Beyond the Kidney: Extra-Renal Manifestations of Monogenic Nephrolithiasis and Their Significance

ObjectiveTo explore the frequency of occurrence of extra-renal manifestations associated with monogenic kidney stone diseases. MethodsA literature review was conducted to identify genes that are well-established monogenic causes of nephrolithiasis. The Online Mendelian Inheritance in Man (OMIM) and Human Protein Atlas (HPA) databases were used to identify associated diseases and their properties. Disease phenotypes were ascertained using OMIM clinical synopses and sorted into 24 different phenotype categories as classified in OMIM. Disease phenotypes caused by the same gene were merged into a single gene-associated phenotype (GAP) unit such that one GAP encompasses all related disease phenotypes for a specific gene. We measured the total number of GAPs involving each phenotype category and determined the median phenotype category. Phenotype categories were classified as overrepresented or underrepresented if the number of GAPs involving them was higher or lower than the median, respectively. A chi-square test was conducted to determine whether the number of GAPs affecting a given category significantly deviated from the median. ResultsFifty-five genes were identified as monogenic causes of nephrolithiasis. All GAPs comprised at least one extra-renal phenotype category. The median phenotype category was part of 10 (18%) unique GAPs. A total of 6 significantly overrepresented (growth, skeletal, neurologic, abdomen/gastrointestinal, muscle, metabolic features) and 5 significantly underrepresented (mouth, voice, neck, immunology, neoplasia) phenotype categories were identified among our group of monogenic kidney stone diseases (p<0.05) with impaired growth being the most common manifestation. ConclusionMonogenic nephrolithiasis is a multi-system disorder. Recognizing the extra-renal manifestations associated with monogenic causes of kidney stones is critical for earlier diagnosis and optimal prognosis in patients.