#3092 Case report: Renal cystic disease caused to heterozygous NEK8 variant in pediatric patient

Abstract

Abstract Background and Aims Polycystic kidney diseases (PKDs) are the most prevalent inherited kidney disease [1]. They are caused by pathogenic variants in genes encoding for proteins with roles in the functioning of primary cilium, a sensory organelle at the cell surface of almost all cells regulating key signaling pathways. Therefore, they are also classified as Ciliopathy and can occur with isolated renal involvement with/without systemic manifestations. As 1 of the family of “Never in Mitosis A–related kinases” (NEK), NEK8 is a regulator of Hippo pathway that controls cell growth, regulate the renal tubule epithelial cell cytoskeletal structure, and is involved in ciliary biogenesis/function. Biallelic NEK8 mutations are reported as causing a syndromic ciliopathy with multiorgan developmental defects, referred to as renal-hepatic-pancreatic dysplasia [1]. A recent paper [1] analyzed a total of 21 patients from 12 families with heterozygous NEK8 variants and cystic kidney disease and proposed a dominant negative effect for specific heterozygous variants in the NEK8 kinase domain as a new cause of PKD. Method We describe a case report of PKD associated with NEK8 heterozygous mutation. Results 8 years old female patient accessed to Emergency Department with first evidence of isolated macro-hematuria. Previous medical history was unremarkable. The girl was afebrile, in good clinical condition, with elevated blood pressure values (120/82 mmHg) at the physical examination. The laboratory tests showed normal blood count with hemoglobin 11.7 g/dl, serum creatinine 0.42 mg/dl, no inflammatory markers. Urinalysis revealed proteinuria (100 mg/dL), hemoglobinuria, active urinary sediment with microhematuria (3557 red blood cell/microliter) and leukocyturia (535 white blood cells/microliter). An abdominal ultrasound study observed kidneys of increased size (longitudinal diameter of approximately 14 cm) with presence of multiple cystic formations with a maximum diameter of 2 cm and lost cortico-medullary differentiation; other organs were normal. Ultrasound findings were confirmed with MRI. The macrohematuria resolved quickly, however we recorded the persistence of positive urinary sediment. No other concomitant clinical manifestations were recorded and the cardiological evaluation was normal. Suspecting a cystic renal disease, we proposed a genetic analysis by whole exome sequencing (WES): an heterozygous NEK8 variant (c.133C>T, p. Arg45Trp) was found. Due to persistent proteinuria and hypertension we suggested to initiate RAAS inhibitor treatment. Conclusion The patient's clinical history and onset of disease agree with the data described in the literature for the NEK8 variant c.133C>T, p. Arg45Trp. In literature all patients had an early onset of PKD. Enlarged kidney were present in 79%, followed by hypertension in 67% of cases; no patients had liver involvement, as in our patient. Kidney failure occurred before adulthood in non-mosaic case. The absence of a phenotype with systemic involvement, doesn't exclude the possible subsequent appearance of extra-renal manifestations. Therefore, it is necessary to set up a multidisciplinary follow-up, including cardiological evaluation and radiological study of brain structure. An early nephroprotective therapy and behavioral strategy must be established to prevent disease progression. Thus, it is suggested to include NEK8 in the genetic analysis when PKD is suspected.