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

Abstract

SummaryBackground and objectives 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.Design, setting, participants, & measurements 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.Results 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. ConclusionsOur 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.

HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum

“…This situation can in turn lead to perinatal death, the requirement for early renal replacement therapy or parental request for termination of the pregnancy. 1,4 Individuals with HNF1B-associated disease who are likely to require renal replacement therapy should be considered for renal transplantation. This patient group is at increased risk of developing new-onset diabetes after transplantation (NODAT), and an immunosuppressive regimen that avoids tacrolimus and reduces corticosteroid exposure might be beneficial.…”

“…HNF1B has known functions in nephron development and heterozygous mutations are the most common known monogenic cause of developmental renal disease. [1][2][3][4] Renal cysts are the most commonly observed clinical feature in HNF1B-associated disease, and numerous affected individuals additionally exhibit earlyonset diabetes mellitus; this observation led to the description of renal cysts and diabetes (RCAD) syndrome. 5 Since initial reporting of the early cases of HNF1B-associated disease in 1997, it has become evident that additional clinical features are also associated with mutations in HNF1B.…”

“…Genetic changes comprise base substitutions, and small insertions-deletions in 24 of 58 (41%) adult patients and 51 of 116 (44%) affected children or fetuses; deletions of the entire gene account for 34 of 58 (59%) adult patients and 65 of 116 (56%) affected children or fetuses. [1][2][3]13,[18][19][20][21][22][23][24] More than 50 different HNF1B mutations have been reported, including missense, nonsense, frame-shift and splicing mutations (Figure 2, Supplementary Table 1). The majority of identified mutations are clustered in the first four exons of the gene, with exons 2 and 4, and the intron 2 splice site being mutation site hotspots.…”

HNF1B-associated clinical phenotypes: the kidney and beyond

“…Mutations in this gene are found in up to 30 % of children with renal abnormalities, depending on cohort selection [14,26,[29][30][31][32]. Some of these features can be identified by antenatal ultrasound, and the most frequent antenatal presentation is bilateral hyperechogenic kidneys with normal or increased size.…”

Diabetes-Induced Congenital Anomalies of the Kidney and Urinary Tract (CAKUT): Nurture and Nature at Work?

“…DNA testing for human CAKUT is aimed at HNF1B and PAX2 screening because mutations in these genes are causal for syndromes involving CAKUT, as well as isolated forms of CAKUT. 18,19 Dart et al did not investigate genetic predisposition to diabetes and CAKUT, 1 yet HNF1B mutations could explain part of the association found between maternal diabetes and CAKUT. 20 The lack of genetic data is an important limitation of the study.…”