With the development of prenatal ultrasonography, hyperechogenic kidneys are occasionally observed during routine ultrasonography examinations. Obstetricians are increasingly facing the challenge of counseling pregnant women with fetal hyperechogenic kidneys. Fetal hyperechogenic kidney is diagnosed after 17 weeks of gestation when the kidneys appear more echogenic than the spleen and/or the liver. A recent research has shown that such hyperechogenic kidney can be a result of autosomal recessive polycystic kidney diseases, autosomal dominant polycystic kidney diseases, and cystic dysplasia. The remaining causes include tubulopathies, tubular dysgenesis, transient hyperechogenicity, tuberous sclerosis, and miscellaneous diseases [11, 12]. The differential diagnosis should consider the family history and the presence of associated anomalies. Recent studies have shown that some fetal abnormalities are associated with hyperechogenic kidneys, including Meckel-Gruber syndrome, Joubert syndrome, Bardet-Biedl syndrome, and VACTERL syndrome[13]. Our study also showed abnormalities, such as cystic renal dysplasia, enlarged lateral ventricles, choroid plexus cyst, congenital heart disease, polydactyly, and talipes varus. (Tables 1 and 3).
Prenatal ultrasonography examination plays an important role in the detection of fetal renal dysplasia. In the case of a fetus with renal cysts associated with hyperechogenic kidneys, detailed ultrasonography examination is useful, with careful attention to the brain, heart, hands, feet, spine, posterior fossa, etc. Fetal kidneys must be measured for renal echogenicity, CMD, cyst characteristics (size, location, and number), and amniotic fluid volume. In the subjects with isolated fetal hyperechogenic kidneys, amniotic fluid abnormalities were present in about 29.2% of the fetuses (8 cases of hydramnios and 6 cases of oligohydramnios) and about 35.4% had kidney size changes; the bilateral and unilateral ratio was 3:1 (Table 2). However, ultrasonography examination does not provide 100% sensitivity, especially for severe oligohydramnios; therefore, in such cases, fetal magnetic resonance imaging can be used [14, 15].
Studies have shown that about 10% of fetal urinary system abnormalities associated with other systemic malformations is associated with chromosomal abnormalities, including trisomy 21 syndrome, trisomy 18 syndrome, trisomy 13 syndrome, and chromosomal microdeletions [16]. Our retrospective analysis found that 9 fetuses had chromosomal abnormalities, accounting for about 11.25% of all cases. Trisomy 21 syndrome was present in 3 subjects, and trisomy 13 syndrome was present in 2 subjects. In isolated fetal hyperechogenic kidneys, we also detected fetuses with chromosomal abnormalities, including trisomy 21 syndrome and trisomy 13 syndrome, similar to previous reports. Moreover, eight cases of chromosomal microdeletion microduplication syndrome were also detected, including 17q12 microdeletion syndrome (6 cases), Williams-Beuren syndrome, and 4p16.3-p16.1 duplication syndrome.
Chromosomal 17q12 microdeletions and microduplications syndrome have been associated with a wide range of clinical phenotypes. In the prenatal setting, deletion of 17q12 is associated with renal cysts and echogenicity [17], developmental delay [18, 19], autism, and schizophrenia [20]. 17q12 microdeletions encompassing the hepatocyte nuclear factor 1-beta (HNF1B) gene, also referred to as transcription factor 2 (TCF 2). HNF1B plays a crucial role in early development, including causing renal pathology as a result of haploinsufficiency within the commonly deleted region [21]. In humans, mutations in HNF1B cause congenital anomalies of the kidney and the urinary tract, maturity-onset diabetes of the young type 5, and genital malformations [22]. Gondra L, et al. reported that HNF1B mutation is the leading cause of isolated hyperechogenic fetal kidneys with normal or moderately large size and that HNF1B can be associated with polyhydramnios in the absence of maternal diabetes [23]. In their study, Loirat C, found that 3 out of the 53 children had cystic or hyperechogenic kidneys and heterozygous 17q12 deletion encompassing HNF1B mutation [24]. In our study, we found 6 fetuses with hyperechogenic kidneys, including isolated cases with 17q12 deletion and detected HNF1B mutation (which cause Renal cysts and diabetes syndrome, OMIM:137920, autosomal dominance inheritance); 17q12 microdeletion syndrome has a variety of phenotypes. Even if the fetus only has kidney dysplasia without diabetes mellitus or neurocognitive impairment, future occurrence cannot be ruled out. Therefore, phenotypic prediction and consulting after birth are challenging in cases with prenatal diagnosis of fetal 17q12 microdeletion syndrome.
Furthermore, we detected Williams-Beuren syndrome through chromosome microarray analysis. Williams-Beuren syndrome is a common chromosome microdeletion syndrome characterized by a specific dysmorphic face and habitus, postnatal growth deceleration, mild to moderate psychomotor retardation, and multiple organ dysfunction [25, 26]. Sammour et al. have reported a prevalence of 75% for urinary tract abnormalities [27]. We also detected a fetus with multicystic dysplastic kidney and Williams-Beuren syndrome (chromosome 7q11.23 with a 1.43 Mb deletion). Moreover, with the development of whole-exome sequencing techniques, we have identified BBS2 (OMIM:606151), BBS7 (OMIM:607590), HNF1B (OMIM:189907), ACE (OMIM:106180), CEP290 (OMIM:610142), COL4A5 (OMIM:303630), and PKHD1 (OMIM:606702) gene mutations in 9 fetuses with hyperechogenic kidneys. The karyotype analysis and microarray analysis of these nine fetuses did not show any abnormalities.
Mutations in PKHD1 could cause Polycystic kidney disease 4, with or without hepatic disease syndrome (OMIM: 263200). The main clinical manifestations include renal enlargement, cystic kidney, renal failure, enhanced echogenicity of the parenchyma, loss of cortical medulla differentiation, interstitial fibrosis; prenatal ultrasound showed oligohydramnios. Mutations in BBS7 could cause Bardet-Biedl syndrome 7 (OMIM: 615984). Bhowmik A, et al [28] reported that ACE gene mutation could cause Renal tubular dysgenesis (OMOM:267430). Moreover, BBS2 gene mutation also could cause Bardet-Biedl syndrome 2(OMIM:615981), which is manifested as severe retinitis pigmentosa, obesity, polydactyly, renal malformation and mental retardation. All these variants were considered to be pathogenic according to the ACMG criteria and these diseases are inherited in autosomal recessive patterns.
Prenatal diagnosis of hyperechogenic kidneys could benefit fetuses or neonates if the renal disorder is detected and treated early. However, prenatal diagnosis of a fetal renal abnormality may be extremely stressful for the parents, can make prenatal counseling challenging, and could even make the parents decide to terminate the pregnancy, especially when the long-term outcome is uncertain. Estroff et al. reported that the survival rate of non-isolated fetuses with hyperechoic kidneys was significantly lower than that of isolated fetuses, and oligohydramnios predicted a poor prognosis [29]. Kumar et al. suggested that the factors associated with poor prognosis included bilateral disease, absence of amniotic fluid, and presence of associated other malformation [30]. Our study also showed that the pregnancy outcome depends on whether other structural abnormalities are present. Among fetuses with isolated hyperechogenic kidneys, 11.25% had chromosomal abnormalities and 45.8% (22/48) terminated the pregnancy; some parents of fetuses with normal karyotype analysis also chose to terminate the pregnancy. In addition, among fetuses with other structural abnormalities, 25% had chromosomal abnormalities, and 81.25% (26/32) chose to terminate the pregnancy. Further study of fetuses with isolated hyperechogenic kidneys revealed that amniotic fluid volume, the size of the kidney, and the number of kidneys involved were important factors that affected the choice of pregnancy outcomes. Parents of fetuses with oligohydramnios and enlarged kidney volume were more likely to terminate the pregnancy. Moreover, no abnormal growth and development were observed in the follow-up of live births, and we found no abnormalities in the renal function of the newborns; this may be associated with an insufficient follow-up duration; additional regular follow-up may be required at a later stage. We also suggested that kidney size and amniotic fluid volume were the best prenatal predictors of outcome and found that patients with large kidneys and oligohydramnios are likely to have poor outcomes.