This report describes a patient who simultaneously showed musculoskeletal deformities of AMDC such as unilateral facial skeletal deformities, submucosal cleft palate, cervical spine deformities, and scapular anomaly, congenital heart disease, and the rhombencephalic anomaly; medullary neuroschisis with associated mirror movements and unilateral facial palsy. The patient described herein presented with various defects extending to the craniocaudal level with various gradations of severity, and a wide range of CNS malformations, which were detected by physical and neurological examinations, radiological findings, and electrophysiological evaluations. These occurrences of various combinations and the various severity gradations for congenital anomalies have not yet been reported from a Klippel-Feil syndrome 'plus' point of view [
7]. We think that from a Goldenhar syndrome point of view, this co-occurrence of CNS malformations; rhombencephalic anomaly in Goldenhar syndrome may also be a very unusual case.
From the present case, we suggest that these complex malformations with various gradations of severities reflect sequential disruption of the tissues derived from one or more of three germ layers during embryogenesis. Generally, deformities accompanying AMDC are believed to arise from the failure of mesodermal cell migration around the 4th week of embryogenesis [
2]. However, this prevailing hypothesis has a limitation in explaining the pathogenic mechanism of this case, because rhombencephalic malformations, which arise from abnormalities in neuroectodermal development, cannot occur in this period. In particular, the co-existing dysplasia of the musculoskeletal system including cranial and postcranial regions and cranial nerve system may have been derived from sequential disruption of the tissues during extended periods from the early stages of neural tube formation to the period of neuroectodermal differentiation. From previous studies of the period of the occurrence of these anomalies, we found that cervicomedullary neuroschisis occurs during neural tube formation [
8], and brainstem anomaly below pons appears to occur during rhombencephalic development [
6,
9]. A previous study reported that neuroschisis at the level of the cervical spine, induced by neural tube malformation, may affect the sequential development and migration of neural crest cells after neural tube formation, and may induce anomalies in musculoskeletal and CNS maldevelopment [
2]. Moreover, another previous study regarding Mobius syndrome with musculoskeletal deformities, which is believed to be a complex developmental disorder in the period of the 3rd and 8th week of embryogenesis [
10], is in accordance with our observation. Considering these previous results, the present case of dysplasia may result from a failure in neural tube fusion and mesodermal cell migration, which takes place during the 3rd to 4th week of gestation, and the failure of sequential rhombencephalic segmentation after neural tube formation in the 5th week, as well as the abnormal differentiation of the metencephalon and myelencephalon, especially myelencephalon dysplasia. From the point of view of the various combinations and the gradations of anomalies, we can deduce that when abnormalities occur during the vulnerable stages of embryonic development (e.g., neural tube formation, mesodermal migration, and rhombencephalon segmentation), discrete or continuous associated developmental disabilities can occur. Depending on the severity of damage and the ability of the embryo to restore itself, phenotypes after birth can be accompanied by abnormalities of different degrees in internal and external structures of mesodermal origin. We cannot conclusively exclude the AMDC spectrum with dysplasia of the CNS. Therefore, when examining patients with sporadic phenotypes of AMDC, hidden axial mesodermal dysplasia must be closely observed, and neurological screening including CNS examination should be performed simultaneously. In addition, we also suggest that the neurophysiological mechanism of the hind brain abnormality, the medullary neuroschisis, which could lead to the abnormal pyramidal decussation, may induce the neural substrate for the motor organization of the bilateral mirror movements. In accordance with this suggestion, a previous study revealed an association between cervicomedullary neuroschisis and mirror movements in Klippel-Feil syndrome patients [
4]. Therefore, we can propose that the unknown origins of congenital mirror movements may be the result of developmental abnormalities at the cervicomedullary junction occurring as early as the embryonic period.
In conclusion, cases of AMDC with minor sporadic dysplasia should be examined for various anomalies for musculoskeletal structure and internal organs or dysplasia of neural structures that cannot be noted through simple physical and neurological examination. Among the various abnormalities accompanying AMDC, CNS malformations can be encountered. Since CNS malformations with mild symptoms can be easily overlooked, neurological examination, including brain imaging, should be recommended for patients suspected of having AMDC. Further studies on larger cohorts are needed to reveal the underlying cause of this syndrome and to better understand its pathological mechanism.