Moebius syndrome: clinical features, diagnosis, management and early intervention

Moebius syndrome (MBS) is a rare disease characterized by unilateral or bilateral nonprogressive congenital facial palsy (VII cranial nerve) with impairments of ocular abduction (VI cranial nerve); it can also be associated with other cranial nerve (CN) palsies, orofacial anomalies and limb defects [1]. This condition was originally described by Von Graefe in 1880 and by Moebius in 1888. Since then, more than 300 cases have been described and reported in the literature by a number of authors [2‐8].

The prevalence of MBS is estimated to be 1/250.000 live births with equal incidence in both sexes. Most cases are sporadic, but familial cases, representing about 2 % of all affected individuals, have been documented.

The diagnosis of MBS is based exclusively on clinical criteria, although recent studies are beginning to document causative genetic patterns [9]. The lack of diagnostic criteria complicates the clinical assessment, definition of prognosis, and genetic analysis of patients with MBS. To address this concern, a group of clinicians and researchers met in 2007 at the biannual research meeting of Moebius Syndrome Foundation in Bethesda (MD USA) and defined the MBS as “congenital, uni- or bilateral, nonprogressive facial weakness and limited abduction of the eye(s)” [3].

The cause and pathogenesis of MBS remain unclear and controversial since the initial descriptions by von Graefe and Moebius, and there has been a decade long debate whether MBS has a genetic aetiology or not. Fetal toxic exposure, genetically determined vascular rhombencephalic disturbances in development, or an acquired ischemic event occurring after the fifth week of pregnancy have been proposed as determinants.

It has been supposed that a primary insult leads to a sequence of events involving one or more focal areas of damage perhaps in the brainstem where the neurons of the facial, abducens, and lacrimal (salivary) nuclei, are anatomically coincident during this phase of the embryogenesis.

On the other hand, de novo PLXND1 and REV3L mutations have recently been identified in a a number of of MBS patients. However, PLXND1 and REV3L represent totally unrelated pathways involved, respectively, neural migration during hindbrain development, and DNA translesion synthesis, essential for the replication of endogenously damaged DNA [9].

MBS can be recognized and diagnosed early during the neonatal period. 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 have all been observed. Hypotonia and developmental delay can also be present.

Paralysis of the VII CN, is responsible for the absence of mimicry, the lack of smile and the suction deficit. Three specific patterns of ocular motility alterations have been identified [10]: pattern A consists of orthotropia in the primary position with a complete defect in both abduction and adduction ocular movements, found in 41 % of cases; pattern B, with large-angle esotropia (convergent strabismus), crossed fixation, documented in 50 % of cases; and pattern C, characterized by a large-angle exotropia (divergent strabismus) with torticollis, absence of convergence, and vertical eye misalignment with involvement of the III and IV CNs, seen in a minority of patients (9 %).

In a few patients other CNs can be compromised including paralysis of the XII CN giving rise to lingual palsy and hypoplasia; damage of the V CN affecting endo- and perioral sensitivity while damage to the IX CN impairs palatine and pharyngeal motility.

Impairment of the cochlear branch of the VIII CN can contribute to language delay [10‐13].

Among MBS’s patients club foot, hand anomalies (syndactyly, brachydactyly, ectrodactyly) and agenesis of the pectoral muscle and dysmorphisms are occasionally observed. Association with other syndromes like Poland syndrome, Pierre Robin sequence, Carey-Fineman-Ziter, Klippel-Feil anomaly has also been reported [4].

In 1998 Abramson first proposed the acronym CLUFT: C, cranial nerve, L, lower limb; U, upper limb, F, face, T, thorax to define grading of disease, to describe the heterogeneity of the clinical features and establish a level of impairment (Table 1) [4].

MBS consists of complete or partial facial diplegia, often accompanied by other CN deficiencies.

Most of the previous reviews of MBS tend to focus on the neuroradiological and systemic features of the syndrome, but comprehensive developmental evaluations were not specifically investigated [1‐13].

We interpreted the neurofunctional data of the psychometric assessments, taking into account the children’s dysfunctional nutrition (arising from difficulties in feeding), communication and visual-motor function.

The suffering of the children caused by difficulties in management of feeding tubes and the consequent frustration of many of the mothers because they were unable to directly feed their children reduced the pleasure of the food interaction, which plays a large role in building a secure attachment and sense of competency of the mother-child dyad. The lack of facial communicative expressions and the difficulties in speech sounds that negatively affect the reward of the parent-child feedback interaction also can lead to failure of the normal mother-child attachment.

Furthermore, oculomotor dysfunction has serious negative consequences in motor, perceptual and cognitive development. The visual system, provides the function of the "what", the recognition of objects and shapes, but the ocular movements provide the functions of the "where", that is, the location of objects, providing data on spatial orientation, the perception of movement and the third dimension (across saccades, optokinetic nystagmus, smooth pursuit, scanning and visual exploration).

Our experience has suggested that MBS children exhibit not only the above main morpho-functional deficits involving movement, food, vision and language, but also secondary developmental problems.

Primary motor problems consisted of hypotonia, musculo-skeletal dysmorphism, delay in righting, locomotion and clumsiness. Feeding disorders consisted of sucking-swallowing difficulty, breathing problems, lack of the sensitivity of the orofacial area, dysphagia with the need, in severe cases, for a gastrostomy. Language difficulties such as dyslalia, mechanical disorders of phonological coding and speech structure and writing were common. Visual impairment consisted of scanning, exploration and visual-perceptual deficits, and, in some cases, corneal ulcers.

Secondary problems included visual exploration deficits, oral-motor difficulties as well as lack of the categorization of facial expressions affecting cognitive strategies in early development. Pain and other difficulties during eating, maternal concerns, and lack of recognition of emotions, can form the basis of significant emotional distress. From the perspective of social maturity, self-image and communication with peers can be affected adversely both in childhood and in adolescence.

Equally important is the peculiar functional profile of MBS children. In general, they usually present with delay at 1 year of age, with motor emotional and language difficulties persisting until 2 years of age and reduced hand-eye coordination at 3 years of age. Children generally achieve average levels of GQ at five years of age although with retained aspects of clumsiness. Overall 90 % of children reached a normal GQ with only 10 % maintaining cognitive deficits.

The gradual recovery in fragile areas and the progressive harmonization of functions might be explained by early rehabilitation and by support by and of parents. Improving the methods of early intervention, enhancing motor ability and sensory information, and the timely support of parents having emotional difficulties, can improve the prognosis of the child with MBS.

For all of these reasons, the International Classification of functioning Children and Youth (ICF-CY), published by the WHO can be considered the gold standard for describing functioning, disability and health. It appears to be a suitable framework for interpreting functions (vs impairment), activities (vs disability) and participation (vs handicap), in children with MBS and for evaluation and intervention of the familial and social environment [26]. In particular, the ICF-CY framework allows the health care practitioners to investigate and integrate the complexity of signs and functions in children with MBS such as motor skills (musculoskeletal features, posture, posture changes, gait and coordination), feeding (sucking patterns, quality of food, eating habits, sucking-swallowing coordination), communication and language (phonological, articulatory, oral motor skills and functional aspects), and cognitive features. The frequency and uniqueness of medical problems found in patients with MBS suggest the need for such a protocol to carefully define guidelines for the current and continuing care of these patients (Fig. 1).

The main finding of this study is the observation that the patients with MBS exhibit development characterized by global delay at 1 year of age, motor, emotional and speech difficulties at 2 years of age, a trend toward normalization at 3 years of age but with weakness in hand-eye coordination, and finally achieving average results at 5 years of age.

It is important that diagnosis and rehabilitation start simultaneously and that the rehabilitative intervention is updated over time in response to functional assessments. It is also essential that any intervention address both the child and the mother-child relationship. The approach must also be multidisciplinary, involving professionals with different skills and with specific training in cooperative therapies.

Lastly, the analyzed population requires larger numbers and needs a more prolonged follow-up to assess the developmental outcomes and the complexity of these children.