Department of Pediatric Neurology, University Children's Hospital of Zurich, Switzerland.
Orphanet J Rare Dis. 2012 Jan 11;7:4. doi: 10.1186/1750-1172-7-4.
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.
口腔面指综合征 VI 型（OFD VI）是杰特综合征和相关疾病（JSRD）的一种罕见表型亚型。在最初的报告中，多指畸形、口腔表现、智力障碍和死后小脑蚓部缺失是该综合征的特征。随后，在 OFD VI 患者中发现了磨牙征（MTS），促使将 OFD VI 纳入 JSRD。我们研究了一组 16 名 OFD VI 患者的临床、神经发育、神经影像学和遗传发现。我们从文献中得出了以下纳入标准：1）MTS 和一个口腔表现和多指畸形，或 2）MTS 和多个典型的口腔表现。OFD VI 的神经影像学模式比其他 JSRD 亚组更严重，包括小脑蚓部严重发育不良、小脑半球发育不良和畸形、后颅窝显著增大、后脑脊液回流增加、脑干异常，以及经常出现的幕上异常，偶尔包括特征性下丘脑错构瘤。此外，还发现了两个新的 JSRD 神经影像学发现（上升性小脑上脚和融合的丘脑）。舌部错构瘤、额外的系带、上唇切迹和中轴多指是 OFD VI 的特定表现，而唇裂/腭裂和手足其他类型的多指畸形则不是特异性的。其他器官的受累可能包括眼部表现，特别是眶距过宽。大多数患者的运动发育和认知功能均严重受损。在 OFD VI 中，正常的认知功能是可能的，但很罕见。对大多数患者的已知 JSRD 基因进行测序未能检测到致病性突变，因此 OFD VI 的遗传基础尚不清楚。与其他 JSRD 亚组相比，OFD VI 的神经学表现和运动发育及认知功能的损害更为严重，提示与更严重的神经影像学表现相关。基于文献和本研究，我们建议 OFD VI 的诊断标准为：MTS 及以下一项或多项：1）舌部错构瘤和/或额外的系带和/或上唇切迹；2）一个或多个手或脚的中轴多指；3）下丘脑错构瘤。
