Physiopathologic Bases of Moebius Syndrome: Combining Genetic, Vascular, and Teratogenic Theories.

Moebius syndrome (MBS) is a congenital cranial dysinnervation disorder (CCDD) characterized by a bilateral palsy of abducens and facial cranial nerves, which may coexist with other cranial nerves palsies, mostly those found in the dorsal pons and medulla oblongata. MBS is considered a "rare" disease, occurring in only 1:50,000 to 1:500,000 live births, with no gender predominance. Three independent theories have been described to define its etiology: the vascular theory, which talks about a transient blood flow disruption; the genetic theory, which takes place due to mutations related to the facial motor nucleus neurodevelopment; and last, the teratogenic theory, associated with the consumption of agents such as misoprostol during the first trimester of pregnancy. Since the literature has suggested the existence of these theories independently, this review proposes establishing a theory by matching the MBS molecular bases. This review aims to associate the three etiopathogenic theories at a molecular level, thus submitting a combined postulation. MBS is most likely an underdiagnosed disease due to its low prevalence and challenging diagnosis. Researching other elements that may play a key role in the pathogenesis is essential. It is common to assume the difficulty that patients with MBS have in leading an everyday social life. Research by means of PubMed and Google Scholar databases was carried out, same in which 94 articles were collected by using keywords with the likes of "Moebius syndrome," "PLXND1 mutations," "REV3L mutations," "vascular disruption AND teratogens," and "congenital facial nerve palsy." No exclusion criteria were applied.

Echoencephalography of Möbius sequence: A congenital cranial dysinnervation disorder with brainstem calcifications.

BACKGROUND AND PURPOSE: Möbius sequence (MBS) previously known as Möbius syndrome is a rare nonprogressive developmental defect of the rhombencephalon leading to congenital abducens (VIth) and facial (VIIth) nerve palsy. Echoencephalography is the first, safe, noninvasive, and cost-effective imaging modality available at bedside. No study on the use of echoencephalography in neonates for the diagnosis of MBS has been previously reported. METHODS: In this single tertiary center study, more than 18,000 neonates underwent echoencephalographic imaging over the span of two decades. Imaging was performed through the anterior, posterior, and lambdoid fontanelles. All neonates found to have calcifications of brainstem tegmental nuclei underwent additional imaging studies. Each neonate with MBS was carefully examined by the same investigator. RESULTS: Five neonates were shown to have punctate, bilateral, symmetrical tegmental pontine calcifications through all three acoustic windows. These calcifications extended caudally in most patients, and rostrally in 2 patients. Brainstem hypoplasia was best seen through the posterior fontanelle. Three out of five infants were noted to have brainstem hypoplasia with straightening of the floor of the fourth ventricle. In two children, facial collicular bulges and hypoglossal eminences were present. All five infants fulfilled clinical diagnostic criteria of MBS. In addition, a wide array of cerebral defects is identified. Echoencephalographic findings were confirmed by other imaging modalities. CONCLUSION: Knowledge of echoencephalographic features of MBS should improve its early recognition. A detailed description of the various imaging phenotypes of MBS is necessary to characterize the etiology of this heterogeneous congenital cranial dysinnervation disorder.

Poland-Möbius syndrome: a case report implicating a novel mutation of the PLXND1 gene and literature review.

BACKGROUND: Möbius (Moebius) and Poland's syndromes are two rare congenital syndromes characterized by non-progressive bilateral (and often asymmetric) dysfunction of the 6th and 7th cranial nerves and hypoplasia of the pectoral muscles associated with chest wall and upper limb anomalies respectively. Manifest simultaneously as Poland-Möbius (Poland-Moebius) syndrome, debate continues as to whether this is a distinct nosological entity or represents phenotypic variation as part of a spectrum of disorders of rhomboencephalic development. Etiological hypotheses implicate both genetic and environmental factors. The PLXND1 gene codes for a protein expressed in the fetal central nervous system and vascular endothelium and is thus involved in embryonic neurogenesis and vasculogenesis. It is located at chromosome region 3q21-q22, a locus of interest for Möbius syndrome. CASE PRESENTATION: We present the first report of a patient with Poland-Möbius syndrome and a mutation in the PLXND1 gene. A child with Poland-Möbius syndrome and a maternally inherited missense variant (NM_015103.2:ex14:c.2890G > Ap.V964M) in the PLXND1 gene is described. In order to contextualize these findings, the literature was examined to identify other confirmed cases of Poland-Möbius syndrome for which genetic data were available. Fourteen additional cases of Poland-Möbius syndrome with genetic studies are described in the literature. None implicated the PLXND1 gene which has previously been implicated in isolated Möbius syndrome. CONCLUSIONS: This report provides further evidence in support of a role for PLXND1 mutations in Möbius syndrome and reasserts the nosological link between Möbius and Poland's syndromes. LEVEL OF EVIDENCE: Level V, Descriptive Study.

[Clinical characteristics and whole exome sequencing results of patients with Möbius syndrome].

Objective: To analyze the clinical characteristics of patients with Möbius syndrome (MBS) and to explore likely pathogenic genes. Methods: Cross-sectional study. The study enrolled 18 sporadic MBS patients who visited the Eye Center of Beijing Tongren Hospital Affiliated to Capital Medical University from July 2018 to December 2021. All patients completed the general information questionnaire and underwent detailed ophthalmic examinations and general physical examinations. Seventeen patients received MRI examination of cranial nerves and the orbit. The peripheral venous blood of all patients and their nuclear family members was collected, the genomic DNA was extracted, and the pathogenic gene variations that may lead to MBS were identified by whole exome sequencing and bioinformatics analysis. Results: Among the 18 patients, there were 8 males and 10 females, and the age was (4.5±4.0) years (range, 8 months to 17 years). All patients showed congenital, bilateral or unilateral abduction deficit and facial weakness, which met the minimum diagnostic criteria of MBS. Among them, bilateral abduction deficit (16/18) and bilateral facial weakness (15/18) were more common. Nine patients were orthotopic in primary position, eight presented with esotropia, and one showed hypotropia. All patients had ametropia, of which 4 patients were diagnosed as amblyopia. Fifteen patients were also accompanied by other multiple congenital malformations, mainly characterized by abnormal development of glossopharynx (14/18) and limbs (5/18), and 7 patients were also accompanied by motor retardation. In addition, 9 patients had intrauterine exposure to adverse factors. Among the 17 patients who underwent MRI, 15 patients had bilateral hypoplasia of the abducens nerve, two had unilateral hypoplasia of the abducens nerve, 14 showed bilateral hypoplasia of the facial nerve, and three showed hypoplasia of the left facial nerve. Besides, some patients were also accompanied by hypoplasia of other cranial nerves, mainly the glossopharyngeal nerve and the hypoglossal nerve. No definite pathogenic variations were found by whole exome sequencing and bioinformatics analysis. Conclusions: The main clinical features of MBS were congenital abduction deficit and facial weakness, with complicated manifestations and variable severity. MRI showed absence or thinning of the abducens nerve and the facial nerve. The results of MRI can be used as a supplement to the diagnostic criteria of MBS. The mutation detection rate of MBS was low, and half of patients had exposure to adverse factors during pregnancy, suggesting that there was a multifactorial pathogenic mechanism in MBS.

Developmental delay with hypotrophy associated with homozygous functionally relevant REV3L variant.

REV3L encodes a catalytic subunit of DNA polymerase zeta (Pol zeta) which is essential for the tolerance of DNA damage by inducing translesion synthesis (TLS). So far, the only Mendelian disease associated with REV3L was Moebius syndrome (3 patients with dominant REV3L mutations causing monoallelic loss-of-function were reported). We describe a homozygous ultra-rare REV3L variant (T2753R) identified with whole exome sequencing in a child without Moebius syndrome but with developmental delay, hypotrophy, and dysmorphic features who was born to healthy parents (heterozygous carriers of the variant). The variant affects the amino acid adjacent to functionally important KKRY motif. By introducing an equivalent mutation (S1192R) into the REV3 gene in yeasts, we showed that, whereas it retained residual function, it caused clear dysfunction of TLS in the nucleus and instability of mitochondrial genetic information. In particular, the mutation increased UV sensitivity measured by cell survival, decreased both the spontaneous (P < 0.005) and UV-induced (P < 0.0001) mutagenesis rates of nuclear DNA and increased the UV-induced mutagenesis rates of mitochondrial DNA (P < 0.0005). We propose that our proband is the first reported case of a REV3L associated disease different from Moebius syndrome both in terms of clinical manifestations and inheritance (autosomal recessive rather than dominant). KEY MESSAGES: First description of a human recessive disorder associated with a REV3L variant. A study in yeast showed that the variant affected the enzymatic function of the protein. In particular, it caused increased UV sensitivity and abnormal mutagenesis rates.

Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies.

INTRODUCTION: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW. METHODS: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography. RESULTS: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement. DISCUSSION: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.

Carey-Fineman-Ziter Syndrome: A MYMK-Related Myopathy Mimicking Brainstem Dysgenesis.

Carey-Fineman-Ziter syndrome is a congenital myopathy associated with mutations in the MYMK gene. It is clinically defined by the combination of hypotonia, Moebius-Robin sequence, facial anomalies and motor delay. Historically it was considered a brainstem dysgenesis syndrome. We provide detailed information of a Spanish boy with compound heterozygous variants in MYMK gene. A muscle biopsy performed as a toddler only disclosed minimal changes, but muscle MRI showed severe fatty infiltration of gluteus muscles and to a lesser extent in adductors magnus, sartorius and soleus muscles. Clinical course is fairly static, but the identification of new well characterized genetic cases will help to delineate the complete phenotype.

Divergent roles of Plexin D1 in cancer.

Plexin D1 belongs to a family of transmembrane proteins called plexins. It was characterized as a receptor for semaphorins and is known to be essential for axonal guidance and vascular patterning. Mutations in Plexin D1 have been implicated in pathologic conditions such as truncus arteriosus and Möbius syndrome. Emerging data show that expression of Plexin D1 is deregulated in several cancers; it can support tumor development by aiding in tumor metastasis and EMT; and conversely, it can act as a dependence receptor and stimulate cell death in the absence of its canonical ligand, semaphorin 3E. The role of Plexin D1 in tumor development and progression is thereby garnering research interest for its potential as a biomarker and as a therapeutic target. In this review, we describe its discovery, structure, mutations, role(s) in cancer, and therapeutic potential.

Multigenic truncation of the semaphorin-plexin pathway by a germline chromothriptic rearrangement associated with Moebius syndrome.

Moebius syndrome (MBS) is a congenital disorder caused by paralysis of the facial and abducens nerves. Although a number of candidate genes have been suspected, so far only mutations in PLXND1 and REV3L are confirmed to cause MBS. Here, we fine mapped the breakpoints of a complex chromosomal rearrangement (CCR) 46,XY,t(7;8;11;13) in a patient with MBS, which revealed 41 clustered breakpoints with typical hallmarks of chromothripsis. Among 12 truncated protein-coding genes, SEMA3A is known to bind to the MBS-associated PLXND1. Intriguingly, the CCR also truncated PIK3CG, which in silico interacts with REVL3 encoded by the other known MBS-gene REV3L, and with the SEMA3A/PLXND1 complex via FLT1. Additional studies of other complex rearrangements may reveal whether the multiple breakpoints in germline chromothripsis may predispose to complex multigenic disorders.

Congenital facial palsy and emotion processing: The case of Moebius syndrome.

According to the Darwinian perspective, facial expressions of emotions evolved to quickly communicate emotional states and would serve adaptive functions that promote social interactions. Embodied cognition theories suggest that we understand others' emotions by reproducing the perceived expression in our own facial musculature (facial mimicry) and the mere observation of a facial expression can evoke the corresponding emotion in the perceivers. Consequently, the inability to form facial expressions would affect the experience of emotional understanding. In this review, we aimed at providing account on the link between the lack of emotion production and the mechanisms of emotion processing. We address this issue by taking into account Moebius syndrome, a rare neurological disorder that primarily affects the muscles controlling facial expressions. Individuals with Moebius syndrome are born with facial paralysis and inability to form facial expressions. This makes them the ideal population to study whether facial mimicry is necessary for emotion understanding. Here, we discuss behavioral ambiguous/mixed results on emotion recognition deficits in Moebius syndrome suggesting the need to investigate further aspects of emotional processing such as the physiological responses associated with the emotional experience during developmental age.

Síndrome de Moebius incompleto. Presentación de un caso clínico / Incomplete Moebius syndrome. Clinical case presentation

RESUMEN El síndrome de Moebius es un trastorno polimalformativo no progresivo que se caracteriza por parálisis facial congénita. Se define como una "parálisis congénita de los núcleos de los pares craneales VI y VII, cuyo espectro clínico es variable y se asocia a múltiples malformaciones óseas y musculares. Es poco frecuente y de etiología vascular, genética o multifactorial. El trabajo, basándose en los fundamentos teóricos más actualizados, pretendió describir las manifestaciones clínicas del síndrome de Moebius y su posible etiología, a propósito de un caso. Se trató de un paciente de 11 años de edad, que al nacimiento presentó asimetría facial, desviación de la comisura labial hacia la izquierda, boca semiabierta, lagrimeo constante y pabellón auricular derecho malformado. Por ser una entidad clínica poco conocida, se expuso el presente caso, portador de un síndrome de Moebius incompleto de causa vascular y multifactorial (AU).

ABSTRACT Moebius syndrome is a non-progressive poli-formative disorder characterized by facial congenital paralysis. It is defined as a congenital paralysis of the VI and VII cranial nerves nuclei, the clinical spectrum of which is variable and associated to several bone and muscular malformations. It is few frequent and has vascular, genetic or multifactorial etiology. This work, based on more updated theoretical fundaments, pretended to describe the clinical manifestations of the Moebius syndrome and its possible etiology on the purpose of a case. It is the case of a patient, aged 11 years, who presented facial asymmetry, lips commissure deviation to the left, semi-opened mouth, constant lagrimeo and deformed right auricular pavilion (pabellon auricular). Because it is a little known clinical entity, this case of a patient having an incomplete Moebius syndrome of vascular and multifactorial cause was presented (AU).

Síndrome de Moebius incompleto. Presentación de un caso clínico / Incomplete Moebius syndrome. Clinical case presentation

RESUMEN El síndrome de Moebius es un trastorno polimalformativo no progresivo que se caracteriza por parálisis facial congénita. Se define como una "parálisis congénita de los núcleos de los pares craneales VI y VII, cuyo espectro clínico es variable y se asocia a múltiples malformaciones óseas y musculares. Es poco frecuente y de etiología vascular, genética o multifactorial. El trabajo, basándose en los fundamentos teóricos más actualizados, pretendió describir las manifestaciones clínicas del síndrome de Moebius y su posible etiología, a propósito de un caso. Se trató de un paciente de 11 años de edad, que al nacimiento presentó asimetría facial, desviación de la comisura labial hacia la izquierda, boca semiabierta, lagrimeo constante y pabellón auricular derecho malformado. Por ser una entidad clínica poco conocida, se expuso el presente caso, portador de un síndrome de Moebius incompleto de causa vascular y multifactorial (AU).

ABSTRACT Moebius syndrome is a non-progressive poli-formative disorder characterized by facial congenital paralysis. It is defined as a congenital paralysis of the VI and VII cranial nerves nuclei, the clinical spectrum of which is variable and associated to several bone and muscular malformations. It is few frequent and has vascular, genetic or multifactorial etiology. This work, based on more updated theoretical fundaments, pretended to describe the clinical manifestations of the Moebius syndrome and its possible etiology on the purpose of a case. It is the case of a patient, aged 11 years, who presented facial asymmetry, lips commissure deviation to the left, semi-opened mouth, constant lagrimeo and deformed right auricular pavilion (pabellon auricular). Because it is a little known clinical entity, this case of a patient having an incomplete Moebius syndrome of vascular and multifactorial cause was presented (AU).

Orthodontics and Moebius syndrome: an observational study.

BACKGROUND: Moebius syndrome is a rare condition characterized by bilateral facial and abducens nerve paralysis. The aim of this study is to evaluate the main orthodontic features and the frequency of associated clinical characteristics in patients with Moebius syndrome (MS). METHODS: According to Terzis classifications, 58 patients with MS aged 8 months to 46 years old underwent orthodontics and clinical examination. RESULTS: Strabismus, upper and lower limb malformations, lip and palatal cleft were frequently associated with MS. Reduced TM movements were noted (48%). Cephalometric analysis did not allow identifying a typical facies and a characteristic cephalometric pattern; we have noticed a higher prevalence of Class II (56%) with micrognathia and excessive maxillary development probably due to the lack of lip seal. Early treatment is recommended, with a multidisciplinary approach to reduce the impact of sequelae on the lives of MS patients or their families. CONCLUSIONS: Early treatment is recommended, with a multidisciplinary approach to diminish the impact of sequelae on the lives of MS patients or their families.

Möbius syndrome with cardiac rhabdomyomas.

BACKGROUND: Möbius syndrome is a rare congenital condition which presents not merely with 6th and 7th nerve palsies, but involves gaze paresis associated with craniofacial, limb, and other abnormalities. Heterogeneity is well known in patients with Möbius syndrome and rather than being of familial inheritance based on rare cases, it is much more recognized as a sporadic syndrome. We report an infant with features of congenital Möbius syndrome associated with cardiac rhabdomyomas in the absence of tuberous sclerosis. MATERIALS AND METHODS: Observational case report of an infant seen at a tertiary academic center with genetic testing, ophthalmic, neurological, and cardiac clinical examination and imaging. RESULTS: A newborn baby boy at birth was seen with multiple congenital craniofacial malformations, and respiratory distress. He was noted to have micrognathia, retrognathia, wide nasal bridge, low set ears, high arched palate, nonreducing bilateral talipes equinovarus and bilateral large angle esotropia with -4 abduction deficit and facial palsy, findings suggestive of Möbius Syndrome. MRI of the brain was unremarkable except for syringomyelia in the cervical spine. Echocardiography showed two cardiac rhabdomyomas in the right ventricle and ulltrasound of the abdomen showed mild right hydroneprosis. Cytogenetics revealed segmental loss at 21q21.2. Testing for tuberous sclerosis was negative for deletion or duplications of genes TSC1 and TSC2. CONCLUSION: This case highlights the rare co-occurrence of cardiac rhabdomyomas with Möbius syndrome and new segmental loss at 21q21.2 on genetic testing. Findings could indicate not a "suggestion of Möbius", but rather the syndrome itself in association with cardiac defects.

Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.

Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.

A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome.

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymkinsT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.

An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a TUBB3 mutation.

Moebius syndrome is characterized by congenital unilateral or bilateral facial and abducens nerve palsies (sixth and seventh cranial nerves) causing facial weakness, feeding difficulties, and restricted ocular movements. Abnormalities of the chest wall such as Poland anomaly and variable limb defects are frequently associated with this syndrome. Most cases are isolated; however, rare families with autosomal dominant transmission with incomplete penetrance and variable expressivity have been described. The genetic basis of this condition remains unknown. In a cohort study of nine individuals suspected to have Moebius syndrome (six typical, three atypical), we performed whole-exome sequencing to try to identify a commonly mutated gene. Although no such gene was identified and we did not find mutations in PLXND1 and REV3L, we found a de novo heterozygous mutation, p.E410K, in the gene encoding tubulin beta 3 class III (TUBB3), in an individual with atypical Moebius syndrome. This individual was diagnosed with near-complete ophthalmoplegia, agenesis of the corpus callosum, and absence of the septum pellucidum. No substantial limb abnormalities were noted. Mutations in TUBB3 have been associated with complex cortical dysplasia and other brain malformations and congenital fibrosis of extraocular muscles type 3A (CFEOM3A). Our report highlights the overlap of genetic etiology and clinical differences between CFEOM and Moebius syndrome and describes our approach to identifying candidate genes for typical and atypical Moebius syndrome.

Moebius sequence -a multidisciplinary clinical approach.

BACKGROUND: Moebius Sequence (MS) is a rare disorder defined by bilateral congenital paralysis of the abducens and facial nerves in combination with various odontological, craniofacial, ophthalmological and orthopaedic conditions. The aetiology is still unknown; but both genetic (de novo mutations) and vascular events in utero are reported. The purpose of present study was through a multidisciplinary clinical approach to examine children diagnosed with Moebius-like symptoms. Ten children underwent odontological, ophthalmological, obstetric, paediatric, orthopaedic, genetic, radiological and photographical evaluation. Five patients maintained the diagnosis of MS according to the diagnostic criteria. RESULTS: All five patients had bilateral facial and abducens paralysis confirmed by ophthalmological examination. Three of five had normal brain MR imaging. Two had missing facial nerves and one had missing abducens nerves. The Strengths and Difficulties Questionnaire (SDQ) showed normal scores in three of five patients. Interestingly, two of five children were born to mothers with uterine abnormalities (unicornuate/bicornuate uterus). In the odontological examination three of five showed enamel hypomineralisation. All five had abnormal orofacial motor function and maxillary prognathism. Two patients had adactyly, syndactyly and brachydactyly. None of the five patients had Poland anomaly, hip dislocation or dysplasia but all had a mild degree of scoliosis. We observed congenital club-feet, calcaneovalgus deformities, macrodactyly of one or more toes or curly toes. Pedobarography showed plantar pressures within normal ranges. CONCLUSIONS: Adherence to standard diagnostic criteria is central in the diagnosis of MS. An accurate diagnosis is the basis for correct discussion of other relevant concomitant symptoms of MS, genetic testing and evaluation of prognosis. The multidisciplinary approach and adherence to diagnostic criteria taken in present study increases the knowledge on the relationship between genotype, phenotype and symptomatology of MS.

Managing the child with a diagnosis of Moebius syndrome: more than meets the eye.

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.