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

Poretti A, Vitiello G, Hennekam RC, Arrigoni F, Bertini E, Borgatti R, Brancati F, D'Arrigo S, Faravelli F, Giordano L, Huisman TA, 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 - Orphanet J Rare Dis (2012)

Bottom Line: Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified.The majority of the patients have absent motor development and profound cognitive impairment.Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatric Neurology, University Children's Hospital of Zurich, Switzerland.

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.

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Midsagittal T2-weighted MR images of a 22-year-old woman (A) and a 2-day-old neonate (B), modified from Poretti A et al, AJNR, 2008, with permission) with OFD VI reveal an enlarged posterior fossa with marked retrocerebellar CSF collection. Additionally, in both patients the brainstem appears dysmorphic: in A the midbrain is thickened, the tectum dysplastic (white arrow head), and the pons short; in B there is elongation of the mesencephalon, reduced size of the pons, and dysplasia of the tectum (black arrow head). In both patients the cerebellar vermis is hypoplastic and its remnants are dysplastic (black arrow in B), the massa intermedia is prominent, and in B a hypothalamic hamartoma is seen (white arrow) and the pituitary stalk appears thickened (white arrow head).
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Figure 1: Midsagittal T2-weighted MR images of a 22-year-old woman (A) and a 2-day-old neonate (B), modified from Poretti A et al, AJNR, 2008, with permission) with OFD VI reveal an enlarged posterior fossa with marked retrocerebellar CSF collection. Additionally, in both patients the brainstem appears dysmorphic: in A the midbrain is thickened, the tectum dysplastic (white arrow head), and the pons short; in B there is elongation of the mesencephalon, reduced size of the pons, and dysplasia of the tectum (black arrow head). In both patients the cerebellar vermis is hypoplastic and its remnants are dysplastic (black arrow in B), the massa intermedia is prominent, and in B a hypothalamic hamartoma is seen (white arrow) and the pituitary stalk appears thickened (white arrow head).

Mentions: Infratentorial neuroimaging findings are summarized in Table 2. The hypoplasia of the cerebellar vermis was severe in ten patients (67%) and moderate in five (33%) (Figure 1). The vermian remnants appeared dysplastic in all patients (Figure 1). The volume of the cerebellar hemispheres was reduced in six patients (40%) and their folial organization was abnormal in eight (53%). The size of the posterior fossa was enlarged in ten patients (67%) (Figure 1) and in seven patients (47%) an increased amount of retrocerebellar CSF collection was present.


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

Poretti A, Vitiello G, Hennekam RC, Arrigoni F, Bertini E, Borgatti R, Brancati F, D'Arrigo S, Faravelli F, Giordano L, Huisman TA, 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 - Orphanet J Rare Dis (2012)

Midsagittal T2-weighted MR images of a 22-year-old woman (A) and a 2-day-old neonate (B), modified from Poretti A et al, AJNR, 2008, with permission) with OFD VI reveal an enlarged posterior fossa with marked retrocerebellar CSF collection. Additionally, in both patients the brainstem appears dysmorphic: in A the midbrain is thickened, the tectum dysplastic (white arrow head), and the pons short; in B there is elongation of the mesencephalon, reduced size of the pons, and dysplasia of the tectum (black arrow head). In both patients the cerebellar vermis is hypoplastic and its remnants are dysplastic (black arrow in B), the massa intermedia is prominent, and in B a hypothalamic hamartoma is seen (white arrow) and the pituitary stalk appears thickened (white arrow head).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3313869&req=5

Figure 1: Midsagittal T2-weighted MR images of a 22-year-old woman (A) and a 2-day-old neonate (B), modified from Poretti A et al, AJNR, 2008, with permission) with OFD VI reveal an enlarged posterior fossa with marked retrocerebellar CSF collection. Additionally, in both patients the brainstem appears dysmorphic: in A the midbrain is thickened, the tectum dysplastic (white arrow head), and the pons short; in B there is elongation of the mesencephalon, reduced size of the pons, and dysplasia of the tectum (black arrow head). In both patients the cerebellar vermis is hypoplastic and its remnants are dysplastic (black arrow in B), the massa intermedia is prominent, and in B a hypothalamic hamartoma is seen (white arrow) and the pituitary stalk appears thickened (white arrow head).
Mentions: Infratentorial neuroimaging findings are summarized in Table 2. The hypoplasia of the cerebellar vermis was severe in ten patients (67%) and moderate in five (33%) (Figure 1). The vermian remnants appeared dysplastic in all patients (Figure 1). The volume of the cerebellar hemispheres was reduced in six patients (40%) and their folial organization was abnormal in eight (53%). The size of the posterior fossa was enlarged in ten patients (67%) (Figure 1) and in seven patients (47%) an increased amount of retrocerebellar CSF collection was present.

Bottom Line: Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified.The majority of the patients have absent motor development and profound cognitive impairment.Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatric Neurology, University Children's Hospital of Zurich, Switzerland.

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.

Show MeSH
Related in: MedlinePlus