Joubert syndrome is a recessive neurodevelopmental disorder characterized by clinical and genetic heterogeneity. Clinical hallmarks include hypotonia, ataxia, facial dysmorphism, abnormal eye movement, irregular breathing pattern cognitive impairment and, the molar tooth sign is the pathognomonic midbrain-hindbrain malformation on magnetic resonance imaging. The disorder is predominantly caused by biallelic mutations in more than 30 genes encoding proteins with a pivotal role in morphology and function of the primary cilium. Oligogenic inheritance or occurrence of genetic modifiers has been suggested to contribute to the variability of the clinical phenotype. We report on a family with peculiar clinical spectrum Joubert syndrome molecularly and clinically dissecting a complex phenotype, in which hypogonadism, pituitary malformation and growth hormone deficiency occur as major features. A 7 year-old male was enrolled in a dedicated “Undiagnosed Patients Program” for a peculiar form of Joubert syndrome complicated by iris and retinochoroidal coloboma, hypogonadism pituitary malformation, and growth hormone deficiency. The molecular basis of the complex phenotype was investigated by whole exome sequencing. The concomitant occurrence of homozygosity for mutations in KIF7 and KIAA0556 was identified, and the assessment of major clinical features associated with mutations in these two genes provided evidence that these two independent events represent the cause underlying the complexity of the present clinical phenotype. Beside the clinical variability of Joubert syndrome, co-occurrence of mutations in ciliopathy-associated genes may contribute to increase the clinical complexity of the trait.

中文翻译：

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Joubert综合征中KIF7和KIAA0556突变与眼球状结肠瘤，垂体畸形和生长激素缺乏症同时发生：一例病例并文献复习

Joubert综合征是一种以临床和遗传异质性为特征的隐性神经发育障碍。临床标志包括肌张力低下，共济失调，面部畸形，眼球运动异常，呼吸模式不规则性认知障碍，而磨牙齿征是磁共振成像上的病理性中脑-后脑畸形。该疾病主要是由30多个基因的双等位基因突变引起的，这些基因编码在初级纤毛的形态和功能中起关键作用的蛋白质。已经提出寡聚遗传或遗传修饰物的出现有助于临床表型的可变性。我们报道了一个具有特殊临床谱系Joubert综合征的家庭，该家族在分子上和临床上都解剖了一个复杂的表型，其中性腺机能减退，垂体畸形和生长激素缺乏症是主要特征。一名7岁男性因特殊的Joubert综合征并发虹膜和视网膜脉络膜大肠瘤，垂体功能低下垂体畸形和生长激素缺乏症而参加了专门的“未诊断患者计划”。通过全外显子组测序研究了复杂表型的分子基础。确定了在KIF7和KIAA0556中突变同时发生的纯合性，并且对与这两个基因突变相关的主要临床特征的评估提供了证据，表明这两个独立事件代表了造成当前临床表型复杂性的原因。除了Joubert综合征的临床变异性，