying transient VCP. Three of our patients required tracheostomy, which was successfully decannulated in one and is now undergoing review in the other two, following improvement in strength with ephedrine. 5. Conclusion It appears that congenital myasthenic syndromes (CMS) are a rare cause of congenital stridor due to bilateral vocal cord palsy. In particular there seems to be a connection with DOK7 CMS. In a patient with bilateral VCP at MLB, which appears to be idiopathic, a diagnosis of CMS should be considered and excluded. Suspicion should increase greatly if there is a concurrent feeding difficulty. A careful neurological examination should look for subtle signs such as ptosis and limb weakness. Recognition of the significance of bilateral VCP in relatively asymptomatic neonates should lead to referral to a neurologist for further investigation. StimSFEMG in the hands of an experienced neurophysiologist is diagnostic of NMJ disorders. Molecular analysis provides the definitive diagnosis of CMS. Early diagnosis of CMS enables more informed management
of the VCP and anticipation of later symptoms. Appropriate treatment may ameliorate weakness, feeding difficulties and the life-threatening respiratory complications of CMS. Pharmacological treatment may allow earlier decannulation and might even avoid the need for tracheostomy altogether. Acknowledgements We are grateful to the National Commissioning Group and the Muscular Dystrophy Campaign for funding to the Dubowitz Neuromuscular Centre and the Oxford Myasthenia Centre. References [1] J. Palace, D. Beeson, The congenital myasthenic syndromes, J. Neuroimmunol. 201–202 (2008) 2–5. [2] M. Pitt, Neurophysiological strategies for the diagnosis of disorders of the neuromuscular junction in children, Dev. Med. Child Neurol. 50 (2008) 328–333. [3] M. Pitt, Workshop on the use of stimulation single fibre electromyography for the diagnosis of myasthenic syndromes in children held in the Institute of Child Health and Great Ormond Street Hospital for Children in London on April 24th, 2009, Neuromuscul. Disord. 19 (2009) 730–732. [4] M. Kinali, D. Beeson, M.C. Pitt, H. Jungbluth, A.K. Simonds, A. Aloysius, et al., Congenital myasthenic syndromes in childhood: diagnostic and management challenges, J. Neuroimmunol. 201–202 (2008) 6–12. [5] J.S. Muller, A. Herczegfalvi, J.J. Vilchez, J. Colomer, L.L. Bachinski, V. Mihaylova, et al., Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes, Brain 130 (2007) 1497–1506. [6] J. Palace, D. Lashley, J. Newsom-Davis, J. Cossins, S. Maxwell, R. Kennett, et al., Clinical features of the DOK7 neuromuscular junction synaptopathy, Brain 130 (2007) 1507–1515. [7] J.A. Anderson, J.J. Ng, C. Bowe, C. McDonald, D.P. Richman, R.L. Wollmann, et al., Variable phenotypes associated with mutations in DOK7, Muscle Nerve 37 (2008) 448–456. [8] D. Beeson, O. Higuchi, J. Palace, J. Cossins, H. Spearman, S. Maxwell, et al., Dok-7 mutations underlie a neuromuscular junction synaptopathy, Science 313 (2006) 1975–1978. [9] D. Selcen, M. Milone, X.M. Shen, C.M. Harper, A.A. Stans, E.D. Wieben, et al., Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients, Ann. Neurol. 64 (2008) 71–87. [10] R. Zoumalan, J. Maddalozzo, L.D. Holinger, Etiology of stridor in infants, Ann. Otol. Rhinol. Laryngol. 116 (2007) 329–334. [11] J.F. Lapena Jr., R.G. Berkowitz, Neuromuscular disorders presenting as congenital bilateral vocal cord paralysis, Ann. Otol. Rhinol. Laryngol. 110 (2001) 952–955. [12] K.W. Altman, R.F. Wetmore, R.R. Marsh, Congenital airway abnormalities requiring tracheotomy: a profile of 56 patients and their diagnoses over a 9 year period, Int. J. Pediatr. Otorhinolaryngol. 41 (1997) 199–206. [13] B. Fearon, D. Ellis, The management of long term airway problems in infants and children, Ann. Otol. Rhinol. Laryngol. 80 (1971) 669–677. [14] P.J. Emery, B. Fearon, Vocal cord palsy in pediatric practice: a review of 71 cases, Int. J. Pediatr. Otorhinolaryngol. 8 (1984) 147–154. [15] H. Daya, A. Hosni, I. Bejar-Solar, J.N. Evans, C.M. Bailey, Pediatric vocal fold paralysis: a long-term retrospective study, Arch. Otolaryngol. Head Neck Surg. 126 (2000) 21–25. [16] A.G. Engel, The therapy of congenital myasthenic syndromes, Neurotherapeutics 4 (2007) 252–257. [17] D. Lashley, J. Palace, S. Jayawant, S. Robb, D. Beeson, Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7, Neurology 74 (2010) 1517–1523. [18] A.A. Ben, F. Petit, N. Alexandri, K. Gaudon, S. Bauche, A. Rouche, et al., Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7, J. Neurol. 257 (2010) 754–766. [19] S. Beri, N. Hussain, A.P. Balky, R. Alzoubidi, J.A. Gosalakkal, S. Kanhere, Bulbar dysfunction: an early presentation of congenital myasthenic syndrome, Eur. J. Paediatr. Neurol. 13 (2009) S1–S46.