Biallelic pathogenic variants in MADD lead to a very rare neurodevelopmental disorder which is phenotypically pleiotropic grossly ranging from severe neonatal hypotonia, failure to thrive, multiple organ dysfunction, and early lethality to a similar but milder phenotype with better survival. Here, we report 5 patients from 3 unrelated Egyptian families in whom 4 patients showed the severe end of the spectrum displaying neonatal respiratory distress, hypotonia and chronic diarrhea while one patient presented with the mild form displaying moderate intellectual disability and myopathy. In addition, we observed distal arthrogryposis and nonspecific structural brain anomalies in all our patients. Interestingly, cerebellar and brainstem hypoplasia were noted in one patient. Whole exome sequencing identified three novel homozygous variants in the MADD gene: two likely pathogenic [c.4321delC p.(Gln1441ArgfsTer46) and c.2620 C > T p.(Arg874Ter)] and one variant of uncertain significance (c.4307 G > A, p.Arg1436Gln). The variants segregated with the disease in all available family members. Our findings confirm that arthrogryposis, genital, cardiac and structural brain anomalies are manifestations of MADD which expand the spectrum of MADD-related neurodevelopmental disorder. Moreover, they further highlight the convergence of MADD variants on different organ systems leading to complex phenotypes.

MADD中的双等位基因致病变异导致一种非常罕见的神经发育障碍，其表型具有多效性，从严重的新生儿肌张力低下、发育迟缓、多器官功能障碍和早期致死到类似但较温和的表型（具有更好的生存率）。在这里，我们报告了来自 3 个不相关的埃及家庭的 5 名患者，其中 4 名患者表现出严重的症状，表现为新生儿呼吸窘迫、肌张力低下和慢性腹泻，而 1 名患者表现出轻度症状，表现为中度智力障碍和肌病。此外，我们在所有患者中观察到远端关节弯曲和非特异性脑结构异常。有趣的是，一名患者发现小脑和脑干发育不全。全外显子组测序鉴定出MADD基因中的三种新的纯合变异：两种可能致病的 [c.4321delC p.(Gln1441ArgfsTer46) 和 c.2620 C > T p.(Arg874Ter)] 和一种意义不确定的变异 (c.4307 G > A，p.Arg1436Gln)。这些变异在所有可用的家庭成员中随疾病一起分离。我们的研究结果证实，关节弯曲、生殖器、心脏和大脑结构异常是MADD的表现，扩大了MADD相关神经发育障碍的范围。此外，他们进一步强调了MADD变异在不同器官系统上的融合，导致复杂的表型。