Beyond the Kidney: A Systematic Review of Extrarenal Manifestations in MAPKBP1-Related Nephronophthisis

Nephronophthisis type 20 (NPHP20; MIM #617271) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in MAPKBP1. Although traditionally considered a kidney-restricted disorder, recent findings suggest that MAPKBP1-related disease may be associated with a broader spectrum of extrarenal manifestations. However, the available evidence remains fragmented across gene-discovery studies, family reports, diagnostic sequencing cohorts, and functional investigations. This systematic review aimed to characterize the extrarenal manifestations of MAPKBP1-related disease and estimate their frequency. A secondary objective was to describe the spectrum of pathogenic or likely pathogenic MAPKBP1 variants and integrate clinical findings with current mechanistic models. Studies were eligible if they reported at least one patient with biallelic MAPKBP1 variants and provided clinical information relevant to the phenotype. PubMed, Embase, ClinVar, and Google Scholar were systematically searched from inception to August 2026. The methodological quality and risk of bias of included reports were assessed using the appropriate Joanna Briggs Institute (JBI) critical appraisal tools. All included reports were judged to be of high or moderate methodological quality. Only one paper was considered at high risk of bias, while the remaining articles or database entries had a moderate or low risk of bias. ClinVar entries were evaluated separately, with additional information obtained from the respective submitters when required. Clinical and molecular data were extracted and descriptively synthesized across included reports. The frequency of individual extrarenal manifestations was calculated based on the total number of identified patients while considering possible reporting biases. The search identified 154 records, including duplicates. After deduplication, 100 records underwent title and abstract screening and 32 full-text reports were assessed for eligibility. Nine articles met the inclusion criteria, comprising 16 patients; three additional patients were identified through ClinVar, yielding a total of 19 patients with MAPKBP1-related nephronophthisis included in the analysis. Most patients presented with at least one extrarenal manifestation, predominantly involving the skeletal system. Scoliosis was the most frequently reported extrarenal feature, occurring in eight of 19 genetically eligible patients. Other reported manifestations included short stature, patellar subluxation, long fingers or feet, craniofacial dysmorphisms, and cardiovascular abnormalities. The identified pathogenic or likely pathogenic MAPKBP1 variants were predominantly stop-gain, splice-site, and frameshift variants. The evidence was limited by the rarity of MAPKBP1-related disease, the small number of reported patients, heterogeneity in clinical assessment and reporting, and the predominance of observational and case-based evidence. This systematic review supports an expanding extrarenal phenotypic spectrum of MAPKBP1-related nephronophthisis, with skeletal abnormalities (e.g., scoliosis) representing a prominent feature. Further systematic phenotyping and genotyping of affected individuals are warranted to formally suggest multidisciplinary surveillance, to clarify genotype-phenotype correlations and to investigate the mechanisms underlying extrarenal disease. Registration: The review was prospectively registered in PROSPERO (CRD420261429078).