Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia.

PURPOSE: This study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable. METHODS: We compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts. RESULTS: In 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient-derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign. CONCLUSION: Taken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome.

Contrast-enhanced MRI of the temporomandibular joint: findings in children without juvenile idiopathic arthritis.

BACKGROUND: Contrast-enhanced magnetic resonance imaging (MRI) is highly sensitive for assessing temporomandibular joint (TMJ) involvement in juvenile idiopathic arthritis (JIA), but only sparse data exist on normal TMJ appearance in children. PURPOSE: To determine normal MRI appearance and enhancement pattern of pediatric TMJ as basis for diagnosing early arthritis. MATERIAL AND METHODS: In 27 children (age range, 1.2-16.8 years) without TMJ pathology undergoing head MRI, fat-saturated T2-weighted (T2W) and postcontrast fat-saturated T1-weighted (T1W) images sagittally aligned to the 54 TMJs, besides standard T1W and T2W images, were assessed for bony and soft tissue signal intensity (SI), the amount of perceptible joint fluid, and contrast enhancement (CE). RESULTS: Bone marrow SI and CE of the mandible were consistent with varying degrees of residual red marrow in 96% of joints. The mandibular condyles were mostly isointense to the ramus, but in 9% showed mild edema-like bone marrow SI and CE. Small amounts of intraarticular fluid were detected in 31% on T2W images without fat saturation and in 83% on T2W images with fat saturation as fine lines in the upper or lower joint compartment or as small dots in an articular recess. Seventy-nine percent of all TMJs showed intense joint enhancement on early images restricted to areas of intraarticular fluid. CONCLUSION: Small amounts of joint fluid with intense CE are a common MRI finding in TMJs of children without JIA and therefore should not be considered diagnostic for early arthritis.