The Reliability of Ultrasound Markers in Identifying Fetuses With a Life-Limiting Skeletal Dysplasia.

OBJECTIVE: To determine the diagnostic performance of ultrasound markers associated with life-limiting fetal skeletal dysplasia in a fortified cohort. METHODS: Retrospective review from 2013 to 2023 of pregnancies with suspected fetal skeletal dysplasia. Ultrasound evaluation included measurements predictive of a life-limiting dysplasia: thoracic circumference/abdominal circumference (TC/AC) < 0.6, femur length/abdominal circumference (FL/AC) < 0.16, and thoracic circumference (TC) < 2.5th percentile. Demographics, ultrasound findings, genetic testing, and fetal/neonatal outcome were reviewed. RESULTS: Of 96 fetuses with complete outcome data, 47 (49%) had a non-life-limiting dysplasia and 49 (51%) had a life-limiting dysplasia. 22 (23%) had no life-limiting markers, 42 (44%) had one, 27 (28%) had two, and 5 (5%) had three. FL/AC < 0.16 and TC < 2.5th percentile were associated with life-limiting dysplasia (p < 0.001; p < 0.001), while TC/AC < 0.6 was rare and did not reach statistical significance (p = 0.056). The positive predictive value (PPV) for predicting life-limiting dysplasia increased from 50% to 78% to 100% with one, two, or three markers. The PPV of the two life-limiting markers was significantly higher in those diagnosed at < versus ≥ 28 weeks (90% vs. 43%, p = 0.02) but the analysis was limited by small numbers in the ≥ 28 weeks cohort. The negative predictive value of no life-limiting markers was 91%. CONCLUSIONS: In our cohort, the presence of two life-limiting ultrasound markers prior to 28 weeks was highly suggestive of a life-limiting dysplasia, whereas the absence of life-limiting markers was strongly associated with a non-life-limiting dysplasia throughout gestation. Nonetheless, individual markers had a poor predictive value of lethality, and a life-limiting diagnosis ≥ 28 weeks is challenging based on ultrasound markers alone. This highlights the importance of integrating thorough sonography, genetic testing, and balanced parental counseling.

Expansion of the prenatal phenotype of Baraitser-Winter syndrome: Presentation of two cases of multiple congenital anomaly syndrome.

Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) is a variable multiple congenital anomaly condition, typically presenting postnatally with neurocognitive delays, distinctive facial features, cortical brain malformations, and in some, a variety of additional congenital malformations. However, only a few cases have reported the prenatal presentation of this syndrome. Here, we report two cases of BWCFF and their associated prenatal findings. One case presented with non-immune hydrops fetalis and a horseshoe kidney and was found to have a de novo heterozygous variant in ACTB (c.158A>G). The second case presented with gastroschisis, bilateral cleft lip and palate, and oligohydramnios, and was found to harbor a different de novo variant in ACTB (c.826G>A). Limited reports exist describing prenatally identified anomalies that include fetal growth restriction, increased nuchal fold, bilateral hydronephrosis, rocker bottom foot, talipes, cystic hygroma, omphalocele, and hydrops fetalis. In addition, only three of these cases have included detailed prenatal imaging findings. The two prenatal cases presented here demonstrate an expansion of the prenatal phenotype of BWCFF to include gastroschisis, lymphatic involvement, and oligohydramnios, which should each warrant consideration of this diagnosis in the setting of additional anomalies.

Fetus with multiple congenital anomaly syndrome caused by novel variant in ATP1A2.

We report a 32-year-old G3P1 at 35 weeks 3 days with a dichorionic, diamniotic twin gestation who presented for evaluation secondary to ventriculomegaly (VM) in one twin. Fetal ultrasound and MRI demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture, indicative of a prior insult in the affected twin. The co-twin was grossly normal. The family pursued a palliative care pathway for the affected twin and was delivered at 37 weeks and 6 days. The affected twin passed away within the first hour of life due to respiratory compromise. Postmortem trio exome sequencing identified a homozygous likely pathogenic variant in ATP1A2 (c.2439+1G>A). Although this variant is novel, it is predicted to affect the donor split site in intron 17, resulting in a frameshift and complete loss-of-function of the gene. Biallelic loss of function variants in this gene have been reported in seven individuals with multiple anomalies similar to those in the affected twin. However, only one other individual with a possible CDH has been previously reported. Our case suggests that CDH be included in the phenotypic spectrum of this disorder and reports the first frameshift mutation causing this autosomal recessive multiple congenital anomaly syndrome.