Delineation and diagnostic criteria of oral-facial-digital syndrome type VI

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, Marten Kyllerman, Magnus Landgren, Melissa M. Lees, Lorenzo Pinelli, Romina Romaniello, Ianina Scheer, Christoph E. Schwarz & 4 others Ronen Spiegel, Daniel Tibussek, Enza Maria Valente, Eugen Boltshauser

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number4
JournalOrphanet Journal of Rare Diseases
Volume7
Issue number1
DOIs
Publication statusPublished - 2012

Fingerprint

Polydactyly
Neuroimaging
Tooth
Hamartoma
Lip
Tongue
Cognition
Foot
Hand
Orofaciodigital syndrome 6
Coloboma
Cleft Lip
Cleft Palate
Nervous System Diseases
Thalamus
Intellectual Disability
Brain Stem
Cerebrospinal Fluid
Joubert syndrome 1
Mutation

Keywords

  • cerebellar malformation
  • Joubert syndrome and related disorders
  • neuroimaging; molar tooth sign
  • Oral-facial-digital syndrome type VI

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Delineation and diagnostic criteria of oral-facial-digital syndrome type VI. / Poretti, Andrea; Vitiello, Giuseppina; Hennekam, Raoul C M; Arrigoni, Filippo; Bertini, Enrico; Borgatti, Renato; Brancati, Francesco; D'Arrigo, Stefano; Faravelli, Francesca; Giordano, Lucio; Huisman, Thierry A G M; Iannicelli, Miriam; Kluger, Gerhard; Kyllerman, Marten; Landgren, Magnus; Lees, Melissa M.; Pinelli, Lorenzo; Romaniello, Romina; Scheer, Ianina; Schwarz, Christoph E.; Spiegel, Ronen; Tibussek, Daniel; Valente, Enza Maria; Boltshauser, Eugen.

In: Orphanet Journal of Rare Diseases, Vol. 7, No. 1, 4, 2012.

Research output: Contribution to journalArticle

Poretti, A, Vitiello, G, Hennekam, RCM, Arrigoni, F, Bertini, E, Borgatti, R, Brancati, F, D'Arrigo, S, Faravelli, F, Giordano, L, Huisman, TAGM, Iannicelli, M, Kluger, G, Kyllerman, M, Landgren, M, Lees, MM, Pinelli, L, Romaniello, R, Scheer, I, Schwarz, CE, Spiegel, R, Tibussek, D, Valente, EM & Boltshauser, E 2012, 'Delineation and diagnostic criteria of oral-facial-digital syndrome type VI', Orphanet Journal of Rare Diseases, vol. 7, no. 1, 4. https://doi.org/10.1186/1750-1172-7-4
Poretti, Andrea ; Vitiello, Giuseppina ; Hennekam, Raoul C M ; Arrigoni, Filippo ; Bertini, Enrico ; Borgatti, Renato ; Brancati, Francesco ; D'Arrigo, Stefano ; Faravelli, Francesca ; Giordano, Lucio ; Huisman, Thierry A G M ; Iannicelli, Miriam ; Kluger, Gerhard ; Kyllerman, Marten ; Landgren, Magnus ; Lees, Melissa M. ; Pinelli, Lorenzo ; Romaniello, Romina ; Scheer, Ianina ; Schwarz, Christoph E. ; Spiegel, Ronen ; Tibussek, Daniel ; Valente, Enza Maria ; Boltshauser, Eugen. / Delineation and diagnostic criteria of oral-facial-digital syndrome type VI. In: Orphanet Journal of Rare Diseases. 2012 ; Vol. 7, No. 1.
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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

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.

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