Article Text
Abstract
Moebius syndrome (MBS) is a congenital, non-progressive facial and abducens nerve palsy in the presence of full vertical gaze and may be associated with limb abnormalities and craniofacial dysmorphisms. MBS is now defined as a disorder of rhombencephalic maldevelopment and recent gene discoveries have shown this to be a dominant disorder in a subset of patients. Accurate diagnosis and management by a multidisciplinary team with expertise in congenital facial palsy is paramount.
- Moebius syndrome
- Möbius sequence
- management
- minimum diagnostic criteria
- rhombencephalic maldevelopment
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Introduction
Much has changed since the first description of Moebius syndrome (MBS) as a congenital facial palsy in 1880.1 A clinical diagnosis is made on the classical findings of congenital cranial nerve VI (abducens) and VII (facial) palsies, often with other congenital abnormalities. Historically thought of as a sporadic disorder, recent gene discoveries have detected heterozygous changes in dominant genes, suggesting a strong genetic component in certain patients.
Parents of children with MBS often feel frustrated at the lack of awareness of Moebius as a specific clinical entity and achieving a diagnosis can sometimes takes months or years. This article addresses just some of the recent advances and gives practical advice for paediatricians in managing the child with suspected Moebius.
Diagnosis
Minimum diagnostic criteria (MDC) for MBS were defined as congenital abducens and facial nerve palsies,2 but this has been further refined by MacKinnon et al3 with the addition of full vertical gaze. This additional criterion serves to exclude disorders with similar features, such as congenital fibrosis of the extraocular muscles (CFEOM). The current MDC for MBS are shown in box 1.
Current minimum diagnostic criteria for Moebius syndrome
Congenital, non-progressive bilateral or unilateral, symmetrical or asymmetrical facial and abducens nerve palsies, in the presence of full vertical gaze.
Commonly associated clinical features
The description of ‘mask-like’ facies of children with MBS comes from the facial nerve palsy, which is often bilateral, mixed and asymmetric (figure 1). The aetiology of the typically asymmetrical clinical presentation is currently poorly understood. Careful examination for any facial dysmorphic features which may suggest another diagnosis is important.
Poor motor coordination and delayed motor milestone attainment can also be seen in children with MBS3 and in some children, cognitive and behavioural delay are also seen. Children with MBS and respiratory problems resulting in feeding difficulties, sleep-disordered breathing or in the requirement for respiratory support are known to the authors. Respiratory issues are thought to be primary in nature and evidence of the brainstem dysfunction discussed later in this article.
Craniofacial dysmorphisms—outwith the features related to the facial palsy—are commonly seen and both upper and lower limb abnormalities of all types are common. Poland anomaly (pectoral hypoplasia) is a frequently reported association.4 The commonly associated clinical features are shown in table 1.
Genetic aetiology
MBS was historically attributed to in utero events such as antepartum haemorrhage or abortion-inducing medications, notably misoprostolol.5 Most patients have no family history, so an environmental cause and a low recurrence risk seemed appropriate. When underlying genetic mutations were considered, de novo autosomal dominant inheritance was proposed6 and reports suggesting familial dominant, recessive and X-linked inheritance were subsequently published.7
Recently, newly discovered genes such as PLXND1 and REV3L have been implicated as causes of dominant MBS.8 These genes are involved in separate pathways controlling neural migration and DNA repair and disrupt the facial nerve nucleus in mouse models.
Developmental hypothesis
The vascular hypothesis for MBS suggested ischaemic events in the lower brainstem secondary to subclavian artery hypoperfusion.9 ,10 However, this does not explain why facial and abducens nerve dysfunctions are the consistent findings in patients with MBS or involvement of structures not supplied by the subclavian artery.
Recent classifications define MBS as a congenital cranial dysinnervation disorder; a congenital, non-progressive neuromuscular disorder.11 This definition, however, includes many related disorders such as congenital ptosis and is not specific to MBS.
Verzijl et al2 proposed evidence for MBS as a disorder of rhombencephalic maldevelopment, that is, a primary disorder of the caudal brainstem and long tracts. They suggest that poor motor coordination in MBS is a result of hypoplasticity of corticospinal or cortico-bulbo-cerebellar long tracts and primary respiratory dysfunction is a reflection of previously reported MRI findings of lower brainstem hypoplasia.2 ,12 Neurophysiological studies have provided further evidence of MBS as a rhombencephalic disorder in a subset of patients with MBS.13
Differential diagnoses
MBS associated with progressive polyneuropathy and hypogonadotropic hypogonadism has been described14 ,15 and segregates in patients with TUBB3 mutations.16 Some patients referred with possible MBS are eventually diagnosed with CFEOM or hereditary congenital facial palsy (HCFP). Other disorders with limb abnormalities such as the hypoglossia-hypodactyly spectrum may cause diagnostic confusion.17
Diagnosis and management of the child with MBS
Clinical genetics
Clinical examination by an experienced geneticist is important to rule out alternative diagnoses. If another diagnosis is strongly suggested by clinical features or family history, specific molecular genetic testing may be appropriate. Although more genes are being identified, access to genetic testing is not always possible. Some families may be offered research study involvement for whole exome sequencing or whole genome sequencing in order to elucidate the underlying genetic pathology.
Another role of the clinical geneticist is to provide accurate recurrence risks for the family. Previous work has suggested that where a limb abnormality is present, recurrence risk is low, often quoted empirically as 2%–3%.18 With the increase in genetic knowledge, where a child has isolated facial and abducens palsies recurrence risk may be higher for parents and up to 50% for the patient's own children, due to the dominant nature of mutations.8
Respiratory
Airway management can be challenging in a neonate with MBS and increased respiratory effort, apnoea during feeds, nasal regurgitation and snoring are indications for initial management by positioning or use of nasopharyngeal airways. Rarely, anaesthetic involvement and higher dependency care or ventilation may be indicated and MBS may be associated with difficult intubation.
Neurology and development
Developmental delay can be variable in MBS, with Baraitser reporting significant delay in 50% of diagnosed cases.18 In the authors’ experience, significant or global developmental delay is not common in MBS, although some patients have motor delay and are often described as having poor motor coordination and most have speech and language delay. Both facial expression and facial identity processing deficits may be specific difficulties in MBS.19
Plastic surgery
Facial palsies are challenging to correct due to the paucity of reconstructive options given the lack of both facial nerve and facial musculature, necessitating microvascular transfer of muscle and careful choice of innervation for facial reanimation.20
Eyes
Children with MBS have abnormal ocular motility: esotropia, exotropia, Duane's retraction syndrome and conjugated gaze palsies. The primary objective is to achieve corneal protection and early referral to ophthalmology is essential for diagnosis and consideration of gaze correction.2 Early botulinum toxin injections to the medial rectus muscle can achieve conjugate gaze by preventing contractures and aid later strabismus surgery. Incomplete lid closure occurs due to a relative imbalance between the eye closing orbicularis oculi (VII) and eye opening elevator palpebral superioris (III). Exposure of the cornea can lead to ulceration and visual loss.2
Speech, language and feeding
Delay in speech and language is common hence early audiology and speech therapy assessments are recommended. Speech can also be impacted due to diplegia with bilabial plosives such as /b/ and /p/ being particularly affected.21 Difficulties sucking and feeding in early life should trigger support for normal prespeech development to optimise the conditions for the most effective speech later on.2 Feeding difficulties are common: reduced lip seal leads to difficulties retaining food in the mouth; the small tongue creates difficulty in moving a food bolus to the back of the oropharynx and lower facial nerve palsies (IX, X, XI) affect the pharyngeal plexus and innervation of the pharyngeal musculature leading to incoordination. This predisposes to swallowing difficulties which can manifest as coughing, choking and aspiration.
Examination of the palate and tongue should be performed to identify any features which may affect feeding.
Early dietician input is essential and weight gain should be monitored closely. Swallow assessment should be performed by clinicians with appropriate expertise, such as highly specialised speech and language therapists or dieticians. Masticatory difficulties may present later due to a combination of weak bite, tongue abnormalities and oromandibular hypoplasia. Most children with MBS overcome these problems and develop compensatory mechanisms.2
Behaviour and sleep
Formal diagnoses of autism and autistic-like behaviours in MBS may not be as reported in the past.22 ,23 This may be due to the refinement of diagnostic tools in recent years and also due to the recognised difficulties of making a diagnosis of autism in the context of social and communication skills that do not fall within the normal range. All children with MBS should have community paediatric follow-up and some may need involvement from Child and Adolescent Mental Health Teams if behaviour becomes a significant issue.
Sleep is often a huge problem for children with MBS—and the siblings and parents that share the house. Frequent night-time arousal is common and once awake, children often do not go back to sleep. Night terrors, sleep-walking and sleep-talking are all common and these autonomic and motor parasomnias may be related to rhombencephalic maldevelopment.2 ,12 ,13 ,24
Patient and family perspective
The five strong, recurrent themes when young people were asked about their feelings of living with MBS were: social engagement; resilience and sensitivity; social stigma; being misunderstood and lack of public awareness of MBS.25 One of the main concerns both parents and young people raise with the authors is the lack of awareness from clinicians of MBS and the delay in diagnosis this often causes.
Conclusion
It is not reasonable to expect every clinician to have seen a patient with MBS, given a reported incidence of 0.002%.2 However, if clinicians suspect a child has a unilateral or bilateral facial palsy, early referral to an expert multidisciplinary facial palsy clinic should be considered.
Precise clinical examination and diagnosis is paramount in any child referred with possible MBS. Expert ophthalmology input is vital as the ability to fully abduct the eyes excludes MBS and limited vertical gaze suggests an alternative diagnosis. Many children referred to the authors and previously reported are eventually diagnosed with another disorder, such as HCFP or CFEOM, as the patients do not meet MDC for MBS.3 Despite previous reports, autism, learning difficulties and high levels of psychological maladjustment are not common in patients with MBS, but more longitudinal studies are needed to further evaluate this.
Coordination of care is one of the biggest issued raised by families to the authors, especially the number of separate appointments that parents need to attend. One family known to the authors attended so many separate appointments with their child, that a parent lost their job as a result. Multidisciplinary care allows clinicians to communicate quickly and effectively. Multidisciplinary care also provides clinicians with a better understanding of each other's approach to treatment, fostering collaboration, innovation, and therefore, excellent patient care by centralising expertise within a region. Referral of children with suspected MBS to expert multidisciplinary facial nerve palsy or craniofacial teams for diagnosis and ongoing management is required, due to the complex needs of these children and their families.
Acknowledgments
We would like to thank all the referring clinicians and specialist who work with us to look after children with Moebius syndrome. Most of all, we would like to thank our patients and families and the Moebius Research Trust, without whom this work would not have been possible. We would also like to thank our patient who gave consent for publication of his clinical photographs in this manuscript.
References
Footnotes
Twitter Follow Victoria McKay at @VickiMcKay83
Contributors VHM, LLT and AYF designed that concept for this article. VHM and LLT drafted the manuscript and all authors edited and produced the final manuscript. AYF organised the figure and patient consent.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.