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.

New insights into genotype–phenotype correlation for GLI3 mutations

“…31 Overlap of PHS with OFD has been previously discussed as oral anomalies (oral frenula, hamartoma, cleft palate) and/or skeletal dysplasia are often associated to GLI3 mutations. 10 Avila et al 32 screened eight patients with OFD associated with midline abnormalities but no mutation was found.…”

Joubert syndrome: genotyping a Northern European patient cohort

“…28 There has been some debate in the literature whether C5orf42 may be the major gene for OFD VI. 26,27 None of the six cases in our cohort showed typical signs of OFD VI, whereas no deleterious variants were found in any of the genes tested in the one case in our cohort with the OFD VI phenotype.…”

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

“…15 Ciliopathies such as Joubert syndrome (JS [MIM: 213300]), acrocallosal syndrome (ACLS [MIM: 200990]), and oral-facial-digital syndromes (MIM: 311200, 277170) frequently present with congenital defects of the CNS (e.g., cerebellar vermis hypoplasia, ''molar tooth sign'' [MTS], defects of the corpus callosum, polymicrogyria), midline facial anomalies, and polydactyly, which are at least partially attributed to altered SHH signaling. [16][17][18][19] Similarly, heterozygous pathogenic variants directly affecting several members of the SHH pathway, including SHH itself (MIM: 600725), PTCH1, SMO (MIM: 601500), GLI2 (MIM: 165230), or GLI3 (MIM: 165240), result in a spectrum of autosomal-dominant developmental disorders including holoprosencephaly (MIM: 142945), schizencephaly with polymicrogyria (MIM: 269160), Curry-Jones syndrome (CJS [MIM: 601707]), Greig cephalopolysyndactyly syndrome (GCPS [MIM: 175700]), Pallister-Hall syndrome (MIM: 146510), and non-syndromic polydactylies (MIM: 174200, 174700), that are variably characterized by anomalies of the brain, midline face, and/or limbs. [20][21][22][23] An aberrant activity of the SHH pathway has also been firmly associated with increased risk of developing cancer.…”