Moebius Syndrome Research Articles

Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction.

Fibroblast growth factor (FGF) 8 is important for GnRH neuronal development with human mutations resulting in Kallmann syndrome. Murine data suggest a role for Fgf8 in hypothalamo-pituitary development; however, its role in the etiology of wider hypothalamo-pituitary dysfunction in humans is unknown. The objective of this study was to screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 was analyzed by PCR and direct sequencing. Ethnically matched controls were then screened for mutated alleles (n = 480-686). Localization of Fgf8/FGF8 expression was analyzed by in situ hybridization in developing murine and human embryos. Finally, Fgf8 hypomorphic mice (Fgf8(loxPNeo/-)) were analyzed for the presence of forebrain and hypothalamo-pituitary defects. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. Second, a heterozygous p.Q216E mutation was identified in a female patient with an absent corpus callosum, hypoplastic optic nerves, and Moebius syndrome. FGF8 was expressed in the ventral diencephalon and anterior commissural plate but not in Rathke's pouch, strongly suggesting early onset hypothalamic and corpus callosal defects in these patients. This was consolidated by significantly reduced vasopressin and oxytocin staining neurons in the hypothalamus of Fgf8 hypomorphic mice compared with controls along with variable hypothalamo-pituitary defects and HPE. We implicate FGF8 in the etiology of recessive HPE and potentially septo-optic dysplasia/Moebius syndrome for the first time to our knowledge. Furthermore, FGF8 is important for the development of the ventral diencephalon, hypothalamus, and pituitary.

Moebius Syndrome: A Rare Case Report

Moebius syndrome is an extremely rare disorder. Only approximately few hundred cases have been reported in literature. In a nationwide survey reported in 2003, the prevalence of this syndrome was at least 0.002% of births for the years 1996 to 1998. The definition and diagnostic criteria for Moebius syndrome vary among authors. In most studies, it is defined as congenital facial weakness combined with abnormal ocular abduction. The list of signs and symptoms mentioned in various sources for Moebius syndrome includes more than 20 peculiar features. Here, we report an interesting case of Moebius syndrome in a 12-year-old male patient with all the important peculiar signs and symptoms.

Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations

Background: To describe clinical and genetic observations in a patient with horizontal gaze palsy and progressive scoliosis (HGPPS) without identified mutations in the ROBO3 gene.Materials and Methods: Neurologic and orthopedic evaluation of the proband; sequencing all exons, exon-intron boundaries, and promoter region of ROBO3 in the proband and his mother. Array CGH was also carried out in the proband and his mother to evaluate possible chromosomal deletion(s) and/or duplication(s).Results: The proband had complete horizontal gaze restriction with full vertical gaze and small amplitude horizontal pendular nystagmus. He also had severe scoliosis and brainstem hypoplasia pathognomonic of HGPPS. However, complete sequencing of ROBO3 twice in both forward and reverse directions did not reveal any mutations. Array CGH investigation revealed no chromosomal abnormalities.Conclusions: This patient had clinical and neuroimaging characteristics considered pathognomonic of HGPPS and yet did not have ROBO3 mutations. A clinical misdiagnosis is unlikely in the absence of facial weakness (typical of Moebius syndrome), deafness (typical of the HOXA1 spectrum), or mental retardation (typical of other central decussation abnormalities). It is perhaps more likely that a phenotype identical to HGPPS can be caused by abnormalities in ROBO3 splice variant expression, by mutations of a gene other than ROBO3, or by some environmental or epigenetic factor(s) inhibiting the action of ROBO3 or its protein product in the developing brainstem.

Ophthalmologic and Systemic Features in Möbius Syndrome: An Italian Case Series

To describe clinical features in a large series of Möbius syndrome (MBS) cases, investigating whether specific neuro-ophthalmologic patterns of disease may provide further insight into MBS pathogenesis. Observational, prospective study. Fifty-five affected subjects. To make an MBS diagnosis, the criteria recommended in the First Scientific Conference on Möbius Syndrome were followed. Patients who did not meet the minimal criteria were classified as Möbius-like cases and were considered separately. Complete ophthalmologic evaluation, eyelid measurements, presence of abnormal tearing, and ocular motility also were assessed. Pattern of ocular motility alteration, visual function disturbances, and eyelid and tearing defect. Forty-six sporadic cases of true MBS were identified, with 3 specific patterns of ocular motility alterations. Pattern A, consisting of orthotopia in primary position with a complete defect in both abduction and adduction ocular movements, was found in 41% of cases. Pattern B, with large-angle esotropia, crossed fixation, and a relative sparing of convergence and adduction, was documented in 50% of cases. Pattern C, characterized by a large-angle exotropia in primary position with torticollis, absence of convergence, and vertical eye misalignment, was present in the minority of the patients (9%). Bilateral complete facial nerve palsy with lagophthalmos was present in 83% of patients; lacrimation showed abnormalities in 33% of cases. Visual acuity was good or impaired only moderately in all tested patients. Binocular function was testable in 31 of 46 patients, and all of them showed a complete absence of stereopsis with suppressive scotoma. Based on the observed 3 different ocular motility defect patterns, the most compatible site and extension of the brainstem damage was inferred. Each pattern may reflect a different type of injury likely occurred during embryogenesis. The comparison of the characteristics of this series with those reported in different geographic areas supports the evidence that MBS does not differ phenotypically worldwide. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Toxicidad del misoprostol sobre la gestación: Revisión de la literatura

Misoprostol, a synthetic analog of prostaglandin E1, is currently used in Chile and other countries as an antiulcer medication, mainly for the prevention of non-steroidal anti-inflammatory-induced gastric ulcers. Due to its uterotonic properties, it is also indicated in obstetrics for induction of labor and termination of pregnancy. In this last case, misoprostol is either used alone or in combination with other oxytocic drugs such as methotrexate or mifepristone. The use of misoprostol as an abortifacient agent is considered to be safe since it rarely causes serious side effects. However up to 15 % of misoprostol-induced-abortions may not be successful, even under medical supervision, leading to in utero exposure to the drug and to the induction of a series of birth defects including limb and joints defects and Moebius syndrome. Reports from the nineties failed to show a strong epidemiological association between in utero drug exposure and induction of defects, a situation that has changed now that the number of cases reported has increased. Since the practice of abortion is illegal in Chile, many women turn to off-medical procedures to interrupt their pregnancy and use misoprostol as an easy and cheap alternative, readily available in the INTERNET. The lack of medical supervision in these cases may lead to situations that favor the induction of congenital defects. Here, we present an updated review of scientific data, to evaluate the risk of birth defects in babies exposed to the drug during pregnancy termination failed attempts.

Developmental toxicity of misoprostol: an update

Misoprostol, a synthetic analog of prostaglandin E1, is currently used in Chile and other countries as an antiulcer medication, mainly for the prevention of non-steroidal anti-inflammatory-induced gastric ulcers. Due to its uterotonic properties, it is also indicated in obstetrics for induction of labor and termination of pregnancy. In this last case, misoprostol is either used alone or in combination with other oxytocic drugs such as methotrexate or mifepristone. The use of misoprostol as an abortifacient agent is considered to be safe since it rarely causes serious side effects. However up to 15 % of misoprostol-induced-abortions may not be successful, even under medical supervision, leading to in utero exposure to the drug and to the induction of a series of birth defects including limb and joints defects and Moebius syndrome. Reports from the nineties failed to show a strong epidemiological association between in utero drug exposure and induction of defects, a situation that has changed now that the number of cases reported has increased. Since the practice of abortion is illegal in Chile, many women turn to off-medical procedures to interrupt their pregnancy and use misoprostol as an easy and cheap alternative, readily available in the INTERNET. The lack of medical supervision in these cases may lead to situations that favor the induction of congenital defects. Here, we present an updated review of scientific data, to evaluate the risk of birth defects in babies exposed to the drug during pregnancy termination failed attempts.

External Mandibular Distraction in Unusual Pediatric Syndromes with Micrognathia and Airway Obstruction

Mandibular hypoplasia is a craniofacial malformation that can cause airway obstruction and may affect the eating process. This anomaly is common in many polimalformed Syndromes, including the Pierre Robin Sequence and the Moebius Syndrome. It is also common in cases related to the dysgenesis of the brainstem. In order to avoid tracheostomy, or to allow for early decannulation in severely affected children, external distraction devices were employed in 3 clinical cases to repair mandibular deficiencies. A successful external mandibular distraction induces the removal of the airway obstruction, allowing spontaneous ventilation without devices, an independent eating process with no need of nasogastric or gastrostomy tubes, apart from the linguistic and facial asymmetry improvement.

Splenogonadal Fusion: Exceptional Association with Moebius Syndrome and Intestinal Intussusception

We present an exceptional association of splenogonadal fusion, Moebius syndrome, and intestinal intussusception. At the age of 1 year, the patient presented with vomiting, bloody stools, and abdominal distension. He underwent a laparotomy that revealed an ileo-ileal intussusception. Three days later, he underwent a new surgery for the reduction of a suspected inguinal hernia. A dark-red tubular structure consisting of splenic tissue was seen passing down through the processus vaginalis and attaching onto the left testicle. Owing to the rarity of the splenogonadal fusion, each case should be reported for a better knowledge of its etiopathogenesis, clinical characteristic and associations.

563 O Audit of the Use of Cerebral Function Monitoring (CFM) in the Management of Term Neonates with Encephalopathy

Objectives: To determine the indications for cerebral function monitoring, the characteristics of babies who had CFM and their outcomes at discharge. Methods: The records of all term newborn babies born between June 2006 - April 2009 who underwent cerebral function monitoring were reviewed. Results: Sixty six term (55% male) babies underwent cerebral function monitoring. Their mean GA was 39.2±1.6wk. The average birth weight was 3.09±0.75kg. 58% of these babies were delivered operatively. The apgar scores were 4± 3, 1min, 6.2± 2.8 ,5min and 7 ± 2.6 ,10min. 46% of these babies were intubated at birth. 43% of the babies had clinical seizures. 3 groups of babies were identified: Group 1- 11 babies had both the lower margin of CFM trace less than 5µV and the upper margin less than 10µV. Group 2- 8 babies had the lower margin less than 5µV but upper margin higher than 10µV. Group 3 - 46 babies had appropriate voltages on CFM tracing. 14 babies from groups 1&2 had moderate or severe encephalopathy and 2 had normal neurological signs at discharge. Normal CFM tracing in encephalopathic babies obviated the need for neuro-protective treatment. CFM was useful in evaluating encephalopathic babies from other causes. These included persistent hypoglycaemia, cortical haemorrhage, periventricular echodensities, kernicterus, propionic acidaemia, middle cerebral artery infarct, generalised hypotonia of unknown cause and moebius syndrome. Conclusion: Majority of babies with encephalopathy had a CFM trace with normal voltages. It is an important tool in the clinical assessment of term neonates with encephalopathy.

Unilateral Cerebellar Hypoplasia with Different Clinical Features

Unilateral cerebellar hypoplasia (UCH) is a rare pathological condition characterized by the loss of volume in cerebellar hemispheres ranging from mild asymptomatic to severe symptomatic cases. As the designation of UCH remains problematic, the underlying etiopathogenesis also lacks explanation. We investigated the patients admitted to Departments of Child Neurology, Neurology, and Genetics between the years 1992 and 2010 and detected 12 patients with unilateral cerebellar volume loss, with the exclusion of all other cerebellar pathologies. The ages of patients ranged between 6 months to 55 years. Five patients had a delay in developmental milestones, and one of these was diagnosed with neurofibromatosis type 1. Two patients had epileptic seizures, one patient had peripheral facial paralysis as a component of Moebius syndrome, and four patients were incidentally diagnosed during etiological work-up for headache. The clinical outcomes of patients varied from healthy subjects to marked developmental impairment. Radiologically, five patients had severe disproportionate UCH, six had moderate disproportionate, and one had mild proportionate UCH. Cerebellar peduncles were affected in all, and vermis was partly hypoplastic in eight patients. Brainstem was involved in four patients, and seven patients showed involvement of white matter and/or corpus callosum. Imaging features supported that patients with severe disproportionate UCH also displayed additional cerebral and commissural changes, which were related to ischemic or vascular injuries, implying a prenatally acquired disruption. In the presence of such a wide spectrum of clinical and radiological features, a prenatally acquired lesion and, thus, a disruption seem to be more explanatory rather than a primary developmental process or malformation in the etiopathogenesis of unilateral cerebellar hypoplasia.

Extended cognition and the space of social interaction

The extended mind thesis (EM) asserts that some cognitive processes are (partially) composed of actions consisting of the manipulation and exploitation of environmental structures. Might some processes at the root of social cognition have a similarly extended structure? In this paper, I argue that social cognition is fundamentally an interactive form of space management--the negotiation and management of "we-space"--and that some of the expressive actions involved in the negotiation and management of we-space (gesture, touch, facial and whole-body expressions) drive basic processes of interpersonal understanding and thus do genuine social-cognitive work. Social interaction is a kind of extended social cognition, driven and at least partially constituted by environmental (non-neural) scaffolding. Challenging the Theory of Mind paradigm, I draw upon research from gesture studies, developmental psychology, and work on Moebius Syndrome to support this thesis.

Moebius Syndrome and Holoprosencephaly Following Exposure to Misoprostol

Moebius syndrome is a rare disease characterized by congenital facial paralysis and abducens palsy. Involvement of other cranial nerves, orofacial dysmorphism, and limb abnormalities are frequently associated. Reported here is the case of a 10-month-old child born with Moebius syndrome and presenting with holoprosencephaly, following exposure in utero to misoprostol. To our knowledge, this is the first published case report describing this association. The etiologic hypotheses of Moebius syndrome are also discussed.

Metodología para trabajar competencias con un estudiante con síndrome de Moebius

This study is the result of experience in applying the model of competency-based education in a student with Moebius syndrome, which consists of congenital paralysis leading to a lack of control of facial expressions and lateral eye movements. We present our experience with a student with Moebius syndrome, which required the teaching faculty to design strategies to develop the student’s learning.

A family with hereditary congenital facial paresis and a brief review of the literature

Hereditary congenital facial paresis is a rare syndrome of isolated facial nerve palsy causing facial asymmetry and ptosis. Most described cases follow an autosomal dominant pattern of inheritance. It differs from Moebius syndrome, which is usually sporadic and associated with the involvement of other cranial nerves, commonly the abducens nerve in addition to orofacial and limb malformations and defects of the musculoskeletal system. We present three patients from the same family with features of congenital hereditary facial paresis. Facial asymmetry and facial weakness were the most remarkable findings. High-resolution imaging showed both facial nerves to be present but symmetrically and markedly hypoplastic with no other structural abnormality in the brainstem. This syndrome has been previously mapped to chromosome 3q21-22 but no gene has been identified as yet.

Möbius Sendromunda Otizm: Eştanı mı, Rastlantı mı?

Pervasive developmental disorders are neuropsychiatric disorders that start in early years of life, last lifelong, and characterized by delay and abnormality in social relationship, communication, behavior and cognitive development. Moebius syndrome is a clinical condition characterized by unilateral or bilateral eye-face palsy associated with muscle or bone malformations in the upper or lower limbs. Most accepted clinical criteria to characterize the sequence are the involvement of the VI and VII cranial nerves. Though some authors suggest a causal relationship between autism and some medical conditions, to draw such result is quite complicated and difficult. Case reports and articles draw attention to the comorbidity of autism in Moebius syndrome. Despite arguments favoring a strong relationship between autism and Moebius syndrome, some questions about this relationship are still left unanswered and controversial. There are some research findings suggesting higher prevalence of autism among patients with Moebius syndrome, however some others did not report an increase in autism prevalence in Moebius syndrome. Clinical features of Moebius syndrome comprise difficulties in making diagnosis of autism. Long term follow-up of larger number of cases are necessary to understand whether the presence of both autism and Moebius syndrome in a patient represents comorbidity or only a coincidental condition.

Aglossia-adactylia sequence and Moebius syndrome involvement.

Adactylia and limb deficiencies are major congenital malformations can be resulted from a long list of etiological factors, in our department the vast majority of these disorders are genetically determined, and only a small fraction of it proved to be sporadic. We report on a-9-months old male child with Aglossia- Adactylia sequence associated with Moebius syndrome involvement, which in our patient is manifesting itself by left facial nerve and bilateral abducens nerve palsies, total absent of the tongue and absent digits of hands and feet respectively.Key words: Aglossia-adactylia sequence, Moebius syndrome, Hanhart syndrome, facial nerve palsy, and abducens nerve palsy

Facial animation in patients with Moebius and Moebius-like syndromes

Moebius syndrome, a rare congenital disorder of varying severity, involves multiple cranial nerves and is characterised predominantly by bilateral or unilateral paralysis of the facial and abducens nerves. Facial paralysis causes inability to smile and bilabial incompetence with speech difficulties, oral incompetence, problems with eating and drinking, including pocketing of food in the cheek and dribbling, as well as severe drooling. Other relevant clinical findings are incomplete eye closure and convergent strabismus. The authors report on 48 patients with Moebius and Moebius-like syndromes seen from 2003 to September 2007 (23 males and 25 females, mean age 13.9 years). In 20 cases a reinnervated gracilis transplant was performed to re-animate the impaired sides of the face. In this series, all free-muscle transplantations survived the transfer, and no flap was lost. In 19 patients complete reinnervation of the muscle was observed with an excellent or good facial symmetry at rest in all patients and whilst smiling in 87% of cases. In conclusion, according to the literature, the gracilis muscle free transfer can be considered a safe and reliable technique for facial reanimation with good aesthetic and functional results.

New report of a familial case of Moebius syndrome presenting skeletal findings

New report of a familial case of Moebius syndrome presenting skeletal findings

Fetopatia por misoprostol caso clínico con análisis postmortem

Many women, especially in countries with restrictive abortion laws, attempt to end an early pregnancy with misoprostol. However, due to the lack of standardized information and instructions, women use misoprostol in a variety of forms, with wide variability in the dose and stage of pregnancy. Misoprostol is a synthetic prostaglandin I 2 analog, used in obstetrics for cervical ripening, medical abortion, uterine evacuation in embryonic and fetal death, and labor induction.Multiple forms of teratogenicity due to the indiscriminate use of this drug have been described, such as Moebius syndrome, club foot, hydrocephalus and arthrogryposis multiplex congenita. We report a case of fetopathy due to misoprostol with postmortem analysis. A review of the topic in the world literature is also provided.

Congenital myotonic dystrophy associated with Moebius syndrome and double‐outlet right ventricle

Congenital myotonic dystrophy associated with Moebius syndrome and double‐outlet right ventricle