Renal–Hepatic–Pancreatic Dysplasia: An Ultra-Rare Ciliopathy with a Novel NPHP3 Genotype

Abstract

Renal–hepatic–pancreatic dysplasia-1 (RHPD1) is an ultra-rare genetic disorder with a high mortality. It is caused by biallelic pathogenic variants in NPHP3, which encode nephrocytin, an important component of the ciliary protein complex. The NPHP3-related disease phenotype is diverse with RHPD1, nephronophthisis-3, and Meckel syndrome-7. In this case report, we present a female infant with hepatomegaly, cholestasis, and elevated transaminases who was found to carry a homozygous c.2975C > T variant of NPHP3. This is the first description of this genotype and RHPD1 phenotype in the literature. The patient is currently being closely monitored for the necessity of combined renal and liver transplantation under supportive treatment.

Keywords

renal–hepatic–pancreatic dysplasia - NPHP3 - ciliopathy

• References

• 1 Neuhaus TJ, Sennhauser F, Briner J, Van Damme B, Leumann EP. Renal-hepatic-pancreatic dysplasia: an autosomal recessive disorder with renal and hepatic failure. Eur J Pediatr 1996; 155 (09) 791-795
• 2 Ivemark BI, Oldfelt V, Zetterstrom R. Familial dysplasia of kidneys, liver and pancreas: a probably genetically determined syndrome. Acta Paediatr (Stockh) 1959; 48 (01) 1-11
• 3 Bergmann C, Fliegauf M, Brüchle NO. , et al. Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am J Hum Genet 2008; 82 (04) 959-970
• 4 Benzing T, Schermer B. Clinical spectrum and pathogenesis of nephronophthisis. Curr Opin Nephrol Hypertens 2012; 21 (03) 272-278
• 5 Hoff S, Halbritter J, Epting D. , et al. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet 2013; 45 (08) 951-956
• 6 Wolf MT. Nephronophthisis and related syndromes. Curr Opin Pediatr 2015; 27 (02) 201-211
• 7 Olbrich H, Fliegauf M, Hoefele J. , et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat Genet 2003; 34 (04) 455-459
• 8 Hoefele J, Wolf MT, O'Toole JF. , et al. Evidence of oligogenic inheritance in nephronophthisis. J Am Soc Nephrol 2007; 18 (10) 2789-2795
• 9 Fiskerstrand T, Houge G, Sund S. , et al. Identification of a gene for renal-hepatic-pancreatic dysplasia by microarray-based homozygosity mapping. J Mol Diagn 2010; 12 (01) 125-131
• 10 Strong A, Muneeruddin S, Parrish R, Lui D, Conley SB. Isosorbide dinitrate in nephronophthisis treatment. Am J Med Genet A 2018; 176 (04) 1023-1026