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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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A, midsagittal, B, coronal, and C, axial T2-weighted MR image of a 2-day-old neonate with OFD VI show a hypothalamic hamartoma (white arrow in A, black arrow in B, and thick white arrow in C). Also shown are significant vermian hypoplasia and dysplasia (black arrow in A), enlarged fourth ventricle and posterior fossa, the characteristic MTS (thin white arrow in C), elongation of the mesencephalon, reduced size of the pons, thin corpus callosum, absent of the left leaf of the septum pellucidum, and a thickened pituitary stalk (white arrow head in A; modified from Poretti A et al, AJNR, 2008, with permission). D, midsagittal and E, coronal T2-weighted MR image of a 2.3-year-old boy with OFD VI show a left paramedian hypothalamic hamartoma (black arrow). Moreover, D shows hypoplasia and dysplasia of the cerebellar vermis and enlargement of the fourth ventricle.
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Figure 4: A, midsagittal, B, coronal, and C, axial T2-weighted MR image of a 2-day-old neonate with OFD VI show a hypothalamic hamartoma (white arrow in A, black arrow in B, and thick white arrow in C). Also shown are significant vermian hypoplasia and dysplasia (black arrow in A), enlarged fourth ventricle and posterior fossa, the characteristic MTS (thin white arrow in C), elongation of the mesencephalon, reduced size of the pons, thin corpus callosum, absent of the left leaf of the septum pellucidum, and a thickened pituitary stalk (white arrow head in A; modified from Poretti A et al, AJNR, 2008, with permission). D, midsagittal and E, coronal T2-weighted MR image of a 2.3-year-old boy with OFD VI show a left paramedian hypothalamic hamartoma (black arrow). Moreover, D shows hypoplasia and dysplasia of the cerebellar vermis and enlargement of the fourth ventricle.

Mentions: Supratentorial neuroimaging findings are summarized in Table 3. Seven patients had hippocampal malrotation (47%). The corpus callosum was dysgenetic (but not absent) in four patients (27%), the septum pellucidum was not identified in three (20%). Observed migrational disorders included bilateral polymicrogyria in three patients (20%), unilateral closed-lip schizencephaly in two (13%), and periventricular nodular heterotopias in one (7%). A ventriculomegaly was present in six patients (40%) and in four the thalami appeared fused (27%). A hypothalamic hamartoma was identified in four patients (27%) (Figure 4). The pituitary gland could be identified in all patients.


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)

A, midsagittal, B, coronal, and C, axial T2-weighted MR image of a 2-day-old neonate with OFD VI show a hypothalamic hamartoma (white arrow in A, black arrow in B, and thick white arrow in C). Also shown are significant vermian hypoplasia and dysplasia (black arrow in A), enlarged fourth ventricle and posterior fossa, the characteristic MTS (thin white arrow in C), elongation of the mesencephalon, reduced size of the pons, thin corpus callosum, absent of the left leaf of the septum pellucidum, and a thickened pituitary stalk (white arrow head in A; modified from Poretti A et al, AJNR, 2008, with permission). D, midsagittal and E, coronal T2-weighted MR image of a 2.3-year-old boy with OFD VI show a left paramedian hypothalamic hamartoma (black arrow). Moreover, D shows hypoplasia and dysplasia of the cerebellar vermis and enlargement of the fourth ventricle.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: A, midsagittal, B, coronal, and C, axial T2-weighted MR image of a 2-day-old neonate with OFD VI show a hypothalamic hamartoma (white arrow in A, black arrow in B, and thick white arrow in C). Also shown are significant vermian hypoplasia and dysplasia (black arrow in A), enlarged fourth ventricle and posterior fossa, the characteristic MTS (thin white arrow in C), elongation of the mesencephalon, reduced size of the pons, thin corpus callosum, absent of the left leaf of the septum pellucidum, and a thickened pituitary stalk (white arrow head in A; modified from Poretti A et al, AJNR, 2008, with permission). D, midsagittal and E, coronal T2-weighted MR image of a 2.3-year-old boy with OFD VI show a left paramedian hypothalamic hamartoma (black arrow). Moreover, D shows hypoplasia and dysplasia of the cerebellar vermis and enlargement of the fourth ventricle.
Mentions: Supratentorial neuroimaging findings are summarized in Table 3. Seven patients had hippocampal malrotation (47%). The corpus callosum was dysgenetic (but not absent) in four patients (27%), the septum pellucidum was not identified in three (20%). Observed migrational disorders included bilateral polymicrogyria in three patients (20%), unilateral closed-lip schizencephaly in two (13%), and periventricular nodular heterotopias in one (7%). A ventriculomegaly was present in six patients (40%) and in four the thalami appeared fused (27%). A hypothalamic hamartoma was identified in four patients (27%) (Figure 4). The pituitary gland could be identified in all patients.

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