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

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.

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).

Figure 2

Parasagittal T2-weighted MR images of a 5-month-old infant (A) and a 22-year-old woman (B) with OFD VI. In JSRD the SCP (white arrows) have a characteristic horizontal sagittal orientation (A). In some patients with OFD VI, however, the SCP (white arrows) have a clearly ascending orientation (B).

Figure 3

A, midsagittal and B, axial T2-weighted MR images of a 5-month-old infant with OFD VI, and C, midsagittal constructive interference in steady-state (CISS) and D, axial T2-weighted MR images of a 2-year old child with OFD VI. In both patients there is a grey matter isointense, nodular tissue mass in the interpeduncular fossa representing an interpeduncular heterotopia (black arrows). Additionally, C demonstrates a hypothalamic hamartoma (white arrow) and a horizontal septum at the distal end of the Sylvian aqueduct is noted on A.

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.

Figure 5

A, tongue hamartomas (black arrows), B, additional prominent oral frenula (black arrows), and C, cleft palate in patients with OFD VI.

Figure 6

A, sagittal T1-weighted and B, sagittal T2-weighted MR image of a 2-week-old newborn with OFD VI demonstrate a T1-isointense (white arrow on A) and T2-hyperintense (white arrow on B) tissue lesion on the surface of the posterior part of the tongue, representing a tongue hamartoma.

Figure 7

A, preaxial poly-syndactyly of the right foot, B, mesoaxial polydactyly of the right hand, C, X-ray of the left hand showing a Y-shaped third metacarpal bone, and D, postaxial polydactyly of the right hand.