Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

• Published in: Clinical journal of the American Society of Nephrology Vol. 8; no. 7; pp. 1179 - 1187
• Main Authors: Leire Madariaga, Vincent Morinière, Cécile Jeanpierre, Raymonde Bouvier, Philippe Loget, Jelena Martinovic, Pierre Dechelotte, Nathalie Leporrier, Christel Thauvin-Robinet, Uffe Birk Jensen, Dominique Gaillard, Michele Mathieu, Bruno Turlin, Tania Attie-Bitach, Rémi Salomon, Marie-Claire Gübler, Corinne Antignac, Laurence Heidet
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01-07-2013
• Subjects: Abortion, Therapeutic; Autopsy; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Hepatocyte Nuclear Factor 1-beta - genetics; Heredity; Humans; Male; Mutation; Original; PAX2 Transcription Factor - genetics; Pedigree; Phenotype; Predictive Value of Tests; Pregnancy; Prenatal Diagnosis - methods; Retrospective Studies; Severity of Illness Index; Ultrasonography, Prenatal; Urogenital Abnormalities; Vesico-Ureteral Reflux - diagnosis; Vesico-Ureteral Reflux - genetics
• ISSN: 1555-9041; 1555-905X
• DOI: 10.2215/CJN.10221012

Congenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy.
This study reports the screening of two genes (HNF1B and PAX2) involved in monogenic syndromic CAKUT in a cohort of 103 fetuses from 91 families with very severe CAKUT that appeared isolated by fetal ultrasound examination and led to termination of pregnancy.
This study identified a disease-causing mutation in HNF1B in 12 cases from 11 families and a mutation in PAX2 in 4 unrelated cases. Various renal phenotypes were observed, but no case of bilateral agenesis was associated with HNF1B or PAX2 mutations. Autopsy identified extrarenal abnormalities not detected by ultrasonography in eight cases but confirmed the absence of extrarenal defects in eight other cases. A positive family history of renal disease was not significantly more frequent in cases with an identified mutation. Moreover, in cases with an inherited mutation, there was a great phenotypic variability regarding the severity of the renal disease within a single family.
Our results suggest that mutations in genes involved in syndromic CAKUT with Mendelian inheritance are not rare in fetal cases with severe CAKUT appearing isolated at prenatal ultrasound, a finding of clinical importance because of genetic counseling.