TY - JOUR
T1 - Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia
AU - The PodoNet Consortium
AU - Lipska-Ziętkiewicz, Beata S.
AU - Gellermann, Jutta
AU - Boyer, Olivia
AU - Gribouval, Olivier
AU - Ziętkiewicz, Szymon
AU - Kari, Jameela A.
AU - Shalaby, Mohamed A.
AU - Ozaltin, Fatih
AU - Dusek, Jiri
AU - Melk, Anette
AU - Bayazit, Aysun K.
AU - Massella, Laura
AU - Hyla-Klekot, Lidia
AU - Habbig, Sandra
AU - Godron, Astrid
AU - Szczepańska, Maria
AU - Bieniaś, Beata
AU - Drożdż, Dorota
AU - Odeh, Rasha
AU - Jarmużek, Wioletta
AU - Zachwieja, Katarzyna
AU - Trautmann, Agnes
AU - Antignac, Corinne
AU - Schaefer, Franz
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.
AB - Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.
UR - http://www.scopus.com/inward/record.url?scp=85027219757&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027219757&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0180926
DO - 10.1371/journal.pone.0180926
M3 - Article
C2 - 28796785
AN - SCOPUS:85027219757
VL - 12
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 8
M1 - e0180926
ER -