Brainstem dysgenesis: Beyond Möbius syndrome

Manuel Roig-Quilis MD,
PhD. Senior Consultant
.


Summary

Brainstem dysgenesis designates all those patients with congenital dysfunction of cranial nerves and muscle tone due to prenatal lesions or malformations of the brainstem. In some patients, the origin of the dysgenesis is geneticaly determined and may present isolated or be part of a more extensive polimalformative syndrome. Prenatal destructive or disruptive lesions of vascular origin or teratogenic agents are main cause of the disorder.  The review of the literature and our experience shows that cases with midbrain and cerebellar involvement and wide spread malformative syndromes have most likely an underlying genetic cause while infants with a predominant Rombencephalic involvement are due to brainstem prenatal disruptive vascular accidents.

Depending on the extension of the lesion, clinical manifestations may range from intrauterine death to mild involvement of several cranial nerves. The clinical presentation findings of some of these patients coincide with the syndromes described by Moebius, Pierre Robin, Cogan and Carey-Finemann-Ziter, if that is the case, the eponym helps in localizing the brainstem lesion. Clinical manifestations in many patients with brainstem dysgenesis do not fit into any of the aforementioned syndromes. In these circumstances the term brainstem dysgenesis should be followed by the detailed description of each patient’s clinical findings and/or the brainstem segment presumably involved.

Prognosis of patients with brainstem dysgenesis due to prenatal destructive lesions depends on the magnitude of the vascular territory involved and, in most cases, is better than the initial clinical manifestations would indicate.

Key Words: Key words: Congenital Facial and abducens nerve palsy. Robin S., Cogan S., Carey-Fineman-Ziter S., Congenital cranial dysinnervation disorders. Temporo-mandibular- anquilosis. Facial Diplegia. Oculomotor Apraxia.


Introduction

Congenital dysfunction of the motor cranial nerves (CN) with nuclei of origin located in the mesencephalon, bulb, or medulla is infrequent. It is well known that lesions at the bulbar or medullary level may be produced by infantile spinal muscular atrophy, congenital tumors, vascular malformations, severe perinatal trauma or hypoxic-ischemic events, and prenatal vascular accidents [1, 2, 3, 4]. These conditions manifest, among other clinical signs, with multiple CN involvement, muscle hypotonia, feeding, and respiratory problems. Once the previously described causes of congenital bulbar palsy have been excluded, the etiology of multiple congenital CN paralysis is difficult to establish. Motor nuclei agenesis, absence of the peripheral nerves, or hypoplasia of the muscles innervated by the motor CN have been implicated along with other motor-neuron diseases [5].

Disordered brainstem (BS) development results in diverse and complex clinical conditions. Several of these combinations of CN involvement have long-standing eponyms while others carry more descriptive names. Because this group of congenital disorders does not lend itself to a brief and accurate descriptive term, the combination of abducens and facial nerve paralysis in infancy reported by Möbius in 1892 [6] gained eponymous recognition to the extent that many authors, even nowadays, use the expressions “unrestricted”, “expanded” or Moebius plus syndrome (MS) to identify all patients in whom the involvement of these two CN is present, irrespective of how many additional clinical findings they exhibit [ 7,8].Various pathogenic theories have been put forward concerning either genetically determined processes or acquired disorders of the BS during the gestation period to elucidate the origin of the “expanded” MS. However, no single theory explains either the variability of clinical signs or the inconsistency of the neuropathological findings. The available post-mortem pathologic studies of the majority of patients with MS, or “unrestricted” MS who died in early infancy revealed old necrotic lesions located in the paramedial zones of the tegmentum extending from the mesencephalon to the superior portion of the medulla [9,10,11]. According to Leong and Ashwell [12], the midline and paramedial zones of the developing BS tegmentum are poorly vascularized relative to the more lateral regions of the same structure and are therefore prone to ischemia. H. Sarnat [9] proposed that BS watershed infarcts during the embryo or fetal period were the cause of most congenital syndromes presenting with multiple CN involvement. From a clinical point of view, the study performed by Verzijl and coworkers in the Netherlands[13], in a series of 37 subjects having  “unrestricted” MS, demonstrated that the clinical manifestations of these patients were more extensive than what Möbius initially described and could only by explained if this syndrome was the consequence of “rhombencephalic maldevelopment”. Studies carried out by Abadie and co-workers [14] in a group of 66 patients diagnosed with the Pierre Robin sequence (PRS) indicated that the clinical manifestations of these patients could not be understood on the basis of bone anatomical anomalies. They proposed that the symptoms of these infants had a neuro-embryological origin that gave rise to a dysfunction of BS structures during fetal development. Several reports based upon studies of cases in humans or experimental animals (mice) indicated that defects in one or more genes belonging to gene families that participated in neural tube differentiation could induce dysgenesis of BS structures in a manner resembling MS or PRS [15,16]. The pioneer work of Engle and co-workers on congenital oculomotility disorders has led to the discovery of mutations in genes governing specifically axon guidance in in the developing hindbrain and spinal cord [17, 18, 19, 20]. Congenital central hypoventilation syndrome (CCHS) is another life-threatening genetic disease in which the defining symptoms consist of respiratory arrest during sleep or a blunted response to hypercapnia. Recently, it was discovered that CCHS is caused by heterozygous mutations of PHOX2b, a transcription factor whose loss specifically induces a loss of PHOX2b-expressing glutamatergic neurons surrounding the VII cranial nerve nuclei [21]. All these theories as well as the unceasing search for gene defects, yet, are restrictive in their approach as they only consider one or two aspects of the problem. From a medical point of view, there is a need for a more global outlook, one that takes into consideration each aspect (clinical, anatomical, etiological, pathogenic and therapeutic) playing a role in this group of disorders characterized by congenital dysfunction of the CN.

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