Moebius syndrome (ORPHA:570)
A very rare congenital cranial dysinnervation disorder characterized by unilateral or bilateral non progressive congenital facial palsy (VII cranial nerve) with impairments of ocular abduction (VI cranial nerve). It can also be associated with other cranial nerves palsies, orofacial anomalies and limb defects.
Epidemiology
Epidemiological data on Moebius syndrome (MBS) is limited. The prevalence at birth is estimated at 1/47,250 in the Netherlands. MBS occurs equally in both sexes.
Clinical description
MBS is a non-progressive disease, present at birth, characterized by high clinical heterogeneity, with frequent asymmetrical presentations. The main feature of the disorder is the paralysis of the VII cranial nerve, responsible for the facial diplegia, often asymmetric and incomplete, sparing the lower face and platysma, resulting in a mask-like facial appearance. The ocular manifestations include alterations of ocular motility with uni- or bilateral abduction defects (esotropia is the most common), ectropion, epiphora and exposure keratopathy, ophthalmoplegia and ptosis. Feeding difficulties and drooling at birth and in infancy are common. Other associated manifestations, due to other cranial nerves deficiencies include: deafness, trigeminal nerve sensitivity disorders, dysphagia, dysphonia and tongue hypoplasia. MBS may be accompanied by hypotonia and global developmental delay with infants demonstrating motor, emotional and speech difficulties. Development tends to normalize at 3 years of age but weakness in hand-eye coordination persists. Minor facial anomalies may include small palpebral fissures, epicanthic folds, hypertelorism, bifid uvula, micrognathia, and microstomia. Clubfoot is described in about 45% of cases. Hand anomalies (syndactyly, brachydactyly, ectrodactyly) and agenesis of the pectoral muscle (Poland-Moebius syndrome) are associated occasionally.
Etiology
The etiology of MBS is currently unknown. It is thought to involve abnormal development of the brainstem, intrauterine hypoxia, teratogen exposure (e.g. misoprostol or cocaine), genetically determined vascular rhombencephalic disturbances in development or an acquired ischemic event occurring after the fifth week of pregnancy. De novo mutations in the PLXND1 (3q21.3) and REV3L (6q22) genes involved in hindbrain development have been found in about 6% of cases.
Diagnostic methods
The diagnosis of MBS is based exclusively on clinical criteria, although recent studies are beginning to document causative genetic patterns. MBS can be recognized and diagnosed early during the neonatal period with electromyographic examination and brain MRI. Key clinical findings include poor or absent sucking due to incomplete closure of the lips, lack of facial mimicking (especially while crying), fixed gaze, incomplete eyelid closure during sleep and ptosis.
Differential diagnosis
Differential diagnoses include Carey-Fineman-Ziter syndrome, Oro-Mandibular-Limb hypogenesis syndrome (OMLH), Moebius-like syndrome, hypoglossia-hypodactyly syndrome and glossopalatine ankylosis.
Antenatal diagnosis
Prenatal genetic diagnosis is possible if pathogenic mutations responsible for the disease have been identified in the family (very rare cases). Clubfeet may be detected by prenatal ultrasound but is non-specific.
Genetic counseling
Most of cases of MBS follows a sporadic pattern of occurrence. Familial cases represent about 2% of all affected individuals. Recurrence in siblings of affected individuals is therefore extremely rare.
Management and treatment
Treatment and management are supportive and symptomatic. A multidisciplinary clinical approach is important in order to optimize the diagnosis, treatment and advice given to these patients. The microneurovascular transfer of a free-muscle transplant is the procedure of choice for facial paralysis and midfacial animation. Ocular manifestations are treated with standard methods. Rehabilitation therapy (physiotherapy, oral motor, psychomotor/speech therapy) must start soon as possible and adapted over time in response to functional assessments. Psychological aspects relate to the patient's facial appearance. Communication between affected infants and their parents should be taken into consideration.
Prognosis
Prognosis is strongly correlated with the degree of brainstem involvement. It is non-progressive. Most of cases with MBS have normal life expectancy; although in severe cases, early demise shortly after birth is possible.

                            Last update: 
                            February 2021


                            - Expert reviewer(s): 
                            Dr Maria Francesca BEDESCHI | ITHACA* - Dr Odoardo PICCIOLINI 


                                * European Reference Network