Fig. 1

Recurrent TOMM7 p.P29L variant in four patients from three unrelated families. (a) Short stature and unique facial features, including low set and protruding ear, beaked nose, and micrognathia in four patients from three families. (b) The brain magnetic resonance imaging (MRI) study of patient 1-III revealed cytotoxic edema of the left parietal lobe (arrows), as shown by T2 hyperintensity (i), high signals on diffusion-weighted imaging (ii), and low apparent diffusion coefficient values (iii), Magnetic resonance arteriography (MRA) indicated bilateral occlusion of distal internal carotid arteries (ICA) and interrupted proximal middle cerebral arteries (MCA) ((iv), arrowheads) and abundance collateral vasculatures (v), compatible with Moyamoya disease. (c) Protruding maxillary central incisors, crowded and irregular teeth, hair thinning with obvious hair loss. (d) Analysis of facial similarity among the patients. Three distributions of mean pairwise distance were shown: our patients (orange), the random selection from the subjects with 328 disorders (red), and the selection from subjects with the same disorder (blue). The orange vertical line indicated the mean pairwise distance of the patients, and the black vertical line indicated the threshold that classifies whether it was from the same disorder or random selection. The entire (100%) distribution of patients was below the threshold. (e) The brain MRI of patient 4-IV showing confluent areas of encephalomalacia in bilateral frontal white matter and right anterior and superior frontal gray matter, suggesting an old border-zone infarction. The periphery of the lesions still showed mild diffusion restriction (i). Time-of-flight MRA revealed severe narrowing of distal ICA to proximal anterior cerebral artery (ACA) and MCA bilaterally with prominent basal collateral vessels, compatible with Moyamoya disease. The M2s and A2s can be seen. The posterior cerebral arteries (PCAs) were prominent with collaterals. Moyamoya disease with bilateral cerebral old infarctions and impaired cerebral perfusion, was more on the right side (ii). (f) The brain MRI of patient 6-III showing abnormal high signal intensity on T2WI at both parietal, both frontal cortical, subcortical areas, left temporal subcortical area, left parietal central parenchyma. Limited diffusion coefficients were evident at the right parietal cortical, left parietal central parenchyma, left temporal subcortical area. Recent ischemic changes were suspected at both parietal and left temporal areas (i). Remarkably decreased flow signals at both supraclinoid internal carotid artery, right petrous, cavernous internal carotid artery, both proximal MCAs and ACAs as well as left proximal PCA (ii). (g) Family pedigree of seven unrelated families in this study. (h) Confirmation of TOMM7 p.P29L variant by Sanger sequencing. (i) Proline 29 locates on the highly conserved transmembrane domain of TOM7 protein (NP_061932.1).