Frank et al. (2013) reported 3 fetuses from a consanguineous pedigree who presented in utero with enlarged organs and cystic/dysplastic changes in the kidney, liver, and pancreas. Two of the affected pregnancies were terminated at 21 and 22 ... Frank et al. (2013) reported 3 fetuses from a consanguineous pedigree who presented in utero with enlarged organs and cystic/dysplastic changes in the kidney, liver, and pancreas. Two of the affected pregnancies were terminated at 21 and 22 weeks' gestation, and the third was terminated at 18 weeks' gestation after intrauterine fetal demise. Additional features found in at least 1 of the fetuses included severe heart defects, such as truncus arteriosus and unseptated atrium and ventricle, hypoplastic lungs with lobulation defects, asplenia, uterine agenesis, and shortened legs due to bowed femurs. One patient had a right-sided stomach, consistent with heterotaxy or isomerism. Two patients had Potter sequence associated with oligo-/anhydramnios. Histologic examination of tissues from 2 of the fetuses showed cystic changes in the liver, kidneys, and pancreas. Liver samples showed hepatic fibrosis with ductal plate malformation, and the pancreas showed rudimentary lobulation and reduced acinar units as well as complete absence of the islets of Langerhans. The kidneys consisted of predominantly immature mesenchyme with no zonal partition between cortical and medullary areas, and the glomeruli were immature and decreased in number.
In 3 fetuses from a consanguineous pedigree with renal-hepatic-pancreatic dysplasia-2, Frank et al. (2013) identified a homozygous nonsense mutation in the NEK8 gene (R599X; 609799.0002). The mutation was found by homozygosity mapping and candidate gene analysis. Cultured fibroblasts ... In 3 fetuses from a consanguineous pedigree with renal-hepatic-pancreatic dysplasia-2, Frank et al. (2013) identified a homozygous nonsense mutation in the NEK8 gene (R599X; 609799.0002). The mutation was found by homozygosity mapping and candidate gene analysis. Cultured fibroblasts derived from the fetuses showed decreased expression of polycystic kidney disease genes PKD1 (601313) and PKD2 (173910) and increased expression of the MYC (190080) oncogene, providing potential explanations for the observed renal phenotype. Patient cells showed downregulation of the TAZ (WWTR1; 607392)/Hippo signaling pathway. The findings suggested that NEK8 is essential for organ development and that the complete loss of NEK8 perturbs multiple pathways important in early embryonic development. Sequencing of the NEK8 gene in 288 patients with cystic kidney disease and/or other ciliopathies did not identify any pathogenic mutations.