TY - JOUR
T1 - Delineation and diagnostic criteria of oral-facial-digital syndrome type VI
AU - Poretti, Andrea
AU - Vitiello, Giuseppina
AU - Hennekam, Raoul C.M.
AU - Arrigoni, Filippo
AU - Bertini, Enrico
AU - Borgatti, Renato
AU - Brancati, Francesco
AU - D'Arrigo, Stefano
AU - Faravelli, Francesca
AU - Giordano, Lucio
AU - Huisman, Thierry A.G.M.
AU - Iannicelli, Miriam
AU - Kluger, Gerhard
AU - Kyllerman, Marten
AU - Landgren, Magnus
AU - Lees, Melissa M.
AU - Pinelli, Lorenzo
AU - Romaniello, Romina
AU - Scheer, Ianina
AU - Schwarz, Christoph E.
AU - Spiegel, Ronen
AU - Tibussek, Daniel
AU - Valente, Enza Maria
AU - Boltshauser, Eugen
N1 - Funding Information:
We thank the patients and their families for their cooperation. This work was partly supported by the Swiss National Science Foundation [PBZHP3-133288 to A.P.], the Italian Ministry of Health [Ricerca Corrente 2011, Ricerca Finalizzata Malattie Rare 2009 to E.M.V.], the Italian Telethon Foundation [project GGP08145 to E.M.V.), the Pierfranco and Luisa Mariani Foundation [project R-09-79 to E.M.V.], and the European Research Council [Starting Grant 260888 to E.M.V.].
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Joubert syndrome and related disorders
KW - Oral-facial-digital syndrome type VI
KW - cerebellar malformation
KW - neuroimaging; molar tooth sign
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U2 - 10.1186/1750-1172-7-4
DO - 10.1186/1750-1172-7-4
M3 - Article
C2 - 22236771
AN - SCOPUS:84855582627
SN - 1750-1172
VL - 7
JO - Orphanet journal of rare diseases
JF - Orphanet journal of rare diseases
IS - 1
M1 - 4
ER -