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Delineation and diagnostic criteria of Oral-Facial-Digital Syndrome type VI.

Journal article
Authors Andrea Poretti
Giuseppina Vitiello
Raoul C M Hennekam
Filippo Arrigoni
Enrico Bertini
Renato Borgatti
Francesco Brancati
Stefano D'Arrigo
Francesca Faravelli
Lucio Giordano
Thierry A G M Huisman
Miriam Iannicelli
Gerhard Kluger
Mårten Kyllerman
Magnus Landgren
Melissa M Lees
Lorenzo Pinelli
Romina Romaniello
Ianina Scheer
Christoph E Schwarz
Ronen Spiegel
Daniel Tibussek
Enza Maria Valente
Eugen Boltshauser
Published in Orphanet journal of rare diseases
Volume 7
Pages 4
ISSN 1750-1172
Publication year 2012
Published at
Pages 4
Language en
Keywords Abnormalities, Multiple, diagnosis, pathology, Adolescent, Adult, Cerebellar Diseases, classification, diagnosis, genetics, pathology, Child, Child, Preschool, Eye Abnormalities, classification, diagnosis, genetics, pathology, Female, Humans, Infant, Infant, Newborn, Kidney Diseases, Cystic, classification, diagnosis, genetics, pathology, Magnetic Resonance Imaging, methods, Male, Neuroimaging, methods, Orofaciodigital Syndromes, classification, diagnosis, genetics, pathology, Phenotype, Polydactyly, diagnosis, pathology, Retina, abnormalities, pathology, Young Adult
Subject categories Clinical Medicine, Neurology


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.

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