DOI: 10.1002/pd.4264
ORIGINAL ARTICLE
TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia Delphine Body-Bechou1, Philippe Loget2, Dominique D’Herve3, Bernard Le Fiblec4, Anne-Gaelle Grebille4, Hélène Le Guern5, Caroline Labarthe6, Margaret Redpath7, Anne-Sophie Cabaret-Dufour1, Odent Sylvie8, Alice Fievet8, Corinne Antignac9, Laurence Heidet10, Sophie Taque11 and Poulain Patrice1* 1
Obstetrics and Gynecology, CHU Rennes, Rennes, France Pathology laboratory, CHU Rennes, Rennes, France 3 Ultrasound, Clinique Mutualiste de la Sagesse, Rennes, France 4 Gynécologie-obstétrique, CH Yves Le Foll, Saint-Brieuc, France 5 Obstetrics, CH Saint Brieuc, Saint Brieuc, France 6 Obstetrics, CHP Saint Grégoire, Saint Grégoire, France 7 Lady Davis Institut, Jewish General Hospital, McGill University, Montreal, Quebec, Canada 8 Clinical Genetics, CHU RennesCHU Rennes, Rennes, France 9 Genetics, Hôpital Necker, Paris, France 10 Centre de Référence des Maladies Rénales Héréditaires de l’Enfant et de l’Adulte, Pediatric Nephrology, AP-HP, Necker-Enfants Malades Hospital, Paris, France 11 Pediatrics, CHU Rennes, Rennes, France *Correspondence to: Poulain Patrice. E-mail: [email protected] 2
ABSTRACT Objective The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. Methodology We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. Cases Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. Conclusion TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered. © 2013 John Wiley & Sons, Ltd.
Funding sources: None Conflicts of interest: None declared
INTRODUCTION The hepatocyte nuclear factor-1beta, encoded by the transcription factor 2 (TCF2) gene, plays a key role in the specific regulation of gene expression in the kidney, liver, lung, intestine, genital tract and pancreas. Hepatocyte nuclear factor-1beta is involved in the embryonic development of these organs. Individuals heterozygous for TCF2 mutations may present with maturity-onset diabetes of the young type 5 and renal manifestations.1 The detection of TCF2-related anomalies is not trivial: TCF2 mutations are the leading monogenic cause of abnormal
Prenatal Diagnosis 2014, 34, 90–93
kidney development, and fetal kidney malformations are a frequent diagnosis found in 0,3 to 0,5% of pregnancies. In such cases, the sonographer and obstetrician should search for other associated anomalies allowing accurate prenatal diagnosis. They also need to try to measure fetal renal function and to predict renal adaptation post-delivery. Prenatal counseling is particularly difficult in cases of TCF2 gene mutations because of poor correlation between genotype and phenotype. Also, very little has been reported in the literature about the association between TCF2 mutations and pancreatic malformation.
© 2013 John Wiley & Sons, Ltd.
TCF2/HNF-1beta mutations
We describe the phenotype of the pancreas and kidneys in three fetuses each heterozygous for a mutation of TCF2.
CASES The first case involved a 25-year-old pregnant woman with an unremarkable medical and family history. Her obstetrical history included two normal pregnancies delivered at term and a third pregnancy complicated by premature rupture of the membranes at 23 weeks leading to a fetal loss. For her fourth pregnancy, ultrasound (US) screening at 12 weeks showed a crown-rump length of 63 mm with a nuchal fold of 1.8 mm. The combined risk of aneuploidy was calculated to be 1/1300. US at 22 weeks revealed bilateral, hyperechogenic, multicystic, large (+2SD) kidneys with no corticomedullary differentiation (Figure 1) and bilateral clubfoot, which was confirmed at 27 weeks by an expert specialist. The amniotic fluid was normal. The fetal serum β-2-microglobulin concentration was 8.3 mg/L (normal value + 2SD) hyperechogenic and polycystic kidneys with no corticomedullary differentiation and oligohydramnios (Figure 1). The fetal karyotype was normal, 46 XY. The husband had chronic renal failure related to a left pyelocalyceal syndrome and pancreatic cysts discovered by US following genetic counseling. Before pregnancy, the father had not been tested for mutations of the TCF2 gene. The couple opted to terminate the pregnancy. At 22 weeks +3 days, she delivered a stillborn 511 g male baby. Autopsy confirmed bilateral multicystic renal dysplasia and revealed a pancreatic agenesis that had not been diagnosed in utero (Figure 2). Given the association of pancreatic anomaly with uronephropathy in both the father and the child, they were both screened for TCF2 mutations. Genomic sequencing revealed a heterozygous deletion in exons 5 to 9. This mutation was paternally inherited. The third case involved a 31-year-old woman who was referred at 22 weeks of gestation for investigations to
Figure 1 Ultrasound images of the three cases showing multicystic renal dysplasia, hyperechogenicity of the cortex and no corticomedullary differentiation
Prenatal Diagnosis 2014, 34, 90–93
© 2013 John Wiley & Sons, Ltd.
D. Body-Bechou et al.
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Figure 2 Autopsy of the three cases: bilateral renal dysplasia and pancreatic agenesis or hypoplasia
determine the cause of her fetus’ multicystic renal dysplasia (more pronounced on the left side) with normal amniotic index. Her obstetrical history consisted of one normal pregnancy with term delivery. Her medical and family history was unremarkable. The first US screening was normal. Subsequent US investigations, at 28 and 32 weeks, revealed renal dysplasia, which worsened between 28 and 32 weeks, with poor corticomedullary differentiation and severe oligohydramnios (Figure 1). The concentration of β-2-microglobulin in fetal serum was 8.16 mg/L. Amniocentesis was performed revealing a normal karyotype, 46 XY. The couple opted to terminate the pregnancy. A 2344 g stillborn male baby was delivered at 35 weeks. Autopsy confirmed bilateral multicystic renal dysplasia and revealed hypoplasia of the tail of the pancreas (Figure 2). Testing for TCF2 mutations by genomic sequencing identified a heterozygous mutation in exon 4 (c.827G > A–p. R276Q). This mutation was a de novo mutation; the parents were not carriers of the mutation and were phenotypically normal.
DISCUSSION These three cases presented some of the most severe clinical phenotypes in the clinical spectrum associated with TCF2 Prenatal Diagnosis 2014, 34, 90–93
mutations. Indeed, the absence of genotype–phenotype correlations makes genetic counseling extremely difficult in cases of TCF2 mutation: there is no established relationship between the type of mutation and the severity of the symptoms, and different patients harboring the same mutation can display very different phenotypes.2,3 Mutations of the TCF2 gene show an autosomal dominant pattern of inheritance. In the case of de novo TCF2 anomalies, the probability of recurrence is very low except if there is germline mosaicism. Transcription factor 2 mutations are frequently discovered in fetuses following the observation of bilateral hyperechogenic kidneys on prenatal US examination. Decramer et al.4 studied 62 such fetuses and found TCF2 gene mutations in 29% of them; the mutations were de novo in more than half of these cases. Two main antenatal renal phenotypes were found: bilateral normal-sized hyperechogenic kidneys with or without cortical microcysts and a unilateral normal-sized hyperechogenic kidney with a bigger contralateral kidney and diffuse macrocysts. As a support for genetic counseling, signs of kidney failure should be sought by US. These signs include severe oligohydramnios, poor corticomedullary differentiation and significant renal dysplasia. © 2013 John Wiley & Sons, Ltd.
TCF2/HNF-1beta mutations
The spectrum of symptoms associated with transcription factor 2 mutations may include pancreatic hypoplasia or agenesis Mutations in three genes – PDX1, PTF1A, and GATA6 – have been shown to cause pancreatic agenesis in humans.5 To our knowledge, pancreatic agenesis associated with TCF2 mutation has not previously been reported. TCF2 is required for adult pancreatic function and for normal pancreatic development. The absence of TCF2 expression in mice leads to pancreatic agenesis, implicating the gene in pancreatic development. Pancreatic hypoplasia has been reported in two fetuses carrying a mutation in the TCF2 gene,6 and heterozygous TCF2 mutations are associated with maturity-onset diabetes of the young type 5. The pancreas is not systematically examined during antenatal US screening despite being visible at both 22 and 32 weeks of gestation. The pancreas, appears more echogenic than the liver, is located in front of the spine behind the stomach and ends at the splenic hilum. Hata et al.7 reported that the rate of visualization of the pancreas by US was 51.7% for all gestational ages combined (64.2% at 22 weeks and 36.8% at 32 weeks); however, this study is old (1988) and current US equipment is more powerful, such that visualization of the pancreas is likely to be easier. An analysis of the current feasibility of studying the fetal pancreas by US would be useful. A fetus with pancreatic agenesis is viable but requires insulin treatment and pancreatic enzyme replacement
93
therapy. Therefore, identifying this condition is of prognostic significance. In view of the association, we report between pancreatic agenesis and renal malformation, searching for the pancreas in cases in which renal abnormalities are found by US would appear to be justified. This is particularly true for cases with moderate or unilateral multicystic renal dysplasia. The detection of pancreatic agenesis should prompt testing for TCF2 mutations. The findings of these various investigations could help families make informed decisions about the pregnancy; pregnancy termination, palliative support at birth or therapeutic management could be offered to the parents.
WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? • TCF2 mutations are the leading cause of monogenic abnormal kidney development. • The absence of genotype–phenotype correlations makes genetic counseling extremely difficult.
WHAT DOES THIS STUDY ADD? • The first report of pancreatic agenesis associated with TCF2 mutation. • Indicates the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered.
REFERENCES 1. Haumaitre C, et al. Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Proc Natl Acad Sci U S A 2005;102:1490–5. 2. Heidet L, et al. Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol: CJASN juin 2010;5(6):1079-90. 3. Madariaga L, et al. Severe prenatal renal anomalies associated with mutations in HNF1B or PAX2 genes. Clin J Am Soc Nephrol: CJASN (28 mars 2013). doi:10.2215/CJN.10221012 4. Decramer S, et al. Anomalies of the TCF2 gene are the main cause of fetal bilateral hyperechogenic kidneys. Clin J Am Soc Nephrol: JASN 2007;18:923–33.
Prenatal Diagnosis 2014, 34, 90–93
5. Allen HL, et al. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet janvier 2012;44(1):20-2. 6. Haumaitre C, et al. Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1beta/MODY5 mutations. Hum Mol Genet 2006;15:2363–75. 7. Hata K, Hata T, Kitao M. Ultrasonographic identification and measurement of the human fetal pancreas in utero. Int J Gynaecol Obstet 1988;26:61–4.
© 2013 John Wiley & Sons, Ltd.
ORIGINAL ARTICLE
TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia Delphine Body-Bechou1, Philippe Loget2, Dominique D’Herve3, Bernard Le Fiblec4, Anne-Gaelle Grebille4, Hélène Le Guern5, Caroline Labarthe6, Margaret Redpath7, Anne-Sophie Cabaret-Dufour1, Odent Sylvie8, Alice Fievet8, Corinne Antignac9, Laurence Heidet10, Sophie Taque11 and Poulain Patrice1* 1
Obstetrics and Gynecology, CHU Rennes, Rennes, France Pathology laboratory, CHU Rennes, Rennes, France 3 Ultrasound, Clinique Mutualiste de la Sagesse, Rennes, France 4 Gynécologie-obstétrique, CH Yves Le Foll, Saint-Brieuc, France 5 Obstetrics, CH Saint Brieuc, Saint Brieuc, France 6 Obstetrics, CHP Saint Grégoire, Saint Grégoire, France 7 Lady Davis Institut, Jewish General Hospital, McGill University, Montreal, Quebec, Canada 8 Clinical Genetics, CHU RennesCHU Rennes, Rennes, France 9 Genetics, Hôpital Necker, Paris, France 10 Centre de Référence des Maladies Rénales Héréditaires de l’Enfant et de l’Adulte, Pediatric Nephrology, AP-HP, Necker-Enfants Malades Hospital, Paris, France 11 Pediatrics, CHU Rennes, Rennes, France *Correspondence to: Poulain Patrice. E-mail: [email protected] 2
ABSTRACT Objective The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. Methodology We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. Cases Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. Conclusion TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered. © 2013 John Wiley & Sons, Ltd.
Funding sources: None Conflicts of interest: None declared
INTRODUCTION The hepatocyte nuclear factor-1beta, encoded by the transcription factor 2 (TCF2) gene, plays a key role in the specific regulation of gene expression in the kidney, liver, lung, intestine, genital tract and pancreas. Hepatocyte nuclear factor-1beta is involved in the embryonic development of these organs. Individuals heterozygous for TCF2 mutations may present with maturity-onset diabetes of the young type 5 and renal manifestations.1 The detection of TCF2-related anomalies is not trivial: TCF2 mutations are the leading monogenic cause of abnormal
Prenatal Diagnosis 2014, 34, 90–93
kidney development, and fetal kidney malformations are a frequent diagnosis found in 0,3 to 0,5% of pregnancies. In such cases, the sonographer and obstetrician should search for other associated anomalies allowing accurate prenatal diagnosis. They also need to try to measure fetal renal function and to predict renal adaptation post-delivery. Prenatal counseling is particularly difficult in cases of TCF2 gene mutations because of poor correlation between genotype and phenotype. Also, very little has been reported in the literature about the association between TCF2 mutations and pancreatic malformation.
© 2013 John Wiley & Sons, Ltd.
TCF2/HNF-1beta mutations
We describe the phenotype of the pancreas and kidneys in three fetuses each heterozygous for a mutation of TCF2.
CASES The first case involved a 25-year-old pregnant woman with an unremarkable medical and family history. Her obstetrical history included two normal pregnancies delivered at term and a third pregnancy complicated by premature rupture of the membranes at 23 weeks leading to a fetal loss. For her fourth pregnancy, ultrasound (US) screening at 12 weeks showed a crown-rump length of 63 mm with a nuchal fold of 1.8 mm. The combined risk of aneuploidy was calculated to be 1/1300. US at 22 weeks revealed bilateral, hyperechogenic, multicystic, large (+2SD) kidneys with no corticomedullary differentiation (Figure 1) and bilateral clubfoot, which was confirmed at 27 weeks by an expert specialist. The amniotic fluid was normal. The fetal serum β-2-microglobulin concentration was 8.3 mg/L (normal value + 2SD) hyperechogenic and polycystic kidneys with no corticomedullary differentiation and oligohydramnios (Figure 1). The fetal karyotype was normal, 46 XY. The husband had chronic renal failure related to a left pyelocalyceal syndrome and pancreatic cysts discovered by US following genetic counseling. Before pregnancy, the father had not been tested for mutations of the TCF2 gene. The couple opted to terminate the pregnancy. At 22 weeks +3 days, she delivered a stillborn 511 g male baby. Autopsy confirmed bilateral multicystic renal dysplasia and revealed a pancreatic agenesis that had not been diagnosed in utero (Figure 2). Given the association of pancreatic anomaly with uronephropathy in both the father and the child, they were both screened for TCF2 mutations. Genomic sequencing revealed a heterozygous deletion in exons 5 to 9. This mutation was paternally inherited. The third case involved a 31-year-old woman who was referred at 22 weeks of gestation for investigations to
Figure 1 Ultrasound images of the three cases showing multicystic renal dysplasia, hyperechogenicity of the cortex and no corticomedullary differentiation
Prenatal Diagnosis 2014, 34, 90–93
© 2013 John Wiley & Sons, Ltd.
D. Body-Bechou et al.
92
Figure 2 Autopsy of the three cases: bilateral renal dysplasia and pancreatic agenesis or hypoplasia
determine the cause of her fetus’ multicystic renal dysplasia (more pronounced on the left side) with normal amniotic index. Her obstetrical history consisted of one normal pregnancy with term delivery. Her medical and family history was unremarkable. The first US screening was normal. Subsequent US investigations, at 28 and 32 weeks, revealed renal dysplasia, which worsened between 28 and 32 weeks, with poor corticomedullary differentiation and severe oligohydramnios (Figure 1). The concentration of β-2-microglobulin in fetal serum was 8.16 mg/L. Amniocentesis was performed revealing a normal karyotype, 46 XY. The couple opted to terminate the pregnancy. A 2344 g stillborn male baby was delivered at 35 weeks. Autopsy confirmed bilateral multicystic renal dysplasia and revealed hypoplasia of the tail of the pancreas (Figure 2). Testing for TCF2 mutations by genomic sequencing identified a heterozygous mutation in exon 4 (c.827G > A–p. R276Q). This mutation was a de novo mutation; the parents were not carriers of the mutation and were phenotypically normal.
DISCUSSION These three cases presented some of the most severe clinical phenotypes in the clinical spectrum associated with TCF2 Prenatal Diagnosis 2014, 34, 90–93
mutations. Indeed, the absence of genotype–phenotype correlations makes genetic counseling extremely difficult in cases of TCF2 mutation: there is no established relationship between the type of mutation and the severity of the symptoms, and different patients harboring the same mutation can display very different phenotypes.2,3 Mutations of the TCF2 gene show an autosomal dominant pattern of inheritance. In the case of de novo TCF2 anomalies, the probability of recurrence is very low except if there is germline mosaicism. Transcription factor 2 mutations are frequently discovered in fetuses following the observation of bilateral hyperechogenic kidneys on prenatal US examination. Decramer et al.4 studied 62 such fetuses and found TCF2 gene mutations in 29% of them; the mutations were de novo in more than half of these cases. Two main antenatal renal phenotypes were found: bilateral normal-sized hyperechogenic kidneys with or without cortical microcysts and a unilateral normal-sized hyperechogenic kidney with a bigger contralateral kidney and diffuse macrocysts. As a support for genetic counseling, signs of kidney failure should be sought by US. These signs include severe oligohydramnios, poor corticomedullary differentiation and significant renal dysplasia. © 2013 John Wiley & Sons, Ltd.
TCF2/HNF-1beta mutations
The spectrum of symptoms associated with transcription factor 2 mutations may include pancreatic hypoplasia or agenesis Mutations in three genes – PDX1, PTF1A, and GATA6 – have been shown to cause pancreatic agenesis in humans.5 To our knowledge, pancreatic agenesis associated with TCF2 mutation has not previously been reported. TCF2 is required for adult pancreatic function and for normal pancreatic development. The absence of TCF2 expression in mice leads to pancreatic agenesis, implicating the gene in pancreatic development. Pancreatic hypoplasia has been reported in two fetuses carrying a mutation in the TCF2 gene,6 and heterozygous TCF2 mutations are associated with maturity-onset diabetes of the young type 5. The pancreas is not systematically examined during antenatal US screening despite being visible at both 22 and 32 weeks of gestation. The pancreas, appears more echogenic than the liver, is located in front of the spine behind the stomach and ends at the splenic hilum. Hata et al.7 reported that the rate of visualization of the pancreas by US was 51.7% for all gestational ages combined (64.2% at 22 weeks and 36.8% at 32 weeks); however, this study is old (1988) and current US equipment is more powerful, such that visualization of the pancreas is likely to be easier. An analysis of the current feasibility of studying the fetal pancreas by US would be useful. A fetus with pancreatic agenesis is viable but requires insulin treatment and pancreatic enzyme replacement
93
therapy. Therefore, identifying this condition is of prognostic significance. In view of the association, we report between pancreatic agenesis and renal malformation, searching for the pancreas in cases in which renal abnormalities are found by US would appear to be justified. This is particularly true for cases with moderate or unilateral multicystic renal dysplasia. The detection of pancreatic agenesis should prompt testing for TCF2 mutations. The findings of these various investigations could help families make informed decisions about the pregnancy; pregnancy termination, palliative support at birth or therapeutic management could be offered to the parents.
WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? • TCF2 mutations are the leading cause of monogenic abnormal kidney development. • The absence of genotype–phenotype correlations makes genetic counseling extremely difficult.
WHAT DOES THIS STUDY ADD? • The first report of pancreatic agenesis associated with TCF2 mutation. • Indicates the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered.
REFERENCES 1. Haumaitre C, et al. Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Proc Natl Acad Sci U S A 2005;102:1490–5. 2. Heidet L, et al. Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol: CJASN juin 2010;5(6):1079-90. 3. Madariaga L, et al. Severe prenatal renal anomalies associated with mutations in HNF1B or PAX2 genes. Clin J Am Soc Nephrol: CJASN (28 mars 2013). doi:10.2215/CJN.10221012 4. Decramer S, et al. Anomalies of the TCF2 gene are the main cause of fetal bilateral hyperechogenic kidneys. Clin J Am Soc Nephrol: JASN 2007;18:923–33.
Prenatal Diagnosis 2014, 34, 90–93
5. Allen HL, et al. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet janvier 2012;44(1):20-2. 6. Haumaitre C, et al. Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1beta/MODY5 mutations. Hum Mol Genet 2006;15:2363–75. 7. Hata K, Hata T, Kitao M. Ultrasonographic identification and measurement of the human fetal pancreas in utero. Int J Gynaecol Obstet 1988;26:61–4.
© 2013 John Wiley & Sons, Ltd.
