Three-dimensional ultrasound in prenatal diagnosis of skeletal dysplasia

A lethal form of bone dysplasia, platylospondylic lethal chondrodysplasia, was diagnosed prenatally using three-dimensional ultrasound. The various types of three-dimensional imaging mode provided diagnostic details not available by conventional two-dimensional ultrasound. The diagnosis was made after referral in the 23rd week of gestation, allowing termination of pregnancy due to the poor prognosis. Prenatal sonograms were compared with postnatal radiographs.     

A sonographic approach to the prenatal diagnosis of skeletal dysplasias

Skeletal dysplasias are a heterogeneous group of conditions, many of which present unexpectedly in the prenatal period with a variety of ultrasound findings. Accurate prenatal diagnosis can now be facilitated using exome sequencing approaches, but in order to interpret results, accurate and detailed phenotyping is required. Here, we describe the sonographic approach to the prenatal diagnosis of skeletal abnormalities and illustrate how taking a systematic approach can facilitate diagnosis.     

Transvaginal sonographic detection of skeletal anomalies in the first and early second trimesters

We report the detection of 42 cases of musculoskeletal anomalies routinely screened by transvaginal sonography at 12-16 weeks of gestation out of 7325 examined pregnant women (incidence of 0·57 per cent).     

Shortened fetal long bones: A notable intrauterine phenotypic feature in SHOX-associated skeletal dysplasia

Objective

To explore the intrauterine phenotypic spectrum of short stature homeobox-containing (SHOX) gene-associated skeletal dysplasia and provide genetic counseling at-risk pregnancies.

Method

We analyzed the fetuses with SHOX-microdeletions identified by single nucleotide polymorphism (SNP)-array. The intrauterine phenotypes and outcomes were further elaborated.

Results

Nine fetuses carrying a single SHOX-microdeletion were reported, with deletion sizes ranging from 0.134 to 1.35 Mb. Shortened long bones were observed in all fetuses, varying from −2.0 standard deviation (SD) to −5.3 SD. Moreover, all cases had a femur length/foot ratio less than 0.87 and a femur/abdominal circumference ratio greater than 0.16, suggesting that non-lethal skeletal dysplasia may be involved. Two fetuses showed intrauterine growth restriction, and two had nasal bone hypoplasia. Prenatal ultrasonography did not reveal other obvious anomalies, including the Madelung deformity. Five microdeletions were inherited and one was de novo. Five terminations and four newborns were recorded. Two newborns had normal stature, and two were short-statured (height <3rd percentile), with one having inflexible wrists.

Conclusions

SHOX haploinsufficiency may manifest with shortened fetal long bones. The combination of history taking, prenatal ultrasonography, and SNP-array can prompt early prenatal diagnosis and timely postnatal treatment of SHOX-associated skeletal dysplasia.     

Fetal marfan syndrome: Prenatal ultrasound diagnosis with pathological confirmation of skeletal and aortic lesions

Sonography was performed during the second trimester in two pregnancies at risk for the Marfan syndrome. In one, the limbs were significantly longer than expected (p < 0·0025) and a diagnosis of the Marfan syndrome was established. Pathological examination of the fetus after pregnancy interruption showed typical foci of cystic medial necrosis in the ascending aorta.     

Fetal de novo heterozygous variant in the isocitrate dehydrogenase 1 gene associated with growth restriction,skeletal, cerebral and vascular anomalies

Germline pathogenic variants in isocitrate dehydrogenase 1 (IDH1) can lead to a rare neurodevelopmental disorder called metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, including severe skeletal and cerebral anomalies. To the best of our knowledge, no prenatal case of an IDH1 pathogenic variant has been reported in literature. Somatic sequence variants in IDH1/2 genes are described in distinct cancers, premalignant diseases and rare inherited metabolic disorders. Amniocentesis and further genetic testing including trio exome sequencing were performed due to suspicious findings on a second trimester routine prenatal ultrasound examination. The fetus was found to have growth restriction, cerebral abnormalities (ex vacuo hydrocephalus, cerebellar and vermian hypoplasia, corpus callosum dysgenesis), brachycephaly, narrow chest, persistent left superior vena cava, liver calcifications, hyperechogenic bowel, short tubular bones and joint contractures. A de novo heterozygous variant in the IDH1 gene was detected via trio exome sequencing. The prenatal diagnosis of a de novo pathogenic variant in IDH1 in a fetus with the described phenotype, obtained through trio exome sequencing, helped parents and providers with an informed decision making about pregnancy management.