Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood.

BACKGROUND: Dandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown. OBJECTIVE: To identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families. METHODS: Medical assessment, sonographic, MRI and pathological studies were used to define phenotype. Chromosomal microarray analysis and whole-exome sequence were performed to unravel the genotype. RESULTS: We report four subjects from two unrelated families with homozygous mutations in the Exocyst Complex Component 3-Like-2 gene (EXOC3L2).EXOC3L2 functions in trafficking of post-Golgi vesicles to the plasma membrane. In the first family a missense mutation in a highly conserved amino acid, p.Leu41Gln, was found in three fetuses; all had severe forms of Dandy-Walker malformation that was detectable by prenatal ultrasonography and confirmed by autopsy. In the second family, the affected child carried a nonsense mutation, p.Arg72*, and no detected protein. He had peritrigonal and cerebellar white matter abnormalities with enlargement of the ventricular trigones, developmental delay, pituitary hypoplasia, severe renal dysplasia and bone marrow failure. CONCLUSION: We propose that biallelic EXOC3L2 mutations lead to a novel syndrome that affects hindbrain development, kidney and possibly the bone marrow.

Early Transient Prenatal Ultrasound Features of Choanal Atresia.

We present a case series of early second-trimester prenatal ultrasound (US) features in 4 fetuses with a confirmed diagnosis of choanal atresia. The clinical characteristics and outcomes evaluated included prenatal US findings, genetic analyses, postmortem autopsies (2 cases), and computed tomographic findings. A transient large nasal cavity was detected by US in all 4 fetuses. This finding disappeared a few weeks later. Three cases were unilateral choanal atresia, and 1 was bilateral. Transient enlargement of the nasal cavity in early pregnancy appears to be a US sign of choanal atresia.

Sonography of the fetal cochlea in the early second trimester of pregnancy.

OBJECTIVES: To examine the feasibility of imaging the fetal cochlea in the early second trimester. METHODS: This study included 42 healthy fetuses of low-risk pregnancies between 14 and 16 weeks. The coronal head sections via sagittal and lateral acoustic windows were used for cochlear visualization. The coronal plane was directed across the thalamus, oriented to the petrous part of the temporal bones. All fetuses were examined by 2-dimensional(2D) transvaginal sonography. Transabdominal scans were added in 11 fetuses at 16 weeks. Three-dimensional (3D) multiplanar reconstruction was used for coronal plane reformatting in cases with inappropriate head positioning for 2D scanning. RESULTS: Because of temporal bone hypomineralization in the early second trimester, sonographic depiction of the cochlear labyrinth was possible. On coronal imaging, the cochleas showed ringlike echogenic borders containing hypoechoic liquid content. The cochlear modiolus appeared as a central echogenic round spot ("cochlear target sign"). The cochleas were observed caudad to the temporal lobes, separated by the clivus. Shifting of the coronal plane showed progressive coiling of the basal cochlear turn toward the second turn ("cochlear whirlpool sign"). Two-dimensional transvaginal scanning showed at least 1 cochlea in 79% (33 of 42) of the cases. Adding 3D multiplanar reconstruction, at least 1 cochlear target sign was observed in 83% (35 of 42). The cochlear whirlpool sign on at least one side was shown in 57% (24 of 42). The maximal cochlear diameter was measured in fetuses with clear cochlear margin visualization. In this subgroup, the mean gestational age ± SD was 15.8 ± 0.5 weeks, and the mean maximal cochlear diameter was 6.4 ± 0.8 mm. CONCLUSIONS: Prenatal sonographic inner ear depiction was previously considered impossible. Using a unique time window in the early second trimester, we achieved feasible fetal cochlear imaging.

Fetal Ebstein's anomaly: early and late appearance.

OBJECTIVE: To present sonographic findings in early and late appearance of fetal Ebstein's anomaly. METHODS: Fetal sonography was performed in 53,447 consecutive pregnant women at 14 to 16 weeks' gestation. RESULTS: Ebstein's anomaly was detected in eight fetuses, in four of them additional anomalies were observed. All eight pregnancies were terminated. In an additional fetus, a normal four-chamber view without valvular regurgitation was visualized at 15 weeks' gestation. At 24 weeks, a normal four-chamber view was depicted. No Doppler examination was performed at that time. The newborn was found to have Ebstein's anomaly with pulmonary stenosis. A balloon pulmonary valvuloplasty was performed with a good outcome at three months of age. CONCLUSION: Fetal Ebstein's anomaly may be detected in early pregnancy. The incidence is higher than what is reported in newborns. Depiction of a normal fetal heart in early and midpregnancy does not exclude the possibility of subsequent development of Ebstein's anomaly.