Department of Pediatrics and Adolescent Medicine, Division of Pediatric Pulmonology, Allergology and Endocrinology, Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
Department of Pediatric Orthopaedics, Orthopaedic Hospital Speising, 1130 Vienna, Austria.
Genes (Basel). 2021 Oct 20;12(11):1648. doi: 10.3390/genes12111648.
Biallelic truncating variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI, respectively. We report here on three adult siblings, 18 to 40 years of age, homozygous for the known c.354_357delinsCACTC (p.Gln118Hisfs*20) variant. Detailed clinical examinations were performed including ocular and gait analyses, skeletal- and neuroimaging. All three patients presented with neurological and oculomotor symptoms since birth and mild skeletal dysplasia in infancy resulting in characteristic gait abnormalities. We document mild skeletal dysplasia, abnormal gait with increased hip rotation and increased external foot rotation, ataxia, variable polydactyly, ocular Duane syndrome, progressive ophthalmoplegia, nystagmus, situs inversus of the retinal vessels, olfactory bulb aplasia, and corpus callosal dysgenesis as novel features in -ciliopathy. We show that intellectual disability is mild to moderate and retinal, renal and liver function is normal in these affected adults. Our study thus expands the -related Joubert syndrome to a mainly neurological and skeletal ciliopathy phenotype with predominant oculomotor dysfunction but otherwise stable outcome in adults. Diagnosis of -related disorder was impeded by segregation of multiple neurogenetic disorders in the same family, highlighting the importance of extended clinical and genetic studies in families with complex phenotypes.
双等位基因截断变异导致纤毛功能障碍，分别在 4 名杰特综合征和 6 型口面指骨综合征患者中报道过。我们在此报告了 3 名年龄在 18 至 40 岁之间的同胞，均为已知的 c.354_357delinsCACTC（p.Gln118Hisfs*20）变异的纯合子。进行了详细的临床检查，包括眼部和步态分析、骨骼和神经影像学检查。所有 3 名患者自出生以来均存在神经和眼球运动症状以及轻度骨骼发育不良，导致特征性的步态异常。我们记录了轻度骨骼发育不良、步态异常伴髋关节旋转增加和足部外旋增加、共济失调、可变多指畸形、眼部 Duane 综合征、进行性眼肌麻痹、眼球震颤、视网膜血管反转、嗅球发育不全和胼胝体发育不良，这些都是 -纤毛病的新特征。我们表明，这些受影响的成年人的智力残疾为轻度至中度，视网膜、肾脏和肝脏功能正常。因此，我们的研究将主要是神经和骨骼纤毛病的 Joubert 综合征扩展到 -相关疾病，表现为主要的眼球运动功能障碍，但成年人的预后稳定。在同一家庭中存在多种神经遗传疾病的分离，阻碍了 -相关疾病的诊断，这突出了在具有复杂表型的家庭中进行扩展临床和遗传研究的重要性。
