Pediatric renal failure and adult-onset end-stage renal disease are typically due to congenital anomalies of the kidney and urinary tract (CAKUT). Renal hypoplasia, i.e., abnormally small kidneys with normal morphology and reduced nephron number, may be present in up to 2% of the general population, with an incidence of approximately 1 in 400 births. There is often confusion and misapplication of the definition, however, as the majority of congenitally small kidneys also exhibit evidence of tissue mal differentiation, defined as renal dysplasia (Cain et al., 2010). Pediatric end stage renal disease is typically caused by significant nephron number reductions which are indicative of renal hypoplasia/dysplasia. Affected individuals have a lifelong predisposition to hypertension and cardiovascular disease (Song and Yosypiv, 2011). Severe presentation of these disorders may result in significantly impaired fetal renal function which can in turn cause the lethal oligohydramnios sequence. On the most severe end of the CAKUT spectrum is bilateral renal agenesis, which is uniformly lethal.

Copy number variants have been observed in individuals with both isolated renal disease as well as those with extra-renal manifestations (Cai et al., 2020; Westland et al., 2020). More than 75 genes have been associated with isolated or syndromic renal agenesis, hypoplasia, and dysplasia, although altogether only about 10-15% of cases have an identifiable genetic cause (Sanna-Cherchi et al., 2017). In most families, these genes are inherited in an autosomal dominant manner with significant variability in phenotype and penetrance (Hwang et al., 2014). Isolated renal hypoplasia has been associated with pathogenic variants in the HNF1B, BMP4, PAX2, RET and SIX2 genes, though these pathogenic variants may also cause additional features such as coloboma (PAX2) and Hirschsprung’s disease (RET) (Bower et al., 2007; Sugimoto et al., 2016). SALL1, EYA1, DSTYK, WNT4, and SIX5 are other genes that have been implicated in unilateral renal agenesis (Wu et al., 2017). There are also a number of genetic syndromes that have renal hypoplasia or renal dysplasia as an associated feature, such as Rubinstein-Taybi, Branchio-Oto-Renal syndrome, and Pallister-Hall syndrome. Genetic testing may be warranted to confirm a diagnosis and direct surveillance/management as well as give appropriate risk of recurrence, particularly if a syndromic cause is suspected.