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Isolated idiopathic bilateral vocal cord paralysis in two sisters: Case report and review of familial vocal cord paralysis
International Journal of Pediatric Otorhinolaryngology Extra 6 (2011) 368–372
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology Extra journal homepage: www.elsevier.com/locate/ijporl
Case report
Isolated idiopathic bilateral vocal cord paralysis in two sisters: Case report and review of familial vocal cord paralysis Vanessa Abdelhalim a, Jean-Philippe Vaccani b,* a b
University of Ottawa, Faculty of Medicine, Canada Department of Otolaryngology, University of Ottawa, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ontario K1H 8L1, Ottawa, Canada
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 March 2011 Accepted 12 April 2011 Available online 25 May 2011
Two sisters noted to have neonatal stridor were diagnosed with isolated idiopathic bilateral vocal cord paralysis. The vocal cord paralysis spontaneously resolved in both after being tracheostomy tubedependent for varying periods of time. This is the third known isolated case documented in sisters. An updated literature review of this uncommon complex condition is presented. ß 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Vocal cord paralysis Stridor Hereditary
1. Introduction
2. Case studies
The second most common cause of stridor in infants is vocal cord paralysis (VCP) [1]. VCP in the pediatric population can be classified as unilateral or bilateral. Unilateral VCP is more common, associated with iatrogenic causes, and patients being asymptomatic. Bilateral VCP (BVCP) is most often idiopathic and associated with more pronounced obstructive airway symptoms. A high proportion of patients with BVCP will require a tracheostomy [2]. VCP is being diagnosed more frequently due to increased recognition, advances in diagnostic techniques, and improved survival of premature infants [3]. Familial cases of VCP have been described infrequently. Their occurrence indicates a genetic component to normal laryngeal development and function [2]. This paper will present a case of two sisters noted to have stridor at birth who were eventually diagnosed with isolated idiopathic BVCP requiring tracheostomies. An updated review of the current literature on familial vocal cord paralysis will also be provided (Table 1).
2.1. Case 1: A.T.
* Corresponding author. E-mail addresses: [email protected] (V. Abdelhalim), [email protected] (J.-P. Vaccani). 1871-4048/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pedex.2011.04.003
A.T. was born to non-consanguineous parents at term by an atraumatic vaginal delivery. At birth she was noted to have inspiratory stridor. She was subsequently seen in the ENT clinic at 6 days of life (DOL). She was initially diagnosed with laryngomalacia as the cords could not be visualized on flexible fiberoptic laryngoscopy (FFL). A rigid bronchoscopy and CO2 laser supraglottoplasty were performed on DOL 26. Her symptoms failed to improve after the procedure and on repeat FFL she was found to have BVCP. Magnetic resonance imaging (MRI) of the head, neck, and upper thorax were normal. Direct laryngoscopy and tracheostomy were performed at 6 weeks of age. At 4 months of age routine FFL examination demonstrated a return of function in her vocal cords. She was successfully decannulated at 5 months of age. 2.2. Case 2: N.T. N.T. is the younger sister of A.T. by 2 years. She was the product of an uncomplicated pregnancy and vaginal delivery. She was noted to be stridorous at birth, requiring bag and mask ventilator support. She was transferred to the Neonatal Intensive Care Unit (NICU) for ENT evaluation. She was found to have laryngomalacia and normal vocal cord mobility. At 2 months of age repeat FFL revealed BVCP. MRI of the head, and computed tomography (CT) of the chest and neck failed to reveal any abnormalities. She was admitted to hospital for rigid bronchoscopy and tracheostomy and
Table 1 Case reports of familial vocal cord paralysis. Author
Affected family members
Associated abnormalities
Most likely mode of inheritance
Spontaneous recovery
4 m, 1 f – over 3 gen Mother, son, 2 dghtrs
None None
AD AD
N ?
Brother, 2 sisters Mother, dghtr M infant, 2 f maternal cousins Brother, sister
None None None None
Y Y Y Y
Khodaei et al. [13]
2 brothers
Younger bro had LTM, marked reflux laryngitis, epilepsy None None
AD AD with new mutation AD with variable expressivity AR – 1st degree parental consanguinity, paracentric balanced inversion of ch13 in mother and 2 sibs ? Difficult to ascertain AD with variable penetrance AD
Y N
XR
Y 1 death ? 1 death N N N
Tarin et al. [14] Father, son Omland and Brondbo [15] Twin boy and girl Idiopathic VCP associated with anomalies or an underlying genetic syndrome Plott [5] 4 brothers Watters and Fitch [16]
2 brothers, 1st cousin once removed
Gacek [17] Hollinger et al. [18] Young and Harper [19]
Father, 2 sons Mother, son 9 family members – 3 m, 6 f
Morelli et al. [20] Grundfast and Milmoe [21] Tucker [22]
7 (4 m and 3 f) across 3 generations Father, son, dghtr Father, dghtr
Serratrice et al. [23] (French paper)
Brother, sister
Boltshauser et al. [24]
Mother, dghtr, grandfather
Hawkins et al. [25]
Mother, identical m twins, m sibling, 1st m cousin Mother, son, 2 dghtr
Schinzel et al. [26] Pridmore et al. [27]
MR, generalized neuromuscular incoordination, inner ear deafness in 1 Severe MR, psychomotor retardation, blindness in 1 bro Motor nerve deficits of UE and LE CMT Insidious onset of progressive, chronic distal spinal muscular atrophy and weakness 2 with clubfoot Swallowing difficulty during infancy Bilateral ptosis of eyelids at birth Prematurity, ?mild MR in dghtr Proximal and distal atrophy and proximal muscle weakness consistent with chronic spinal muscular atrophy Progressive distal spinal muscular atrophy and weakness and SNHL Digital anomalies Moderate MR, youngest girl was microcephalic Progressive distal spinal muscular atrophy and weakness Variable degree of muscle weakness of limbs, vocal folds, intercostal muscles, a sx sensory loss CMT II-C 5 had VCP Swallowing problems, delayed neurodevelopment
Lacy et al. [29]
Mother, son, dghtr
Cuesta et al. [30]
2 small families and 1 large inbred Spanish family
CMT II-C Son had normal intelligence, deep inspiratory stridor, moderate pectus excavatum, peroneal atrophy, weakness in all 4 extremities. Dghtr had weakness of instrinsic muscles of hands and bilateral dorsiflexion of feet and toes Axonal CMT Childhood onset Weakness, foot and hand wasting
Dyck et al. [28]
AD ? AD AD AD Possibility of new sx complex of congenital origin AD
N Y N
AD – pleiotropic effect of a single mutant gene AD with variable penetrance and male predilection – single inherited trait AD with variable expression – remotely consanguineous, parents AD
N
Y for 2; N for 1 N
AD
N
AR – parents are double 1st cousins, maternal grandparents are first cousins and paternal grandparents are 2nd or 3rd cousins AD
N
AR
N
?
Y
N
369
Koppel et al. [7]
7 family members in 3 successive gen (3 m and 4 f) 2 kindreds with 14 pt 8/11 in kindred 1 had sx of VC/resp involvement. (6f, 2 m). Kindred 2 had 2/3 (2f) affected 2 brothers
XR
Y
V. Abdelhalim, J.-P. Vaccani / International Journal of Pediatric Otorhinolaryngology Extra 6 (2011) 368–372
Isolated Idiopathic BVCP Mace et al. [8] Brunner and Herrmann [9] (German paper) Cunningham et al. [10] Isaacson and Moya [11] Manaligod and Smith [2] Raza et al. [12]
VCP, vocal cord paralysis; AD, autosomal dominant; AR, autosomal recessive; XR, x-linked recessive; trach, tracheostomy; PVCM, paradoxical vocal cord movement; CMT, Charcot-Marie-Tooth disease; yo, years old; mo, month; PVCM paradoxical vocal cord movement; sx, symptoms; hx, history; LTM, laryngotracheomalacia; dghtr, daughter; MR, mental retardation; HMSN, Heriditary Motor and Sensory Neuropathy; m, male; f, female; UE, upper extremity; LE, lower extremity. ? – Spontaneous recovery unknown.
AR 2 sisters, unaffected parents and brother Stojkovic et al. [31]
CMT with severe motor weakness, VC and diaphragm paralysis. Delayed milestones
Most likely mode of inheritance Associated abnormalities Affected family members Author
Table 1 (Continued )
N
V. Abdelhalim, J.-P. Vaccani / International Journal of Pediatric Otorhinolaryngology Extra 6 (2011) 368–372 Spontaneous recovery
370
diagnosed with isolated idiopathic BVCP. She was referred to a geneticist who found no evidence of an underlying syndrome or developmental delay and made no further recommendations. At two and a half years of age she underwent a successful decannulation procedure. 3. Discussion VCP accounts for 10% of congenital laryngeal abnormalities and is the second most common cause of neonatal stridor after laryngomalacia [4]. It can occur as an isolated abnormality, in association with other anomalies, or as a feature of a genetic syndrome. Familial cases are uncommon, the first reported by Plott [5]. Reports of VCP occurring in siblings, particularly sisters, is even more rare. Several modes of inheritance have been proposed to explain the transmission in families. Animal studies have supported both autosomal dominant [6] and autosomal recessive [7] modes. At this time there remains no consensus. The case of the two girls presented here appears to be the fifth of BVCP documented in sisters [9,10,26,31]; the third isolated case [9,10]. Several previous studies have documented a male predilection in the presented families [25]. This literature review did not demonstrate gender predominance (53 males and 47 females). There is no known underlying genetic disorder or associated abnormality present in the two sisters. A geneticist was consulted; karyotyping was deemed unnecessary as the girls were not syndromic and had no developmental delay. Electromyography (EMG) was not performed as the diagnostic and prognostic value is still unclear [2]. The father has late onset asthma and is otherwise healthy. Interestingly, the mother reports experiencing undiagnosed stridor that resolved spontaneously as an infant. She developed a hoarse voice 8 years ago and was diagnosed with vocal cord polyps. She also reports experiencing swallowing difficulties. There are no other offspring in the family. Isaacson and Moya [11] documented a similar case involving a mother and daughter with no associated abnormalities. They proposed that the BVCP trait is being passed through a new mutation that is inherited in an autosomal dominant fashion. This is a possibility in our case, with the addition of variable phenotypic expression, as no other family members are affected and the severity between mother and daughters varies. The most likely mode of inheritance can be ascertained more definitively if the parents decide to expand their family. In addition, the mother’s brother and father both have unilateral sensorineural hearing loss (SNHL) since birth. The significance of this is unclear. Plott [5] described one sibling in the presented family to have SNHL and Bolthauser et al. [24] documented SNHL and BVCP in three subjects of one family. They hypothesized that the clinical findings were caused by a pleiotropic effect of a single mutant gene. Several molecular genetic studies have been conducted to identify the genetic basis of VCP. Mace et al. [8] suggested linkage to human leukocyte antigen (HLA) and assigned the genetic locus for this disorder to chromosome 6. Manaligod et al. [32] demonstrated a statistically significant linkage to a region on chromosome 6q16. The authors suggested focusing on genes expressed in the central nervous system that are known to be implicated in neural development and differentiation to identify the specific VCP mutation. The linkage to HLA on chromosome 6 was refuted by Raza et al. [12], who stated many linkages assigned to this area have been erroneous, as this was one of the only few sites available to examination at that time. Cuesta et al. [30] identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal CMT disease and VCP. They hypothesized involvement of this gene in signal transduction
V. Abdelhalim, J.-P. Vaccani / International Journal of Pediatric Otorhinolaryngology Extra 6 (2011) 368–372
during neuronal development. Weakness of laryngeal muscles in CMT disease can be explained by a length-dependent neuropathy [33]. The originally proposed underlying pathophysiology of VCP [5] has been supported throughout the literature. It is believed to be due to dysgenesis of the abductor portion of the nucleus ambiguus (the brainstem nucleus responsible for VC function). In addition to this, a poorly responsive chemoreceptor ventilator control reflex, which projects through the nucleus ambiguus, has been suggested [10]. Incoordination of laryngeal stimulation has also been proposed [11]. The spontaneous resolution of symptoms gradually over time supports the theory of maturation and plasticity of the neuromuscular pathway [10]. This pathway involves the carotid body, nucleus ambiguus, posterior crico-arytenoid muscles, and neural connections. Symptom improvement can also be accounted for by an increase in glottic airway with growth [10]. There are several chart reviews in the literature documenting outcome of BVCP [1,34]. Most recently, King and Blumin [4] stated children with idiopathic causes of BVCP required tracheotomy in 68% of cases and recovered over a range of 6 months to 11 years. 48–62% of children with BVCP have spontaneous recovery of VC function [3]. The current consensus is to wait at least 12 months before intervening surgically or until the child can actively participate in the decision process [4]. The case presented here demonstrated spontaneous return of VC function in the older sister by 4 months of age with successful decannulation at 5 months old. The younger sister also spontaneously recovered and was successfully decannulated at two and a half years old. In the review of the literature, nine reports documented twenty-five patients with isolated idiopathic BVCP. Eleven patients have shown evidence of spontaneous resolution (the results of Brunner and Herrmann [9] are unaccounted for). Mace et al. [8] documents the only case of isolated BVCP with progressive severity of paralysis with age. The majority of VCP cases associated with anomalies or an underlying genetic condition showed a more severe course with less instances of spontaneous recovery. BVCP in the presence of a chromosomal abnormality has been suggested as a poor prognostic indicator [35]. Referral to a geneticist for evaluation and chromosomal analysis is necessary for patients with BVCP if there is an association with other congenital anomalies or no symptomatic improvement is seen [35]. Similarly, if chromosomal disorder anomalies are discovered in a patient the possibility of VCP should be investigated in those with symptoms of laryngeal dysfunction [35]. BVCP is a very complicated entity in terms of its genetic transmission, pathophysiology, and prognosis for spontaneous recovery. The mainstays of conservative management include neurologic imaging, routine interval cord visualization, referral to a Geneticist, continual evaluation of the patient’s overall health, and a heightened suspicion for affected family members. 4. Conclusion It will be important to follow the two sisters longitudinally to investigate if any other physical findings become apparent that may point to the presence of an underlying genetic syndrome. The fact that the mother also experienced neonatal stridor makes this possibility even more probable. Preparing for new children, if the family so decides, by examining them after birth will be important for earlier diagnoses and treatment as well as confirming our inheritance hypothesis. The literature review illustrates the complexity of familial VCP. There remain many unanswered questions on this heterogeneous topic. Continued documentation of these rare cases is vital to
371
expanding the knowledge base and providing further insight into this complex problem. Conflict of interest The authors have no conflict of interest to declare. References [1] S.R. Cohen, R.D. Eavey, M.S. Desmond, B.C. May, Endoscopy and tracheotomy in the neonatal period: a 10-year review, 1967–1976, Ann. Otol. Rhinol. Laryngol. 86 (September–October (5 Pt 1)) (1977) 577–583. [2] J.M. Manaligod, R.J.H. Smith, Familial laryngeal paralysis, Am. J. Med. Genet. 77 (1998) 277–280. [3] E.Y. Chen, A.F. Inglis Jr., Bilateral vocal cord paralysis in children, Otolaryngol. Clin. North Am. 41 (2008) 889–901. [4] E.F. King, J.H. Blumin, Vocal cord paralysis in children, Curr. Opin. Otolaryngol. Head Neck Surg. 17 (December (6)) (2009) 483–487 (Review). [5] D. Plott, Congenital laryngeal-abductor vocal cord paralysis due to nucleus ambiguus dysgenesis in three brothers, N. Engl. J. Med. 271 (1964) 593–597. [6] H.M. Burbidge, A review of laryngeal paralysis in dogs, Br. Vet. J. 151 (January– February (1)) (1995) 71–82. [7] R. Koppel, S. Friedman, S. Fallet, Congenital vocal cord paralysis with possible autosomal recessive inheritance: case report and review of the literature, Am. J. Med. Genet. 64 (August (3)) (1996) 485–487. [8] M. Mace, E. Williamson, D. Worgan, Autosomal dominantly inherited adductor laryngeal paralysis—a new syndrome with a suggestion of linkage to HLA, Clin. Genet. 14 (November (5)) (1978) 265–270. [9] F. Brunner, I. Herrmann, Familial recurrent laryngeal nerve paralysis, a genetically fixed syndrome—additional remark on linkage of deficiency gene and HLA (author’s transl), Laryngol. Rhinol. Otol. (Stuttg.) 61 (April (4)) (1982) 186–188. [10] M.J. Cunningham, R.D. Eavey, D.C. Shannon, Familial vocal cord dysfunction, Pediatrics 76 (November (5)) (1985) 750–753. [11] G. Isaacson, F. Moya, Hereditary congenital laryngeal abductor paralysis, Ann. Otol. Rhinol. Laryngol. 96 (November–December (6)) (1987) 701–704. [12] S.A. Raza, S. Mahendran, N. Rahman, R.G. Williams, Familial vocal fold paralysis, J. Laryngol. Otol. 116 (December (12)) (2002) 1047–1049. [13] I. Khodaei, K. Howarth, A. Karkanevatos, R. Clarke, A. Fryer, Heriditary vocal cord palsy, Int. J. Pediatr. Otorhinolaryngol. 67 (2003) 427–428. [14] T.T. Tarin, J.A. Martinez, N.L. Shapiro, Familial bilateral abductor vocal cord paralysis, Int. J. Pediatr. Otorhinolaryngol. 69 (2005) 1693–1696. [15] T. Omland, K. Brondbo, Paradoxical vocal cord movement in newborn and congenital idiopathic vocal cord paralysis: two of a kind? Eur. Arch. Otorhinolaryngol. 265 (July (7)) (2008) 803–807. [16] G.V. Watters, N. Fitch, Familial laryngeal abductor paralysis and psychomotor retardation, Clin. Genet. 4 (1973) 429–433. [17] R.R. Gacek, Hereditary abductor vocal cord paralysis, Ann. Otol. 85 (1976) 90–93. [18] P.C. Holinger, D.M. Vuckovich, L.D. Holinger, P.H. Holinger, Bilateral abductor vocal cord paralysis in Charcot-Marie-Tooth disease, Ann. Otol. Rhinol. Laryngol. 88 (March–April (2 Pt 1)) (1979) 205–209. [19] I. Young, P. Harper, Hereditary distal spinal muscular atrophy with vocal cord paralysis, J. Neurol. Neurosurg. Psychiatry 43 (May (5)) (1980) 413–418. [20] G. Morelli, C. Mesolella, F. Costa, B. Testa, V. Ventruto, S. Santulli, Familial laryngeal abductor paralysis with presumed autosomal dominant inheritance, Ann. Otol. Rhinol. Laryngol. 91 (May–June (3 Pt 1)) (1982) 323–324. [21] K. Grundfast, G. Milmoe, Congenital hereditary bilateral abductor vocal cord paralysis, Ann. Otol. Rhinol. Laryngol. 91 (November–December (6 Pt 1)) (1982) 564–566. [22] H. Tucker, Congenital bilateral recurrent nerve paralysis and ptosis: a new syndrome? Laryngoscope 93 (November (11 Pt 1)) (1983) 1405–1407. [23] G. Serratrice, J.F. Pellissier, J.L. Gastaut, C. Desnuelle, Chronic spinal amotrophy with paralysis of the vocal cords: Young–Harper syndrome, Rev. Neurol. (Paris) 140 (11) (1984) 657–658. [24] E. Boltshauser, W. Lang, T. Spillmann, E. Hof, Hereditary distal muscular atrophy with vocal cord paralysis and sensorineural hearing loss: a dominant form of spinal muscular atrophy? J. Med. Genet. 26 (February (2)) (1989) 105–108. [25] D.B. Hawkins, M. Liu-Shindo, E.J. Kahlstrom, E.F. MacLaughlin, Familial vocal cord dysfunction associated with digital anomalies, Laryngoscope 100 (September (9)) (1990) 1001–1004. [26] A. Schinzel, E. Hof, P. Dangel, W. Robinson, Familial congenital laryngeal abductor paralysis: different expression in a family with one male and three females affected, J. Med. Genet. 27 (November (11)) (1990) 715–716. [27] C. Pridmore, M. Baraitser, E.M. Brett, A.E. Harding, Distal spinal muscular atrophy with vocal cord paralysis, J. Med. Genet. 29 (March (3)) (1992) 197–199. [28] P.J. Dyck, W.J. Litchy, S. Minnerath, T.D. Bird, P.F. Chance, D.J. Schaid, et al., Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis, Ann. Neurol. 35 (May (5)) (1994) 608–615. [29] P.D. Lacy, B.E. Hartley, M.J. Rutter, R.T. Cotton, Familial bilateral vocal cord paralysis and Charcot-Marie-Tooth disease type II-C, Arch. Otolarynogol. Head Neck Surg. 127 (2001) 322–324. [30] A. Cuesta, L. Pedrola, T. Sevilla, J. Garcı´a-Planells, M.J. Chumillas, F. Mayordomo, et al., The gene encoding ganglioside-induced differentiation-associated protein 1
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is mutated in axonal Charcot-Marie-Tooth type 4A disease, Nat. Genet. 30 (January (1)) (2002) 22–25. [31] T. Stojkovic, P. Latour, G. Viet, J. de Seze, J.F. Hurtevent, A. Vandenberghe, et al., Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene, Neuromuscul. Disord. 14 (2004) 261–264. [32] J.M. Manaligod, J. Skaggs, R.J. Smith, Localization of the gene for familial laryngeal abductor paralysis to chromosome 6q16, Arch. Otolaryngol. Head Neck Surg. 127 (August (8)) (2001) 913–917.
[33] P.K. Thomas, W. Marques Jr., M.B. Davis, M.G. Sweeney, R.H. King, J.L. Bradley, et al., The phenotypic manifestations of chromosome 17p11.2 duplication, Brain 120 (1997) 465–478. [34] I. de Gaudemar, M. Roudaire, M. Franc¸ois, P. Narcy, Outcome of laryngeal paralysis in neonates: a long term retrospective study of 113 cases, Int. J. Pediatr. Otorhinolaryngol. 34 (January (1–2)) (1996) 101–110. [35] R.G. Berkowitz, A. Bankier, J.P. Moxham, R.J. Gardner, Chromosomal abnormalities in idiopathic congenital bilateral vocal cord paralysis, Ann. Otol. Rhinol. Laryngol. 110 (7) (2001) 624–626.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology Extra journal homepage: www.elsevier.com/locate/ijporl
Case report
Isolated idiopathic bilateral vocal cord paralysis in two sisters: Case report and review of familial vocal cord paralysis Vanessa Abdelhalim a, Jean-Philippe Vaccani b,* a b
University of Ottawa, Faculty of Medicine, Canada Department of Otolaryngology, University of Ottawa, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ontario K1H 8L1, Ottawa, Canada
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 March 2011 Accepted 12 April 2011 Available online 25 May 2011
Two sisters noted to have neonatal stridor were diagnosed with isolated idiopathic bilateral vocal cord paralysis. The vocal cord paralysis spontaneously resolved in both after being tracheostomy tubedependent for varying periods of time. This is the third known isolated case documented in sisters. An updated literature review of this uncommon complex condition is presented. ß 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Vocal cord paralysis Stridor Hereditary
1. Introduction
2. Case studies
The second most common cause of stridor in infants is vocal cord paralysis (VCP) [1]. VCP in the pediatric population can be classified as unilateral or bilateral. Unilateral VCP is more common, associated with iatrogenic causes, and patients being asymptomatic. Bilateral VCP (BVCP) is most often idiopathic and associated with more pronounced obstructive airway symptoms. A high proportion of patients with BVCP will require a tracheostomy [2]. VCP is being diagnosed more frequently due to increased recognition, advances in diagnostic techniques, and improved survival of premature infants [3]. Familial cases of VCP have been described infrequently. Their occurrence indicates a genetic component to normal laryngeal development and function [2]. This paper will present a case of two sisters noted to have stridor at birth who were eventually diagnosed with isolated idiopathic BVCP requiring tracheostomies. An updated review of the current literature on familial vocal cord paralysis will also be provided (Table 1).
2.1. Case 1: A.T.
* Corresponding author. E-mail addresses: [email protected] (V. Abdelhalim), [email protected] (J.-P. Vaccani). 1871-4048/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pedex.2011.04.003
A.T. was born to non-consanguineous parents at term by an atraumatic vaginal delivery. At birth she was noted to have inspiratory stridor. She was subsequently seen in the ENT clinic at 6 days of life (DOL). She was initially diagnosed with laryngomalacia as the cords could not be visualized on flexible fiberoptic laryngoscopy (FFL). A rigid bronchoscopy and CO2 laser supraglottoplasty were performed on DOL 26. Her symptoms failed to improve after the procedure and on repeat FFL she was found to have BVCP. Magnetic resonance imaging (MRI) of the head, neck, and upper thorax were normal. Direct laryngoscopy and tracheostomy were performed at 6 weeks of age. At 4 months of age routine FFL examination demonstrated a return of function in her vocal cords. She was successfully decannulated at 5 months of age. 2.2. Case 2: N.T. N.T. is the younger sister of A.T. by 2 years. She was the product of an uncomplicated pregnancy and vaginal delivery. She was noted to be stridorous at birth, requiring bag and mask ventilator support. She was transferred to the Neonatal Intensive Care Unit (NICU) for ENT evaluation. She was found to have laryngomalacia and normal vocal cord mobility. At 2 months of age repeat FFL revealed BVCP. MRI of the head, and computed tomography (CT) of the chest and neck failed to reveal any abnormalities. She was admitted to hospital for rigid bronchoscopy and tracheostomy and
Table 1 Case reports of familial vocal cord paralysis. Author
Affected family members
Associated abnormalities
Most likely mode of inheritance
Spontaneous recovery
4 m, 1 f – over 3 gen Mother, son, 2 dghtrs
None None
AD AD
N ?
Brother, 2 sisters Mother, dghtr M infant, 2 f maternal cousins Brother, sister
None None None None
Y Y Y Y
Khodaei et al. [13]
2 brothers
Younger bro had LTM, marked reflux laryngitis, epilepsy None None
AD AD with new mutation AD with variable expressivity AR – 1st degree parental consanguinity, paracentric balanced inversion of ch13 in mother and 2 sibs ? Difficult to ascertain AD with variable penetrance AD
Y N
XR
Y 1 death ? 1 death N N N
Tarin et al. [14] Father, son Omland and Brondbo [15] Twin boy and girl Idiopathic VCP associated with anomalies or an underlying genetic syndrome Plott [5] 4 brothers Watters and Fitch [16]
2 brothers, 1st cousin once removed
Gacek [17] Hollinger et al. [18] Young and Harper [19]
Father, 2 sons Mother, son 9 family members – 3 m, 6 f
Morelli et al. [20] Grundfast and Milmoe [21] Tucker [22]
7 (4 m and 3 f) across 3 generations Father, son, dghtr Father, dghtr
Serratrice et al. [23] (French paper)
Brother, sister
Boltshauser et al. [24]
Mother, dghtr, grandfather
Hawkins et al. [25]
Mother, identical m twins, m sibling, 1st m cousin Mother, son, 2 dghtr
Schinzel et al. [26] Pridmore et al. [27]
MR, generalized neuromuscular incoordination, inner ear deafness in 1 Severe MR, psychomotor retardation, blindness in 1 bro Motor nerve deficits of UE and LE CMT Insidious onset of progressive, chronic distal spinal muscular atrophy and weakness 2 with clubfoot Swallowing difficulty during infancy Bilateral ptosis of eyelids at birth Prematurity, ?mild MR in dghtr Proximal and distal atrophy and proximal muscle weakness consistent with chronic spinal muscular atrophy Progressive distal spinal muscular atrophy and weakness and SNHL Digital anomalies Moderate MR, youngest girl was microcephalic Progressive distal spinal muscular atrophy and weakness Variable degree of muscle weakness of limbs, vocal folds, intercostal muscles, a sx sensory loss CMT II-C 5 had VCP Swallowing problems, delayed neurodevelopment
Lacy et al. [29]
Mother, son, dghtr
Cuesta et al. [30]
2 small families and 1 large inbred Spanish family
CMT II-C Son had normal intelligence, deep inspiratory stridor, moderate pectus excavatum, peroneal atrophy, weakness in all 4 extremities. Dghtr had weakness of instrinsic muscles of hands and bilateral dorsiflexion of feet and toes Axonal CMT Childhood onset Weakness, foot and hand wasting
Dyck et al. [28]
AD ? AD AD AD Possibility of new sx complex of congenital origin AD
N Y N
AD – pleiotropic effect of a single mutant gene AD with variable penetrance and male predilection – single inherited trait AD with variable expression – remotely consanguineous, parents AD
N
Y for 2; N for 1 N
AD
N
AR – parents are double 1st cousins, maternal grandparents are first cousins and paternal grandparents are 2nd or 3rd cousins AD
N
AR
N
?
Y
N
369
Koppel et al. [7]
7 family members in 3 successive gen (3 m and 4 f) 2 kindreds with 14 pt 8/11 in kindred 1 had sx of VC/resp involvement. (6f, 2 m). Kindred 2 had 2/3 (2f) affected 2 brothers
XR
Y
V. Abdelhalim, J.-P. Vaccani / International Journal of Pediatric Otorhinolaryngology Extra 6 (2011) 368–372
Isolated Idiopathic BVCP Mace et al. [8] Brunner and Herrmann [9] (German paper) Cunningham et al. [10] Isaacson and Moya [11] Manaligod and Smith [2] Raza et al. [12]
VCP, vocal cord paralysis; AD, autosomal dominant; AR, autosomal recessive; XR, x-linked recessive; trach, tracheostomy; PVCM, paradoxical vocal cord movement; CMT, Charcot-Marie-Tooth disease; yo, years old; mo, month; PVCM paradoxical vocal cord movement; sx, symptoms; hx, history; LTM, laryngotracheomalacia; dghtr, daughter; MR, mental retardation; HMSN, Heriditary Motor and Sensory Neuropathy; m, male; f, female; UE, upper extremity; LE, lower extremity. ? – Spontaneous recovery unknown.
AR 2 sisters, unaffected parents and brother Stojkovic et al. [31]
CMT with severe motor weakness, VC and diaphragm paralysis. Delayed milestones
Most likely mode of inheritance Associated abnormalities Affected family members Author
Table 1 (Continued )
N
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diagnosed with isolated idiopathic BVCP. She was referred to a geneticist who found no evidence of an underlying syndrome or developmental delay and made no further recommendations. At two and a half years of age she underwent a successful decannulation procedure. 3. Discussion VCP accounts for 10% of congenital laryngeal abnormalities and is the second most common cause of neonatal stridor after laryngomalacia [4]. It can occur as an isolated abnormality, in association with other anomalies, or as a feature of a genetic syndrome. Familial cases are uncommon, the first reported by Plott [5]. Reports of VCP occurring in siblings, particularly sisters, is even more rare. Several modes of inheritance have been proposed to explain the transmission in families. Animal studies have supported both autosomal dominant [6] and autosomal recessive [7] modes. At this time there remains no consensus. The case of the two girls presented here appears to be the fifth of BVCP documented in sisters [9,10,26,31]; the third isolated case [9,10]. Several previous studies have documented a male predilection in the presented families [25]. This literature review did not demonstrate gender predominance (53 males and 47 females). There is no known underlying genetic disorder or associated abnormality present in the two sisters. A geneticist was consulted; karyotyping was deemed unnecessary as the girls were not syndromic and had no developmental delay. Electromyography (EMG) was not performed as the diagnostic and prognostic value is still unclear [2]. The father has late onset asthma and is otherwise healthy. Interestingly, the mother reports experiencing undiagnosed stridor that resolved spontaneously as an infant. She developed a hoarse voice 8 years ago and was diagnosed with vocal cord polyps. She also reports experiencing swallowing difficulties. There are no other offspring in the family. Isaacson and Moya [11] documented a similar case involving a mother and daughter with no associated abnormalities. They proposed that the BVCP trait is being passed through a new mutation that is inherited in an autosomal dominant fashion. This is a possibility in our case, with the addition of variable phenotypic expression, as no other family members are affected and the severity between mother and daughters varies. The most likely mode of inheritance can be ascertained more definitively if the parents decide to expand their family. In addition, the mother’s brother and father both have unilateral sensorineural hearing loss (SNHL) since birth. The significance of this is unclear. Plott [5] described one sibling in the presented family to have SNHL and Bolthauser et al. [24] documented SNHL and BVCP in three subjects of one family. They hypothesized that the clinical findings were caused by a pleiotropic effect of a single mutant gene. Several molecular genetic studies have been conducted to identify the genetic basis of VCP. Mace et al. [8] suggested linkage to human leukocyte antigen (HLA) and assigned the genetic locus for this disorder to chromosome 6. Manaligod et al. [32] demonstrated a statistically significant linkage to a region on chromosome 6q16. The authors suggested focusing on genes expressed in the central nervous system that are known to be implicated in neural development and differentiation to identify the specific VCP mutation. The linkage to HLA on chromosome 6 was refuted by Raza et al. [12], who stated many linkages assigned to this area have been erroneous, as this was one of the only few sites available to examination at that time. Cuesta et al. [30] identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal CMT disease and VCP. They hypothesized involvement of this gene in signal transduction
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during neuronal development. Weakness of laryngeal muscles in CMT disease can be explained by a length-dependent neuropathy [33]. The originally proposed underlying pathophysiology of VCP [5] has been supported throughout the literature. It is believed to be due to dysgenesis of the abductor portion of the nucleus ambiguus (the brainstem nucleus responsible for VC function). In addition to this, a poorly responsive chemoreceptor ventilator control reflex, which projects through the nucleus ambiguus, has been suggested [10]. Incoordination of laryngeal stimulation has also been proposed [11]. The spontaneous resolution of symptoms gradually over time supports the theory of maturation and plasticity of the neuromuscular pathway [10]. This pathway involves the carotid body, nucleus ambiguus, posterior crico-arytenoid muscles, and neural connections. Symptom improvement can also be accounted for by an increase in glottic airway with growth [10]. There are several chart reviews in the literature documenting outcome of BVCP [1,34]. Most recently, King and Blumin [4] stated children with idiopathic causes of BVCP required tracheotomy in 68% of cases and recovered over a range of 6 months to 11 years. 48–62% of children with BVCP have spontaneous recovery of VC function [3]. The current consensus is to wait at least 12 months before intervening surgically or until the child can actively participate in the decision process [4]. The case presented here demonstrated spontaneous return of VC function in the older sister by 4 months of age with successful decannulation at 5 months old. The younger sister also spontaneously recovered and was successfully decannulated at two and a half years old. In the review of the literature, nine reports documented twenty-five patients with isolated idiopathic BVCP. Eleven patients have shown evidence of spontaneous resolution (the results of Brunner and Herrmann [9] are unaccounted for). Mace et al. [8] documents the only case of isolated BVCP with progressive severity of paralysis with age. The majority of VCP cases associated with anomalies or an underlying genetic condition showed a more severe course with less instances of spontaneous recovery. BVCP in the presence of a chromosomal abnormality has been suggested as a poor prognostic indicator [35]. Referral to a geneticist for evaluation and chromosomal analysis is necessary for patients with BVCP if there is an association with other congenital anomalies or no symptomatic improvement is seen [35]. Similarly, if chromosomal disorder anomalies are discovered in a patient the possibility of VCP should be investigated in those with symptoms of laryngeal dysfunction [35]. BVCP is a very complicated entity in terms of its genetic transmission, pathophysiology, and prognosis for spontaneous recovery. The mainstays of conservative management include neurologic imaging, routine interval cord visualization, referral to a Geneticist, continual evaluation of the patient’s overall health, and a heightened suspicion for affected family members. 4. Conclusion It will be important to follow the two sisters longitudinally to investigate if any other physical findings become apparent that may point to the presence of an underlying genetic syndrome. The fact that the mother also experienced neonatal stridor makes this possibility even more probable. Preparing for new children, if the family so decides, by examining them after birth will be important for earlier diagnoses and treatment as well as confirming our inheritance hypothesis. The literature review illustrates the complexity of familial VCP. There remain many unanswered questions on this heterogeneous topic. Continued documentation of these rare cases is vital to
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