Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome
Authors: Lydie Burglen
Christel Thauvin-Robinet
Brunella Franco
Bérénice Doray
Bernard Aral
Melissa L Crenshaw
Matthew Pastore
Diana Rodriguez
Véronique Darmency-Stamboul
Nadège Gigot
Laurence Faivre
Marie Gonzales
Isabelle Desguerres
Estelle Lopez
Tania Attié-Bitach
Frédéric Huet
Didier Lacombe
Laurent Pasquier
John Dean
Valérie Cormier-Daire
Nathalie Mejean
Patrick Callier
Journal: European Journal of Medical Genetics (2013)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Oral-facial-digital syndrome type VI; OFD VI; cerebellar malformations; molar tooth sign; Joubert syndrome related disorders
Affiliations: Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Grand-Est, Hôpital d'Enfants, CHU Dijon, France.

Abstract:  Oral-facial-digital syndrome type VI (OFD VI) is characterized by the association of malformations of the face, oral cavity and extremities, distinguished from the 12 other OFD syndromes by cerebellar and metacarpal abnormalities. Cerebellar malformations in OFD VI have been described as a molar tooth sign (MTS), thus, including OFD VI among the "Joubert syndrome related disorders" (JSRD). OFD VI diagnostic criteria have recently been suggested: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of hands or feet; 3) hypothalamic hamartoma. In order to further delineate this rare entity, we present the neurological and radiological data of 6 additional OFD VI patients. All patients presented oral malformations, facial dysmorphism and distal abnormalities including frequent polydactyly (66%), as well as neurological symptoms with moderate to severe mental retardation. Contrary to historically reported patients, mesoaxial polydactyly did not appear to be a predominant clinical feature in OFD VI. Sequencing analyzes of the 14 genes implicated in JSRD up to 2011 revealed only an OFD1 frameshift mutation in one female OFD VI patient, strengthening the link between these two oral-facial-digital syndromes and JSRD. 

Retracted: No

PubPeer comments:
 The authors described 6 cases they considered as oral-facial-digital syndrome type VI. Patient 6 is a case of OFD I since a mutation of the causal gene has been evidenced (*OFD1* c.1840delG). I just want to discuss patient 2: female patient 7 year-old ![file] On this sagittal section (T1-weighted sequence), the authors considered the lesion pointed by a star as an interhemispheric cyst. ![file] On coronal section it seems much more complicated than a simple  interhemispheric cyst ![file] The grey matter is interrupted (see my yellow arrows on this magnification of the previous cerebral MRI). I suppose that this feature is much more likely a ischemic destruction of the brain. This is likely since this patient presented a ventricular septal defect. I guess, if I am right, that a homonymous hemianopia could be evidenced on clinical examination. , 
 ![file] According to table 3, these patients presented temporal lobe hypoplasia. I don t see such a hypoplasia. Could the authors be more precise? , 
 Another problem with cerebral MRI (patient 4: 9 year-old) ![file] Legend: Sagittal T2 CISS 3D image reveals hypoplasia of the cerebellar vermis (star), a severe midbrain dysplasia (black arrow) and a thin corpus callosum with enlarged ventricles (patient 4). Midbrain dysplasia is not obvious. I suggest that this image corresponds to a deep interpeduncular fossa (molar tooth sign). What about axial section? ![file] The thickness of the corpus callosum is 8 mm. This corresponds to a thick corpus callosum at the age of the patient (see Garel C *et al*. Am J Neuroradiol 2011;32:1436-1443). At last: ![file] The star does not correspond to the vermis but to the most caudal part of the cerebellar hemispheres. The vermis is indicated by yellow arrows. Many radiological data of this article are problematic. Corrections should be proposed by the authors with the help of a neuroradiologist. ,