TSC2/PKD1 Contiguous Gene Deletion Syndrome: A Case Series

Abstract

Rationale & objective: TSC2/PKD1 contiguous gene deletion syndrome (CGS) has been associated with a more severe kidney phenotype than observed in autosomal dominant polycystic kidney disease (ADPKD), displaying childhood onset and progression to end-stage kidney disease (ESKD) within the first 3 decades of life. Because recent case reports have suggested a more variable clinical course, we characterized a series of patients with CGS.

Study design: Case series.

Setting & participants: Eleven patients and a clinically unaffected individual from two CGS pedigrees.

Findings: The pedigree patients presented with widely variable kidney survival, with 2 reaching the fourth decade of life without ESKD even in the absence of mosaicism. The median age of individuals who developed ESKD was 22.5 (IQR, 20-25) years, whereas the median age among those who did not develop ESKD was 25.5 (IQR, 25-35) years.

Limitations: Retrospective study, limited number of patients with complete clinical data. Possible incomplete evaluation of tuberous sclerosis complex (TSC) clinical features.

Conclusions: Patients with CGS have a variable clinical course and may reach ESKD later than previously reported, even in the absence of mosaicism. Some patients with CGS may have a kidney phenotype similar to severe ADPKD. Other patients with CGS may have TSC manifestations associated with severe progression of cystic kidney disease but not as fast as previously expected for CGS.

Plain-language summary: The TSC2/PKD1 contiguous gene deletion syndrome (CGS) includes features of tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD). It has been associated with fast progression to end-stage kidney disease (ESKD) in children and young adults, but more recent data suggest a more variable clinical course. This case series, including 12 CGS-affected individuals, brings key information to the characterization of this disorder's clinical spectrum and natural history. This case series revealed a widely variable kidney prognosis even among patients with the same deletion, with the age of ESKD onset in milder cases overlapping with severe cases of ADPKD. CGS should, therefore, be considered in patients diagnosed with severe ADPKD who are apparently not presenting TSC manifestations as well as in patients diagnosed with TSC with severe progression of cystic kidney disease.

Keywords: TSC2/PKD1 contiguous gene syndrome; autosomal dominant polycystic kidney disease; early-onset polycystic kidney disease; genetic chronic kidney disease; tuberous sclerosis complex.