Antenatal diagnosis of lethal skeletal dysplasias

Abstract

Lethal skeletal dysplasias (LSD) are a heterogeneous group of rare but important genetic disorders characterized by abnormal growth and development of bone and cartilage. We describe the diagnosis and outcome of 29 cases of lethal skeletal dysplasias evaluated between January 1989 and December 1996 at the University of Maryland Medical Center and the Ultrasound Institute of Baltimore. Two cases presented at delivery with no prenatal care while the remaining 27 cases were identified by antenatal sonography. Final diagnoses included thanatophoric dysplasia (14), osteogenesis imperfecta, type II (6), achondrogenesis (2), short rib syndromes (3), campomelic syndrome (2), atelosteogenesis (1), and no evidence of a skeletal dysplasia (1). Twenty out of 27 pregnancies were terminated with an average at detection of 21.6 weeks. The other 7 pregnancies that went on to deliver had an average age at detection of 29.2 weeks. Fetal abnormalities in the terminated pregnancies were identified at a significantly earlier gestational age (P = 0.0016) than the pregnancies that continued. While the identification of LSD by sonography was excellent (26/27), only 13/27 (48%) were given an accurate specific antenatal diagnosis. In 8/14 (57%) cases with an inaccurate or nonspecific diagnosis there was a significant or crucial change in the genetic counseling. Thus, while antenatal sonography is an excellent method for discovering LSD, clinical examination, radiographs, and autopsy are mandatory for making a specific diagnosis.

Deletion of the GATA Domain of TRPS1 Causes an Absence of Facial Hair and Provides New Insights into the Bone Disorder in Inherited Tricho-Rhino-Phalangeal Syndromes

“…Again, our findings directly implicate the GATA zinc finger motif in this essential function. The phenotype resembles features of lethal human skeletal dysplasias, including thanatophoric and campomelic dwarfism, and of mice with mutations in the Myf-5 or MRF4 gene, where congenital rib abnormalities cause perinatal respiratory mortality (2,14,39,53). The specific skeletal defects in TRPS1 ⌬gt homozygotes most closely resemble findings for mice with combined absence of the homeobox genes Dlx5 and Dlx 6 (46).…”

“…Combined with the clinical and pathological evidence for respiratory failure, these findings suggest a scenario wherein structural thoracic defects compromise inspiratory function and lead to pulmonary atelectasis and progressive respiratory compromise in TRPS1 ⌬gt/⌬gt mice. Similar skeletal defects serve as the basis for respiratory neonatal lethality in a variety of engineered mouse strains (2,39,46,60) and in human syndromes of severe dwarfism and skeletal dysplasia (14,53).…”

Detailed ultrasonographic findings in Greenberg dysplasia

“…Differentiation between lethal and non-lethal anomaly is relatively easy. However, a precise antenatal ultrasonographic diagnosis of a lethal bone dysplasia may be very dif®cult, and in one large study a speci®c diagnosis could only be made in 48% of cases (Tretter et al, 1998). Establishing a diagnosis requires interaction between a perinatologist, geneticist and fetal/neonatal pathologist.…”

Prenatal diagnosis of a novelCOL1A1 mutation in osteogenesis imperfecta type I carried through full term pregnancy

“…In previously reported cases of prenatally diagnosed OI that applied DNA based techniques, the indication was either a severe form of the disease (type II or III) (Valli et al, 1993;DiMaio et al, 1993;Raghunath et al, 1994;Gomez-Lira et al, 1994), or an ultrasonographic abnormality compatible with OI in the appropriate familial context (Ghosh et al, 1984;Robinson et al, 1987;Constantine et al, 1991;Thompson, 1993;Bulas et al, 1994;Berge et al, 1995). Evaluation of the accuracy of ultrasonography in assigning speci®c diagnoses in lethal skeletal dysplasias, including OI, yielded a rate of about 50%, and in 8/14 cases, the erroneous diagnosis impacted the accuracy of genetic counselling (Tretter et al, 1998). The other alternative for prenatal diagnosis, biochemical assessment of the amount and integrity of procollagen, is not readily available worldwide, and also requires CVS rather then amniocentesis, as the protein is not expressed in amniocytes (Grange et al, 1990).…”