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Familial congenital bilateral vocal fold paralysis: A novel gene translocation
International Journal of Pediatric Otorhinolaryngology 79 (2015) 323–327
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International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Familial congenital bilateral vocal fold paralysis: A novel gene translocation§ Amy K Hsu a,1, David E. Rosow b,1,*, Robert J. Wallerstein c, Max M. April d,1 a
Department of Otolaryngology/Head and Neck Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, United States c Department of Pediatrics, Santa Clara Valley Medical Center, San Jose, CA, United States d Department of Otolaryngology/Head and Neck Surgery, New York University School of Medicine, New York, NY, United States b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 29 September 2014 Received in revised form 8 December 2014 Accepted 9 December 2014 Available online 16 December 2014
Objectives: True vocal fold (TVF) paralysis is a common cause of neonatal stridor and airway obstruction, though bilateral TVF paralysis is seen less frequently. Rare cases of familial congenital TVF paralysis have been described with implied genetic origin, but few genetic abnormalities have been discovered to date. The purpose of this study is to describe a novel chromosomal translocation responsible for congenital bilateral TVF immobility. Methods: The charts of three patients were retrospectively reviewed: a 35 year-old woman and her two children. The mother had bilateral TVF paralysis at birth requiring tracheotomy. Her oldest child had a similar presentation at birth and also required tracheotomy, while the younger child had laryngomalacia without TVF paralysis. Standard karyotype analysis was done using samples from all three patients and the parents of the mother, to assess whether a chromosomal abnormality was responsible. Results: Karyotype analysis revealed the same balanced translocation between chromosomes 5 and 14, t(5;14) (p15.3, q11.2) in the mother and her two daughters. No other genetic abnormalities were identified. Neither maternal grandparent had the translocation, which appeared to be a spontaneous mutation in the mother with autosomal dominant inheritance and variable penetrance. Conclusions: A novel chromosomal translocation was identified that appears to be responsible for familial congenital bilateral TVF paralysis. While there are other reports of genetic abnormalities responsible for this condition, we believe this is the first describing this particular translocation. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Vocal cord paralysis Genetic translocation Stridor Congenital stridor
1. Introduction Congenital true vocal fold (TVF) paralysis is a well documented phenomenon. While unilateral TVF paralysis is one of the most common causes of neonatal stridor, congenital bilateral TVF paralysis is a relatively rare cause of airway obstruction in the infant. Whether it presents as an isolated finding or as part of a complex set of abnormalities in multiple organ systems, it has a profound impact on a newborn’s health. One recent systematic review found that 59% of patients with congenital bilateral TVF
§ Presented at the 2009 Annual Meeting of the Eastern Section of the Triological Society, Boston, MA. * Corresponding author. Tel.: +1 305 243 1451; fax: +1 305 243 2009. E-mail address: [email protected] (D.E. Rosow). 1 Previously affiliated with Department of Otolaryngology/Head and Neck Surgery, Weill Cornell Medical College, New York, NY, United States.
http://dx.doi.org/10.1016/j.ijporl.2014.12.009 0165-5876/ß 2014 Elsevier Ireland Ltd. All rights reserved.
paralysis required tracheotomy, although 61% of patients did see some degree of functional improvement [1]. A number of different etiologies for congenital TVF paralysis have been described including neurologic injury, iatrogenic insult, and idiopathic causes. Once the airway is secured and stabilized, patients with congenital TVF paralysis typically undergo magnetic resonance imaging scan and other diagnostic testing to rule out central etiologies, as correction of a central lesion (e.g., Chiari malformation) can potentially lead to improvement in vocal fold function. In patients without a central etiology, the cause of TVF paralysis often remains unknown. However, in certain patients the occurrence of familial propagation of TVF paralysis implies a genetic origin. Genetic causes of TVF paralysis represent an appealing area of study, as advance knowledge that a newborn is at risk for this condition can lead to potentially life-saving preparedness for securing a compromised airway as well as allow for improved prenatal counseling for the parents. Also, if other congenital anomalies
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genetic or chromosomal abnormalities resulting in TVF paralysis. This left a total of 35 articles, the contents of which are summarized in Table 1. Of these 35 articles, only 15 described true congenital TVF paralysis, with neonatal onset and either a known chromosomal or genetic cause. The remaining articles detailed childhood or adult-onset TVF paralysis resulting from a genetic derangement.
should be found to be associated with a given case of TVF paralysis, these can have significant implications for other family members. To date, few such genetic abnormalities have been discovered. We present a case series of familial congenital bilateral TVF paralysis, with genetic analysis identifying a unique chromosomal abnormality. A comprehensive literature review is also conducted to summarize the presently known genetic abnormalities causing this condition.
2.3. Case review and Karyotype analysis 2. Methods Patient no. 1: A 35 year old female presented with a history of traumatic delivery, as well as significant stridor and cyanosis at birth. She was intubated shortly after birth and unable to be weaned from mechanical ventilation. A tracheotomy was performed at 4 days of age. She was examined by an otolaryngologist and noted to have bilateral TVF paralysis, which was initially thought to be iatrogenic. She later developed tracheal stenosis and underwent multiple operations including placement of a T-tube at age 4. She was eventually decannulated at age 6. She currently has a paralyzed right vocal fold and has limited exercise tolerance (Fig. 1). She has no other medical conditions. Patient no. 2: A 16 month old female, daughter of Patient 1, was delivered at 35 weeks gestational age. At birth she was noted to have a nuchal cord that was easily removed, but she continued to have bluish discoloration. She had significant stridor with her initial breaths. She was intubated at birth and noted to have bilateral vocal fold paralysis. Tracheotomy was performed at two weeks of age after failed extubation. At 1 year of age, the patient failed a decannulation attempt. Flexible laryngoscopy was significant for bilateral vocal fold hypomobility with inadequate
2.1. Chart review and genetic analysis Institutional review board approval was obtained from Weill Cornell Medical College for this study. Charts and stored digital images were reviewed for pertinent patient history. After informed consent was given, blood samples were obtained from the three patients as well as the maternal grandparents. Karyotype studies of the patients’ blood specimens were performed using standard cytogenetic techniques and analyzed with G banding at the 550 to 750 band level. 2.2. Literature review Articles from 1965 to 2014 were searched by means of a Medline database query performed using the search string ‘‘(vocal cord OR vocal fold OR laryngeal) AND (paralysis OR palsy OR immobility) AND (genetic OR chromosome OR chromosomal OR mutation)’’. A total of 117 articles were initially returned. Of these, 82 were excluded as they were not original clinical reports on
Table 1 Summary of comprehensive literature review of articles detailing genetic or chromosomal causes of TVF paralysis. Year
Authors
Syndrome
Chromosomal alteration
Gene affected
Type of TVF paralysis
Age of onset
2014
Peterson
17q23.1–q23.2
TBX4
Bilateral
Neonatal
2014
Suh
–
SPTLC1
Bilateral
Adult
2013
Gandomi
17q21.31
EFTUD2
Unilateral
Neonatal
2013, 2010 2013 2013 2013 2013, 2010 2012 2012, 2011, 2005, 2004 2011 2010 2010 2009 2008, 2001 2008, 2003 2005 2004 2003 2003 2002
Klein, Jephson Chew Leshinsky-Silver Hida Fiorillo, Chen, Zimon Leopold Origone, Hermann, Fukae, Tan Nouioua Li Benson Moroni Dick, McEntegart Sevilla, Sevilla McEntegart Stojkovic Berkowitz Vaux Raza
Congenital clubfoot and other anomalies Hereditary sensory and autonomic neuropathy Type 1 Mandibulofacial dysostosis with microcephaly Congenital myasthenic syndrome Novel syndrome Hereditary neuralgic amyotrophy Alexander syndrome Charcot–Marie–Tooth 2 22q11 microdeletion syndrome Amyotrophic lateral sclerosis
– – – – – 22q11 –
DOK7 TUBB3 SEPT9 GFAP TRPV4 – SOD1
Bilateral Bilateral Bilateral Bilateral Both Unilateral Bilateral
Neonatal Neonatal Neonatal Adult Childhood Neonatal Adult
Charcot–Marie–Tooth 4 Charcot–Marie–Tooth X Charcot–Marie–Tooth 1, 1b, 2 Charcot–Marie–Tooth 4a Distal hereditary motor neuropathy Charcot–Marie–Tooth 2 Hereditary motor sensory neuropathy Charcot–Marie–Tooth 4a Robinow syndrome, 22q deletion Williams syndrome –
PRX, MTMR2 GJB1 PRX, NEFL, MPZ GDAP1 – GDAP1 – GDAP1 – ELN –
Not described Both Both Unilateral Both Both Bilateral Not described Bilateral adductor Bilateral Bilateral
Childhood Adult Adult Childhood Childhood Adult Childhood Childhood Neonatal Neonatal Neonatal
2002 2002 2001
Santoro Kovach Hahn
– PMP22 –
Bilateral Bilateral Bilateral
Adult Neonatal Neonatal
2001 2001
Manaligod Berkowitz
Charcot–Marie–Tooth 2c Charcot–Marie–Tooth 1, 1b, 2 Congenital hypomyelination neuropathy – Trisomy 21, 22q deletion
– – – – 2q14.2 – 12q23–24 8q21.1 22q 7q11.23 Paracentric inversion of chromosome 13 – 17p11.2–12 –
– –
Bilateral Bilateral
Neonatal Neonatal
1978
Mace
–
6q16 14;18 rearrangement, 5;11 transposition, trisomy 21, 22q deletion 6p21?
HLA?, GLO?
Bilateral adductor
Neonatal, adult
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Fig. 1. Flexible fiber optic laryngoscopy of Patient no. 1 showing TVF in adducted position (a) and abducted position (b). Note lateral position of right paralyzed TVF with anteromedial prolapse of the arytenoid.
abduction. A direct laryngoscopy was performed with removal of suprastomal granulation tissue. The patient does not tolerate capping and remains with a tracheotomy. She is otherwise healthy. Patient no. 3: A 12 week old female, also a daughter of Patient 1, was born at 37 weeks gestational age. She was noted to have stridor in the delivery room but did not require intubation. She was evaluated by an otolaryngologist at 1 month of age and noted to have a collapsible larynx. She was started on anti-reflux therapy and did well, with intermittent noisy breathing but no stridor. She continued to have nasal regurgitation and vomiting with feeding. Flexible laryngoscopy at age 12 weeks showed a collapsible posterior larynx and posterior cricoid swelling consistent with laryngomalacia and laryngopharyngeal reflux (Fig. 2). She was noted to have adequate vocal fold mobility and has not required tracheotomy. She has no other medical issues. Karyotype analysis: The karyotype of the maternal grandparents revealed no abnormalities. All three of the patients, however, displayed the same translocation between chromosomes 5 and 14—t(5;14) (p15.3, q11.2) (Fig. 3). Given the lack of the same finding in the maternal grandparents, the conclusion was reached that this represented a spontaneous mutation in the mother resulting in her congenital bilateral TVF paralysis. The translocation was then passed on through autosomal dominant transmission, but with variable penetrance given the different phenotypes seen in the two daughters.
3. Discussion Congenital TVF paralysis is second only to laryngomalacia as a cause of neonatal stridor, and it is the leading cause of neonatal respiratory distress. Patients typically have respiratory symptoms with normal voice and swallowing function. Stridor and respiratory distress may present at delivery or in a delayed fashion as a
Fig. 2. Laryngoscopy of Patient no. 3 showing TVF in abducted position with significant post cricoid edema.
result of vocal fold edema associated with infection or reflux. Respiratory symptoms may necessitate acute airway management, including endotracheal intubation or tracheotomy in severe cases. Many patients have spontaneous improvement in vocal fold function, with rates of recovery related to etiology of TVF immobility [2,3]. Neonatal TVF paralysis can be classified as acquired or congenital. Causes of acquired TVF paralysis include traumatic delivery, infection, and cardiothoracic surgery [4]. Congenital TVF paralysis can be caused by central neurologic disorders or anatomic anomalies that affect the recurrent laryngeal nerve or larynx. Congenital TVF paralysis is frequently associated with other congenital anomalies. However, it may also occur as an isolated abnormality with no identifiable cause. In idiopathic cases such as these, a familial pattern of involvement is sometimes seen. Small series of families with autosomal dominant, autosomal recessive, and X-linked inheritance patterns of TVF paralysis have been described [5–10], while other studies have managed to identify the specific genetic abnormalities responsible for this phenotype [11–44]. Perhaps the most studied genetic disorder causing TVF paralysis is Charcot–Marie–Tooth disease. This disorder is the most common genetic neuropathy and accounts for 20% of all neuropathies [27]. Several subtypes of the disease exist, all of which involve a progressive demyelination syndrome affecting numerous neuromuscular sites. There are many genetic loci responsible for the wide spectrum of clinical presentation. Most subtypes present with distal lower limb involvement, muscle weakness, and sensory loss, and some demonstrate unilateral or bilateral vocal fold paralysis. As seen in Table 1, in the majority of studies describing patients with Charcot–Marie–Tooth disease and TVF paralysis, the paralysis occurs in childhood or adulthood, although one report described a congenital case in a family that experienced increasing severity with each generation [41]. Other syndromes with reports of associated congenital TVF paralysis include Williams Syndrome, Alexander Syndrome, congenital myasthenic syndrome, 22q11 microdeletion syndrome, and Down syndrome (Trisomy 21). Several other reports exist of isolated chromosomal or genetic alterations causing congenital TVF paralysis. Manaligod et al. described a family with inherited neonatal vocal fold paralysis and used linkage analysis to determine that the abnormality in question mapped to chromosome 6q16 with an autosomal recessive inheritance pattern [11]. Peterson et al. found a duplication anomaly at 17q23 associated with the TBX4 gene, a limb development transcription factor [12]. This genetic alteration resulted in congenital bilateral TVF paralysis as well as a constellation of other abnormalities, including bilateral clubfoot, midfacial hypoplasia, microcephaly, and heart defects. Other family members with this alteration had clubfoot but no TVF paralysis, indicating incomplete penetrance. Another case of
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Fig. 3. Karyotype analysis from Patient no. 2. Long arm of chromosome 14 (oval) is translocated to short arm of chromosome 5 (arrow).
congenital familial TVF paralysis has been linked with a point mutation in the SEPT9 gene on 17q26, which is responsible for cell division and has been associated with hereditary neuralgic amyotrophy [14]. In this case, the patient had a course notable for relapsing and remitting episodes of aphonia associated with bilateral TVF paralysis, but no airway distress. Chew et al. described a novel syndrome resulting from a missense mutation in the TUBB3 gene, which is responsible for formation of neuronal microtubules [19]. Seven of eight affected neonates were afflicted with Moebius syndrome. All individuals had facial weakness and oculomotor weakness, and two of the eight had bilateral TVF paralysis. This report appears to be only the 16th described series of congenital bilateral TVF paralysis associated with a genetic or chromosomal abnormality. In this case, the breakpoint of the translocation causing disruption at 5p15.3 likely contributes to the clinical presentation. The 5p15.3 region is within the critical region for the cri-du-chat syndrome, and when deleted it is associated with laryngeal malformation and abnormal cry [45]. While not specifically associated with complete vocal fold paralysis, cri-duchat syndrome is known to cause persistent posterior glottic insufficiency and is associated with tubular epiglottis and laryngomalacia [46,47]. It is reasonable to postulate that a novel translocation in this area might therefore lead to unpredictable laryngeal abnormalities, including bilateral vocal fold paralysis. Finding these associated alterations thus is critical not only for counseling of affected patients and their families, but also in understanding the potential pathophysiology behind congenital TVF paralysis. Genetic targets also provide possible options for molecular therapeutics or gene therapy in the future. To be clear, this report does not establish a definitive link between the observed translocation and the congenital laryngeal malformations seen in the study family. It is theoretically possible that another genetic mutation could be causing these findings.
Also, it is reasonable to question why Patients 1 and 2 had bilateral vocal fold paralysis, while Patient 3 was only born with laryngomalacia that improved over time. The likeliest explanation for this is that the responsible gene demonstrates incomplete penetrance; i.e., not all people with the mutation will necessarily develop the abnormal phenotype. This could lead to the mother and one child being born with the severe phenotype of bilateral vocal fold paralysis while the second child, with incomplete penetrance seen, only had mildly symptomatic laryngomalacia. There may also be epigenetic phenomena at work, whereby the gene in question could be expressed to differing degrees, resulting in a variety of phenotypes. Given that all 3 family members with the translocation were born with congenital stridor, and that the grandparents lacked both the mutation and any airway symptoms, the most compelling cause would be the 5p15.3 genetic disruption. 4. Conclusions We have identified a novel chromosomal translocation shared by three family members; one parent and child were afflicted with congenital vocal fold immobility and a second child had laryngomalacia. The translocation has an apparent autosomal dominant mode of inheritance with variable penetrance, as one child did not have TVF paralysis or severe enough symptoms to require tracheotomy. Based on a comprehensive review of the literature, this to our knowledge represents the first description of a chromosome 5 and 14 translocation associated with congenital bilateral vocal fold paralysis. The region of the chromosomal breakpoint is within the critical region for cri du chat syndrome, which is known to cause laryngeal malformation and abnormal cry. Given this finding, further research into this area may focus on candidate genes and proteins responsible for the phenotype
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Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Familial congenital bilateral vocal fold paralysis: A novel gene translocation§ Amy K Hsu a,1, David E. Rosow b,1,*, Robert J. Wallerstein c, Max M. April d,1 a
Department of Otolaryngology/Head and Neck Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, United States c Department of Pediatrics, Santa Clara Valley Medical Center, San Jose, CA, United States d Department of Otolaryngology/Head and Neck Surgery, New York University School of Medicine, New York, NY, United States b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 29 September 2014 Received in revised form 8 December 2014 Accepted 9 December 2014 Available online 16 December 2014
Objectives: True vocal fold (TVF) paralysis is a common cause of neonatal stridor and airway obstruction, though bilateral TVF paralysis is seen less frequently. Rare cases of familial congenital TVF paralysis have been described with implied genetic origin, but few genetic abnormalities have been discovered to date. The purpose of this study is to describe a novel chromosomal translocation responsible for congenital bilateral TVF immobility. Methods: The charts of three patients were retrospectively reviewed: a 35 year-old woman and her two children. The mother had bilateral TVF paralysis at birth requiring tracheotomy. Her oldest child had a similar presentation at birth and also required tracheotomy, while the younger child had laryngomalacia without TVF paralysis. Standard karyotype analysis was done using samples from all three patients and the parents of the mother, to assess whether a chromosomal abnormality was responsible. Results: Karyotype analysis revealed the same balanced translocation between chromosomes 5 and 14, t(5;14) (p15.3, q11.2) in the mother and her two daughters. No other genetic abnormalities were identified. Neither maternal grandparent had the translocation, which appeared to be a spontaneous mutation in the mother with autosomal dominant inheritance and variable penetrance. Conclusions: A novel chromosomal translocation was identified that appears to be responsible for familial congenital bilateral TVF paralysis. While there are other reports of genetic abnormalities responsible for this condition, we believe this is the first describing this particular translocation. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Vocal cord paralysis Genetic translocation Stridor Congenital stridor
1. Introduction Congenital true vocal fold (TVF) paralysis is a well documented phenomenon. While unilateral TVF paralysis is one of the most common causes of neonatal stridor, congenital bilateral TVF paralysis is a relatively rare cause of airway obstruction in the infant. Whether it presents as an isolated finding or as part of a complex set of abnormalities in multiple organ systems, it has a profound impact on a newborn’s health. One recent systematic review found that 59% of patients with congenital bilateral TVF
§ Presented at the 2009 Annual Meeting of the Eastern Section of the Triological Society, Boston, MA. * Corresponding author. Tel.: +1 305 243 1451; fax: +1 305 243 2009. E-mail address: [email protected] (D.E. Rosow). 1 Previously affiliated with Department of Otolaryngology/Head and Neck Surgery, Weill Cornell Medical College, New York, NY, United States.
http://dx.doi.org/10.1016/j.ijporl.2014.12.009 0165-5876/ß 2014 Elsevier Ireland Ltd. All rights reserved.
paralysis required tracheotomy, although 61% of patients did see some degree of functional improvement [1]. A number of different etiologies for congenital TVF paralysis have been described including neurologic injury, iatrogenic insult, and idiopathic causes. Once the airway is secured and stabilized, patients with congenital TVF paralysis typically undergo magnetic resonance imaging scan and other diagnostic testing to rule out central etiologies, as correction of a central lesion (e.g., Chiari malformation) can potentially lead to improvement in vocal fold function. In patients without a central etiology, the cause of TVF paralysis often remains unknown. However, in certain patients the occurrence of familial propagation of TVF paralysis implies a genetic origin. Genetic causes of TVF paralysis represent an appealing area of study, as advance knowledge that a newborn is at risk for this condition can lead to potentially life-saving preparedness for securing a compromised airway as well as allow for improved prenatal counseling for the parents. Also, if other congenital anomalies
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genetic or chromosomal abnormalities resulting in TVF paralysis. This left a total of 35 articles, the contents of which are summarized in Table 1. Of these 35 articles, only 15 described true congenital TVF paralysis, with neonatal onset and either a known chromosomal or genetic cause. The remaining articles detailed childhood or adult-onset TVF paralysis resulting from a genetic derangement.
should be found to be associated with a given case of TVF paralysis, these can have significant implications for other family members. To date, few such genetic abnormalities have been discovered. We present a case series of familial congenital bilateral TVF paralysis, with genetic analysis identifying a unique chromosomal abnormality. A comprehensive literature review is also conducted to summarize the presently known genetic abnormalities causing this condition.
2.3. Case review and Karyotype analysis 2. Methods Patient no. 1: A 35 year old female presented with a history of traumatic delivery, as well as significant stridor and cyanosis at birth. She was intubated shortly after birth and unable to be weaned from mechanical ventilation. A tracheotomy was performed at 4 days of age. She was examined by an otolaryngologist and noted to have bilateral TVF paralysis, which was initially thought to be iatrogenic. She later developed tracheal stenosis and underwent multiple operations including placement of a T-tube at age 4. She was eventually decannulated at age 6. She currently has a paralyzed right vocal fold and has limited exercise tolerance (Fig. 1). She has no other medical conditions. Patient no. 2: A 16 month old female, daughter of Patient 1, was delivered at 35 weeks gestational age. At birth she was noted to have a nuchal cord that was easily removed, but she continued to have bluish discoloration. She had significant stridor with her initial breaths. She was intubated at birth and noted to have bilateral vocal fold paralysis. Tracheotomy was performed at two weeks of age after failed extubation. At 1 year of age, the patient failed a decannulation attempt. Flexible laryngoscopy was significant for bilateral vocal fold hypomobility with inadequate
2.1. Chart review and genetic analysis Institutional review board approval was obtained from Weill Cornell Medical College for this study. Charts and stored digital images were reviewed for pertinent patient history. After informed consent was given, blood samples were obtained from the three patients as well as the maternal grandparents. Karyotype studies of the patients’ blood specimens were performed using standard cytogenetic techniques and analyzed with G banding at the 550 to 750 band level. 2.2. Literature review Articles from 1965 to 2014 were searched by means of a Medline database query performed using the search string ‘‘(vocal cord OR vocal fold OR laryngeal) AND (paralysis OR palsy OR immobility) AND (genetic OR chromosome OR chromosomal OR mutation)’’. A total of 117 articles were initially returned. Of these, 82 were excluded as they were not original clinical reports on
Table 1 Summary of comprehensive literature review of articles detailing genetic or chromosomal causes of TVF paralysis. Year
Authors
Syndrome
Chromosomal alteration
Gene affected
Type of TVF paralysis
Age of onset
2014
Peterson
17q23.1–q23.2
TBX4
Bilateral
Neonatal
2014
Suh
–
SPTLC1
Bilateral
Adult
2013
Gandomi
17q21.31
EFTUD2
Unilateral
Neonatal
2013, 2010 2013 2013 2013 2013, 2010 2012 2012, 2011, 2005, 2004 2011 2010 2010 2009 2008, 2001 2008, 2003 2005 2004 2003 2003 2002
Klein, Jephson Chew Leshinsky-Silver Hida Fiorillo, Chen, Zimon Leopold Origone, Hermann, Fukae, Tan Nouioua Li Benson Moroni Dick, McEntegart Sevilla, Sevilla McEntegart Stojkovic Berkowitz Vaux Raza
Congenital clubfoot and other anomalies Hereditary sensory and autonomic neuropathy Type 1 Mandibulofacial dysostosis with microcephaly Congenital myasthenic syndrome Novel syndrome Hereditary neuralgic amyotrophy Alexander syndrome Charcot–Marie–Tooth 2 22q11 microdeletion syndrome Amyotrophic lateral sclerosis
– – – – – 22q11 –
DOK7 TUBB3 SEPT9 GFAP TRPV4 – SOD1
Bilateral Bilateral Bilateral Bilateral Both Unilateral Bilateral
Neonatal Neonatal Neonatal Adult Childhood Neonatal Adult
Charcot–Marie–Tooth 4 Charcot–Marie–Tooth X Charcot–Marie–Tooth 1, 1b, 2 Charcot–Marie–Tooth 4a Distal hereditary motor neuropathy Charcot–Marie–Tooth 2 Hereditary motor sensory neuropathy Charcot–Marie–Tooth 4a Robinow syndrome, 22q deletion Williams syndrome –
PRX, MTMR2 GJB1 PRX, NEFL, MPZ GDAP1 – GDAP1 – GDAP1 – ELN –
Not described Both Both Unilateral Both Both Bilateral Not described Bilateral adductor Bilateral Bilateral
Childhood Adult Adult Childhood Childhood Adult Childhood Childhood Neonatal Neonatal Neonatal
2002 2002 2001
Santoro Kovach Hahn
– PMP22 –
Bilateral Bilateral Bilateral
Adult Neonatal Neonatal
2001 2001
Manaligod Berkowitz
Charcot–Marie–Tooth 2c Charcot–Marie–Tooth 1, 1b, 2 Congenital hypomyelination neuropathy – Trisomy 21, 22q deletion
– – – – 2q14.2 – 12q23–24 8q21.1 22q 7q11.23 Paracentric inversion of chromosome 13 – 17p11.2–12 –
– –
Bilateral Bilateral
Neonatal Neonatal
1978
Mace
–
6q16 14;18 rearrangement, 5;11 transposition, trisomy 21, 22q deletion 6p21?
HLA?, GLO?
Bilateral adductor
Neonatal, adult
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Fig. 1. Flexible fiber optic laryngoscopy of Patient no. 1 showing TVF in adducted position (a) and abducted position (b). Note lateral position of right paralyzed TVF with anteromedial prolapse of the arytenoid.
abduction. A direct laryngoscopy was performed with removal of suprastomal granulation tissue. The patient does not tolerate capping and remains with a tracheotomy. She is otherwise healthy. Patient no. 3: A 12 week old female, also a daughter of Patient 1, was born at 37 weeks gestational age. She was noted to have stridor in the delivery room but did not require intubation. She was evaluated by an otolaryngologist at 1 month of age and noted to have a collapsible larynx. She was started on anti-reflux therapy and did well, with intermittent noisy breathing but no stridor. She continued to have nasal regurgitation and vomiting with feeding. Flexible laryngoscopy at age 12 weeks showed a collapsible posterior larynx and posterior cricoid swelling consistent with laryngomalacia and laryngopharyngeal reflux (Fig. 2). She was noted to have adequate vocal fold mobility and has not required tracheotomy. She has no other medical issues. Karyotype analysis: The karyotype of the maternal grandparents revealed no abnormalities. All three of the patients, however, displayed the same translocation between chromosomes 5 and 14—t(5;14) (p15.3, q11.2) (Fig. 3). Given the lack of the same finding in the maternal grandparents, the conclusion was reached that this represented a spontaneous mutation in the mother resulting in her congenital bilateral TVF paralysis. The translocation was then passed on through autosomal dominant transmission, but with variable penetrance given the different phenotypes seen in the two daughters.
3. Discussion Congenital TVF paralysis is second only to laryngomalacia as a cause of neonatal stridor, and it is the leading cause of neonatal respiratory distress. Patients typically have respiratory symptoms with normal voice and swallowing function. Stridor and respiratory distress may present at delivery or in a delayed fashion as a
Fig. 2. Laryngoscopy of Patient no. 3 showing TVF in abducted position with significant post cricoid edema.
result of vocal fold edema associated with infection or reflux. Respiratory symptoms may necessitate acute airway management, including endotracheal intubation or tracheotomy in severe cases. Many patients have spontaneous improvement in vocal fold function, with rates of recovery related to etiology of TVF immobility [2,3]. Neonatal TVF paralysis can be classified as acquired or congenital. Causes of acquired TVF paralysis include traumatic delivery, infection, and cardiothoracic surgery [4]. Congenital TVF paralysis can be caused by central neurologic disorders or anatomic anomalies that affect the recurrent laryngeal nerve or larynx. Congenital TVF paralysis is frequently associated with other congenital anomalies. However, it may also occur as an isolated abnormality with no identifiable cause. In idiopathic cases such as these, a familial pattern of involvement is sometimes seen. Small series of families with autosomal dominant, autosomal recessive, and X-linked inheritance patterns of TVF paralysis have been described [5–10], while other studies have managed to identify the specific genetic abnormalities responsible for this phenotype [11–44]. Perhaps the most studied genetic disorder causing TVF paralysis is Charcot–Marie–Tooth disease. This disorder is the most common genetic neuropathy and accounts for 20% of all neuropathies [27]. Several subtypes of the disease exist, all of which involve a progressive demyelination syndrome affecting numerous neuromuscular sites. There are many genetic loci responsible for the wide spectrum of clinical presentation. Most subtypes present with distal lower limb involvement, muscle weakness, and sensory loss, and some demonstrate unilateral or bilateral vocal fold paralysis. As seen in Table 1, in the majority of studies describing patients with Charcot–Marie–Tooth disease and TVF paralysis, the paralysis occurs in childhood or adulthood, although one report described a congenital case in a family that experienced increasing severity with each generation [41]. Other syndromes with reports of associated congenital TVF paralysis include Williams Syndrome, Alexander Syndrome, congenital myasthenic syndrome, 22q11 microdeletion syndrome, and Down syndrome (Trisomy 21). Several other reports exist of isolated chromosomal or genetic alterations causing congenital TVF paralysis. Manaligod et al. described a family with inherited neonatal vocal fold paralysis and used linkage analysis to determine that the abnormality in question mapped to chromosome 6q16 with an autosomal recessive inheritance pattern [11]. Peterson et al. found a duplication anomaly at 17q23 associated with the TBX4 gene, a limb development transcription factor [12]. This genetic alteration resulted in congenital bilateral TVF paralysis as well as a constellation of other abnormalities, including bilateral clubfoot, midfacial hypoplasia, microcephaly, and heart defects. Other family members with this alteration had clubfoot but no TVF paralysis, indicating incomplete penetrance. Another case of
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Fig. 3. Karyotype analysis from Patient no. 2. Long arm of chromosome 14 (oval) is translocated to short arm of chromosome 5 (arrow).
congenital familial TVF paralysis has been linked with a point mutation in the SEPT9 gene on 17q26, which is responsible for cell division and has been associated with hereditary neuralgic amyotrophy [14]. In this case, the patient had a course notable for relapsing and remitting episodes of aphonia associated with bilateral TVF paralysis, but no airway distress. Chew et al. described a novel syndrome resulting from a missense mutation in the TUBB3 gene, which is responsible for formation of neuronal microtubules [19]. Seven of eight affected neonates were afflicted with Moebius syndrome. All individuals had facial weakness and oculomotor weakness, and two of the eight had bilateral TVF paralysis. This report appears to be only the 16th described series of congenital bilateral TVF paralysis associated with a genetic or chromosomal abnormality. In this case, the breakpoint of the translocation causing disruption at 5p15.3 likely contributes to the clinical presentation. The 5p15.3 region is within the critical region for the cri-du-chat syndrome, and when deleted it is associated with laryngeal malformation and abnormal cry [45]. While not specifically associated with complete vocal fold paralysis, cri-duchat syndrome is known to cause persistent posterior glottic insufficiency and is associated with tubular epiglottis and laryngomalacia [46,47]. It is reasonable to postulate that a novel translocation in this area might therefore lead to unpredictable laryngeal abnormalities, including bilateral vocal fold paralysis. Finding these associated alterations thus is critical not only for counseling of affected patients and their families, but also in understanding the potential pathophysiology behind congenital TVF paralysis. Genetic targets also provide possible options for molecular therapeutics or gene therapy in the future. To be clear, this report does not establish a definitive link between the observed translocation and the congenital laryngeal malformations seen in the study family. It is theoretically possible that another genetic mutation could be causing these findings.
Also, it is reasonable to question why Patients 1 and 2 had bilateral vocal fold paralysis, while Patient 3 was only born with laryngomalacia that improved over time. The likeliest explanation for this is that the responsible gene demonstrates incomplete penetrance; i.e., not all people with the mutation will necessarily develop the abnormal phenotype. This could lead to the mother and one child being born with the severe phenotype of bilateral vocal fold paralysis while the second child, with incomplete penetrance seen, only had mildly symptomatic laryngomalacia. There may also be epigenetic phenomena at work, whereby the gene in question could be expressed to differing degrees, resulting in a variety of phenotypes. Given that all 3 family members with the translocation were born with congenital stridor, and that the grandparents lacked both the mutation and any airway symptoms, the most compelling cause would be the 5p15.3 genetic disruption. 4. Conclusions We have identified a novel chromosomal translocation shared by three family members; one parent and child were afflicted with congenital vocal fold immobility and a second child had laryngomalacia. The translocation has an apparent autosomal dominant mode of inheritance with variable penetrance, as one child did not have TVF paralysis or severe enough symptoms to require tracheotomy. Based on a comprehensive review of the literature, this to our knowledge represents the first description of a chromosome 5 and 14 translocation associated with congenital bilateral vocal fold paralysis. The region of the chromosomal breakpoint is within the critical region for cri du chat syndrome, which is known to cause laryngeal malformation and abnormal cry. Given this finding, further research into this area may focus on candidate genes and proteins responsible for the phenotype
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