Research
Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI
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* Corresponding authors: Enza M Valente e.valente@css-mendel.it - Eugen Boltshauser Eugen.Boltshauser@kispi.uzh.ch
- † Equal contributors
1 Department of Pediatric Neurology, University Children's Hospital of Zurich, Switzerland
2 Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
3 Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza Institute, San Giovanni Rotondo, Italy
4 Department of Pediatrics, Academic Medical Centre, Amsterdam, The Netherlands
5 Department of Neuroradiology, Scientific Institute 'E. Medea', Bosisio Parini (LC), Italy
6 Unit of Molecular Medicine, Department of Neurosciences, Bambino Gesù Hospital, Rome, Italy
7 Department of Neurorehabilitation 1, Scientific Institute 'E. Medea', Bosisio Parini (LC), Italy
8 Department of Biomedical Sciences, Ce.S.I. Aging Research Center, Gabriele d'Annunzio University Foundation, Chieti, Italy
9 Department of Developmental Neurology, IRCCS Istituto Neurologico C. Besta, Milan, Italy
10 Department of Medical Genetics, Ospedale Galliera, Genoa, Italy
11 Division of Child Neurology, Spedali Civili, Brescia, Italy
12 Division of Pediatric Neurology, Epilepsy Center, Vogtareuth, Germany
13 Paracelsus Medical University, Salzburg, Austria
14 Department of Neuropaediatrics, The Queen Silvia Children's Hospital, Sahlgrenska University, Gothenberg, Sweden
15 Department of Pediatrics, Developmental Neurology, Skaraborg Hospital, Skövde, Sweden
16 Clinical Genetics Unit, Great Ormond Street Hospital for Children, London, UK
17 Division of Neuroradiology, Spedali Civili, Brescia, Italy
18 Division of Diagnostic Imaging, University Children's Hospital of Zurich, Switzerland
19 Department of Neonatology, University Children's Hospital, Tübingen, Germany
20 Department of Pediatrics A, HaEmek Medical Center, Afula and Rappaport School of Medicine, Haifa, Israel
21 Department of General Pediatrics, University Children's Hospital, Düsseldorf, Germany
22 Department of Medical and Surgical Pediatric Sciences, University of Messina, Messina, Italy
Orphanet Journal of Rare Diseases 2012, 7:4 doi:10.1186/1750-1172-7-4
Published: 11 January 2012Abstract
Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: 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 one or more hands or feet; 3) hypothalamic hamartoma.