三例矮小同源盒基因杂合性缺失致胎儿骨骼发育异常的产前诊断

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

目的探讨骨骼发育异常胎儿基因型与产前超声表型的关系，以及产前诊断和咨询方法。方法2016年5月至2017年11月，因产前超声检查发现胎儿结构异常，至同济大学附属第一妇婴保健院胎儿医学部行单核苷酸多态性微阵列芯片（singlen ucleotidepolymor phismarray。SNP-array）检测的孕妇中3例胎儿（胎儿1和3为单胎，胎儿2为双胎之一）诊断为矮小同源盒（short stature homeobox，SHOX）基因杂合性缺失，纳人分析。3例胎儿及其双亲，行SNP-array检测，确定胎儿染色体微缺失情况及其来源。结果3例胎儿均于孕中期超声检查提示骨骼发育异常，股骨、肱骨、胫骨、腓骨、尺骨及桡骨均小于该孕周的第5百分位。3例胎儿羊水染色体核型均未见异常，SNP-array结果显示x或Y染色体短臂末端区域1～2．5Mb的杂合性缺失，缺失区域均包含SHOX基因，3例胎儿的骨骼发育异常均由SHOX基因单倍剂量不足造成。双亲外周血SNP-array检测显示胎儿1和3的微缺失遗传自其母亲，胎儿2的微缺失遗传自其父亲。经遗传咨询，3例孕妇中2例选择终止妊娠，1例（双胎妊娠之一胎儿骨骼异常）行选择性减胎术。结论产前超声结合SNP-array检测可以快速有效地诊断由SHOX基因杂合性缺失造成的遗传性骨病，有助于产前咨询。

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 ceils 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 SHOXgene deficiency.