Prevalence of Hand Malformations in Patients With Moebius Syndrome and Their Management.

BACKGROUND: Moebius syndrome is a disorder characterized by facial and abducens nerve paralysis. Patients can present a wide range of upper extremity malformations. Literature focused on orthopedic manifestations of Moebius syndrome shows variability in the prevalence and clinical presentation of upper extremity anomalies. The aim of this work is to evaluate the prevalence of upper extremity malformations in patients with Moebius syndrome, clarify its various clinical presentations, and present treatment strategies for their management. METHODS: This is a retrospective, cross-sectional study including patients with Moebius syndrome and upper extremity malformations between 2012 and 2019. Data include demographic characteristics, Moebius syndrome subtype, type of malformation, affected extremity, and surgical procedures underwent. Quantitative data were recorded as mean (standard deviation [SD]), and qualitative data were expressed in terms of totals and percentages. Statistical association between Moebius syndrome subtype and development of upper extremity anomalies was evaluated using binary logistic regression. RESULTS: Twenty-five out of 153 patients (16.3%) presented upper extremity malformations (48% male). Mean age of presentation was 9.08 ± 9.43 years. Sixty-eight percent of the malformations were unilateral. The most common presentations included Poland syndrome and simple syndactyly with 8 cases each (32%), followed by 5 cases of brachysyndactyly (20%), 3 cases of amniotic band syndrome (12%), and 1 case of cleft hand (4%). No statistical association was found between Moebius syndrome subtype and odds ratio for development of upper extremity anomalies. Thirteen patients (52%) underwent reconstructive procedures. CONCLUSION: Poland syndrome and syndactyly are the most common anomalies in patients with Moebius syndrome. Patients may present with a wide range of hand malformations, each patient should be carefully evaluated in order to determine whether surgical treatment is needed and to optimize rehabilitation protocols.

The epidemiology of Moebius syndrome in Italy.

BACKGROUND: The epidemiology of Moebius syndrome (MBS) is difficult to assess. In the present study, we investigated the epidemiology of MBS in a well-defined population within a precise geographical area. MATERIALS AND METHODS: Our university hospital is the only national referral center for the diagnosis and treatment of MBS. Participants in this cross-sectional study were patients affected by MBS who had been periodically followed by our medical staff since 1998. Most of the patients were referred to our hospital by the Italian Association of Moebius Syndrome (AISMO). Demographic data necessary for study purposes were made available in the AISMO database, updated to April 2018. Subjects were assigned to geographical macroareas that are conventionally used in surveys and epidemiological investigations by the Italian National Institute of Statistics. The rates and prevalence of MBS cases were calculated on the basis of the last available survey of the Italian population. Each study parameter was then calculated with reference to the whole country and macroarea partition. The sex rate and the corresponding prevalence were calculated with respect to the weighted whole population and to the respective sex population. Chi-square analysis was adopted to investigate possible differences among geographical regions and/or sexes. A p value < 0.05 was considered statistically significant. RESULTS: One hundred and sixty-four out of 212 MBS patients fulfilled our inclusion criteria. All cases occurred in Caucasian patients and were sporadic. The median age at diagnosis was 3.6 years, ranging from 0 to 55 years; this range was significantly reduced to 0-5 years (median age at diagnosis: 2.2 years) in patients included after 2007. The calculated prevalence at birth was 0.06 cases per 10,000 live births, with an overall prevalence of 0.27/100,000, without any sex or geographical predominance. CONCLUSIONS: The prevalence of MBS observed herein, rounded for possible underestimation, was 0.3/100,000 people, without any regional difference in the distribution of cases. Our data confirm the rarity of the disease on a national level.

Will the real Moebius syndrome please stand up? A systematic review of the literature and statistical cluster analysis of clinical features.

Moebius syndrome is a highly variable syndrome with abducens and facial nerve palsy as core features. Strict diagnostic criteria do not exist and the inconsistency of the associated features makes determination difficult. To determine what features are associated with Moebius syndrome we performed a systematic literature review resulting in a composite case series of 449 individuals labeled with Moebius syndrome. We applied minimum criteria (facial and abducens palsy) to determine the prevalence of associated clinical features in this series. Additionally, we performed statistical cluster analysis to determine which features tended to occur together. Our study comprises the largest series of patients with Moebius syndrome and the first to apply statistical methodology to elucidate clinical relationships. We present evidence for two groups within the Moebius diagnosis. Type 1: exhibiting micrognathia, limb anomalies and feeding/swallowing difficulty that tend to occur together. Type 2: phenotypically diverse but more associated with radiologically detectable neurologic abnormalities and developmental delay.

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

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

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

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

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

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

Misoprostol exposure during the first trimester of pregnancy: Is the malformation risk varying depending on the indication?

OBJECTIVE: To report the prospective follow-up of pregnancies exposed to misoprostol during the first trimester and analyse the teratogenic risk depending on the indication for use. STUDY DESIGN: Prospective observational study of 265 women exposed to misoprostol during the first 12 weeks of pregnancy and followed until the delivery. Women were included if they or their physician had contacted a French pharmacovigilance centre before 22 weeks of gestation (WG) to obtain information on the risk of misoprostol exposure, and if there had been misoprostol exposure before 13 WG. Data were collected at the time of the first contact, and the pregnancy outcome was recorded at follow-up. Women were prospectively enrolled from January 1988 to December 2013. RESULTS: The main indication for misoprostol was voluntary abortion (60.9%). Ten major malformations (5.5%) (95% CI 2.65-9.82%) were reported and five of them were consistent with the pattern of malformations attributed to misoprostol: Möbius sequence, hydrocephalus, terminal transverse limb reduction associated with a clubfoot, syndactyly, and complete posterior encephalocele. The rate of malformations was higher, but not significantly, in women exposed to misoprostol for voluntary abortion (7.9%) compared with women exposed to misoprostol for other or unknown indications (3.2%). CONCLUSIONS: Our results confirmed a specific pattern of malformations due to misoprostol use in early pregnancy, even with low dose of misoprostol. Despite the small number of cases, we observed a higher proportion of major malformations in fetuses born to women who continued their pregnancy after a failed voluntary abortion with misoprostol. Further studies should be conducted to evaluate other potential factors, such as combination treatment with mifepristone and the socio-environmental characteristics in this group of women.

Birth defects after exposure to misoprostol in the first trimester of pregnancy: prospective follow-up study.

Misoprostol during the first trimester of pregnancy is associated with a specific malformative pattern (Moebius sequence and limb defects) whose incidence remains unknown. Data originate mostly from illegal use for abortion and are mainly retrospective. The present prospective controlled study analyses outcomes of first trimester misoprostol exposures after medical prescriptions. Malformation rate was higher among 236 pregnancies exposed before 12 gestational weeks (4%) than in 255 controls (1.8%), although not statistically significant (OR=2.2 [95% CI=0.6-7.7]). Three malformations (2%) in the exposed group were consistent with the misoprostol malformative pattern. This is the largest prospective study on first trimester misoprostol exposure and the first one relying on prescriptions. A trend toward a doubling of the overall rate of malformations was observed and for the first time an estimation of the incidence of misoprostol specific spectrum is proposed (2%). Brainstem injuries including severe trismus might be added to this specific pattern.

Síndrome de Moebius: ¿misoprostol como teratógeno? / Möbius syndrome: misoprostol as a teratogenic?

El síndrome de Moebius (SM) es una alteración congénita poco frecuente, caracterizada por la parálisis del nervio facial y del motor ocular externo, asociada a otras malformaciones craneofaciales y musculoesqueléticas. Su etiología no está clara, aunque en su aparición se asocian algunos agentes teratógenos, como el misoprostol. El mecanismo etiopatogénico se explicaría por la disrupción vascular secundaria al efecto vasoconstrictor del fármaco, en el territorio troncoencefálico. A continuación se describe el caso de un recién nacido afectado de SM, cuya madre usó misoprostol con fines abortivos durante el primer trimestre de la gestación. En los últimos años se ha documentado un número cada vez mayor de casos de SM asociados a esta práctica (AU)

The Möbius syndrome (Moebius syndrome) is an infrequent congenital disorder characterized by facial and abducens nerve palsy as well as the external ocular motor palsy. It is associated with other craniofacial and orthopedic anomalies. Its etiology is still unclear, although in its appearance teratogenics agents such as misoprostol have been related. Misoprostol’s etiopathogenic mechanism would be explained due to a secondary vascular disruption due to the vasoconstrictor effect of the medication, in the level of the area of the brain stem. Here we report a newborn with the Möbius syndrome whose mother had used misoprostol as an abortive during the first trimester of pregnancy. There has been a large number of Möbius syndrome associated with the use of misoprostol due to abortion attempt during the last years (AU)

Moebius sequence and autism spectrum disorders--less frequently associated than formerly thought.

Moebius sequence is a rare congenital disorder usually defined as a combination of facial weakness with impairment of ocular abduction. It is questionable, whether there is a strong association of the sequence with autism spectrum disorders (ASDs) as suggested in some earlier case reports and studies. Twenty-two participants with Möbius sequence aged 6-16 years followed a request of the German Moebius foundation to participate in a nationwide study. All patients had a physical examination and intelligence testing. Primary caregivers were asked to complete two screening measures of ASD (Behaviour and Communication Questionnaire, VSK; Marburger Asperger's Syndrome Rating Scale, MBAS). For those who reached the cut-off for ASD and/or showed behavioural aspects indicative of ASDs during IQ testing and/or physical examination, well standardized diagnostic instruments (Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and Kinder-DIPS) were administered. Minimal diagnostic criteria for Möbius sequence were congenital facial weakness (uni- or bilateral) and impairment of ocular abduction (uni- or bilateral). Three boys (one of them mentally retarded) out of 22 participants (12 males and 10 females) were found suspicious of ASD by screening, but none of them fulfilled diagnostic criteria of ASD on a clinical consensus conference. Therefore, ASDs seem to be not as frequent as reported in previous studies on patients with Möbius sequence.

[Poland-Möbius syndrome associated with lacrimal punctal and canalicular agenesis]. / Syndrome de Poland-Möbius associé à une agénésie des points et des canalicules lacrymaux.

We report the case of a 21-year-old patient who presented with epiphora in the left eye and a bilateral ocular motility problem. The clinical examination revealed bilateral moderate abduction limitation (impairment of the VIth cranial nerve), facial diplegia with amimic face (impairment of the VIIth cranial nerve), punctal agenesis of the left eye, absence of the left pectoralis major muscle, left breast aplasia, and hypoplasia of the left upper limb and hand. Neither the lacrimal puncta nor the canaliculi could be found during surgical exploration of left lacrimal system using operating microscope. Based on these findings, the patient was diagnosed with Poland-Möbius syndrome associated with punctal and canalicular agenesis. Poland-Möbius syndrome is a rare entity characterized by the association of two different syndromes: Poland syndrome and Möbius syndrome. Several abnormalities in association with this syndrome have been published. However, punctal and canalicular agenesis is not among these reported abnormalities.

Síndrome de Moebius: diagnóstico neonatal / Moebius syndrome: neonatal diagnosis

El síndrome de Moebius es un trastorno congénito caracterizado por la asociación de parálisis facial y afectación de la musculatura oculomotora secundaria a la agenesia de los pares craneales VII y VI. Pueden estar implicados otros pares craneales y/o asociarse otras malformaciones como consecuencia de una disrupción en la morfogénesis tronco encefálica durante el periodo embrionario, presumiblemente de carácter vascular. Se presenta un caso de síndrome de Moebius diagnosticado durante el periodo neonatal, realizando una revisión de sus características clínicas y evolutivas (AU)

Moebius syndrome is a congenital disorder characterized by the association of facial paralysis and involvement of the oculomotor muscles, secondary to the agenesis of cranial nerves VII and VI. Other cranial nerves can be implicated and/or it can be associated with other malformations as a consequence of a disruption of brainstem morphogenesis, presumably of vascularnature, during the embryonic period. We present a case of Moebius syndrome diagnosed during the neonatal period, reviewing the clinical features and its course (AU)

Moebius sequence: behaviour problems of preschool children and parental stress.

This study investigates behaviour problems of preschool children with Moebius sequence, and their primary caregivers' stress. To this end, parents of all preschool children with Moebius sequence known to the German Moebius foundation were anonymously asked to fill out questionnaires, e.g. the Child Behavior Checklist [CBCL] 1.5-5. The primary caregivers of 13/22 children (seven males, six females; mean age: 3;10 [2;1-5;11] years) sent back filled-out questionnaires. Two children were rated as clinical on the CBCL-1.5-5. Boys had significantly higher scores on the scales aggressive behavior and total problems than girls. Compared to the general population, but not to other parents of mentally and / or physically handicapped children, the primary caregivers experienced higher levels of stress. In conclusion, preschool children with Moebius sequence do not show essentially increased rates of clinical behaviour problems. Nevertheless, their primary caregivers experience increased stress and need early and adequate support.

Audiologic results in patients with Moebiüs sequence.

OBJECTIVE: Moebiüs sequence is a pathology not very well understood regarding to the hearing status. The main goal of this study was to describe the audiologic findings in children and adolescent who carry Moebiüs sequence. METHOD: Participated in this study 17 children and adolescent, with age ranging from 3 to 13 years old. Prior to the testing, the family answered an interview. It was realized external auditory canal inspection, and the hearing testing (auditory instrumentation, pure tone audiometry, speech audiometry, immittanciometric measures, and otoacoustic emissions) on the participants. RESULTS: The auditory instrumentation evaluation (n=6) was present in all participants. The pure tone audiometry presented normal hearing levels in 75.0% of the tested ears, one ear with conductive hearing loss, two ears with sensory neural hearing loss, and one ear with mixed hearing loss. The tympanometric measures showed Type A tympanograms in 63.0% of the ears, Type B in 11.1%, Type C in 18.5%, and Type As in 7.4%. T the acoustic reflexes measure showed contralateral acoustic reflexes present in 50.0% of the ears, and ipsilateral acoustic reflexes present in 34.6% ears. The OAE results showed presence in 73.0%, for the TOAE, and 76.9% for the DPOAE. CONCLUSION: These results support the idea that there is no audiologic pattern for conductive hearing loss. The majority of the participants presented hearing in the normal range. Care should be taken in drawing conclusions regarding to auditory status of the individual with Moebiüs sequence, but what can be said is that not always those individuals present hearing loss.

Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review.

Autism is a complex developmental disorder without an established single etiology but with significant contributions from genetic studies, functional research, and neuropsychiatric and neuroradiologic investigations. The purpose of this paper is to review the findings in five studies involving individuals manifesting the characteristic findings of autism spectrum disorder associated with malformations and dysfunctions known to result from early embryogenic defects. These investigations include two associated with teratogens (thalidomide embryopathy, Mobius sequence with misoprostol) and three (most Mobius sequence cases, CHARGE association, Goldenhar syndrome) with no known etiology. These studies suggest that early embryonic development errors often involving cranial nerve palsies, internal and external ear malformations, ophthalmologic anomalies, and a variety of systemic malformations may be associated with autism spectrum disorders statistically more frequently than expected in a normal population. Although the exact time of developmental insult for each condition cannot be identified, the evidence is that it may occur as early as week 4 to 6+ of embryogenesis.

Secuencia de Mobius: hallazgos genético-clínicos

Introducción: La teoría más aceptada en cuanto a la etiopatogenia de la Secuencia de Mõbius, es la que resulta de una disrupción vascular en la edad temprana de la embriogenesis debido a factores genéticos o ambientales. Este estudio tiene como objetivo principal, describir los hallazgos Clínico-genéticos en pacientes con Secuencia de Mobius cuyas madres usaron o no, misoprostol durante el embarazo. MÉTODOS: fueron examinados 28 pacientes con el diagnóstico previo de secuencia de Mõbius, atendidos em tres servicios de referencia, através de un estudio clínico de corte transversal. Se realizó una completa evaluación por un equipo multidisciplinario, siguiendo un protocolo previamente elaborado. Los critérios de inclusión para dicho estudio fueron: la presencia de parálisis congênita, uni o bilateral del Vl y Vll nervios craneanos. Se evaluaron los pacientes en cuanto a los hallazgos genético-clínicos. RESULTADOS: un total de 28 casos atendieron a los criterios de inclusión para el estudio, con edades comprendidas entre 1 a 141 meses, media de 43 meses, desvación estandard de 41 meses. El periodo de daño al embrión fue en media en la quinta semana post fertilización. Fui evidenciado el epicanto en 25 casos (89.3 por cento). La limitación a la abducción fue vista en todos los pacientes (100.0 por cento), boca de cúpido en 18 casos (66.7 por cento),pies equinovarus en 12 casos (44.4 por cento). La secuencia Poland-Mõbius y la anomalia de Poland-Mõbius, fueran vistas en un caso (3,6 por cento) respectivamente. Tres casos (10.7 por cento) tuveron antecedentes familiares positivos de patologías de miembros en el grupo de pacientes no expuestos al misoprostal. CONCLUSIÓN: En este estudios los principales hallazgos clínico-genéticos observados fueron anomalías craneo-faciales y de miembros, habiendo también compromiso de los nervios craneanos. En la muestra estudiada hubo elevada asociación entre el uso del misoprostol y la secuencia de Mõbius. Otros autores sugieren que esta droga actuaría como probable teratógeno, aumentando la incidencia de anomalías congénitas.

Perfil sócio demográfico e gestacional de pacientes com a seqüência de Möbius / Social demographics and pregnancy profile of patiens with Möbius sequence

Analisar o perfil sócio-demográfico e gestacional de uma amostra de pacientes com a sequência de Möbius. Aplicou-se um questionário estruturado em genitores de pacientes com diagnóstico de sequência de Möbius, atendidos em três centros de referência do Estado de Permancuco. Os pacientes foram analisados quanto a dados sócio-demofráficos e gestacionais. Dividiram-se os pacientes em dois grupos, de acordo com a exposição ao misoprostol durante a gestação, sendo o grupo I composto de pacientes não expostos e o II de casos expostos. Dos 28 pacientes estudados, 16 (57,1por cento) eram mulheres. A média de idade dos pacientes foi de 60,5 meses. O grupo II era composto de 17 casos (60,7por cento), sendo que o misoprostol foi utilizado via oral e vaginal em 14 casos (82,4por cento), com dose variandode três (600µg) a 14 comprimifos (2.800µg).nos pacientes do grupo I, não houve queixa de dores na gravidez, e em quatro (14,3por cento), houve sangramento, entretanto, nos do grupo II, houve dor em oito casos (47,1por cento) e hemorragia em 15 (88,2por cento) (p=0,010). O período do dano ao embrião através do uso do misoprostol foi, em média, na quinta semana pós fertilização. História de aborto prévio provocado foi referido em quatro casos (36,4por cento) no grupo I e em um 5,9por cento) no II. Em 25 casos entrevistados a média de idade das genitora foi de 29,3 anos no grupo I, e de 27,6 anos no grupo II, e a dos genitores foi de 30,9 anos no grupo I, e de 25,7 anos no grupo II. Observou-se que 10(66,7por cemto) genitores do grupo II não eram casados, e a profissão paterna mais frequente era comerciante, dois eram desempregados (p=0,049). A avaliação do perfil soció-demográfico e gestacional das genitoras de pacientes com a seqüência de Möbius, mostrou-se como um instrumento válido na análise dos possíveis fatores elucidativos da problemática dessa entidade, observando-se a associação entre o uso do misoprostol no primeiro trimestre da gestação com maior prevalência desses casos, o que foi visto principalmente em pacientes pertencentes a classe social menos privilegiada, com menor freqüência de parceiro estável

Taking drugs during pregnancy. How safe are the unsafe?

QUESTION: I prescribed misoprostol to one of my patients with a peptic ulcer. When she found out she was pregnant while on the drug, both she and, admittedly, I were very scared to learn that the drug is teratogenic in that it causes Möbius syndrome. How great is the risk? ANSWER: Very small. Although women who use misoprostol during the first trimester have a 30-fold higher risk of having babies with Möbius syndrome, the malformation is so rare that, even if you see 1000 women who took misoprostol during embryogenesis, you might not see a single child with the syndrome. It is crucial to explain the size of the risk; otherwise women tend to believe the risk is huge even when, in fact, it is hardly measurable.