Congenital urinary tract anomalies are a variable finding associated with nevoid basal cell carcinoma syndrome
Cancer Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal dominant disorder commonly associated with germline loss-of-function variants in PTCH1, a tumor suppressor gene that regulates the sonic hedgehog signaling pathway. NBCCS is classically associated with multiple basal cell carcinomas, odontogenic keratocysts, and skeletal anomalies. However, the phenotypic spectrum of NBCCS varies widely and includes macrocephaly, coarse facial features, cleft lip and/or palate, polydactyly, palmar/plantar pits, lamellar calcification of the falx, cardiac and/or ovarian fibromas, ocular anomalies, and pediatric medulloblastoma. Given the wide phenotypic heterogeneity of NBCCS, diagnosis can often be delayed due to atypical findings. Here, we undertake the first comprehensive characterization of NBCCS and congenital urinary tract anomalies.
Methods:
We first describe a proband with congenital ureteropelvic obstruction and hydrocephalus who underwent molecular evaluation with trio exome sequencing followed by RNA analysis. A retrospective assessment was then conducted of all patients seen at our academic medical center between January 2015 and December 2023 with a molecularly confirmed diagnosis of NBCCS to identify additional patients with congenital urinary tract anomalies. We performed a comprehensive review of the literature for articles published between 1960 and January 2024 to identify patients with either a clinical or molecular diagnosis of NBCCS exhibiting congenital urinary tract anomalies.
Results:
The novel, non-canonical splice-site variant c.349+4delA in PTCH1 was found to occur de novo in our first proband, with RNA analysis confirming exon 2 skipping. Of the additional nine molecularly confirmed NBCCS cases evaluated at our institution, a second proband with a pathogenic nonsense variant in PTCH1 was identified with renal agenesis and a bladder diverticulum. Our review of the literature identified eleven case reports of NBCCS patients with congenital urinary tract anomalies. Significant heterogeneity in urinary tract anomalies was observed among the reported cases. The most common anomaly was unilateral renal agenesis, present in five of the reported patients. Other described urinary tract anomalies included renal cysts, horseshoe kidney, ureteral reflux, and strictures. No other patient exhibited congenital hydronephrosis due to ureteropelvic obstruction, as described in our first proband.
Conclusion:
The evidence assembled here argues that congenital urinary tract anomalies are a variable finding associated with NBCCS. Previous work has corroborated this association, as strong expression of PTCH1 has been described in the urinary tract of human fetuses at 16 weeks gestation and persisting through the newborn period. In addition, studies of Ptch-1-deficient mice have identified the presence of congenital urinary tract anomalies, including renal hypoplasia, renal cysts, and hydronephrosis due to ureteropelvic junction obstruction. As such, consideration should be given to the inclusion of PTCH1 in multigene panels for congenital urinary tract disorders. These findings also suggest that evaluation of the urinary tract with renal ultrasound may be appropriate upon the initial diagnosis of NBCCS. Larger cohort studies will be needed, however, to more precisely estimate the prevalence of urinary tract anomalies in this population and determine genotype-phenotype correlation.
Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal dominant disorder commonly associated with germline loss-of-function variants in PTCH1, a tumor suppressor gene that regulates the sonic hedgehog signaling pathway. NBCCS is classically associated with multiple basal cell carcinomas, odontogenic keratocysts, and skeletal anomalies. However, the phenotypic spectrum of NBCCS varies widely and includes macrocephaly, coarse facial features, cleft lip and/or palate, polydactyly, palmar/plantar pits, lamellar calcification of the falx, cardiac and/or ovarian fibromas, ocular anomalies, and pediatric medulloblastoma. Given the wide phenotypic heterogeneity of NBCCS, diagnosis can often be delayed due to atypical findings. Here, we undertake the first comprehensive characterization of NBCCS and congenital urinary tract anomalies.
Methods:
We first describe a proband with congenital ureteropelvic obstruction and hydrocephalus who underwent molecular evaluation with trio exome sequencing followed by RNA analysis. A retrospective assessment was then conducted of all patients seen at our academic medical center between January 2015 and December 2023 with a molecularly confirmed diagnosis of NBCCS to identify additional patients with congenital urinary tract anomalies. We performed a comprehensive review of the literature for articles published between 1960 and January 2024 to identify patients with either a clinical or molecular diagnosis of NBCCS exhibiting congenital urinary tract anomalies.
Results:
The novel, non-canonical splice-site variant c.349+4delA in PTCH1 was found to occur de novo in our first proband, with RNA analysis confirming exon 2 skipping. Of the additional nine molecularly confirmed NBCCS cases evaluated at our institution, a second proband with a pathogenic nonsense variant in PTCH1 was identified with renal agenesis and a bladder diverticulum. Our review of the literature identified eleven case reports of NBCCS patients with congenital urinary tract anomalies. Significant heterogeneity in urinary tract anomalies was observed among the reported cases. The most common anomaly was unilateral renal agenesis, present in five of the reported patients. Other described urinary tract anomalies included renal cysts, horseshoe kidney, ureteral reflux, and strictures. No other patient exhibited congenital hydronephrosis due to ureteropelvic obstruction, as described in our first proband.
Conclusion:
The evidence assembled here argues that congenital urinary tract anomalies are a variable finding associated with NBCCS. Previous work has corroborated this association, as strong expression of PTCH1 has been described in the urinary tract of human fetuses at 16 weeks gestation and persisting through the newborn period. In addition, studies of Ptch-1-deficient mice have identified the presence of congenital urinary tract anomalies, including renal hypoplasia, renal cysts, and hydronephrosis due to ureteropelvic junction obstruction. As such, consideration should be given to the inclusion of PTCH1 in multigene panels for congenital urinary tract disorders. These findings also suggest that evaluation of the urinary tract with renal ultrasound may be appropriate upon the initial diagnosis of NBCCS. Larger cohort studies will be needed, however, to more precisely estimate the prevalence of urinary tract anomalies in this population and determine genotype-phenotype correlation.