Möbius Sequence (and Poland-Möbius) and the Oromandibular-Limb Spectrum (OMLH)

Congenital cranial dysinnervation disorders of predominantly non-Mendelian cause and vascular disruption defects of the face and limbs: Möbius sequence or syndrome, Poland-Möbius association and the oromandibular-limb hypogenesis spectrum (hypoglossia-hypodactyly/Hanhart, glossopalatine ankylosis, splenogonadal fusion with limb defects)

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Historical overview

Congenital, non-progressive palsy of the facial and abducens nerves was described by Albrecht von Graefe in 1880 and, systematically, by the German neurologist Paul Julius Moebius (1853–1907) in 1888, in a paper entitled “On congenital bilateral abducens and facial palsy” [1, 2]. Henry Thomas described the condition in the United States in 1898, and Wilbrand and Saenger documented families with several affected members in 1921 [2]. Henderson brought together sixty-one cases in 1939 under the designation “congenital facial diplegia syndrome”, and the Moebius eponym became established during the twentieth century, applied to an increasingly heterogeneous group of patients [1]. The original description included bilateral facial and abducens palsies without ptosis or limitation of vertical movements, a restriction that the subsequent literature lost and that was only recovered in the twenty-first century [10].

In 1986, Bouwes Bavinck and Weaver proposed that the Poland, Klippel-Feil and Möbius anomalies, which frequently coexist in the same individual, result from reduced flow in the subclavian artery, the vertebral artery or their branches around the sixth week of development, grouping them under the “subclavian artery supply disruption sequence” [15, 29]. The coexistence of Möbius with the Poland anomaly, described by Stark and Sugarman in 1973, led Parker and colleagues to gather at least twelve documented cases in 1981 and to argue for a distinct entity, Poland-Möbius syndrome [2, 27]. In parallel, Rosenthal described aglossia with other malformations in 1932, Hanhart published three cases of peromelia with micrognathia in 1950, and Kaplan and colleagues emphasised in 1976 the existence of a “community” of face-limb syndromes with shared developmental mechanisms [5, 6].

The surge in the use of misoprostol as an abortifacient in Brazil in the 1990s provided the strongest epidemiological demonstration of an environmental cause: in a seven-hospital case-control study, half of the mothers of infants with Möbius had used the drug in the first trimester [30]. In the same decade, clusters of oromandibular-limb hypogenesis cases after early chorionic villus sampling strengthened the vascular disruption hypothesis [31, 32].

1.2. Definition of each entity

Möbius syndrome was defined at the Moebius Syndrome Foundation research conference in Bethesda in 2007 as congenital, non-progressive facial weakness, unilateral or bilateral, with limited abduction of one or both eyes; hearing loss, dysfunction of other cranial nerves and motor, orofacial, musculoskeletal, neurodevelopmental and social problems may coexist [2, 10]. MacKinnon and colleagues, after examining 112 participants at three North American conferences, proposed in 2014 adding “full vertical motility” to the minimum criteria, because patients with exotropia, vertical deficit and ptosis had CFEOM3 due to TUBB3 variants rather than classic Möbius [33]. The study of 149 patients published in 2025 applied strict criteria that exclude restriction of elevation beyond the −3 position before any surgery and any limitation of elevation accompanied by ptosis, understood as weakness of the levator palpebrae and not as dysmorphic narrowing of the palpebral fissure; the authors recommend universal adoption of these parameters [10]. Patients who do not meet the criteria are designated “Moebius-like” and should be investigated for other congenital cranial dysinnervation disorders (CCDD) [3].

Smith's Recognizable Patterns prefers the term “sequence”, because the condition results from at least four modes of developmental pathology rather than a single cause [1]. The terms “syndrome” and “sequence” coexist in the literature and are used here as equivalents. Verzijl and colleagues redefined Möbius in 2003 as a rhombencephalic malformation syndrome, involving mainly motor nuclei and axons and also long tracts crossing the brainstem, and not merely a nuclear defect of the cranial nerves [34].

The Poland-Möbius association is defined by the coexistence of the Möbius criteria with hypoplasia or agenesis of the pectoralis major, with a hypoplastic or displaced nipple and variable ipsilateral hand anomalies [10]. It is not a distinct genetic entity: in the cohort of 149 patients, the Poland anomaly was associated with limb defects but not with other features, and no phenotypic subgroup emerged from cluster analysis [10].

The oromandibular-limb hypogenesis spectrum (OMLH) brings together presentations with micrognathia, hypoglossia or aglossia, clefts or aberrant insertions of the tongue, intraoral fusions and limb reduction defects, sometimes accompanied by Möbius [5]. Hall classified them in 1971 into five types: type I, isolated hypoglossia or aglossia; type II, hypoglossia with hypomelia or hypodactyly (hypoglossia-hypodactyly); type III, glossopalatine ankylosis with hypoglossia or with hypoglossia and limb defects; type IV, intraoral bands or fusions with hypoglossia, with or without limb defects; and type V, syndromes such as Hanhart, Robin, Möbius and amniotic bands [6]. Chicarilli and Polayes proposed an alternative classification in 1985, and recent literature tends to group these conditions into a spectrum rather than separating them, because the face and limbs develop simultaneously between the fourth and eighth weeks and share susceptibility to the same disruptive stimuli [35, 36]. Splenogonadal fusion with limb defects and micrognathia overlaps with the Hanhart complex and is treated within the same spectrum [7].

1.3. Nosological position and related classes

Möbius belongs to the congenital cranial dysinnervation disorders, together with Duane syndrome, the CFEOMs, horizontal gaze palsy with progressive scoliosis and hereditary congenital facial palsy [21, 37]. Unlike these, strictly defined Möbius has no identified genetic cause and may result from non-Mendelian causes [37]. Mendelian CCDDs, isolated Poland anomaly, Klippel-Feil syndrome, Robin sequence, thalidomide embryopathy, Carey-Fineman-Ziter syndrome and arthrogryposis multiplex congenita enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Embryology of the hindbrain and anatomical basis

The cranial nerves supplying the head and neck form from distinct brainstem nuclei between the fourth and eighth weeks after fertilisation [10]. Abducens motor neurons arise in rhombomeres 5 and 6 and their axons exit at the pontomedullary junction to innervate the ipsilateral lateral rectus. The abducens nucleus also contains interneurons whose axons cross the midline and ascend in the medial longitudinal fasciculus (MLF) to the contralateral medial rectus subnucleus, which forms the substrate of horizontal conjugate gaze [10]. Facial branchiomotor neurons arise in rhombomere 4 and migrate caudally to rhombomere 6; the axons trail behind, loop around the abducens nucleus and exit the pons at the level of rhombomere 4 [10]. This proximity explains the association of the abduction deficit with facial palsy and, when the lesion extends to the interneurons, horizontal conjugate gaze paresis with an adduction deficit, present in 48% of Dutch patients and with bilateral limitation of adduction in 46.3% of the North American cohort [10, 34].

2.2. Pathological mechanisms

Autopsies reveal at least four modes of pathology: hypoplasia or absence of the central nuclei; destructive degeneration of the nuclei, the most common type; peripheral nerve involvement; and myopathy [1]. Towfighi and colleagues classified fifteen cases in 1979 into four groups: hypoplasia of the nuclei due to rhombomeric malformation (group I); neuronal loss and degeneration secondary to a defect of the peripheral facial nerve (group II); focal necrosis, gliosis and calcification of the nuclei attributed to vascular insufficiency or infection (group III); and primary myopathic changes without lesions of the nuclei or nerves (group IV) [2]. In a newborn who died at 11 days, the brainstem was asymmetric and hypoplastic, with dysplastic inferior olives, non-decussating pyramidal tracts and neuronal loss with gliosis and microcalcifications in the nuclei of cranial nerves VI, VII and XII and in the medial reticular nuclei, in contrast to three cases of hereditary congenital facial palsy, which had isolated loss of the facial nuclei [2].

Electrophysiology supports this heterogeneity. Among 24 sporadic patients, eight had increased distal motor latency after facial nerve stimulation, consistent with a rhombencephalic malformation with small motor neurons, and nine had a chronic neuropathic pattern with enlarged motor units, consistent with axonal or neuronal loss acquired in the prenatal period [2]. Diffusion tensor imaging showed a small volumetric reduction in the paramedian pontine reticular formation and the MLF that distinguishes Möbius from isolated congenital facial palsy and from controls, with a magnitude correlated with severity and with neurological and other-system involvement; whether it reflects a primary malformation or a destructive lesion is unknown [10].

2.3. Vascular and teratogenic hypothesis

The most widely accepted hypothesis is a transient vascular disruption. The hindbrain lies in a vascular watershed territory, and premature regression of the primitive trigeminal artery or interruption of the vertebral supply before the vertebral arteries adequately perfuse the brainstem would cause ischaemia of the VI and VII nuclei; more extensive ischaemia or haemorrhage would explain additional palsies [10, 38]. In the association with pectoral hypoplasia, a more proximal event at the level of the subclavian artery is postulated, and the pattern of defects would depend on the area of reduced flow [10, 29]. Most sporadic cases would be explained by insufficient supply to the structures perfused by the primitive subclavian artery, and many mothers report events capable of causing transient ischaemic or hypoxic insults [1].

Drugs that cause vasoconstriction or increased uterine tone, such as misoprostol, ergotamine, thalidomide and cocaine, have been associated with Möbius; cephalocaudal compression from uterine contraction would compromise the VI and VII nuclei, located at a vulnerable level of the embryo [10]. Misoprostol, a synthetic prostaglandin E1 analogue, increases uterine artery resistance measured by Doppler and induces contractions, and the critical period for Möbius after exposure lies between 5 and 8 weeks of gestation [39]. The Brazilian textbook of genetic syndromes also lists alcohol, benzodiazepines and infection among the environmental factors [22], and maternal hyperthermia has also been associated with Möbius, OMLH and amyoplasia [40]. Epidemiological data on misoprostol are given in section 8.

In OMLH, Poswillo's experimental studies support the view that the defects result from disruptive haemorrhagic lesions, more likely in distal regions (distal limbs, tongue and parts of the brain) [5]. Chorionic villus sampling, especially between 56 and 66 days of gestation, and misoprostol used as an abortifacient reinforce the vascular pathogenesis [5]. In splenogonadal fusion with limb defects, a vascular event between the fifth and seventh weeks would explain the limb defects, mandibular hypoplasia and fusion of the spleen with the gonad [7]. In 2026 a child with Möbius and additional malformations and a non-diagnostic genome showed a moderately positive methylation episignature for the “recurrent constellation of embryonic malformations” (RCEM), suggesting an embryological pathway common to some of these conditions [41].

2.4. Cytogenetics and loci

A reciprocal translocation t(1;13)(p34;q13) cosegregated with facial diplegia and finger flexion contractures in seven members over three generations, and a 13q12.2 deletion was described in a 2.5-year-old girl with Möbius, which underpinned the provisional MBS1 locus at 13q12.2–q13 [2]. A t(1;2)(p22.3;q21.1) translocation in a boy with a similar presentation and a t(1;11)(p22;p13) in a patient with Möbius, Poland, cleft palate, dextrocardia and mandibular hypoplasia suggested a gene at 1p22 [2]. The 3q21–q22 and 10q21.3–q22.1 loci, initially designated MBS2 and MBS3, now correspond to hereditary congenital facial palsy types 1 and 2 (HCFP1, OMIM 601471; HCFP2, OMIM 604185), with no gene identified [4, 42]. A 3q23 gain was described in one case of Poland-Möbius and a REV3L deletion in another [4].

2.5. Proposed genes: PLXND1 and REV3L

In 2015, Tomas-Roca and colleagues described de novo variants in two genes from unrelated pathways, PLXND1 and REV3L, and showed in mice that both converge on the facial branchiomotor nucleus, affecting motor neuron migration or proliferation [43]. Smith's lists PLXND1 and REV3L among the genes implicated in sporadic cases [1]. PLXND1 (3q22.1) encodes plexin D1, a class 3 semaphorin receptor highly expressed in the vascular endothelium; Plxnd1-null mice have hypoplasia of the corpus callosum, anterior commissure and fasciculus retroflexus, fewer motor neurons in the facial nucleus and abnormal migration, also in heterozygotes [8]. REV3L (6q21) encodes the catalytic subunit of DNA polymerase zeta, responsible for translesion synthesis; heterozygous mice have a smaller hindbrain and fewer motor neurons, and embryonic fibroblasts show replication stress [9].

The variants, normalised in VariantValidator to the MANE Select transcripts, are as follows [44]. In PLXND1 (NM_015103.3): c.5685C>A p.(Asn1895Lys), de novo, identified by trio exome; c.4454_4455delinsCA p.(Arg1485Pro), de novo, found by Sanger sequencing in 103 patients; and a synonymous variant c.3018C>T of no demonstrated significance [8]. In REV3L (MANE NM_001372078.1, with numbering identical to that of NM_002912.5 used in the original paper at these positions): c.1096+1G>A p.?, de novo, with reduced normal transcript in patient cells; c.1160A>G p.(Glu387Gly) and c.2662A>T p.(Lys888Ter), both de novo [9, 44]. No functional studies of these variants were performed, and OMIM keeps both associations as provisional [2].

Replication failed. An exome study in nine patients (six typical and three atypical) found no variants in PLXND1 or REV3L, but revealed de novo TUBB3 NM_006086.4:c.1228G>A p.(Glu410Lys) in an atypical case, with near-complete ophthalmoplegia and agenesis of the corpus callosum, which corresponded to CFEOM3A [45]. A trio exome study of 37 Italian patients with Möbius or a similar presentation found no de novo variants in either gene [46]. The cohort of 149 patients with strict criteria, with exome or genome sequencing in 67 probands and 117 relatives, also found no rare variants in PLXND1 or REV3L; the authors note that the patients described by Tomas-Roca and by Moresco included cases without VI nerve palsy or with III nerve involvement, who do not meet the criteria [10]. GeneGuidance curation does not recognise an established Mendelian gene-disease relationship for REV3L: ClinGen has no curation, the OMIM phenotype map lists no phenotype and the four GenCC submissions diverge (Limited, Limited, Supportive and Strong) [47]. A Polish child homozygous for REV3L c.8258C>G p.(Thr2753Arg), designation published on transcript NM_001286431.2 (= MANE NM_001372078.1:c.8492C>G p.(Thr2831Arg); NC_000006.12:g.111313464G>C), had developmental delay, hypotrophy and dysmorphism without Möbius [9]. For PLXND1, the only phenotype on the OMIM map is cardiac and autosomal recessive (congenital heart defects type 9, with truncus arteriosus and aortic arch anomalies), and the association with Möbius should be presented as an autosomal dominant candidate [48]. In practice, a variant in REV3L or PLXND1 in a report does not establish a diagnosis of Möbius [47].

2.6. Results of the 2025 genomic study

The cohort of 149 patients sequenced 52 trios and 3 quartets and filtered 173 single-nucleotide variants or small insertions/deletions in 113 genes and 46 structural variants in 23 trios [10]. Seven genes with de novo variants (USP15, STMN3, PALM, CNTRL, KPNA3, POU2F1, MINDY1) and five with biallelic variants (ZNF407, PBXIP1, KCNAB2, ZRANB1, MORC2) were prioritised, all classified as variants of uncertain significance (VUS) and each present in a single family; TTN and COL24A1, affected in more than one proband, were deprioritised because of their size, low missense constraint and lack of expression in VI and VII neurons [10]. The de novo variant rate did not differ from that of patients with other CCDDs sequenced in parallel, and the variants in 79 thrombophilia genes found in 8 of 52 mothers had no clinical expression [10]. The authors conclude that a unifying germline aetiology is unlikely and that research should turn to post-zygotic somatic variants, environmental exposures and oligogenic or multifactorial models [10]. A 2025 review proposes knock-in mouse models carrying the human variants and the chick embryo to test the vascular hypothesis [49].

2.7. Mendelian differentials with overlapping phenotype

Hereditary congenital facial palsy type 3 (HCFP3) is due to biallelic HOXB1 variants (17q21.32) and is the model of how a Mendelian disorder can be labelled as Möbius. The founder variant NM_002144.4:c.619C>T p.(Arg207Cys), homozygous in two families from a conservative German-American population, alters Arg5 of the homeodomain and destabilises the HOXB1:PBX1:DNA complex; patients had bilateral facial palsy, hearing loss and strabismus, but full abduction [44, 50]. The homozygous variant c.66C>G p.(Tyr22Ter) was described in a consanguineous Moroccan family with pinna malformations, and compound heterozygous variants in a child with axonal facial neuropathy [42, 44]. In MacKinnon's series, two siblings with comitant strabismus and a HOXB1 variant had been diagnosed with Möbius [33].

TUBB3 variants, especially NM_006086.4:c.1228G>A p.(Glu410Lys), cause syndromic CFEOM3 with facial palsy, vocal cord paralysis, intellectual disability, Kallmann syndrome and peripheral neuropathy; the combination of CFEOM3 with facial weakness, other cranial nerves, neuropathy, micropenis or cryptorchidism or contractures suggests these variants [21]. This overlap explains the patients described with “Möbius, peripheral neuropathy and hypogonadotropic hypogonadism” (ORPHA:2560), in whom pulsatile gonadotropin-releasing hormone administration for 3 months had a mild effect in one case [2, 16]. Congenital myopathies with facial weakness and ophthalmoplegia, such as Carey-Fineman-Ziter syndrome (MYMK), STAC3- and RYR1-related myopathies, facioscapulohumeral dystrophy and congenital myotonic dystrophy, complete the group of phenocopies [10, 24].

2.8. Inheritance and penetrance

In series with strict criteria, Möbius is sporadic: no recurrence in 140 families with available history, in 160 siblings or in 16 offspring of eight probands, and no familial case among 164 Italian patients, except for a pair of monozygotic twins both affected with different expression [3, 10]. The published families with vertical transmission (three generations in 1963; one dominant family, one consanguineous family compatible with recessive inheritance and one with two brothers and a cousin, children of sisters, suggestive of X-linked inheritance) frequently included presentations without skeletal defects, with isolated facial palsy, deafness, ophthalmoplegia or digital contractures, which today would be classified as HCFP, CFEOM or myopathies [2, 10]. Orphanet records autosomal dominant inheritance for ORPHA:570, which corresponds to these rare families and not to the classic sequence [11, 38]. Two families with Poland in a parent or an aunt and Poland-Möbius in the proband were interpreted as expression of an autosomal dominant gene, without molecular confirmation [12, 13]. The published cases of OMLH and splenogonadal fusion are sporadic; parental consanguinity in three Turkish cases was attributed to the high consanguinity of the population [6, 7].

3. Clinical Spectrum and Manifestations by System

3.1. Reference cohorts

Published frequencies vary with inclusion criteria, recruitment method and patient age. The table summarises the main series, all of treated or followed-up disease rather than pure natural history.

3.2. Face and cranial nerves

The face is expressionless and mask-like, with difficulty smiling, frowning and closing the eyes; the mouth is small, with drooping corners, and the nasal root high; patients recruit the platysma to increase facial movement [1, 10]. In the 2025 cohort, facial palsy was bilateral in 92.0% and the abduction deficit bilateral in 95.3% [10]. In 62% of Dutch patients with bilateral palsy the lower half of the face was relatively spared, and in the Colombian series the forehead was completely rigid, with minimal chin movements [2, 52]. Cranial nerves III, IV, V, IX, X and XII may be involved; in the review of 449 cases the frequencies were 48.4% (III), 37.5% (IV), 25.6% (V), 30.8% (VIII), 43.7% (IX), 53% (X), 21.7% (XI) and 45.3% (XII) [1, 24]. In the Colombian series, 91.43% had another cranial nerve affected besides VI and VII and 71.43% had XII involvement, almost always with tongue hypotrophy, fasciculations at rest in more than half and lateral deviation in 48% [52]. Four Dutch patients had sensory loss of the lip, face, forehead and cornea due to a partial defect of the trigeminal sensory root, and 16% had a weak bite or absent mandibular rotation [2].

3.3. Eyes

Esotropia due to unopposed action of the medial rectus is the most common presentation. Carta described three patterns: A (41%), orthotropia in primary position with complete abduction and adduction deficit; B (50%), large-angle esotropia with cross-fixation and relative preservation of convergence and adduction; and C (9%), large-angle exotropia with torticollis, absent convergence and vertical misalignment [27]. The 2025 cohort found bilateral adduction deficit in 46.3% and unilateral in 19.5%, mild vertical limitation below the −3 position in 15.4% and no ptosis; 43.6% had undergone eye surgery [10]. Smith's describes refractive errors in 42%, adduction deficit in 83%, voluntary Bell phenomenon in 43%, intorsion on fixation in 42%, near-normal convergence and dysinnervation in 41%, manifested by tearing when eating or when attempting to look laterally; the voluntary Bell phenomenon and intorsion on fixation were described by MacKinnon as features specific to classic Möbius [1, 33]. Lacrimation may begin late, between 4 and 6 months, be followed by crocodile tears and coexist with dry eye; lagophthalmos rarely causes corneal damage because the Bell phenomenon is preserved [24, 27]. The Brazilian textbook also includes microphthalmia, myopia and hypermetropia [22].

3.4. Oropharynx, feeding and airway

Sucking and swallowing are impaired from birth: 86% of Dutch patients had neonatal feeding problems due to palatal and pharyngeal involvement, and 19.5% of the 2025 cohort required gastrostomy [2, 10]. The tongue is hypoplastic (81.9%), sometimes furrowed and with fasciculations; micrognathia (66.4%) results from an early neuromuscular deficit of mandibular movement and is associated with a U-shaped cleft palate or bifid uvula in about one third of cases in Smith's, in a Robin sequence, and in 16.8% in the strict cohort [1, 10]. Tracheostomy was required in 12.8% [10]. In the review of 449 cases, 10 patients needed prolonged ventilation for apnoeas or altered central respiratory control and 20 died of apnoeas, aspiration or aspiration pneumonia; two of 37 Dutch patients died in the neonatal period, and 7 had neonatal respiratory distress [2, 24]. Sialorrhoea is frequent, owing to insufficient lip closure and ineffective swallowing, with normal saliva production [24]. Gastro-oesophageal reflux is common [24].

3.5. Speech, hearing and communication

Dysarthria is almost constant (89.2% in the review; nasal dysarthria in 76% of Dutch patients), because lip palsy prevents the bilabial phonemes /p/, /b/ and /m/ and tongue dysfunction the phonemes /t/, /d/, /n/ and /s/ [2, 24]. Language delay affected 55% of the Dutch patients [2]. Hearing loss, sensorineural or conductive, was identified in 26.2% of the 2025 cohort; Smith's attributes it mainly to chronic otitis media, and conductive deafness occurred in 24.6% in the review [1, 10, 24]. The lack of facial expression limits non-verbal communication of emotion, which affects social interaction [24].

3.6. Limbs, chest and spine

Clubfoot (talipes equinovarus) is the most frequent musculoskeletal anomaly: 42.3% in the 2025 cohort, bilateral in 73.0%, and 41% in Smith's [1, 10]. Major limb anomalies (transverse reduction, complete syndactyly, absent digits) affected 31.5%, involving one limb in 61.7%, two in 27.7%, three in 8.5% and four in 4.3% [10]. In the Mexican series, 25 of 153 patients (16.3%) had upper limb malformations, unilateral in 68%: Poland anomaly and simple syndactyly in 8 each (32%), brachysyndactyly in 5 (20%), amniotic bands in 3 (12%) and cleft hand in 1 (4%) [54]. Scoliosis affects 14–17.4% and was more frequent in females (27% versus 9.7%), as was micrognathia (79% versus 55%) [1, 10]. Klippel-Feil sequence, hip dysplasia, arthrogryposis, hypodontia and splenogonadal fusion have been described [1]. Motor incoordination affected 88% of the Dutch patients [2].

3.7. Poland-Möbius association

The Poland anomaly occurred in 14.1% of the strict cohort, 11% of Dutch patients, 20% in Smith's and 2% in the Italian series, with a published range of 2.0% to 38.2% [1, 3, 10, 15]. It includes hypoplasia or agenesis of the pectoralis major, a hypoplastic or displaced nipple and ipsilateral hand anomalies (brachymelia, small or absent hand, oligodactyly, brachydactyly or symbrachydactyly, thumb hypoplasia, camptodactyly); the Dutch patients also had dextrocardia, aplasia of the abdominal muscles and nipple agenesis [10, 15]. Isolated Poland anomaly is three times more frequent in males and right-sided in 75% of cases; isolated dextrocardia is associated with two or more ipsilateral rib defects in the left-sided form [29]. In patients with Poland and Möbius, imaging may show malformation of the pons, cerebellum and midbrain, and the bulbar palsy of Möbius is the main cause of morbidity, since isolated Poland anomaly has mainly aesthetic consequences [55]. One patient with Klippel-Feil, Poland and Möbius has been described [15] and another with palsy of VI, VII and IX, pectoral hypoplasia, a disruptive upper limb defect and splenogonadal fusion [25].

3.8. Neurodevelopment, behaviour and sleep

The frequency of intellectual disability varies between 6.1% and 73.3% across series; the strict cohort found 30.9%, Smith's estimates 10–15% and the Italian series recorded developmental, cognitive or behavioural delay in 4% [1, 3, 10]. Autism spectrum disorder affected 10.1% of the 2025 cohort (published range 3.6–36.8%), and Smith's considers the old estimate of 25% excessive [1, 10]. In the Swedish series, six patients had autism and one a similar condition, all with intellectual disability; a review linked autism to errors of early embryogenesis between the fourth and sixth weeks [53, 56]. Attention-deficit hyperactivity disorder or other psychiatric disorders (anxiety, depression) occurred in 27.5%, mirror movements in 12.8% and seizures in 10.7% [10]. Intellectual disability and seizures were associated with gastrointestinal anomalies, vocal cord paralysis or tracheostomy and cleft palate, whereas limb defects and the Poland anomaly were not associated with neurological manifestations [10]. The review of 449 cases separated a type 1, with micrognathia, limb anomalies and feeding difficulty, from a more heterogeneous type 2, with brain anomalies on imaging and developmental delay, but the strict cohort did not confirm distinct subgroups [10, 51]. Preschool children assessed by questionnaire had behavioural problems in 16.7%, similar to controls, but caregivers reported more stress, and self-perception studies document resilience [1, 2].

Sleep disturbance is frequent (22.8% in the strict cohort). In a North American survey, 46 adults reported insomnia in 56%, apnoea in 26%, nightmares in 35%, daytime sleepiness in 30%, cataplexy in 26%, symptoms of REM sleep behaviour disorder in 61% and parasomnias in all; among the 17 children assessed by their parents, 71% had a sleep disorder and 82% daytime impairment [57]. The reticular formation involved in the sleep-wake cycle lies in the affected region of the brainstem [24].

3.9. Other systems

Congenital heart defects occurred in 8.7% of the strict cohort and in 33.3% in the review of 449 cases, including ventricular and atrial septal defects, patent ductus arteriosus, dextrocardia, transposition of the great arteries and total anomalous pulmonary venous return [10, 24, 58]. Gastroschisis (2.0%), hypospadias, hydronephrosis, cervical hydromyelia and hypopituitarism have been described [10, 58]. Dental anomalies include hypodontia, microdontia, enamel hypoplasia, caries and periodontal disease; a systematic review of 124 patients also found microstomia, high-arched palate, anterior open bite and class II malocclusion [1, 59]. Magnetic resonance imaging showed an absent or hypoplastic facial nerve in all 15 patients studied at the NIH, an absent or hypoplastic abducens nerve in 10 (5 with non-diagnostic imaging), a small lateral rectus in 6, a small anterior commissure in 5 and no anomaly of cranial nerves III, IX, X and XI [10]. Six Dutch patients had a pons with a smaller anteroposterior diameter than controls (19.7 versus 22.5 mm), and three had posterior fossa anomalies; brainstem hypoplasia has been described in 32% of the radiological literature [2].

3.10. Oromandibular-limb hypogenesis spectrum

The combination of findings varies from case to case: small mouth, micrognathia (sometimes extreme, with an almost absent mandible), hypoglossia, clefts or aberrant insertions of the tongue, mandibular hypodontia, bony fusion of the maxilla and mandible (synognathia), choanal atresia, cleft palate, cranial nerve palsies including Möbius, broad nose, telecanthus, lower eyelid defect and facial asymmetry [5, 6]. The limbs show hypoplasia up to adactyly, syndactyly and “angel-shaped” phalanx; other findings are brain defects, splenogonadal fusion, hypoplasia of the atlas with craniocervical junction malformation and gastroschisis [5]. Early feeding and speech difficulties are frequent; intelligence and stature are generally normal, and children with amputation of all four limbs may suffer severe hyperthermia owing to the reduced heat-dissipating surface [5]. A 20-year-old man with severe Hanhart syndrome had normal intelligence, a height of 150 cm, an almost absent mandible, a very small tongue, symbrachydactyly and transverse defects at the wrist and knee [6]. Glossopalatine ankylosis with hypodactyly may be associated with fatal pulmonary hypoplasia, and three of 14 cases with limb defects reviewed in 1985 died [35]. A Turkish infant without hands or feet died of pneumonia at 9 months [6]. The overlap with Möbius is illustrated by a Brazilian newborn girl with VI and VII palsy, distal transverse agenesis of all four limbs, micrognathia, cleft lip and palate and superior ankyloglossia [36].

In splenogonadal fusion, the continuous form (a cord between the spleen and the gonad) is associated with additional malformations in 48% and the discontinuous form in 9% [7]. The form with limb defects (SGFLD) combines variable terminal transverse hemimelia, micrognathia and oral anomalies, affects males almost exclusively (1 female in 15 cases reviewed in 1982) and may be lethal in the perinatal period, although there are survivors into adolescence; more than 30 cases of SGFLD and 145 of splenogonadal fusion had been published by 2003 [7].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

Prenatal diagnosis is rare and relies on indirect signs: polyhydramnios due to impaired swallowing, absence of breathing movements and reduced fetal movements, micrognathia with an immobile mandible, non-visualised stomach and clubfoot [27, 60]. Fetal MRI in one case showed flattening of the posterior aspect of the pons and medulla and a beaked tectum [27]. A history of misoprostol exposure, first-trimester bleeding or early chorionic villus sampling should heighten vigilance [10, 30, 32]. When limb defects are detected on ultrasound, the tongue and mandible, which point to OMLH, can rarely be assessed.

4.2. Newborn and infant

Bilateral facial palsy is easily missed in the newborn, because the lack of expression is symmetrical; the Oxford Desk Reference recommends examining the eyes and face for VI and VII palsies in all newborns with limb reduction defects, the tongue and mandible for OMLH, and the pectoral muscle and chest when there is an upper limb defect [61]. The warning signs are difficulty sucking from the first hour of life, an expressionless or asymmetric cry, incomplete eyelid closure during sleep, esotropia with limited abduction, a small tongue or one with fasciculations, micrognathia and clubfoot [24, 62]. Urgent signs are airway obstruction during feeding or handling, apnoeas, episodes of aspiration and a red or irritated eye, which requires immediate lubrication and ophthalmological review [24]. There is no specific newborn screening; universal hearing screening may detect associated hearing loss [24].

4.3. Older child and adult

Diagnosis is often late and suggested by the parents themselves after searching the internet [24]. In Italy, the median age at diagnosis fell from 3.6 years (0–55) to 2.2 years (0–5) after the 2007 definition [3]. In the child, poorly intelligible speech with difficulty in bilabial phonemes, sialorrhoea, esotropia and inability to smile lead to consultation [24]. Ptosis, marked vertical limitation or large-angle exotropia, facial palsy with full ocular motility, a family history, generalised or progressive muscle weakness and peripheral neuropathy are signs that argue against classic Möbius and should prompt a search for a Mendelian CCDD, a myopathy or a neuromuscular disease [10, 33].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The Bethesda criteria were not developed using a formal consensus methodology and there is no evidence-based guideline; diagnosis is clinical and, in practice, one of exclusion [22, 24]. The anomalies can be systematised using Abramson's CLUFT classification, which grades cranial nerves (C), lower limbs (L), upper limbs (U), face (F) and thorax (T), or by a functional approach using the International Classification of Functioning for children and youth [27].

5.2. Initial assessment

The Alder Hey (Liverpool) protocol organises the initial assessment around the priorities of stabilising the airway and ensuring safe swallowing, protecting the ocular surface and maintaining nutrition and weight gain [24]. The recommended investigations are brain MRI to assess brainstem morphology and associated anomalies, ophthalmological and orthoptic assessment, echocardiography, phenotyping and genetic testing, myopathy screening, videofluoroscopy if there is choking or recurrent respiratory infections, and photography of all clinical signs [24]. All children with suspected Möbius, especially those with signs beyond the classic ones (“Moebius-plus”), should be seen by a paediatric neurologist with a detailed prenatal history (trauma, toxins, infection) and complete examination of the cranial nerves, tone, strength, reflexes, abnormal movements, contractures, torticollis and scoliosis [24].

5.3. Oculomotor examination

Standardised examination of ocular motility is the most discriminating element. In MacKinnon's series, 19% of patients with a previous diagnosis of Möbius did not meet the minimum criteria (limited abduction without facial palsy, or facial palsy with full ocular motility), and the five families with two affected members included at least one of these patients [33]. The 79% who met the criteria with full vertical motility formed a homogeneous group, with no family history [33]. In practice, abduction and adduction of each eye, convergence, vertical motility, the presence of true ptosis (levator weakness), globe retraction on adduction (Duane), the Bell phenomenon and corneal sensation are documented [10, 24].

5.4. Imaging and neurophysiology

High-resolution MRI with volumetric T1- and T2-weighted sequences (for example, CISS or DRIVE) allows visualisation of the cranial nerves in the cisterns: the VII nerve is absent or hypoplastic in practically all strict patients, and the VI nerve absent or hypoplastic in most diagnostic studies [10, 27]. Other findings are straightening of the floor of the fourth ventricle with absence of the facial colliculus, absence of the hypoglossal eminence, brainstem and cerebellar hypoplasia and, in some, pontine calcifications, for which CT is more sensitive [2, 24, 27]. Neonatal MRI is less sensitive for small changes but excludes major malformations [24]. Clinical examination may underestimate bilaterality: in a study of nine patients, one had bilateral absence of the VI nerve on MRI and unilateral limitation [27]. In a Portuguese case, 3D T2 DRIVE MRI showed bilateral absence of the VII nerve and absence of the left VI nerve in a newborn girl born at 34 weeks [62]. Electromyography and nerve conduction studies distinguish Möbius from myopathic and neuropathic causes of congenital facial weakness, and modified diffusion tensor imaging has been proposed to separate it from other congenital facial palsies [24, 27]. Spinal MRI is indicated if tone or strength are abnormal or there are contractures, and muscle biopsy is guided by electrophysiology and imaging [24].

5.5. Genetic testing and its limits

As there is no common causal gene, genetic testing mainly serves to exclude alternative diagnoses [24]. Chromosomal microarray is the first-line test in patients with multiple malformations, and exome or genome sequencing, with targeted analysis of TUBB3, KIF21A, TUBB6, HOXB1, HOXA1, ROBO3, MYMK and the congenital myopathy genes, serves cases with a normal microarray or an atypical phenotype [3, 24]. In patients meeting the strict criteria, the yield of exome and genome sequencing is very low: no convincing causal variant in 67 probands sequenced in 2025, nor in 37 patients studied by trio exome in 2024; the 2025 authors also cite negative series of 18 and 30 probands [10, 46]. A negative result does not exclude a genetic cause undetectable by these techniques (non-coding variants, somatic mosaicism limited to the brainstem, complex inheritance), and searching for somatic variants in dysplastic brainstem tissue is not feasible in clinical practice [10]. Conversely, a variant of uncertain significance in a candidate gene, such as PLXND1 or REV3L, does not confirm the diagnosis [47, 48]. The molecular report should state the gene, the reference transcript with version (MANE Select: PLXND1 NM_015103.3, REV3L NM_001372078.1, HOXB1 NM_002144.4), the variant in HGVS nomenclature, zygosity, the mode of inheritance established by segregation and the class according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria [44]. Methylation episignature analysis, which identified an RCEM pattern in a child with Möbius and a negative genome, is an investigational option for cases with multiple malformations [41].

5.6. Investigation of OMLH and the Poland-Möbius association

In OMLH, diagnosis is clinical and radiological: assessment of the mandible (including synechiae and ankylosis), tongue, palate and choanae, limb radiographs and a search for cranial nerve palsies [5, 63]. In boys with limb defects and a scrotal or inguinal mass, splenogonadal fusion should be considered before an orchidectomy [25]. In the Poland-Möbius association, the chest radiograph shows unilateral hyperlucency, and hand radiographs document brachydactyly or symbrachydactyly [55]. Karyotype and microarray were normal in 11 of 14 cases of Poland-Möbius with genetic testing [4].

5.7. Prenatal and preimplantation diagnosis

There is no prenatal test for sporadic Möbius; preimplantation or molecular prenatal diagnosis is only applicable when an alternative Mendelian cause has been identified in the family (for example, HOXB1 or TUBB3) [10]. Ultrasound may show clubfoot, limb defects, micrognathia or polyhydramnios, but not the palsies [27, 60].

6. Differential Diagnosis

The main differential diagnosis is made on oculomotor examination. Facial palsy with full ocular motility indicates hereditary congenital facial palsy or facial muscle hypoplasia, and vertical limitation with ptosis indicates CFEOM, especially TUBB3-related [10, 33]. Globe retraction and narrowing of the palpebral fissure on adduction distinguish Duane syndrome, which coexisted with Möbius in 34% of Dutch patients [34, 64]. Congenital myopathies and myotonic dystrophy mimic the Möbius facies, but are accompanied by generalised weakness, hypotonia and electromyographic changes; the maternal history and the triplet expansion resolve the diagnosis of myotonic dystrophy [24, 66]. STAC3- and RYR1-related myopathies have anaesthetic implications, owing to the risk of malignant hyperthermia [10, 58].

In OMLH, isolated Robin sequence has no limb defects or palsies, Adams-Oliver syndrome is associated with aplasia cutis and is frequently familial, and amniotic bands produce constriction rings and asymmetric amputations with distal syndactylies [61]. Femur-fibula-ulna dysostosis and femoral-facial syndrome overlap with splenogonadal fusion with limb defects [7]. Isolated hypoglossia with situs inversus (OMIM 612776) and superior ankyloglossia belong to the same spectrum [6, 36].

7. Treatments and Risk Management Strategies

7.1. Principles and guidance documents

There is no therapy that alters the course of Möbius, the Poland-Möbius association or OMLH, nor an evidence-based guideline with graded recommendations. The available guidance documents are the 2007 consensus criteria and their revisions, the multidisciplinary protocol published in 2024 by the Alder Hey service in Liverpool, and retrospective surgical series [10, 24]. The Alder Hey protocol organises care by “ABC”-style priorities, with airway, feeding, vision and speech as priorities in the first years and psychological support as the focus of school age and adolescence; the core team includes a coordinating physician, a geneticist, a speech and language therapist, a psychologist and a clinical nurse specialist, extended to the other specialties [24]. The protocol of the Italian national centre in Parma includes an ophthalmologist, a neonatologist or paediatrician, a speech and language therapist, an orthodontist, an orthopaedic surgeon and a maxillofacial surgeon experienced in smile surgery, with visits every 6 to 24 months depending on severity [3]. The Brazilian textbook summarises the aim as reducing the effects and intensity of sequelae through surgical treatment and early stimulation and rehabilitation [22].

7.2. Airway

In the newborn with obstruction, transfer to a neonatal high-dependency unit allows oxygenation to be monitored and ventilatory support to be given [24]. The first measure is positioning; a nasopharyngeal airway is indicated when obstruction increases during feeding (the most common situation), appears with handling or does not improve with positioning [24]. Emergency endotracheal intubation is rare, and prolonged airway problems require tracheostomy, needed in 12.8% of the strict cohort [10, 24]. Central apnoea has been described in several cases; polysomnography is indicated if central or obstructive apnoea is suspected, obstructive apnoea requires ENT review, and signs of nocturnal hypoventilation (difficulty waking, morning drowsiness, poor appetite, hyperactivity, deterioration of behaviour and school performance, unexplained weight loss, morning headaches) justify polysomnography or transcutaneous pCO2 monitoring and oximetry [24]. If there is a risk of nocturnal aspiration, raising the head of the bed may help [24].

7.3. Feeding and nutrition

Early assessment of feeding and swallowing, with videofluoroscopy when indicated, establishes safety with different consistencies [24]. If there is aspiration, the texture is modified to slow the flow; if swallowing is safe and the problem is sucking, cleft palate strategies (cup feeding, soft bottles and different teats) are used under the supervision of a speech and language therapist [24]. If weight gain is poor despite these measures, an orogastric tube is placed, preferable to a nasal tube in infants who are obligate nasal breathers, and replaceable by a nasogastric tube if there are no airway problems; if there is no improvement after about 6 weeks, gastrostomy is considered, which the Alder Hey centre prefers for prolonged difficulties because it reduces oral aversion and facilitates the return to oral feeding [24]. Weaning uses the usual strategies, with flat spoons because the lips do not seal over the curved surface of a normal spoon; in older children, foods requiring intensive chewing or that crumble are avoided [24]. Reflux is treated as in the general population: upright feeding and spaced meals, alginates mixed with milk as first line, thickeners, proton pump inhibitors (for example omeprazole) in severe cases and prokinetics (for example domperidone) reserved for the most severe cases, owing to safety and efficacy concerns, in accordance with local protocols [24].

7.4. Eyes and strabismus

All children require ophthalmological assessment of corneal integrity, acuity and eye movements [24]. The Bell phenomenon, usually preserved, acts as a protective mechanism, and corneal ulceration is rare; if there is a red eye or irritation, preservative-free lubrication is started immediately and the child is referred to ophthalmology [24]. Corneal sensation should be tested, because V1 involvement may make the cornea anaesthetic; in that case referral to a centre performing corneal neurotisation to restore sensation is recommended [24].

Esotropia results from the unopposed action of the medial rectus, which contracts over time and makes surgery more difficult. The Alder Hey protocol proposes botulinum toxin injections into the medial rectus from 6 months, as indicated, to relax the muscle and facilitate future surgery, and considering strabismus surgery from 18 months [24]. In the strict cohort, 43.6% had undergone eye surgery, generally early to improve eye contact and restore binocular vision [10]. Early surgery reduces the risk of amblyopia and allows some degree of binocularity, and isolated recession of the medial recti has been proposed as first line because of the low rate of anterior segment ischaemia and new vertical deviation [3, 27].

7.5. Drugs with dosing

The glycopyrronium dose differs between labels: the maximum dose of Sialanar (64 µg/kg glycopyrronium) is lower than that of Cuvposa (0.1 mg/kg glycopyrrolate), and the products are not interchangeable without adjustment [71, 72]. There is no Möbius-specific guideline dose for any of these drugs; the doses given are those of the official labels, and their application to Möbius is an extrapolation from the approved indication.

7.6. Sialorrhoea: stepwise approach

Sialorrhoea aggravates the psychosocial impact of facial difference and is treated stepwise: postural management, training of oral awareness and oral skills, orthodontic appliances, pharmacotherapy, botulinum toxin injection into the salivary glands and, finally, salivary gland surgery [24]. Behavioural therapies that condition swallowing or wiping of saliva improve oral awareness but are difficult in children with cognitive impairment [24]. The Alder Hey centre uses glycopyrronium as first line, because it is easy to titrate and well tolerated, and the hyoscine patch as an alternative; the effects on oral hygiene should be monitored [24].

7.7. Speech, language and hearing

Speech and language therapy starts early and is adapted to age: informal speech assessment with video of feeding at 18 months and formal assessment from 3 years, including oromotor skills, articulation, receptive and expressive language and resonance; video analysis serves as a baseline [24]. Many children develop intelligible speech, but a subgroup depends on augmentative and alternative communication (pictures, gestures, sign language, electronic devices); sign language may be limited by limb anomalies [24]. Newborn hearing screening identifies hearing loss, and the threshold for objective testing should be low, because behavioural tests depend on cognitive and communicative skills; formal audiovestibular assessment is best done at around 6 to 8 years, with audiometry and CT of the labyrinths if there is concern [24].

7.8. Teeth and orthodontics

Inability to close the mouth, viscous saliva, dry mouth and dental hypoplasia make these patients highly susceptible to caries, so the preventive programme starts with the eruption of the first tooth [24]. During the mixed dentition, the orthodontist monitors occlusion and facial growth; orthognathic surgery at skeletal maturity corrects the long face and micrognathia [24]. In the systematic review of 124 patients, 60.86% were treated in paediatric dentistry and 56.52% with a surgical approach, and 78.26% of the studies described surgical, orthodontic and orthopaedic protocols [59].

7.9. Facial reanimation

Smile reconstruction is the only treatment that creates facial movement where none exists. The most widely used technique is free gracilis muscle transfer to the face, through a facelift incision, innervated by the masseteric nerve, a branch of the trigeminal nerve not affected by the syndrome, which produces a predictable voluntary smile; in selected patients with active facial branches, these may innervate the muscle [24]. Facial physiotherapy (neuromuscular retraining, stretching, massage, mirror feedback) is only useful when some movement exists, and post-operative rehabilitation teaches the child to use the muscle [24]. Surgery is usually offered after 4 years of age; the Alder Hey protocol proposes it from 6 years and recommends prior psychological assessment, waiting until the child understands what surgery can achieve and engages in physiotherapy, because patient-reported data on psychological benefit are lacking [24]. The Italian centre advocates surgery at preschool age after early diagnosis [3].

These series are retrospective, single-centre, with different assessment scales (surgeon score, independent panel, spontaneous smile) and no control group; they do not allow techniques to be compared across centres, and the spontaneous smile rate depends on the definition used [26, 73]. In adults with bilateral palsy, orthodromic temporalis tendon transfer has been described [74].

7.10. Limbs, chest and spine

Clubfoot and limb malformations are treated by teams specialised in limb differences, with plastic and orthopaedic surgeons, occupational therapists and physiotherapists [24]. In the Mexican series, 52% of patients with upper limb malformations underwent reconstruction, and each case should be assessed to decide on surgery and optimise rehabilitation [54]. In the Poland-Möbius association, hand surgery (for example, release of syndactyly webs) and chest wall and breast reconstruction aim at function and symmetry [4, 27]. Scoliosis is monitored and treated according to the usual criteria [24]. In OMLH, orthopaedic and plastic limb surgery, prostheses and maxillofacial surgery for synechiae and micrognathia are individualised [5].

7.11. Sleep, neurodevelopment and psychological support

Parents should keep sleep diaries and ensure a suitable environment; if the amount of sleep meets the child's needs, a pragmatic approach can be adopted that adapts the schedule to the child, with a safe space to play while the family sleeps; the experience of the Alder Hey centre is that sleep improves with growth [24]. In the North American survey, adults reported few therapeutic successes, and the authors advocate personalised approaches [57]. Development is screened with the Ages and Stages Questionnaire (ASQ) at 18 months and 3 years, and the Strengths and Difficulties Questionnaire (SDQ) is applied at 9, 13 and 16 years, with Wechsler scales when indicated [24]. Motor assessment may use the Alberta Infant Motor Scale or the Gross Motor Function Measure, not validated for Möbius [24].

Psychological support distinguishes two groups: patients with typical cognitive development, whose concerns relate to the visible difference, and those with special educational needs [24]. Common themes are low self-esteem, bullying, anxiety and low mood and difficulty expressing emotions through the face; interventions include psychoeducation for parents and school, cognitive behavioural therapy, compassion-focused therapy and social skills training, and transitions (starting school, changing school stage, leaving school, adult life, relationships and employment, including legal protection against discrimination) are points for assessment [24].

7.12. Anaesthesia and the perioperative period

Patients undergo many operations, and the airway may be difficult because of micrognathia, retrognathia, cleft palate, trismus, limited mouth opening, cervical spine anomalies and kyphoscoliosis [58]. In a 30-year-old man with Möbius, the Mallampati class progressed from II to IV over successive operations, possibly due to fibrosis; awake fibreoptic intubation failed owing to copious secretions, despite intravenous glycopyrrolate 0.2 mg, and difficulty cooperating, and intubation was achieved by videolaryngoscopy under dexmedetomidine sedation [58]. The recommendations of this report are to review previous anaesthetic records (tracheostomy, aspirations, feeding difficulties), have videolaryngoscopy, fibreoptic and surgical airway equipment available, administer antisialagogues, use opioids cautiously because of the risk of central hypoventilation, assess for heart disease, take care with positioning and venous access in patients with limb anomalies, and consider the risk of malignant hyperthermia when there is hypotonia or suspected myopathy [58]. Suspicion of an RYR1- or STAC3-related myopathy among the differentials reinforces this last precaution [10].

7.13. Agents to avoid, pregnancy and lactation

In women of childbearing potential, misoprostol carries a boxed warning on the FDA label: it can cause birth defects, abortion, premature birth or uterine rupture; it must not be used by pregnant women to reduce the risk of non-steroidal anti-inflammatory drug-induced ulcers, and in women of childbearing potential it may only be prescribed with a negative pregnancy test within the previous two weeks, effective contraception, oral and written warnings and initiation on the second or third day of menstruation [75]. Primary prevention of teratogenic Möbius and OMLH rests on information about misoprostol, cocaine, thalidomide, alcohol and benzodiazepines [22, 76]. Glycopyrronium (Sialanar®) is contraindicated in pregnancy and breastfeeding [71]. The sources consulted do not describe the course of pregnancy in women with Möbius; the difficult airway, scoliosis and limb anomalies justify early obstetric anaesthetic planning, by extension of the perioperative recommendations [58].

7.14. Regulatory status

No medicinal product is authorised specifically for Möbius, the Poland-Möbius association or OMLH. The sources consulted did not include ANVISA data on these products in Brazil.

7.15. Clinical research and developments in the last 12 months

ClinicalTrials.gov lists no therapeutic trials; the registered studies are observational: the National Human Genome Research Institute study of Möbius and congenital facial weakness (NCT02055248, 207 participants, completed in April 2020), which gave rise to the 2025 cohort, and the Boston Children's Hospital genetic study of CCDDs (NCT03059420, recruiting until 2030) [10, 77, 78]. There is therefore no table of randomised trials to present, and the therapeutic evidence rests on retrospective series without controlled comparison.

7.16. Transition and adult care

The Alder Hey protocol provides for formal genetic counselling and transition to adult services at around 20 years, with clinical photography for the record [24]. Adult problems include sleep disturbance, parasomnias and daytime sleepiness, the difficult airway accumulated through surgery and the social impact of facial difference [24, 57, 58].

8. Reproductive Options and Family Counselling

8.1. Recurrence risk

The empirical risk should be based on the proband's exact phenotype. MacDermot and colleagues identified as higher-risk features the absence of skeletal defects, isolated facial palsy, deafness, ophthalmoplegia and digital contractures, which are precisely the features of the Mendelian phenocopies [2]. In MacKinnon's series, all families with two affected members had at least one member who did not meet the criteria [33]. In families in which a Mendelian cause is identified (HOXB1, TUBB3, HOXA1, MYMK), counselling follows the corresponding inheritance and makes cascade testing, prenatal diagnosis and preimplantation genetic testing possible [10, 42]. In families with Poland-Möbius and Poland in a relative, autosomal dominant inheritance was postulated, with no gene identified [12, 13].

8.2. Exposures in pregnancy and prevention

The association with misoprostol is the most robust. In the Brazilian case-control study, 47 of 96 mothers (49%) of infants with Möbius and 3 of 96 (3%) mothers of infants with neural tube defects had used misoprostol in the first trimester (odds ratio 29.7; 95% confidence interval [95% CI] 11.6–76.0), almost always in a failed abortion attempt [30]. In a multicentre study of vascular disruption defects, exposure was 34.4% versus 4.3% in controls with other defects [79]. In São Paulo, of 42 exposed infants with anomalies, 17 had talipes equinovarus with cranial nerve defects and 9 terminal transverse limb defects with or without Möbius; the most frequently reported dose was 800 µg (range 200–16,000 µg) [76]. Meta-analyses of case-control studies estimated odds ratios of 25.31 (95% CI 11.11–57.66) and 26.48 (11.30–62.01) for Möbius and of 11.86 (4.86–28.90) and 10.75 (3.93–29.41) for terminal transverse limb defects [80, 81]. However, the Brazilian prospective cohort of 86 exposed pregnant women and 86 controls found no increase in major defects (2/67 versus 2/81), but did find more miscarriages (17.1% versus 5.8%; relative risk 2.97; 95% CI 1.12–7.88), with limited statistical power [82]. The high odds ratio in case-control studies reflects a strong association, but the absolute risk of Möbius after exposure is low [60, 82]. Women who continue a pregnancy after a failed medical abortion with misoprostol should be informed of this risk [39].

Early chorionic villus sampling is associated with limb defects and OMLH: in 289 pregnancies with sampling at 56–66 days, five babies had severe limb anomalies, four with OMLH [31]; in 75 babies with reduction defects after sampling, severity correlated with earliness (median 56 days in the most severe defects and 72 days in the less severe) [32]; in Taiwan, the incidence of severe limb defects was 0.22% after sampling versus 0.0026% in the population [83]. The Oxford Desk Reference associates OMLH with very early sampling, before the tenth week [61]. Prevention involves avoiding sampling before 10 weeks and avoiding vasoactive teratogens; the Brazilian textbook stresses that there is no safe minimum dose of a teratogen [22, 61].

8.3. Prenatal diagnosis, twins and counselling of minors

There is no prenatal test for sporadic Möbius, and ultrasound mainly detects the associated defects (clubfoot, limb defects, micrognathia, polyhydramnios) [27, 60]. In the 2025 cohort, ten probands resulted from recognised multiple pregnancies, six had a living unaffected fraternal twin and three had a history of a vanishing twin; in Italy, one pair of monozygotic twins was concordant with different expression [3, 10]. Counselling should address parental guilt when there was exposure to teratogens or procedures, explaining the multifactorial nature of the condition. Affected adolescents and young adults should receive their own genetic counselling before reproductive age, which the Alder Hey protocol places at around 20 years [24].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and incidence

The Italian study is the only population-based study with current criteria; the authors consider that the tenfold higher prevalence in the Netherlands and the high estimates from the United States, Sweden and Brazil reflect broader criteria and the absence of a population basis [3]. There was no difference by sex or by Italian region after weighting for population, which argues against regional environmental factors [3]. In the 2025 North American cohort, the sexes were equally represented, and the genetic ancestry of the 67 sequenced patients was European in 49, Hispanic in 12, Asian in 3 and African in 2 [10].

9.2. Misoprostol and Latin America

The frequency of misoprostol-associated Möbius reflects the use of the drug as an abortifacient in countries where abortion is illegal or restricted, especially Brazil and other countries of South and Central America [76, 82]. In the Colombian series of 140 patients (2008–2018), 47% had prenatal exposure to misoprostol, almost always with abortive intent, with no difference in craniofacial manifestations between exposed and unexposed patients [52]. In Italy, where misoprostol is not used, and in the North American cohort, with 2 exposures in 131 prenatal histories, the contribution of this drug is minimal [3, 10]. The recent European cases occurred after failed medical abortion (France, 2008; Netherlands, 2026) [39, 60].

9.3. Portugal and Brazil

In Portugal, the case of a newborn girl born at 34 weeks with Möbius and hypoplasia of the depressor anguli oris muscle, with bilateral absence of the VII nerve and absence of the left VI nerve on MRI, has been published [62]. The sources consulted do not describe the prevalence in Portugal. In Brazil, the reference textbook estimates 1 in 250,000 live births and highlights misoprostol as the predominant environmental factor; the large misoprostol studies, a family with Poland and Poland-Möbius and a case of OMLH with superior ankyloglossia were Brazilian [13, 22, 30, 36]. A Brazilian family of a mother and son with Möbius and skeletal anomalies was described in 2010 [2].

9.4. Reference networks and patient organisations

The relevant European Reference Network is ERN CRANIO, dedicated to rare or complex craniofacial anomalies and ear, nose and throat disorders, which covers craniofacial anomalies, cleft lip and palate and orodental anomalies [28]. Patient organisations include the Moebius Syndrome Foundation (United States, www.moebiussyndrome.com), which also welcomes patients with syndromic CFEOM3 with facial weakness [21], the Associazione Italiana Sindrome di Moebius (AISMO, www.moebius-italia.it), which maintains the Italian registry in partnership with the Parma centre [3], the Moebius Foundation of Colombia [52] and the Spanish Moebius syndrome foundation [43]. The family conferences of the North American foundation made it possible to recruit 73.8% of the largest published cohort [10].

10. Illustrative Clinical Case

10.1. Poland-Möbius with a PLXND1 variant of uncertain significance

Glass and colleagues published in 2022 the case of a boy, the second child of Pakistani parents who were first cousins, born at term by elective caesarean section, with an uneventful pregnancy and no maternal exposure to medicines or drugs [4]. At birth he had right facial palsy; left-sided palsy was also noted later. The left upper limb showed symbrachydactyly, with chest wall deformity, apparent absence of the pectoralis major and absence of the nipple-areola complex [4].

In the neonatal period he had an aspiration of milk that led to a 20-day admission to intensive care. Echocardiography showed a patent ductus arteriosus and a moderate atrial septal defect, managed expectantly; oral feeding was poorly coordinated and was supported by a nasogastric tube; flexible laryngoscopy revealed mild to moderate laryngomalacia with pooling of saliva, and brain MRI, requested for generalised hypotonia, showed only a left frontal developmental venous anomaly [4]. Because of persistent reflux and further aspiration, a gastrostomy with fundoplication was performed [4].

Before 12 months, he was seen by plastic surgeons specialised in facial palsy and congenital limb anomalies: asymmetric bilateral facial palsy, worse on the right; bilateral failure of abduction; bilateral blepharoptosis; no facial skeletal dysmorphism; a high-arched but intact hard palate; and good bilateral masseteric contraction, a finding relevant to future facial reanimation innervated by the masseteric nerve [4]. On the left, the pectoralis major and the nipple-areola complex were completely absent, with axillary hollowing; the forearm and hand were hypoplastic, with symbrachydactyly, a thumb with a reasonable thenar eminence and hypoplastic, biphalangeal and syndactylous index, middle and ring fingers [4]. At 18 months the first and fourth web spaces were released, and the patient became a candidate for bilateral facial reanimation [4].

Genetic testing identified two heterozygous variants in PLXND1: a likely benign synonymous variant, NM_015103.2:c.4677C>T p.(Asn1559=) (identical numbering in MANE NM_015103.3), and a missense variant, c.2890G>A p.(Val964Met) (rs553781761; gnomAD frequency 8.38×10⁻⁵), classified as a variant of uncertain significance and inherited from the mother, who had neither Poland nor Möbius [4]. On the MANE transcript NM_015103.3, the variant is described as c.2890G>A p.(Val964Met) (NC_000003.12:g.129572889C>T) [44]. Figure 1 of the article shows the face with asymmetric bilateral facial palsy, esotropia and blepharoptosis, the left chest wall and the hand after web space release: https://pmc.ncbi.nlm.nih.gov/articles/PMC9801559/figure/Fig1/ [4].

10.2. Critical appraisal

The case illustrates the Poland-Möbius phenotype and the typical needs of the first months: airway and aspiration, tube feeding and gastrostomy, reflux, mild heart disease and early hand surgery [4, 24]. Three aspects limit its interpretation. The bilateral blepharoptosis places the patient outside the strict 2025 criteria, which exclude limitation of elevation associated with ptosis and recommend, in such cases, searching for alternative causes such as CFEOM [10]. The PLXND1 variant was inherited from an unaffected mother, is of uncertain significance and was not confirmed by functional studies; the authors themselves allow for highly variable penetrance or other factors, and the large cohorts found no variants in this gene [4, 10]. Parental consanguinity makes a search for recessive causes by exome or genome sequencing desirable. The management described corresponds to the practice of reference centres, but should not be read as proof of genetic causality [24].

10.3. Portuguese case

In Portugal, a newborn girl born at 34 weeks, daughter of a healthy second-para mother, with Apgar scores of 9, 9 and 10, had feeding difficulty in the first hour of life, hypomimia, an asymmetric cry due to hypoplasia of the depressor anguli oris muscle, incomplete eyelid closure, limited horizontal eye movements and generalised hypotonia [62]. 3D T2 DRIVE MRI showed bilateral absence of the VII nerve and absence of the left VI nerve; she was discharged at 19 days, with progressive improvement in feeding, and at 20 months still had esotropia and mild feeding difficulties, under multidisciplinary follow-up with paediatric neurology [62]. The case shows the usefulness of high-resolution MRI of the cranial nerves in the newborn and the need to examine the whole face in the presence of an asymmetric cry.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Möbius is not progressive, and most patients have normal intelligence; intellectual disability affects about 10–15% according to Smith's and 30.9% in the strict North American cohort, recruited at family conferences that include children with complex needs [1, 10]. Mortality is concentrated in the neonatal period and in patients with bulbar involvement: two of 37 Dutch patients died as newborns, and in the review of 449 cases 20 died of apnoeas, aspiration or aspiration pneumonia and 10 required prolonged ventilation [2, 24]. In the Italian series of 164 patients, without misoprostol and with follow-up at a reference centre, there were no known deaths [3]. Functional prognosis depends on the associated anomalies and on the earliness of intervention [22]. Children with cleft palate, vocal cord paralysis or tracheostomy and gastrointestinal anomalies more frequently have intellectual disability and seizures, which allows some stratification, although there are no robust phenotypic subgroups [10]. The expressionless face and speech difficulties affect social acceptance, but self-perception studies document resilience [1]; adults report sleep disturbances persisting since childhood [57]. Bilateral facial reanimation produces symmetry and function rated excellent or good in 96% in a series of 56 patients and a spontaneous smile in 59% [26]. In OMLH, intelligence and stature are generally normal, but forms with pulmonary hypoplasia or extensive defects may be lethal [5, 35].

11.2. Surveillance plan

12. Summary and Final Considerations

Möbius sequence is defined by congenital, non-progressive facial palsy with limited abduction, with full vertical motility and no ptosis; this strict definition, consolidated between 2007 and 2025, separates Möbius from a set of Mendelian phenocopies (hereditary congenital facial palsy due to HOXB1, CFEOM3 due to TUBB3, HOXA1 syndromes, congenital myopathies such as Carey-Fineman-Ziter and congenital myotonic dystrophy) that accounted for most of the families with vertical transmission described in the past. In patients who meet the strict criteria, the condition is sporadic, with no recurrence in siblings or offspring in the largest published cohort, and exome and genome sequencing identify no germline cause; the associations with PLXND1 and REV3L have not been replicated and remain provisional.

The most consistent pathogenic model is a vascular disruption of the hindbrain between the fourth and eighth weeks, shared with the Poland anomaly, the Klippel-Feil sequence and the oromandibular-limb hypogenesis spectrum, with contributions from vasoactive teratogens, above all misoprostol used as an abortifacient, and from early chorionic villus sampling in OMLH. The Poland-Möbius association occurs in about one in seven patients with Möbius and is not a distinct genetic entity. Population prevalence, measured with current criteria in Italy, is about 0.3 per 100,000 inhabitants, and in Latin American series almost half of the patients had prenatal exposure to misoprostol.

Diagnosis is clinical and rests on rigorous oculomotor examination and high-resolution MRI of the cranial nerves; genetic testing mainly serves to exclude differentials and a negative result is to be expected. Management is multidisciplinary and sequential: airway, feeding and corneal protection in the newborn; botulinum toxin and strabismus surgery, speech therapy, hearing and oral health in the first years; facial reanimation by free muscle transfer innervated by the masseteric nerve at school age; psychological support, sleep and transition in adolescence. There is no specific drug therapy, and the drugs used (botulinum toxin, glycopyrronium) are extrapolations from their approved indications. Genetic counselling depends on phenotypic rigour: in strict Möbius the recurrence risk is low, whereas a familial “Moebius-like” presentation requires a search for a Mendelian cause.

13. References

1. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Moebius sequence; p. 322–325.
2. OMIM® Online Mendelian Inheritance in Man. %157900 MOEBIUS SYNDROME; MBS. Johns Hopkins University; last edited 17/09/2025. https://omim.org/entry/157900. Accessed 28 October 2026.
3. Carta A, Favilla S, Calzetti G, Casalini MC, Ferrari PF, Bianchi B, et al. The epidemiology of Moebius syndrome in Italy. Orphanet J Rare Dis. 2021;16(1):162. doi:10.1186/s13023-021-01808-2. PMID: 33827605. PMC8028757.
4. Glass GE, Mohammedali S, Sivakumar B, Stotland MA, Abdulkader F, Prosser DO, et al. Poland-Möbius syndrome: a case report implicating a novel mutation of the PLXND1 gene and literature review. BMC Pediatr. 2022;22(1):745. doi:10.1186/s12887-022-03803-3. PMID: 36581828. PMC9801559.
5. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Oromandibular-limb hypogenesis spectrum; p. 908–909.
6. OMIM® Online Mendelian Inheritance in Man. %103300 HYPOGLOSSIA-HYPODACTYLY SYNDROME. Johns Hopkins University. https://omim.org/entry/103300. Accessed October 2026.
7. OMIM® Online Mendelian Inheritance in Man. 183300 SPLENOGONADAL FUSION WITH LIMB DEFECTS AND MICROGNATHIA. Johns Hopkins University. https://omim.org/entry/183300. Accessed October 2026.
8. OMIM® Online Mendelian Inheritance in Man. *604282 PLEXIN D1; PLXND1. Johns Hopkins University. https://omim.org/entry/604282. Accessed October 2026.
9. OMIM® Online Mendelian Inheritance in Man. *602776 REV3-LIKE, POLYMERASE (DNA-DIRECTED), ZETA, CATALYTIC SUBUNIT; REV3L. Johns Hopkins University. https://omim.org/entry/602776. Accessed October 2026.
10. Webb BD, Jurgens JA, Narisu N, Zhang Z, Barry BJ, Van Ryzin C, et al. Systematic phenotype and genotype characterization of Moebius syndrome. Genet Med Open. 2025;3:103437. doi:10.1016/j.gimo.2025.103437. PMID: 40662098. PMC12256340.
11. Orphanet. Moebius syndrome. ORPHA:570. https://www.orpha.net/en/disease/detail/570
12. Rojas-Martínez A, García-Cruz D, Rodríguez García A, Sánchez-Corona J, Rivas F. Poland-Moebius syndrome in a boy and Poland syndrome in his mother. Clin Genet. 1991;40(3):225-8. doi:10.1111/j.1399-0004.1991.tb03081.x. PMID: 1773538.
13. Larrandaburu M, Schüler L, Ehlers JA, Reis AM, Silveira EL. The occurrence of Poland and Poland-Moebius syndromes in the same family: further evidence of their genetic component. Clin Dysmorphol. 1999;8(2):93-9. PMID: 10319197.
14. OMIM® Online Mendelian Inheritance in Man. #614744 FACIAL PARESIS, HEREDITARY CONGENITAL, 3; HCFP3. Johns Hopkins University; last edited 07/03/2018. https://omim.org/entry/614744. Accessed 28 October 2026.
15. OMIM® Online Mendelian Inheritance in Man. %173800 POLAND SYNDROME. Johns Hopkins University. https://omim.org/entry/173800. Accessed October 2026.
16. Orphanet. Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome. ORPHA:2560. https://www.orpha.net/en/disease/detail/2560
17. Orphanet. Poland syndrome. ORPHA:2911. https://www.orpha.net/en/disease/detail/2911
18. Orphanet. Oromandibular-limb hypogenesis syndrome. ORPHA:2749. https://www.orpha.net/en/disease/detail/2749
19. Orphanet. Hypoglossia-hypodactyly syndrome. ORPHA:989. https://www.orpha.net/en/disease/detail/989
20. Orphanet. Splenogonadal fusion-limb defects-micrognathia syndrome. ORPHA:2063. https://www.orpha.net/en/disease/detail/2063
21. Whitman MC, Jurgens JA, Hunter DG, Engle EC. Congenital Fibrosis of the Extraocular Muscles Overview. 2004 Apr 27 [updated 2021 Aug 12]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1348/
22. Sousa JGO, Vasconcelos MAS. Síndrome de Moebius. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 180–181.
23. Gruber B, Burton BK. Oromandibular-limb hypogenesis syndrome following chorionic villus sampling. Int J Pediatr Otorhinolaryngol. 1994;29(1):59-63. doi:10.1016/0165-5876(94)90109-0. PMID: 8169048.
24. Odedra A, Blumenow W, Dainty J, Dasgupta S, Dominguez-Gonzalez S, Gonzalez-Martin J, et al. Multidisciplinary Care for Moebius Syndrome and Related Disorders: Building a Management Protocol. J Clin Med. 2024;13(11). doi:10.3390/jcm13113309. PMID: 38893020. PMC11172851.
25. Cabrera Viteri MI, Acosta Farina D, Morales Mayorga H, Cabrera Johnson M, Albán Castro S. Splenogonadal fusion associated with Moebius and Poland syndromes: first case reported. Cir Pediatr. 2021;34(4):219-222. PMID: 34606704.
26. Panzenbeck P, Zubler C, de Buitleir E, Grobbelaar AO, Leckenby JI. Facial reanimation in Moebius syndrome - 25-Year experience in treating bilateral facial paralysis. J Plast Reconstr Aesthet Surg. 2025;106:238-245. doi:10.1016/j.bjps.2025.05.013. PMID: 40446611.
27. Monawwer SA, Ali S, Naeem R, Ali SH, Rabbani A, Khan M, et al. Moebius Syndrome: An Updated Review of Literature. Child Neurol Open. 2023;10:2329048X231205405. doi:10.1177/2329048X231205405. PMID: 37868706. PMC10588417.
28. ERN CRANIO. European Reference Network for rare and/or complex craniofacial anomalies and ear, nose and throat (ENT) disorders. https://www.ern-cranio.eu/ . Accessed 1 November 2026.
29. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Poland sequence; p. 428–429.
30. Pastuszak AL, Schüler L, Speck-Martins CE, Coelho KE, Cordello SM, Vargas F, et al. Use of misoprostol during pregnancy and Möbius' syndrome in infants. N Engl J Med. 1998;338(26):1881-5. doi:10.1056/NEJM199806253382604. PMID: 9637807.
31. Firth HV, Boyd PA, Chamberlain P, MacKenzie IZ, Lindenbaum RH, Huson SM. Severe limb abnormalities after chorion villus sampling at 56-66 days' gestation. Lancet. 1991;337(8744):762-3. doi:10.1016/0140-6736(91)91374-4. PMID: 1672394.
32. Firth HV, Boyd PA, Chamberlain PF, MacKenzie IZ, Morriss-Kay GM, Huson SM. Analysis of limb reduction defects in babies exposed to chorionic villus sampling. Lancet. 1994;343(8905):1069-71. doi:10.1016/s0140-6736(94)90182-1. PMID: 7909100.
33. MacKinnon S, Oystreck DT, Andrews C, Chan WM, Hunter DG, Engle EC. Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome. Ophthalmology. 2014;121(7):1461-8. doi:10.1016/j.ophtha.2014.01.006. PMID: 24612975. PMC4082742.
34. Verzijl HT, van der Zwaag B, Cruysberg JR, Padberg GW. Möbius syndrome redefined: a syndrome of rhombencephalic maldevelopment. Neurology. 2003;61(3):327-33. doi:10.1212/01.wnl.0000076484.91275.cd. PMID: 12913192.
35. Chicarilli ZN, Polayes IM. Oromandibular limb hypogenesis syndromes. Plast Reconstr Surg. 1985;76(1):13-24. doi:10.1097/00006534-198507000-00003. PMID: 4011767.
36. Carvalho LRRA, Pinto LSS, de Sousa GP, Correia JPDP, de Moura MS. Oromandibular Limb Hypogenesis Syndrome: Overlap of Moebius and Ankyloglossia Superior With Severe Limb Defects. Cleft Palate Craniofac J. 2021;58(4):518-524. doi:10.1177/1055665620954736. PMID: 32909817.
37. Aufderheide K, Whitman MC. Update on Congenital Cranial Dysinnervation Disorders (CCDDs). Int Ophthalmol Clin. 2026;66(2):180-186. doi:10.1097/IIO.0000000000000602. PMID: 41870107.
38. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Facial asymmetry; p. 146–149.
39. Bos-Thompson MA, Hillaire-Buys D, Roux C, Faillie JL, Amram D. Möbius syndrome in a neonate after mifepristone and misoprostol elective abortion failure. Ann Pharmacother. 2008;42(6):888-92. doi:10.1345/aph.1K550. PMID: 18460590.
40. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Hyperthermia-induced spectrum of defects; p. 808–811.
41. Peck H, Krueger LA, Sperry ED, Monsberger R, Grunwald S, Swarr DT, et al. Moebius-Plus Phenotype With Positive RCEM Episignature May Indicate Broader Embryologic Malformation Spectrum Detectable by Methylation Profiling. Am J Med Genet A. 2026;. doi:10.1002/ajmg.a.70300. PMID: 42753165.
42. GeneGuidance. HOXB1 — clinical gene curation (HCFP3). Local GeneGuidance database; accessed 1 November 2026.
43. Tomas-Roca L, Tsaalbi-Shtylik A, Jansen JG, Singh MK, Epstein JA, Altunoglu U, et al. De novo mutations in PLXND1 and REV3L cause Möbius syndrome. Nat Commun. 2015;6:7199. doi:10.1038/ncomms8199. PMID: 26068067. PMC4648025.
44. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. https://variantvalidator.org. Accessed 1 November 2026.
45. Patel RM, Liu D, Gonzaga-Jauregui C, Jhangiani S, Lu JT, Sutton VR, et al. An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a TUBB3 mutation. Cold Spring Harb Mol Case Stud. 2017;3(2):a000984. doi:10.1101/mcs.a000984. PMID: 28299356. PMC5334472.
46. Moresco G, Bedeschi MF, Venturin M, Villa R, Costanza J, Mauri A, et al. Exploring the Impact of Genetics in a Large Cohort of Moebius Patients by Trio Whole Exome Sequencing. Genes (Basel). 2024;15(8). doi:10.3390/genes15080971. PMID: 39202332. PMC11353404.
47. GeneGuidance. REV3L — clinical gene curation and condition Moebius syndrome (ORPHA:570). Local GeneGuidance database; accessed 1 November 2026.
48. GeneGuidance. PLXND1 — clinical gene curation. Local GeneGuidance database; accessed 1 November 2026.
49. Tracicaru MP, Tracicaru RV, Hînganu D, Hînganu MV. The Etiology of Moebius Syndrome-Making the Case for Animal Models. Int J Mol Sci. 2025;26(9). doi:10.3390/ijms26094217. PMID: 40362454. PMC12072003.
50. Webb BD, Shaaban S, Gaspar H, Cunha LF, Schubert CR, Hao K, et al. HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1-/- mice. Am J Hum Genet. 2012;91(1):171-9. doi:10.1016/j.ajhg.2012.05.018. PMID: 22770981. PMC3397264.
51. Bell C, Nevitt S, McKay VH, Fattah AY. Will the real Moebius syndrome please stand up? A systematic review of the literature and statistical cluster analysis of clinical features. Am J Med Genet A. 2019;179(2):257-265. doi:10.1002/ajmg.a.60683. PMID: 30556292.
52. Ruge-Peña NO, Valencia C, Cabrera D, Aguirre DC, Lopera F. Moebius syndrome: Craniofacial clinical manifestations and their association with prenatal exposure to misoprostol. Laryngoscope Investig Otolaryngol. 2020;5(4):727-733. doi:10.1002/lio2.377. PMID: 32864445. PMC7444781.
53. Strömland K, Sjögreen L, Miller M, Gillberg C, Wentz E, Johansson M, et al. Mobius sequence--a Swedish multidiscipline study. Eur J Paediatr Neurol. 2002;6(1):35-45. doi:10.1053/ejpn.2001.0540. PMID: 11993954.
54. Telich-Tarriba JE, Navarro-Barquin DF, Verdezoto-Gaibor K, Cardenas-Mejia A. Prevalence of Hand Malformations in Patients With Moebius Syndrome and Their Management. Hand (N Y). 2022;17(6):1292-1296. doi:10.1177/1558944721994265. PMID: 33641474. PMC9608308.
55. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. Poland syndrome; p. 883–885.
56. Miller MT, Strömland K, Ventura L, Johansson M, Bandim JM, Gillberg C. Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review. Int J Dev Neurosci. 2005;23(2-3):201-19. doi:10.1016/j.ijdevneu.2004.06.007. PMID: 15749246.
57. Dietch JR, Sy JRT, Anderson E, Bogart K. Sleep health of adults and children with Moebius syndrome. Res Dev Disabil. 2025;158:104924. doi:10.1016/j.ridd.2025.104924. PMID: 39864265. PMC12011210.
58. Vegunta G, Patafio G, Gade S, Awuku K, Kalyoussef E, Shah SP. Anesthetic Challenges of Caring for an Adult With Moebius Syndrome: A Case Report. Case Rep Anesthesiol. 2025;2025:1908098. doi:10.1155/cria/1908098. PMID: 41278114. PMC12636042.
59. Alarcón-Sánchez MA, Romero-Servin S, Yessayan L, Mosaddad SA, Heboyan A. Oral findings and comprehensive dental management of Moebius syndrome: a systematic review. BMC Oral Health. 2024;24(1):192. doi:10.1186/s12903-024-03968-6. PMID: 38321523. PMC10845393.
60. de Groot-van der Mooren MD, Mulder-de Tollenaer SM, Flach HZ, Bouman K, Manten GTR. [Moebius syndrome after maternal misoprostol use]. Ned Tijdschr Geneeskd. 2026;169. PMID: 41569079.
61. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Limb reduction defects; p. 212–215.
62. Borges J, São-Pedro M, Correia S, Rocha S. Moebius syndrome and depressor anguli oris muscle hypoplasia. Port J Pediatr. 2021;52:64-7. doi:10.25754/pjp.2021.19327.
63. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Micrognathia and Robin sequence; p. 232–235.
64. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Duane retraction syndrome; p. 132–133.
65. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Syndactyly; p. 328–329.
66. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Myotonic dystrophy (DM1); p. 496–499.
67. López Gutierrez D, Luna López I, Medina Mata BA, Moreno Castro S, García Rangel FY. Physiopathologic Bases of Moebius Syndrome: Combining Genetic, Vascular, and Teratogenic Theories. Pediatr Neurol. 2024;153:1-10. doi:10.1016/j.pediatrneurol.2024.01.007. PMID: 38306744.
68. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Amyoplasia congenita disruptive sequence; p. 226–229.
69. U.S. Food and Drug Administration. BOTOX (onabotulinumtoxinA) for injection — prescribing information. BLA 103000. Version of 18/11/2023. Available via openFDA/DailyMed.
70. INFARMED. Botox 100 Unidades Allergan, pó para solução injetável — Resumo das Características do Medicamento (Abbvie, Lda.). Infomed, med_id 29406. https://extranet.infarmed.pt/INFOMED-fo/ . Accessed 1 November 2026.
71. European Medicines Agency. Sialanar (glycopyrronium) — EPAR product information (Summary of Product Characteristics). https://www.ema.europa.eu/en/documents/product-information/sialanar-epar-product-information_en.pdf. Accessed 1 November 2026.
72. U.S. Food and Drug Administration. CUVPOSA (glycopyrrolate) oral solution — prescribing information. NDA 022571. Version of 19/12/2024. Available via openFDA/DailyMed.
73. Fukumoto-Inukai KA, Palafox D, Chávez-Serna E, Mendoza-Molina NA, Prieto-Vargas V, Telich-Tarriba JE, et al. Facial Reanimation in Moebius Syndrome Using Bilateral Free Gracilis Transfer: 1-Stage versus 2-Stage Procedures. Plast Reconstr Surg. 2025;156(4):567e-575e. doi:10.1097/PRS.0000000000012106. PMID: 40100160.
74. He M, Azizzadeh B. Orthodromic Reshaping Temporalis Tendon Transfer for Aesthetic Facial Reanimation in Adults with Moebius Syndrome and Bilateral Facial Paralysis: Technical Insights and Indications. Facial Plast Surg Aesthet Med. 2025;27(4):327-329. doi:10.1089/fpsam.2024.0303. PMID: 39834316.
75. U.S. Food and Drug Administration. CYTOTEC (misoprostol) tablets — prescribing information. NDA 019268. Version of 04/06/2026. Available via openFDA/DailyMed.
76. Gonzalez CH, Marques-Dias MJ, Kim CA, Sugayama SM, Da Paz JA, Huson SM, et al. Congenital abnormalities in Brazilian children associated with misoprostol misuse in first trimester of pregnancy. Lancet. 1998;351(9116):1624-7. doi:10.1016/S0140-6736(97)12363-7. PMID: 9620717.
77. ClinicalTrials.gov. Study on Moebius Syndrome and Congenital Facial Weakness Disorders. NCT02055248. https://clinicaltrials.gov/study/NCT02055248 . Accessed 1 November 2026.
78. ClinicalTrials.gov. Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies. NCT03059420. https://clinicaltrials.gov/study/NCT03059420 . Accessed 1 November 2026.
79. Vargas FR, Schuler-Faccini L, Brunoni D, Kim C, Meloni VF, Sugayama SM, et al. Prenatal exposure to misoprostol and vascular disruption defects: a case-control study. Am J Med Genet. 2000;95(4):302-6. doi:10.1002/1096-8628(20001211)95:4<302::aid-ajmg2>3.0.co;2-b. PMID: 11186881.
80. da Silva Dal Pizzol T, Knop FP, Mengue SS. Prenatal exposure to misoprostol and congenital anomalies: systematic review and meta-analysis. Reprod Toxicol. 2006;22(4):666-71. doi:10.1016/j.reprotox.2006.03.015. PMID: 16750609.
81. Jingran G, Yan D, Xiaoying Y. Risk of teratogenicity in continued pregnancy after gestational exposure to mifepristone and/or misoprostol: a systematic review and meta-analysis. Arch Gynecol Obstet. 2024;310(3):1331-1342. doi:10.1007/s00404-024-07616-w. PMID: 38980347.
82. Schüler L, Pastuszak A, Sanseverino TV, Orioli IM, Brunoni D, Ashton-Prolla P, et al. Pregnancy outcome after exposure to misoprostol in Brazil: a prospective, controlled study. Reprod Toxicol. 1999;13(2):147-51. doi:10.1016/s0890-6238(98)00072-0. PMID: 10213522.
83. Hsieh FJ, Shyu MK, Sheu BC, Lin SP, Chen CP, Huang FY. Limb defects after chorionic villus sampling. Obstet Gynecol. 1995;85(1):84-8. doi:10.1016/0029-7844(94)00332-8. PMID: 7800331.