Developmental facial paralysis: A review

Journal of Plastic, Reconstructive & Aesthetic Surgery (2011) 64, 1318e1333

Developmental facial paralysis: A review Julia K. Terzis a,*, Katerina Anesti b a

Department of Surgery, Division of Plastic & Reconstructive Surgery, Eastern Virginia Medical School and the International Institute of Reconstructive Microsurgery, Norfolk, VA 23501, USA b Department of Surgery, Division of Plastic & Reconstructive Surgery, Eastern Virginia Medical School, Microsurgical Research Center, Norfolk, VA 23501, USA Received 15 December 2010; accepted 11 April 2011

KEYWORDS Developmental facial paralysis; Facial palsy at birth; Genetic anomalies; Vascular disruptions; Facial nerve agenesis; Role of teratogens in developmental malformations; Associated anomalies; Hemifacial microsomia; Asymmetrical crying faces; CHARGE

Summary The purpose of this study is to clarify the confusing nomenclature and pathogenesis of Developmental Facial Paralysis, and how it can be differentiated from other causes of facial paralysis present at birth. Differentiating developmental from traumatic facial paralysis noted at birth is important for determining prognosis, but also for medicolegal reasons. Given the dramatic presentation of this condition, accurate and reliable guidelines are necessary in order to facilitate early diagnosis and initiate appropriate therapy, while providing support and counselling to the family. The 30 years experience of our center in the management of developmental facial paralysis is dependent upon a thorough understanding of facial nerve embryology, anatomy, nerve physiology, and an appreciation of well-recognized mishaps during fetal development. It is hoped that a better understanding of this condition will in the future lead to early targeted screening, accurate diagnosis and prompt treatment in this population of facially disfigured patients, which will facilitate their emotional and social rehabilitation, and their reintegration among their peers. ª 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Introduction Congenital facial paralysis (CFP) refers to conditions that are acquired during or at birth (e.g. from trauma), while developmental facial paralysis (DFP) is the result of developmental mishaps during fetal development.1 DFP can present in isolation or as part of a recognised syndrome, such as Mo ¨bius, Goldenhar, CHARGE, etc. (Figure 1).

Studies on the incidence of facial paralysis in the newborn demonstrate great heterogeneity, (from 1.4 up to 64 per 1000) while the nomenclature has been confusing.2e5 Given the dramatic presentation of this condition, accurate and reliable guidelines are necessary in order to facilitate early diagnosis and initiate appropriate therapy, while providing support and counselling to the family.

* Corresponding author. E-mail address: [email protected] (J.K. Terzis). 1748-6815/$ - see front matter ª 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjps.2011.04.015

Developmental facial paralysis

1319

Figure 1 Example of Developmental facial paralysis with multiple anomalies. This 10-year old girl presented with left (L) sided developmental facial paralysis (Figure 1a). She was born at full term gestation with normal delivery and her antenatal and birth history was unremarkable. Left facial paralysis was noted at birth. She also had associated cleft lip and palate anomaly that were repaired at the age of 3 weeks and 11 months respectively, aberrant right subclavian artery, bilateral developmental conductive hearing loss (VIII) and external ear deformities (cupping and constriction) and left spinal accessory nerve (XI) deficit with weak shoulder and left neck webbing. Genetic screening was normal. She had CFNGs X 3 in our Center and fifteen months later she had a right free pectoralis minor transfer to left cheek for smile restoration. Sixteen months later she had a right pedicle frontalis muscle transfer to the left upper and lower eyelid, neurotized by the upper CFNG that carried motor fibers from the upper zygomatic branch of the right facial never, to substitute for the missing orbicularis oculi muscle. Her last surgery involved pedicle transfer of the left digastric muscle to substitute for the left depressor complex, neurotized by the lower CFNG that carried motor fibers from the mandibular branch of the right facial nerve, along with a Rhinoplasty, and scar revision of her previously repaired cleft lip. Patient at her last follow-up visit when she was 16 years old (Figure 1b).

Differentiating developmental from traumatic facial paralysis noted at birth is important for determining prognosis, but also for medicolegal reasons.6,7 In general, DFP carries a poor functional prognosis and the importance of early recognition and treatment has been stressed by many authors, while most traumatic cases are likely to recover spontaneously.3e5 The purpose of this study is a thorough literature review of the pathogenesis and evaluation of Developmental Facial Paralysis, and how it can be differentiated from other causes of facial paralysis present at birth.

Methods A literature search for the years 1966e2010 using the NLM PubMed using the keyword groups “facial nerve paralysis pediatric, developmental, congenital” was performed. In addition, Embase, CINAHL, Citation Manager and a number of other key biomedical electronic databases were searched. Relevant information was also identified by hand searching all the Plastic Surgery Journals since 2000, by scrutinizing the cited references of all facial paralysis articles and the Conference Proceedings.

Anatomy The facial nerve arises from the brain stem nuclei.8,9 The motor fibers of the facial nerve loop dorsally around the abducens nerve nucleus and exit at the cerebellopontine angle. The parasympathetic and sensory fibers form the nervus intermedius which join the motor root of the facial nerve as it exits the brain stem. The course of the facial nerve is divided into the cisternal segment in the cerebellopontine angle, the intracanalicular segment, the labyrinthine segment and the tympanic segment (separated by the anterior genu), the mastoid segment (separated by the posterior genu), and the extracranial segment.10,11 Several branches are given off during the intrapetrosal course. The extracranial segment consists mainly of the parotid portion of the facial nerve and its terminal branches that innervate the facial musculature.

Embryology The facial nerve begins to develop at 3 weeks of life from the facio-acoustic primordium and is intimately related to the structures of the middle ear, external ear, parotid

1320 gland, and facial muscles. The neural connections are completely established by the 16th week of fetal life,12 while the facial nerve separates from the acoustic nerve at 5e6 weeks of fetal life. Therefore, an in utero insult prior to this time, can affect both nerves. The facial canal continues to develop after the 16th week and the ossification is completed by the end of the first year of life. The inner ear and internal auditory canal undergo a different embryogenesis. Although causes of DFP have been attributed to an agenesis of the petrous portion of the temporal bone, with resulting agenesis of the facial nerve, it should be pointed out, that the bone and cartilage formation occur after the development of the facial nerve and thus appear unable to influence the nerve itself.12 At birth, the anatomy of the facial nerve approximates that of the adult with the exception of the nerve’s exit through the superficially located stylomastoid foramen, making the facial nerve vulnerable to compression injury from the shoulder during intrauterine life, the maternal pelvis in labor, or the forceps during delivery.13 The mastoid tip develops postnatally which affords greater protection to the nerve in later life.

J.K. Terzis, K. Anesti the pathogenesis of syndromes as Poland, Klippel-Feil, Goldenhar and Mo ¨bius.18,19

Teratogens An extensive review on the relationship of teratogens and craniofacial malformations has been produced by Sulik KK et al. in 1988.20 Environmental agents including ethanol, 13-cisretinoic acid, the antimetabolite methotrexate, periods of hypoxia, ionizing radiation or hyperthermic stress, when administered acutely to pregnant experimental animals, induce stage-dependent craniofacial malformations comparable to those in corresponding human teratogen syndromes.21 The pattern of these malformations is related to the particular vulnerability of cells in the vicinity of normal programmed cell death, for which the embryo may be unable to compensate. The close relationship of the brachial arches, the cardiogenic region, the cervical somites and the pronephros during early embryogenesis can explain the relationship between the malformations observed in the cranial and caudal regions.14

Genetic factors

Aetiology In general, the anatomical presentation of the various anomalies of the facial nerve in DFP can be summarized in four categories: 1. aplasia or hypoplasia of cranial nerve nuclei; 2. nuclear agenesis; 3. peripheral nerve abnormalities; (aplasia or hypoplasia, bifurcation, anomalies in the course of facial nerve). 4. primary myopathy.14 There appears to be two main pathways through which cranial nerve dysfunction occurs. The first involves failure of the cranial nerve nuclei to develop normally and their motor neuron pools to differentiate, aggregate, and establish proper neuronal connections. Genetic factors, vascular events, or teratogenic insults have been implicated. The second mechanism involves genetic defects that lead to abnormal axonal transport of molecules necessary for normal muscle function and development.15 The timing and exact location of errors may have different effects, accounting in part for the diversity of clinical presentations.16

Vascular theory In the embryo, the hindbrain is supplied by paired longitudinal arteries that coalesce between days 32 and 34 to form the basilar artery. The basilar flow is initially cranial to caudal. Between days 37 and 40, the vertebral arteries develop, resulting in a reversal of flow. Occlusion of vessels by intrinsic or extrinsic mechanisms, anomalies of vessel development, or environmental factors such as infection, hyperthermia, hypoxia, vasculitis, or drug effects can disturb blood flow.17 Many investigators have demonstrated links between vascular disruptions and genetic anomalies that can explain

In the course of embryonic development, a number of genes, including homeobox genes are involved in the organization of cranial nerves.22,23 Clinical and genetic data on patients with developmental facial palsy and its variants have identified abnormalities of cranial nerve nuclear development and autopsy studies have supported these concepts.24,25 Mice harbouring mutations at each loci of four Hox genes and deficits for several genes in the endothelin pathway have been generated, and the corresponding defects in the cranial nerves and craniofacial structures have been investigated extensively.22 These models might allow study of the etiology of these diseases in greater detail in humans and serve as models for developing more effective therapies.

Syndromes and associated deformities ¨bius Mo Mo ¨bius’ syndrome represents a broad spectrum of clinical findings ranging from isolated unilateral facial paralysis to bilateral absence of facial and abducens nerve function (Figure 2). Multiple other cranial nerves, including the glossopharyngeal, vagus, hypoglossal, and other extraocular motor nerves, can be affected. Genetic factors, teratogens and vascular anomalies have been linked with the aetiopathogenesis of the syndrome.18 During the time of blood supply transition, cardiac partitioning and dissolution of interdigital webs to form discrete fingers are also occurring, explaining the associated anomalies in these regions.19

Associations Most cases of developmental facial weakness have obvious associated defects.26 These include limb anomalies such as

Developmental facial paralysis

1321

Figure 2 Example of classical Mo ¨bius syndrome case. Preoperative picture of a 9-year old boy with bilateral developmental facial palsy (Mo ¨bius syndrome), left side more involved than the right. Note the absence of expression and the mask-like face appearance (Figure 2a). Neurological examination in addition to the bilateral seventh nerve involvement (L > R), revealed deficits to the third (III) bilaterally, (inability to gaze upward), bilateral sixth (VI) (paralysis of lateral gaze) and twelve cranial nerves (XII). He had undergone a left otoplasty for correction of prominent ear deformity and a static fascial sling procedure to his left commissure, performed elsewhere at a younger age. He was treated with a two-stage free gracilis muscle to the left cheek neurotized from motor fibers from the contralateral facial nerve. Secondary revisional surgery took place two years later that included a minitemporalis pedicle transfer to the left commissure. Appearance of the patient in his last follow-up two years after the secondary surgery (Figure 2b).

talipes equinovarus, syndactyly, hemimelia, Poland’s anomaly, craniofacial deformities, etc. (Figures 3 and 4).

Hemifacial microsomia (HFM) A common association is Hemifacial Microsomia (HFM), an umbrella term that covers a variety of developmental defects. HFM involves first and second branchial arch derivatives with a highly variable phenotype. Deformities may include auricular defects, preauricular tags and fistulae, microtia-atresia, mandibular, maxillary, and orbital hypoplasia, micropthalmia, epibulbar dermoid, strabismus, conductive or sensoneural hearing loss, and hypoplastic facial muscles27 (Figure 5a and b). OMENS and the expanded OMENS-Plus classifications are the most widely acceptable systems of describing the craniofacial and extracranial anomalies of HFM.28,29 Goldenhar syndrome, which often shows additional defects of vertebrae, heart, and kidneys, is included. Gorlin et al.30 suggested the term oculoauriculovertebral dysplasia (OAVS) for this disorder. The phenotypic characteristics of OAVS and variants have been analyzed recently.27,31,32 Facial palsy has been reported to occur in 22%e50% of patients with HFM.33e36 The observations of anatomic variables of HFM are supported by the pathogenic theory of axial mesodermal dysplasia.35e39 Findings from a recent ongoing case e control study40 are consistent with the

vascular disruption hypothesis. However, links between HFM risk and other pathogenetic processes such as oxygen free radical generation,41,42 maternal diabetes,43 or exposure to teratogens39 and finally, assisted reproductive technologies have been postulated by many authors.44e46

Neonatal asymmetric crying faces (ACF) The clinical hallmark of this condition is a symmetric appearance at rest, but significant unilateral depression of the lower lip with crying (Figure 6). A variety of terms have been used to characterize the dysfunction as: asymmetric crying faces, congenital hypoplasia of the depressor anguli oris muscle, or developmental unilateral lower lip palsy. Pape and Pickering named the phenotype ACF in 1972.47 Cayler first described the association of ACF with congenital cardiac disease, and subsequently named it ‘cardiofacial syndrome’.48 The cause is either facial nerve compression or faulty muscle and/or nerve development. Approximately 10% of developmental cases have associated major malformations, and cardiac anomalies, which should provoke an evaluation for cardiofacial syndrome.49,50 Many of these patients have the 22q11.2 deletion. Further investigation for other anomalies is indicated in selected cases with no signs of improvement by obtaining a FISH (Fluorescence ‘’in situ’’ hybridization) analysis for a chromosomal microdeletion of 22q11.2.

1322

J.K. Terzis, K. Anesti

Figure 3 Example of developmental facial paralysis with multiple associated anomalies. This is a 14-year old boy with left (L) sided developmental facial paralysis and multiple associated defects (Figure 3a). He was born at 39 weeks of gestation with normal delivery and without any history of birth trauma. Left (L) facial paralysis was evident at birth with associated anomalies: tracheoesophageal fistula (TOF), aberrant right subclavian artery, bilateral neck webbing and undescended testis. His physical and neurological examination revealed in addition to the left facial nerve paralysis (VII), loss of smell (I), diplopia and paralysis of lateral gaze (VI), left weak masseter (V), left hearing loss (VIII), external ear deformities and left preauricular skin tag, left palate insufficiency (X), bilateral shoulder weakness (XI) and mild articulation deficit (XII). On animation, there is weakness in the left face with inability to elevate the left eyebrow, and widening of the interpalpebral fissure. The blink reflex is normal bilaterally and he has excellent Bell’s phenomenon. The left facial paralysis involves the left frontalis, left nasalis, left lip elevators and bilateral paralysis of the depressor complex, with inversion of the lower lip (Figure 3a). He was treated with bilateral pedicle digastric muscle transfers for substitution of the right and left depressor complex, neurotized directly by interposition nerve grafts from the right hypoglossal (only 40% of the right hypoglossal was used). A year later, he had placement of three CFNGs after harvesting of bilateral sural nerves, along with transfer of Minitendon graft to suspend left lower eyelid. A right free gracilis was transferred a year later to the left cheek for smile restoration. Patient is seen here a year after the free muscle transfer and prior to any revisional surgery (Figure 3b). Note eversion of lower lip and a pleasing left nasolabial fold excursion yielding a symmetrical coordinated smile. No secondary surgery took place as patient was lost to follow-up.

CHARGE

Hereditary developmental facial paresis (HDFP)

The association between choanal atresia and other developmental malformations was reported by Hall and Hittner in 1979.51,52 Pagon et al.53 used the term CHARGE in 1981 to represent a group of non-randomly associated malformations:

Hereditary developmental facial paresis (HDFP) is the isolated dysfunction of the facial nerve (CN VII). Several families have been identified and observed with developmental unilateral hereditary facial palsy worldwide.24 A multi-disciplinary group of 13 clinicians and researchers from six countries convened in 2002 to study a group of developmental neuromuscular diseases characterized by abnormal eye, eyelid and/or facial movements.57 They have now chosen to be referred as ‘congenital cranial dysinnervation disorders’ or CCDDs. So far, the consortium has identified ten CCDD genetic loci and two CCDD disease genes.58,59 Future genetic studies will enhance the understanding of the pathophysiology and treatment of these disorders.56

C: coloboma of the iris or retina; H: heart defects; A: atresia of the choanae; R: retardation of growth and/or development; G: genital anomalies; E: ear anomalies. Early evaluation for cranial nerve abnormalities should be encouraged, as many children with the CHARGE malformation have associated facial paralysis or swallowing difficulties.54,55 Recently the gene CHD7 was identified at chromosome 8q12.1 as a causative gene of CHARGE association.56

Investigations The initial optimal assessment of the neonate born with unilateral facial paralysis should be performed as soon after

Developmental facial paralysis

1323

Figure 4 Example of DFP with multiple developmental anomalies. Eleven year old boy who was born with (R) right-sided developmental facial paralysis, without evidence of any birth trauma (Figure 4a). He has multiple other developmental anomalies that include: Hypognathia with mandibular asymmetry, marked swallowing difficulties (IX), palatal dysfunction (X), bilateral sensory and conductive hearing loss (VIII), external ear deformities (prominent ears), and right kidney agenesis. His physical examination revealed speech and language developmental delay but normal intelligence. His nerve conduction studies and preoperative electromyography confirmed partial right facial paralysis with some residual activity in the Orbicularis Oculi muscle and Oral Sphincter and an almost intact right lower lip Depressor. He was treated with CFNGs X 3, followed a year later by a free pectoralis minor transfer to the right cheek for smile restoration. Patient is seen two years later exhibiting a reasonable smile (Figure 4b).

birth as possible with the goal to distinguish between a congenital or developmental aetiology.60

History A complete history including a comprehensive obstetrical history is essential to differentiate developmental from traumatic facial paralysis. Time at which facial palsy was recognized and whether onset was acute or progressive must be established. Partial or complete paralysis of the face and presence or absence of any anomalies should be ascertained. History of upper respiratory tract or ear infection, hearing changes, hyperacusis, tearing or taste changes should be obtained. Family history and maternal medical history are recorded. Prenatal history, gestational age, weight, APGAR scores, presentation of the newborn, use of forceps, route of delivery, duration of labor, and any difficulty with delivery must be obtained.

Physical examination A thorough physical examination is necessary in determining the cause of facial paralysis. The most common finding with developmental facial paralysis is the presence or absence of one or more other anomalies. At birth the

weakness of the hemiface becomes evident on crying with the inability to close the eye and the angle of the mouth pulling toward the unaffected side. Evaluation of facial musculature function is recorded on special charts (Figure 8a and b). Presence or absence of synkinesis and/or mass movement is documented. A head and neck exam (including ears, nose, mouth, tongue, palate and pharynx) and a neurological examination (motor and sensory of cranial nerves) is performed. It is also important to look for dysmorfic features and multisystemic syndromal pathology. The importance of follow up assessments before the formation of a surgical plan should be emphasized, because additional nerve deficits might not be evident in the newborn. May in 198160 provided a list of factors that can aid in differentiating the two forms. The presence of other anomalies and/or bilateral facial paralysis, suggest a developmental type of paralysis, while the absence of these signs and the presence of a history of prolonged labour, forceps delivery, or hematotympanum, or marks over the area of the ear/mastoid suggest birth trauma. Developmental facial paralysis does not improve, whereas traumatic palsy often does. With recovery following trauma, there may be some evidence of faulty regeneration, demonstrated by physical findings such as synkinesis, spasm, or mass action. A thorough diagnostic work up is imperative in order to proceed with the appropriate treatment plan.

1324

J.K. Terzis, K. Anesti

Figure 5 Example of DFP with hemifacial microsomia and auricular defect. Thirteen year old girl with left (L) sided developmental facial paralysis and Hemifacial Microsomia (Figure 5a). She was born full term, with normal delivery. Pregnancy and family history were unremarkable. In addition to the left facial paralysis, she had multiple developmental anomalies including: Patent ductus arteriosus (PDA) and septal defect, plagiocephaly (craniosynostosis with unilateral coronal suture involvement), hypoplastic left maxilla and mandible, left microtia Class III and hearing loss (VIII), and weakness of the left hypoglossal nerve (XII). On attempted animation, there is weakness in the left face with inability to elevate the left eyebrow, and widening of the interpalpebral fissure. (The blink reflex is normal bilateral.) She has asymmetrical smile with no left commissure elevation, no dental show and absent left nasolabial fold. There is no depressor function on the left side (Figure 5a). She had multiple procedures elsewhere for left (L) Microtia (Figure 5b). Note: Complete hypoplasia of the external ear and atresia of the external auditory canal. Appearance of the (R) right normal ear for comparison (Figure 5b). Unfortunately, no follow-up is available on this patient.

Figure 6 Example of developmental unilateral lower lip paralysis. One year old boy has a classical developmental unilateral left (L) lower lip paralysis (Asymmetric Crying Facies). He was born full term, with normal delivery and no history of birth trauma. The rest of his physical and neurological examination was unremarkable. There is facial symmetry at rest and the facial palsy is evident with attempted smiling or crying (Figure 6a). There is inability to depress the left lower lip and weakness in left commissure retraction. Usually the cervicofacial portion of the affected facial nerve is hypoplastic or absent. The patient was treated with two CFNGs carrying motor fibers from the buccal and mandibular branches of the right facial nerve. A year later a pedicle left digastric transfer took place neurotized by the contralateral mandibular nerve fibers through the lower CFNG. The second CFNG that carried buccal nerve motor fibers was coapted to the hypoplastic buccal branch on the left side by end-to-side coaptations. The patient displayed excellent depressor complex function in his follow-up visits (Figure 6b and c).

Developmental facial paralysis

1325

Figure 7 Example of CHARGE association. Seven year old boy presented with (R) right-sided developmental facial paralysis (Figure 7a). He was born with multiple developmental defects, including choanal atresia, tracheoesophageal fistula (TOF), patent ductus arteriosus (PDA), undescended testis, and external ear anomalies (lop/cup ear deformity and absence of ear lobe) (CHARGE association). Physical examination revealed small stature for his age, but normal intelligence. Neurological examination confirmed multiple cranial nerve involvement: right VII (facial paralysis), right VI (paralysis of lateral gaze), bilateral VIII (neurosensory hearing loss and Mondini deformity), and right X (palatal weakness). The patient was treated with CFNGs X 2 followed a year later by a free pectoralis minor transfer to the right cheek. Patient is seen in his last follow-up visit five years later after the free muscle transfer (Figure 7b).

Topographic tests for facial nerve function

Electrical tests

Historically, paralysis of facial muscles has been divided into ‘upper motor neuron’ and ‘lower motor neuron disease’. However, Mahadevappa et al 201061 reject the commonly accepted clinical assumptions that the upper facial nucleus receives bilateral cortical input while the lower receives only contralateral. They provide scientific evidence that there are areas in the cortex outside of the middle cerebral artery distribution that control movement of the facial muscles.61 Studies of Miehlke62 and May63 on the cross-sectional anatomy of the facial nerve revealed a spatial orientation of the fascicles. The finding that the upper face is frequently more severely affected in patients with Mo ¨bius syndrome may also relate to the topography of the facial nucleus, where the upper face is represented most dorsally.16 This means that preservation of upper face motility in facial paralysis is not exclusively a sign of central motor lesion. There is great variety of available topographic tests, mainly because of the anatomy of the nerve in the cerebellopontine angle (CPA) and petrosal bone, where direct examination is not possible, but also because the facial nerve is a mixed nerve with motor, sensory and secretory fibers. The main available tests are: Schirmer Test, Stapedius Reflex, Taste Examination and Salivary Flow Test.64 A detailed diagram clarifying the use of topographic tests and the level that the facial nerve is affected was produced by May in 198160 (Figure 9).

Tests using electric stimulation The basic principle of neurophysiology, i.e. stimulating the nerve proximal to the lesion and recording the activity distally can not be applied in the temporal bone. The nerve fiber degeneration has to reach the extratemporal site of stimulation, which may take at least 4 days, in order to be detected. The technique of electroneurography (ENOG) was introduced and refined by Esslen.65 In unilateral cases, the amplitude of the compound action potential is recorded as a percent of the amplitude of the contralateral, clinically normal side. This percentage value provides an objective measurement of the facial nerve function distal to the site of stimulation. Shapiro NL et al.66 stressed the importance of early electrophysiologic testing in differentiating between facial paralyses of traumatic versus developmental origin. In traumatic facial paralysis, an ENOG within 48 hours of injury typically reveals normal facial nerve function despite traumatic compression or even transection injury as the distal portions of the nerve are still capable of conduction. If the injury is incomplete, subsequent ENOGs will remain near normal, often predictive of eventual clinical recovery of facial function. The percentage decrease in facial function over time as evaluated by subsequent ENOG study indirectly correlates with prognosis in cases of more significant nerve injury.

1326

J.K. Terzis, K. Anesti

Figure 8 a: Chart used in our Center to evaluate the facial musculature in facial paralysis patients. b: Diagrammatic depiction of the muscles of facial expression and the extratemporal branches of the facial nerve (From: Balliet R: Facial paralysis and other neuromuscular dysfunctions of the peripheral nervous system. In Payton OD (ed): Manual of Physical Therapy. New York, Churchill Livingstone, 1989; with permission).

In contrast, in developmental paralysis, the initial ENOG reveals facial nerve function to be absent or weak because the nerve atrophy is longstanding. Subsequent ENOG studies would be expected to show little change. May67 advocated that for the above reasons, patients must be evaluated within a few days of birth. Additional electrodiagnostic studies may include: Blink reflex The brief movement of symmetrical closing and opening the eyelids, as a rapid response to various external

stimuli, provides the basis for further electrophysiological studies in the diagnosis of facial paralysis.68 The ipsilateral facial nucleus is responsible for the initiation of the ipsilateral blink, (response at approximately 10 ms) resulting from orbicularis oculi contraction, while a second signal to the contralateral nucleus is responsible for the contralateral blink (delayed response at approximately 30 msec). Delayed ipsilateral response is demonstrated when the ipsilateral orbicularis oculi muscle is denervated, while the contralateral response is normal.

Developmental facial paralysis

1327

Figure 8

In contrast, the ipsilateral response is absent in cases of ipsilateral facial nucleus hypoplasia or aplasia. Nerve excitability testing This test was described by Campbell et al.69 and consists of stimulating the facial nerve trunk, at the level of the neck of the mandible, and observing the evoked facial movements. The minimal intensity of required current can be useful in very young infants when electrical stimulation is often painful. Normally, there is little or no difference in the stimulation intensity on both sides. If complete denervation is present, no response is obtained; in partial denervation, a higher stimulus is required on the affected side to produce a response.

(Continued)

Large retrospective electrodiagnostic studies of pediatric facial paralysis have been provided by Renault,70 despite these difficulties. Electromyography (EMG) This type of classical investigation records the action potentials of voluntary muscle contraction as well as the spontaneous activity of muscle fibers by needle electrodes. It can provide useful information on developmental facial palsy by detecting: - electrical silence, suggestive of hypoplasia or absence of the facial musculature and/or facial nerve.

1328

J.K. Terzis, K. Anesti a developmental problem.1 The quantity of nerve deficit will parallel the muscle deficit in developmental cases; in traumatic cases the nerve may be injured while the muscle tone may be spared.

ENT/Hearing assessment Hearing assessment is additionally important in the accurate diagnosis of neonatal facial paralysis. Auditory Brainstem Reflexes (ABR) is an electric potential evoked by an auditory stimulus, and its clinical utility has been well described.1 The proximity of the facial nerve nuclei to auditory centers in the brain stem may permit to detect developmental defects affecting both systems. External and middle ear anomalies associated with conductive and sensorineural hearing loss are common, since most patients have abnormal development of embryologic structures derived from the first and second brachial arches.34

Opthalmological assessment Figure 9 Available topographic tests are depicted here in this diagram of facial nerve anatomy. (May M. Facial paralysis in children: differential diagnosis. Otolaryngol Head Neck Surg 1981; 89; 841-8. Reproduced with permission).

- denervation or fibrillation potentials are indicative of active denervation of the target. - decreased numbers of motor units are suggestive of a partial nerve block or hypoplasia of the facial musculature and/or nerve - polyphasic potentials are indicative of regeneration of an injured nerve. Therefore, if the facial nerve is not responsive to stimulation and EMG reveals electrical silence, it is most likely

All patients are evaluated for adequacy of corneal protection and sensitivity. Although complete paresis of the orbicularis muscle can present as lagopthalmos, ectropion and/or epiphora, opthalmologic complications of facial paralysis occur infrequently in the pediatric population due to a combination of well-preserved facial muscle tone, adequate tearing, and an active Bell’s phenomenon.66 Routine ophthalmologic examination is also performed in order to rule out amblyopia, an entity associated with developmental but not traumatic facial palsy.71

Radiology Computed tomography (CT) and magnetic resonance imaging (MRI) are well established imaging modalities for

Figure 10 Example of temporal bone abnormalities in hemifacial microsomia. Computerized coronal tomography of the temporal bones with 0.625 mm contiguous slices (Coronal view) of patient in Figure 5a. The right temporal bone is visualized within normal limits and appropriately developed. On the left side, considerable developmental anomaly involving the external auditory canal, middle ear and facial canal is noted. Atresia of the external auditory canal and underdevelopment of the left external ear is observed (Figure 5b). The left temporal bone is incompletely developed and the facial canal is hypoplastic at the first genu and atretic throughout the mastoid.

Developmental facial paralysis

1329

Figure 11 Management algorithm for upper face revisional and ancillary interventions (Terzis JK, Olivares F. Secondary surgery in adult facial paralysis reanimation. Plast Reconstruct Sur 2009; 124; 1916-31. Used with permission).

examining the facial canal as well as the course of the facial nerve itself.9 The facial canal, as it traverses the temporal bone, may display various anomalies that can be classified according to the level at which they involve the facial nerve.10 Aberrations in the course of the mastoid segment can be subdivided into the following categories: 1. anomalies of the course of the facial nerve72 2. hypoplasia of the facial nerve73 3. bifurcations of the facial nerve; i.e.: development of the nervous intermedius component and aplasia of the mastoid component74 (Figure 10). Two useful guides have been produced for guidance in identifying the landmarks of the facial nerve and facial canal in computed tomography of the temporal bone scans and predicting the level of injury.75,76

Primary surgical exploration The concept of nerve exploration as a diagnostic procedure is not generally discussed. However, in developmental facial palsy, without evidence of external trauma, the diagnosis may never be confirmed without exploration of the nerve.1 Medicolegal reasons may also necessitate

surgical exploration in these occasions. This is especially true in case of total nerve paralysis, where EMG shows electrical silence or decreased motor units and other diagnostic procedures such as ABR and mastoid polytomography are unrevealing. On the other hand, if decreasing responses are seen in the involved branch of the nerve on repeated testing while the remainder of the nerve stimulates normally, axonal degeneration is still implied and warrants consideration of nerve exploration and transmastoid decompression.1 Absence or narrowing of the facial nerve in the fallopian canal, sometimes with normal nuclei in the brainstem has been reported.77,78 Jervis in 200179 reported the first case of complete facial nerve agenesis, diagnosed incidentally during surgical exploration, which makes this case one of developmental etiology. We believe that in selected cases, the nerve should be explored at the time of reconstruction to establish a firm diagnosis and rule out the possibility of an acquired lesion.

Arriving at a treatment plan The goals of facial reanimation are to restore facial symmetry, synchronous coordinated animation of the facial

1330

J.K. Terzis, K. Anesti

Figure 12 Management of algorithm for midface revisional and ancillary interventions. (Terzis JK, Olivares F. Secondary surgery in adult facial paralysis reanimation. Plast Reconstruct Sur 2009; 124; 1916-31. Used with permission).

musculature, enable the patient to express emotion, protection of the eye and restoration of blink, and provide oral continence. Formulation of the appropriate surgical management, meticulous technique and aggressive physiotherapy with motor re-education are all critical in obtaining an excellent result with minimal synkinesis and facial asymmetry. The experience of this unit in the evaluation and treatment of facial paralysis patients in Adult and Pediatric Population has been presented before,80e83 as well as detailed management algorithms84 (Figures 11,12 and 13). Reanimation of the paralyzed face is accomplished in a multi-staged setting. The factors that influence surgical strategies used in reanimation of the face are: denervation time, complete versus partial involvement of the facial nerve, and availability of proximal segment of the facial nerve or other motor donors that can be used for innervation. Procedures that attempt to restore neural input to a functionally intact neuromuscular junction give the best results in global paralysis. If there is atrophy or compromised function of the existing muscle, for dynamic reanimation, contiguous or free muscle transfer is used to restore the missing target. During the first stage functional motor nerve fibers are introduced to the paralyzed side of the face with the Cross Facial Nerve Grafts (CFNG) procedure, for direct

neurotization85,86 or banking for future free muscle transfer. Axonal regeneration across the face can be followed by the Tinel’s sign. The ‘’babysitter principle’’ (mini-Hypoglossal to facial nerve transfer) introduced by Terzis in 1984 is a technique to rapidly provide neuronal input to the denervated muscles while the contralateral facial nerve fibers are regenerating through the cross facial nerve grafts. The wisdom of proceeding with the babysitter procedure, in these cases, is that there is possibility that some function might return from the powerful ipsilateral donors that will make secondary surgery more successful.87 In the second stage, six to nine months later, the distal ends of the sural nerve grafts are exposed and secondary microcoaptations or free muscle transfer is accomplished. Angiography may be helpful in evaluating the recipient facial vessels, prior to muscle transfer. Sculptured gracilis or pectoralis minor muscles are ideal candidates for transfer for smile restoration. The smile pattern based on preoperative video and photographs, guide the insetting of the individual muscle slips to the commissure, upper and lower lips, nasolabial fold, lateral ala and infraorbital area. The revisional stage, in six to twelve months after completion of the first two stages, is for reanimation of the eye, lip depressors and refinements in the midface after free muscle transfer. Such procedures include adjustments of the free muscle tension, debulking of the cheek if

Developmental facial paralysis

1331

Figure 13 Management algorithm for lower face revisional and ancillary interventions. (Terzis JK, Olivares F. Secondary surgery in adult facial paralysis reanimation. Plast Reconstruct Sur 2009; 124; 1916-31. Used with permission).

needed, or introduction of additional muscle such as the minitemporalis, in cases that the produced smile is considered inadequate. Protection of the eye can be achieved by using eye spring or gold weight for the upper eyelid and transfer of palmaris tendon graft to suspend the lower eyelid. The various sequelae and stigmata of DFP can be addressed at this stage (i.e.: nasal valve collapse, alar base deformity, ear anomalies, etc.). In a late follow-up, there might be need for a fourth stage of final revision, due especially to changes with passage of time and growth.

It is hoped that the experience of this Unit in meeting the needs of patients’ expectations and the problems related to the disfigurement of DFP, will serve as a model for the establishment of further centers worldwide.

Conflict of interest statement The authors have no conflict of interest.

Funding source Conclusion Future studies on morphogenesis, gene expression and molecular identity, will broaden our perspectives and deduce the function/outcomes of the whole nervous system development.88e90 With the advent of new imaging technology and discovery of genes directing brainstem formation, a more coherent clinical picture of the developmental disorders is emerging. The clinicians will be able to approach them with a framework of proper evaluation, management, and counselling.91 As it has been previously stated, there is a need to provide a more comprehensive service for people with disfigurements over and beyond that of surgical intervention. Physicians should demonstrate concern, sensibility, and acceptance of the individual and recommend attention to all important aspects of the lesion.

There is no funding for this study. This study was approved by the Institutional Review Board (IRB) at Eastern Virginia Medical School (EVMS), Norfolk, VA, USA.

References 1. Harris JP, Davidson TM, May M, et al. Evaluation and treatment of congenital facial paralysis. Arch Otolaryngol 1983;109: 145e51. 2. Hepner JR. Some observations on facial paresis in the newborn infant: etiology and incidence. Pediatrics 1951;8:494e7. 3. Rubin A. Birth injuries: incidence, mechanisms, and end results. Obstet Gynecol 1964;23:218. 4. Falco NA, Eriksson E. Facial nerve palsy in the newborn: incidence and outcome. Plast Reconstr Surg 1990;85:1e4.

1332 5. Toelle SP, Boltshauser E. Long-term outcome in children with congenital unilateral facial nerve palsy. Neuropediatrics 2001; 32:130e5. 6. Illingworth R. Why blame the obstetrician? A review. BMJ 1971; 1:797e801. 7. Laing JHE, Harrison DH, Jones BM, et al. Is permanent congenital facial palsy caused by birth trauma? Arch Dis Child 1996;74:56e8. 8. Agur AMR, Dalley AF. Grant’s atlas of anatomy. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009. 9. Jager L, Reiser M. CT and MR imaging of the normal and pathologic conditions of the facial nerve. Eur J Radiol 2001;40: 133e46. 10. Proctor B, Nager GT. The facial canal: normal anatomy, variations and anomalies. Annals of otology, rhinology. Laryngol Suppl 1982;97:33e44. 11. Nager GT, Proctor II B. Anatomical variations and anomalies involving the facial canal. Ann Otology Rhinology Laryngol Suppl 1982;97:45e61. 12. Raghavan P, Mukherjee S, Phillips DC. Imaging of the facial nerve. Neuroimag Clin N Am 2009;19:407e25. 13. Smith JD, Oregon P, Crumley R, et al. Facial paralysis in the newborn. Otolaryngol Head Neck Surg 1981;89:1021e4. 14. Lammer EJ, Chen DT, Hoar RM, et al. Retinoid acid embryopathy. N Engl J Med 1985;313:837e41. 15. Song M-R. Moving cell bodies: understanding the migratory mechanism of facial motor neurons. Arch Pharm Res 2007;30: 1273e82. 16. Carr MM, Ross DA, Zuker RM. Cranial nerve defects in congenital facial palsy. J Otolaryngol 1997;26:80e7. 17. Poswillo D. The pathogenesis of the first and second brachial arch syndrome. Or Surg, Or Med Or Path 1973;35:302e20. 18. Bavinck JB, Weaver DD. Subclavian artery supply disruption sequence. Hypothesis of a vascular etiology for Poland, Klippelfeil, and Mobius anomalies. Am J Med Genet 1983;23:903e18. 19. Leong S, Ashwel KWS. Is there a zone of vascular vulnerability in the fetal brainstem? Neurotoxicol Teratol 1997;19:265e75. 20. Sulik KK, Cook CS, Webster WS. Teratogens and craniofacial malformations: relationships to cell death. Development 1988; 103:213e32. 21. Poswillo DE. Orofacial malformations. Proc Roy Soc Med 1974; 67:343e9. 22. Barrow JR, Stadler HS, Capecchi MR. Roles of Hoxa1 and Hoxa2 in patterning the early hindbrain of the mouse. Development 2000;127:933e44. 23. Yamamoto M, Schwarting G. The formation of axonal pathways in developing cranial nerves. Neurosci Res 1991;11:229e60. 24. Kremer H, Kuyt LP, Van den Helm B, et al. Localization of a gene for Moebius syndrome to chromosome 3q by linkage analysis in a Dutch family. Hum Molec Genet 1996;5:1367e71. 25. Verzijl H, Van der Zwaag B, Lammens M, et al. The neuropathology of hereditary congenital facial palsy vs mobius syndrome. Neurology 2005;64:649e6539. 26. Bergstrom L, Baker B. Syndromes associated with congenital facial paralysis. Otolaryngol Head Neck Surg 1981;89:336e42. 27. Rollnick BR, Kaye CI, Nagatoshi K. Oculoauriculovertebral dysplasia and variants: phenotypic characteristics of 294 patients. Am J Med Genet 1987;26:361e75. 28. Vento RA, LABrie RA, Mulliken JB. The O.M.E.N.S. classification of Hemifacial Microsomia. Cleft Palate-Craniofacial J 1991;28: 68e77. 29. Horgan JE, Padwa BL, LABrie RA, et al. OMENS-Plus: analysis of craniofacial and extracraniofacial anomalies in Hemifacial Microsomia. Cleft Palate-Craniofacial J 1995;32:405e12. 30. Gorlin RJ, Jue KL, Jacobsen V, Goldschmidt E. Oculoauriculovertebral dysplasia. J Pediat 1963;63:991e9. 31. Rollnick BR, Kaye CI. Hemifacial microsomia and variants: pedigree data. Am J Med Gen 1983;15:233e53.

J.K. Terzis, K. Anesti 32. Rosa RFM, Graziadio C, Lenhardt R, et al. Central nervous system abnormalities in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome). Postgrad Med J 1977;53: 517e22. 33. Murray JE, Kaban LB, Mulliken JB. Analysis and treatment of hemifacial microsomia. Plast Reconstr Surg 1984;74:186e99. 34. Carvalho GJ, Song CS, Vargervik K. Auditory and facial nerve dysfunction in patients with hemifacial microsomia. Arch Otolaryngol Head Neck Surg 1999;125:209e12. 35. Rahbar R, Robson CD, Mulliken JB, et al. Craniofacial, temporal bone, and audiologic abnormalities in the spectrum of hemifacial microsomia. Arch Otolaryngol Head Neck Surg 2001;127: 265e71. 36. Vento AR, LaBrie RA, Mulliken JB. The O.M.E.N.S. classification of hemifacial microsomia. Cleft Pal Craniofac J 1991;28:68e77. 37. Horgan JE, Padwa BL, LaBrie R, et al. OMENS-Plus: analysis of craniofacial and extracraniofacial anomalies in hemifacial microsomia. Cleft Pal Craniof J 1995;32:405e12. 38. Johnston MC. Embryology of the head and neck. In: Mc Carthy JG, editor. Plastic surgery, vol. 4. Philadelphia: WB Saunders; 1990. p. 2451e95. 39. Kallen K, Robert E, Castilla E, et al. Relation between oculoauriculo-vertebral (OAV) dysplasia and three other nonrandom associations of malformations (VATER, CHARGE, and OEIS). Am J Med Genet 2004;127A:26e34. 40. Werler MM, Starr JR, Cloonan YK, et al. Hemifacial microsomia: from gestation to childhood. J Craniofac Surg 2009;20:664e9. 41. Reece EA, Homko CJ, Wu YK. Multifactorial basis of the syndrome of diabetic embryopathy. Teratology 1996;54: 171e82. 42. Ornoy A. Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy. Reprod Toxicol 2007;24:31e41. 43. Wang R, Martı´nez-Frı´as ML, Graham JM. Infants of diabetic mothers are at increased risk for the oculo-auriculo-vertebral sequence: a case-based and case-control approach. J Pediatr 2002;141:611e7. 44. Yovich J, Mulcahy M, Matson P. IVF and Goldenhar Syndrome. J Med Genet 1987;24:644. 45. Jongbloet PH. Goldenhar syndrome and overlapping dysplasias, in vitro fertilisation and ovopathy. J Med Genet 1987;24: 616e20. 46. Wieczorek D, Ludwig M, Boehringer S, et al. Reproduction abnormalities and twin pregnancies in parents of sporadic patients with oculo-auriculo-vertebral spectrum/Goldenhar syndrome. Hum Genet 2007;121:369e76. 47. Pape KE, Pickering D. Asymmetric crying faces: an index of other congenital anomalies. J Pediatrics 1972;81:21. 48. Cayler GG. Cardiofacial syndrome congenital heart disease and facial weakness, a hitherto unrecognized association. Arch Dis Childh 1969;44:69e75. 49. Jacobsson C, Granstrom G. Clinical appearance of spontaneous and induced first and second brachial arch syndromes. Scand J Plast Reconstr Hand Surg 1997;31:125e36. 50. Sapin SO, Miller A, Bass HN. Neonatal asymmetric crying faces: a new look at an old problem. Clin Pediatr 2005;44:109e19. 51. Hall BD. Choanal atresia and associated multiple anomalies. J Pediatr 1979;95:395. 52. Hittner HM. Colobomatous micropthalmia, heart disease, hearing loss, and mental retardation- a syndrome. J Pediatr Opthalmol Strabismus 1979;16:122. 53. Pagon RA, Graham JM, Zonana J, et al. Coloboma, congenital heart disease and choanal atresia with multiple anomalies: CHARGE association. J Pediatr 1981;99:223e7. 54. Byerly K, Pauli RM. Cranial nerve abnormalities in CHARGE association. Am J Med Genet 1993;45:751. 55. Edwards BM, Van Riper LA, Kileny PR. Clinical manifestations of CHARGE association. Inter J Ped Otorhinolar 1995;33:23e42.

Developmental facial paralysis 56. Vissers LE, Van Ravenswaaij CM, Admiraal R, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004;36:955. 57. Gutowski NJ, Bosleyb TM, Englec EC. 110th ENMC International Workshop: the congenital cranial dysinnervation disorders (CCDDs). Naarden, The Netherlands, 25e27 October, 2002. Neuromuscular Disord 2003;13:573e8. 58. Van der Zwaag B, Burbach JP, Scharfe C, et al. Identifying new candidate genes for hereditary facial paresis on chromosome 3q21-q22 by RNA in situ hybridization in mouse. Genomics 2005;86:55e67. 59. Michielse CB, Bhat M, Brady A, et al. Refinement of the locus for hereditary congenital facial palsy on chromosome 3q21 in two unrelated families and screening of positional candidate genes. Europ J Hum Genet 2006;14:1306e12. 60. May M. Facial paralysis in children: differential diagnosis. Otolaryngol Head Neck Surg 1981;89:841e8. 61. Mahadevappa K, Vora A, Graham A, et al. Facial paralysis: a critical review of accepted explanation. Med Hypotheses 2010;74:508e9. 62. Miehlke A. Normal and anomalous anatomy of the facial nerve. Trans Am Acad Opthal Otolar 1964;68:1030e44. 63. May M. Anatomy of the facial nerve (spatial orientation of fibers in the temporal bone. Laryngoscope 1973;82:1311e29. 64. Manni JJ, Stennert E. Diagnostic methods in facial nerve pathology. Adv Oto-Rhino-Laryngol 1984;34:202e13. 65. Fisch U. Kugler/ Aesculopius. In: Facial nerve surgery. Zyrich; 1977. p. 93e100. 66. Shapiro NL, Cunningham MJ, Parikh SR, et al. Congenital unilateral facial paralysis. Pediatrics; 1996:261e4. 67. May M. Facial paralysis at birth: medicolegal and clinical implications. Am J Otol 1995;16:711e2. 68. Bender LF, Maynard FM, Hastings SV. The blink reflex as a diagnostic procedure. Arch Phys Med Rehabil 1969;50: 27e31. 69. Campbell EDR, Hickey RP, Nixon KH, et al. Value of nerve excitability measurements in prognosis of facial palsy. Br Med J 1962;2:7e10. 70. Renault F. Facial electromyography in newborn and young infants with congenital facial weakness. Develop Med Child Neurol 2001;43:421e7. 71. Terzis JK, Olivares FS. Secondary surgery in paediatric facial paralysis reanimation. J Plast Reconstr Aesthet Surg 2009;63: 1794e806. 72. Converse JM, Coccaro PJ, Becker M, et al. On hemifacial microsomia: the first and second brachial arch syndrome. Plast Reconstr Surg 1973;51:268e79. 73. Sando I, Ikeda M. Temporal bone histopathologic findings in oculoauriculovertebral dysplasia: Goldenhar’s syndrome. Ann Otol Rhinol Laryngol 1986;95:396e403.

1333 74. Sekhar HKC, Tokita N, Alexic S, et al. Temporal bone findings in hemifacial microsomia. Ann Otol 1978;87:399e404. 75. Bance M, Erb J. A reliable radiologic landmark for the facial nerve in axial temporal bone computed tomography scans. Otolaryngol Head Neck Surg 2003;128:251e6. 76. Rauch R, Taber KH, Manoilidis S, et al. A functioning imaging guide to the bony landmarks of the seventh nerve. J Comput Ass Tom 2002;26:657e9. 77. Saito H, Takeda T, Kishimoto S. Neonatal facial nerve defect. Acta Otolaryngol (Stockh) - Suppl 1994;510:77e81. 78. Kodama A, Sando I, Myers E, et al. Severe middle ear anomaly with underdeveloped facial nerve. Arch Otolaryngol 1982;108: 93e8. 79. Jervis PN, Bull PD. Congenital facial nerve agenesis. J Laryng Otol 2001;115:53e4. 80. Terzis JK. Pectoralis minor. A unique muscle for correction of facial palsy. Plast Reconstr Surg 1989;83:767e76. 81. Terzis JK, Bruno W. Outcomes with eye reanimation microsurgery. Facial Plast Surg 2002;18:101e12. 82. Terzis JK, Kalantarian B. Microsurgical strategies in 74 patients for restoration of dynamic depressor muscle mechanism: a neglected target in facial reanimation. Plast Reconstr Surg 2000;105:1917e31. 83. Terzis JK, Noah EM. Analysis of 100 cases of free-muscle transplantation for facial paralysis. Plast Reconstr Surg 1997; 99:1905e21. 84. Terzis JK, Olivares FS. Secondary surgery in adult facial paralysis reanimation. Plast Reconstr Surg 2009;124:1916e31. 85. Terzis JK, Karypidis D. Outcomes of direct muscle neurotization in adult facial paralysis. J Plast Reconstruct Aesthet Surg 2011;64:174e84. 86. Terzis JK, Karypidis D. Outcomes of direct muscle neurotization in pediatric patients with facial paralysis. Plast Reconstr Surg 2009;124:1486e98. 87. Terzis JK, Tzafetta K. The "babysitter" procedure: minihypoglossal to facial nerve transfer and cross-facial nerve grafting. Plast Reconstr Surg 2009;123:865e76. 88. Barrow JR. Wnt/PCP signaling: a veritable polar star in establishing patterns of polarity in embryonic tissues. Semin Cell Dev Biol 2006;17:185e93. 89. Beahrs T, Tanzer L, Sanders VM, et al. Functional recovery and facial motoneuron survival are influenced by immunodeficiency in crush-axotomized mice. Exp Neurol 2010;221: 225e30. 90. Huppenbauer C, Tanzer L, Don Carlos L, et al. Gonadal steroid attenuation of developing hamster facial motoneuron loss by axomotomy: equal efficacy of testosterone, dihydrotestosterone, and 17-b estradiol. J Neurosci 2005;25:4004e13. 91. Walsh L. Congenital malformations of the human brainstem. Semin Pediatr Neurol 2003;10:241e51.