No abstract

In some cases Neu-Laxova syndrome (NLS) is linked to serine deficiency due to mutations in the phosphoglycerate dehydrogenase (PHGDH) gene. We describe the prenatal and postnatal findings in a fetus with one of the most severe NLS phenotypes described so far, caused by a homozygous nonsense mutation of PHGDH. Serial ultrasound (US) and pre- and postnatal magnetic resonance imaging (MRI) evaluations were performed. Prenatally, serial US evaluations suggested symmetric growth restriction, microcephaly, hypoplasia of the cerebellar vermis, micrognathia, hydrops, shortened limbs, arthrogryposis, and talipes equinovarus. The prenatal MRI confirmed these findings prompting a diagnosis of NLS. After birth, radiological imaging did not detect any gross bone abnormalities. DNA was extracted from fetal and parental peripheral blood, all coding exons of PHGDH were PCR-amplified and subjected to Sanger sequencing. Sequencing of PHGDH identified a homozygous premature stop codon mutation (c.1297C>T; p.Gln433*) in fetal DNA, both parents (first-cousins) being heterozygotes. Based on previous associations of mutations in this gene with a milder NLS phenotype, as well as cases of serine deficiency, these observations lend further support to a genotype-phenotype correlation between the degree of PHGDH inactivation and disease severity.

Objective: To determine the value of routine transvaginal color Doppler assessment of the uterine arteries at 22–24 weeks of gestation in the prediction of placental insufficiency. Methods: Women with singleton pregnancies scheduled for routine ultrasound scans at 22–24 weeks were offered Doppler assessment of the uterine arteries by transvaginal ultrasound. The pulsatility index (PI) was obtained for each artery and the mean value was calculated. A mean PI >95th percentile was considered increased. Screening characteristics for predicting placental insufficiency, defined as preeclampsia, fetal growth restriction or intrauterine death, were calculated. Results: Doppler examination of the uterine arteries was carried out in 1,057 singleton pregnancies. The mean uterine artery PI was 1.03 and the 95th percentile was 1.55. In 54 cases (5.1%) the mean PI was >1.55 (screen-positive). In the study population there were 48 cases of preeclampsia (5.1%), 72 fetal growth restrictions (7.5%) and 7 intrauterine deaths (0.7%). The screen-positive group showed an incidence of 47.1% of combined adverse results. The relative risks after a positive screening test were 7.3 (CI 4.2–12.6) for pre-eclampsia, 3.9 (CI 2.3 – 6.6) for fetal growth restriction and 4.5 (CI 3.2–6.4) for overall placental insufficiency. Conclusions: Uterine artery Doppler at 22–24 weeks identifies women at higher risk for the development of subsequent complications of placental insufficiency. This test could be used in combination with other markers to stratify the level of care offered in the third trimester of pregnancy.

Campomelic dysplasia (CD) is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46, XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2) or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia.