Möbius sequence, Robin complex, and hypotonia: Severe expression of brainstem disruption spectrum versus Carey–Fineman–Ziter syndrome

Abstract

We report on nine unrelated children fitting a diagnosis of Carey-Fineman-Ziter syndrome (CFZS). All children presented with Möbius sequence, Pierre Robin complex (6/9) or micrognathia, and hypotonia. Some had primary hypoventilation, delayed development, and acral anomalies. The neuropathological investigations performed in two patients showed a combination of dysplastic lesions (neuronal heterotopias) and encephaloclastic changes consisting of small foci of necrosis with microcalcifications. The mother of a third child had severe trauma during her 2nd month of pregnancy. Based on a review of the literature on MS and CFZS, we suggest designating as "Robin-Möbius phenotype" a distinct clinical variant of MS with extensive brainstem involvement, Robin complex, hypotonia without specific muscle disorder, clubfeet and variable acral anomalies. This condition appears to bear a higher risk of mental handicap and perhaps a higher recurrence risk than "common" MS. Neuropathology and neuroimaging are suggestive, at least in some cases, of a vascular disruption, which could be exogenous, or secondary to a genetic predisposition. Etiologic heterogeneity seems likely and, in that respect, the original CFZS family could represent a private syndrome fitting on the "Robin-Möbius" spectrum. Despite the existence of two familial reports, recurrence risk is probably much lower than 25%, although exact figures cannot be extracted from the available literature.

Temporomandibular joint ankylosis as part of the clinical spectrum of Carey–Fineman–Ziter syndrome?

“…Similarly, clubfeet and other joint contractures are seen in other non-specific myopathies of prenatal onset, associated with paucity of fetal movements. It has been hypothesized also that CFZ syndrome, instead of being a distinct nosologic entity, may be the severe end of the spectrum in Moebius syndrome: a prenatal ischemic insult to the developing brainstem may explain the association of Moebius sequence and myopathy, correlation with Pierre Robin sequence could be explained by lesions of the lower cranial nerves (and thus not surprisingly associated with Moebius sequence) [Verloes et al, 2004].…”

“…It has been postulated that many clinical features in CFZS may only be secondary effects of muscle weakness during development [Carey, 2004;Verloes et al, 2004]. The facial appearance with downslanting palpebral fissures, ptosis and lack of expression may be the result of facial muscle weakness and immobility (amimic face).…”

“…Muscle biopsies performed in four of the seven cases above reported showed a pattern suggestive for generalized nonspecific myopathy (such as type I fiber atrophy, a finding commonly associated with congenital myopathies). It has been hypothesized that CFZ syndrome, instead of being a distinct nosologic entity, may be the severe end of the spectrum in Moebius syndrome [Verloes et al, 2004].…”

The Carey–Fineman–Ziter syndrome: Follow‐up of the original siblings and comments on pathogenesis

“…1-3) compared to other cases reported in the literature and depicted in the ensuing articles. While I certainly would agree with Verloes et al [2004] that there is a spectrum here that includes patients with Moebius and Robin, I would propose that CFZ syndrome is a more discrete entity. Ideally, having a molecular basis for this and the related disorders will clarify the nosology of this interesting set of conditions.…”

“…The purpose of my Commentary here is to provide an update on the original patients in the context of the ensuing articles in this issue of the Journal [Dufke et al, 2004;Maheshwari et al, 2004;Verloes et al, 2004]. In addition, I will discuss the nosology of the Moebius sequence and its associated syndromes and propose two candidate genes as the potential basis of the CFZ syndrome.…”