Renal-hepatic-pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity

Abstract

Background: Renal-hepatic-pancreatic dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described, with cardiac malformations and cardiomyopathy adding additional variation to the phenotype. Many patients reported are within larger cohorts of congenital anomalies of kidney and urinary tract (CAKUT) or liver failure, and with minimal phenotypic and clinical course data.

Methods: An independent series of phenotypes and prognosis was aggregated from the literature. In this literature review, we describe an additional patient with RHPD2, provide a clinical update on the oldest known living patient, and report the cumulative phenotypes from the existing published patients.

Results: With now examining the 17 known patients in the literature, 13 died within the perinatal period-pregnancy to one year of life. Of the four cases living past the first year of life, one case died at 5 years secondary to renal failure, the other at 30 months secondary to liver and kidney failure. Two are currently alive and well at one year and 13 years. Two cases have had transplantation with one resulting in long-term survival.

Conclusions: These patients serve to expand the existing phenotype of RHPD2 as a perinatal lethal condition into a pediatric disorder with variable expressivity. Additionally, we introduce the consideration of transplantation and outcomes within this cohort and future patients.

Keywords: NEK8; renal-hepatic-pancreatic dysplasia type 2.

FIGURE 1

NEK8, its domains, and its variants. NEK8 consists of 15 coding exons (black and white boxes) with only a single known transcript. It belongs to the regulator of chromosome condensation 1 (RRC1) superfamily. This superfamily is defined by the presence of RCC1‐like domains (RLDs), 7 homologous domains, which form a seven‐bladed β‐propeller. Canonical RCC1 repeats are defined through UniProt(dark blue boxes); however, sequence alignments across the RCC1 superfamily allow for identification of 7 total repeats of similar sequence and length providing non‐canonical RCC1 repeats (light blue boxes) (Hadjebi et al., 2008). There is also a serine/threonine kinase domain (Uniprot, 2021) (dark red boxes). Variants for all patients are provided and numbered: missense—blue, splice—red, nonsense—purple. 8 of 20 variants were identified in the kinase domain, 10 of 20 variants in an RCC1 repeat, 1 variant lies between RCC1 domains, and 1 variant occurs at the terminus of the gene and results in frameshift read through of the canonical stop codon. The tables summarize the numbered variant providing codon and protein variants as reported by original publications and domains in which these variants were identified. Figure is to scale and adopted from Grampa et al. using the UCSC genome browser (Kent et al., 2002) and reference sequence NM_178170.3.