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.
Highlights
Joubert Syndrome (JS) is a rare midbrain-hindbrain malformation with an estimated prevalence between 1:80 000 and 1:100 000 live births [1]
Patient cohort The patients included in this study were collected by the senior authors (EMV and EB): 1) from their personal cohorts of OFD Oral-facial-digital syndrome type VI (VI) patients; 2) from patients who were referred for second opinion; 3) from requests to evaluate clinical and neuroimaging data of patients with a definite or probable diagnosis of Oral-FacialDigital Syndrome type VI (OFD VI); and 4) from patients referred for molecular genetic testing after a diagnosis of OFD VI
Neuroimaging In a recent study of neuroimaging in 75 patients with JS-related disorders (JSRD), we failed to show a specific correlation between neuroimaging and clinical phenotype or genotype in JSRD, but we noted that the four OFD VI patients demonstrated a similar and more severe neuroimaging pattern [21]
Summary
Joubert Syndrome (JS) is a rare midbrain-hindbrain malformation with an estimated prevalence between 1:80 000 and 1:100 000 live births [1]. The characteristic neurological signs of JS include muscular hypotonia (most prominent during infancy), cerebellar ataxia (typically developing later), ocular motor apraxia, and an irregular breathing pattern in the neonatal period [2,3,4]. Involvement of the kidneys (nephronophthisis and/or renal cysts), liver (congenital liver fibrosis), and eyes (retinal dystrophy and/or ocular colobomas) may be associated features of JS, defining the spectrum of socalled JS-related disorders (JSRD) [2,3,4]. Heterozygous, not causative mutations have been found in the JBTS11/TTC21B gene [13]. Primary cilia are subcellular organelles known to play key roles in the development and functioning of several cell types, including retinal photoreceptors, neurons, and the epithelial cells lining kidney tubules and bile ducts [14,15,16]
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