Prenatal diagnosis of three cases of fetal skeletal dysplasia resulting from loss of heterozigosity of short stature homeobox gene

Objective To analyze the genotype-phenotype correlation in fetal skeletal dysplasia, and to investigate the methods of prenatal diagnosis and genetic counseling. Methods From May 2016 to November 2017, three gravidas whose fetuses were diagnosed with short stature homeobox (SHOX) gene deficiency were recruited from those receiving invasive prenatal diagnosis and single nucleotide polymorphism-array (SNP-array) due to fetal structural abnormalities detected by prenatal ultrasound scan in Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine. Fetus 1 and 3 were singleton pregnancies and fetus 2 was twin pregnancy. Amniotic fluid cells were isolated and analyzed by karyotyping and SNP-array. Peripheral blood samples were collected from their parents and also analyzed by SNP-array. Results All three fetuses were diagnosed with fetal skeletal dysplasia based on second trimester ultrasound findings showing the lengths of femora, humeri, tibiae, fibulae, ulnae and radii length below the 5th percentile of corresponding gestational age. Karyotypes of the three fetuses were normal. SNP-array examination showed that each case had 1 to 2.5 Mb deletion in the pseudoautosomal region of the short arms of sex chromosomes, including SHOX gene. Their skeletal dysplasia were all caused by SHOX haploinsufficiency. Microdeletions of fetus 1 and 3 were inherited from their mothers, while that of fetus 2 was inherited from the father. After genetic counseling, two singleton gravidas decided to terminate their pregnancies and the twin pregnant one underwent selective reduction. Conclusion Prenatal ultrasound, in combination with SNP-array, offers fast and efficient detection of fetal skeletal dysplasia due to SHOX gene deficiency. Key words: Osteochondrodysplasias; Chromosome deletion; Polymorphism, single nucleotide; Microarray analysis; Short Stature Homeobox protein; Prenatal diagnosis