Prenatal diagnosis of autosomal recessive renal tubular dysgenesis caused by variants in the ACE gene: Two fetuses with anhydramnios.

INTRODUCTION: Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare genetic disorder with a very high mortality rate. The typical symptoms of the disease during pregnancy are oligohydramnios, anhydramnios, and nearly all affected fetuses die after birth or have a stillbirth in late gestation, which can adversely increase maternal risks. METHODS: Oligohydramnios/anhydramnios can make both amniocentesis for diagnostic testing and morphological evaluation via ultrasound more difficult. In cases of oligohydramnios/anhydramnios suspicious for urinary tract anomalies, amnioinfusion is a meaningful technique that facilitates sampling of amniotic fluid for genetic diagnosis. RESULTS: We report two cases of fetuses with anhydramnios and invisible urinary bladder. Clinical exome sequencing from amniotic fluid revealed a biparentally inherited homozygous pathogenic nonsense ACE variant c.2503G 〉 T [p.Glu853Ter] in proband 1 and a biparentally inherited homozygous pathogenic nonsense ACE variant c.2992C 〉 T [p.Gln998Ter] in proband 2. The prognosis was poor and the patients elected to terminate the pregnancies. Additional post-mortem histopathological examination from the renal tissue of the second fetus showed renal tubular hypoplasia. CONCLUSION: To our knowledge for the first time, we describe the prenatal diagnosis of ARRTD in Vietnam, and highlight the benefit of detecting ACE variants associated with ARRTD in fetuses with oligohydramnios/anhydramnios through amnioinfusion and amniocentesis, which improves genotype-phenotype correlations and provides valuable information for reproductive counseling.

Clinical utility of chromosomal microarray analysis and whole exome sequencing in foetuses with oligohydramnios.

OBJECTIVES: To evaluate the clinical utility of chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in foetuses with oligohydramnios. METHODS: In this retrospective study, 126 fetuses with oligohydramnios at our centre from 2018 to 2021 were reviewed. The results of CMA and WES were analysed. RESULTS: One hundred and twenty-four cases underwent CMA and 32 cases underwent WES. The detection rate of pathogenic/likely pathogenic (P/LP) copy number variant (CNV) by CMA was 1.6% (2/124). WES revealed P/LP variants in 21.8% (7/32) of the foetuses. Six (85.7%, 6/7) foetuses showed an autosomal recessive inheritance pattern. Three (42.9%, 3/7) variants were involved in the renin-angiotensin-aldosterone system (RAAS), which are the known genetic causes of autosomal recessive renal tubular dysgenesis (ARRTD). CONCLUSION: CMA has low diagnostic utility for oligohydramnios, while WES offers obvious advantages in improving the detection rate. WES should be recommended for fetuses with oligohydramnios.

CMA has low diagnostic utility for oligohydramnios.WES offers obvious advantages for improving the detection over CMA, which improves pregnancy management, prenatal counselling and recurrence risk assessment for future pregnancies.

[Clinical phenotype and genetic analysis of a fetus with Glutaracidemia type II C].

OBJECTIVE: To explore the clinical phenotype and genetic variants of a fetus with Glutaracidemia type II C (GA II C). METHODS: Clinical data of a 32-year-old pregnant woman and her fetus with GA II C diagnosed at the Third Affiliated Hospital of Zhengzhou University in December 2021 due to the enlargement and enhanced echo of the kidneys and oligohydramnios fluid at 17 weeks were analyzed retrospectively. Amniotic fluid sample of the fetus and peripheral blood samples of the couple were collected for whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Copy number variation (CNV) was detected by using low-coverage whole genome sequencing (CNV-seq). RESULTS: At 18 weeks' gestation, ultrasound revealed that the fetus had enlargement and enhanced echo of the kidneys along with no echo of renal parenchymal tubular fissure and oligohydramnios. MRI at 22 weeks' gestation confirmed that both kidneys were enlarged with uniformly increased abnormal T2 signal and decreased DWI signal. The volume of both lungs was small, with slightly higher T2 signal. No CNV was detected in the fetus. WES revealed that the fetus has harbored compound heterozygous variants of the ETFDH gene, namely c.1285+1G＞A and c.343_344delTC, which were inherited from its father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as pathogenic (PVS1+PM2_Supporting+PS3_Supporting; PVS1+PM2_Supporting+PM3). CONCLUSION: The c.1285+1G＞A and c.343_344delTC compound heterozygous variants of the ETFDH gene probably underlay the disease in this fetus. Type II C glutaric acidemia may manifest as bilateral kidney enlargement with enhanced echo and oligohydramnios. Discovery of the c.343_344delTC has enriched the spectrum of ETFDH gene variants.

Genetic autopsy and genetic counseling for a case of fatal oligohydramnios due to de novo 17q12 deletion syndrome.

We report here a fatal oligohydramnios case, which was suspected due to autosomal recessive polycystic kidney disease at first, but genetic analysis using chorionic tissue and umbilical cord after stillbirth led to the diagnosis of 17q12 deletion syndrome. Subsequent genetic analysis of the parents showed no 17q12 deletion. In this case, if the fetus had autosomal recessive polycystic kidney disease, the recurrence rate in the next pregnancy was suspected to be 25%, but since it was a de novo autosomal dominant disorder, the recurrence rate is extremely low. When a fetal dysmorphic abnormality is detected, a genetic autopsy not only helps to understand the cause but also provides information about the recurrence rate. This information is important for the next pregnancy. A genetic autopsy is useful in cases of fetal deaths or abortions resulting from fetal dysmorphic abnormalities.

Oligohydramnios or Anhydramnios and Ultrasonically Normal Renal Echotexture Secondary to Autosomal Recessive Renal Tubular Dysgenesis: An Important Consideration in the Prenatal Setting.

INTRODUCTION: Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare disorder of renal tubular development. ARRTD is a severe condition with high risk of fetal demise and early neonatal death, with only limited case reports of survival over 2 years [Clin Kidney J. 2012 Feb 1;5(1):56-8]. Prenatal diagnosis of ARRTD is challenging, and diagnosis has only previously been confirmed after postnatal or post-mortem investigation. CASE: To the best of our knowledge, we describe the first reported case of utilizing targeted genetic testing on the chorionic villous sample (CVS) to identify a homozygous variant in the angiotensinogen (AGT) gene. DISCUSSION: By substantiating the diagnosis of ARRTD prenatally, we allow timely and appropriate counseling during pregnancy.

Estimate of genetic variants using CNV-Seq for fetuses with oligohydramnios or polyhydramnios.

BACKGROUND: Oligohydramnios or polyhydramnios, is associated with chromosomal aberrations, particularly aneuploidy. However, its correlation with copy number variation (CNV) remains unclear. METHODS: We retrospectively analyzed 428 cases with an abnormal level of amniotic fluid, comprising of 139 cases of single ultrasound findings (SU group) and 289 cases of multiple ultrasound findings (MU group), by CNV sequencing (CNV-Seq) and followed their pregnancy outcomes. RESULTS: The overall detection rate of clinically significant findings was 8%, with 5% in the SU group and 11% in MU group. Besides, 18 microdeletion/microduplication syndromes were detected, with the highest rate of renal cysts and diabetes syndrome (22%, 4/18). Also, the rate of termination of pregnancy in MU group was much higher than that in the SU group (29% vs. 10%, ***p < 0.001), and in the MU-oligohydramnios subgroup, it was the highest (34%), regardless of cases with chromosomal anomaly and lost to follow-up. CONCLUSION: Our results showed that the abnormal level of amniotic fluid, especially combined with other ultrasound abnormalities, is closely related to chromosomal abnormalities and genetic CNVs. CNV-Seq may be useful in investigating pregnancies with an abnormal amniotic fluid level.

Clinical phenotype and genetic analysis of a fetus with Glutaracidemia type II C / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical phenotype and genetic variants of a fetus with Glutaracidemia type II C (GA II C).@*METHODS@#Clinical data of a 32-year-old pregnant woman and her fetus with GA II C diagnosed at the Third Affiliated Hospital of Zhengzhou University in December 2021 due to the enlargement and enhanced echo of the kidneys and oligohydramnios fluid at 17 weeks were analyzed retrospectively. Amniotic fluid sample of the fetus and peripheral blood samples of the couple were collected for whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Copy number variation (CNV) was detected by using low-coverage whole genome sequencing (CNV-seq).@*RESULTS@#At 18 weeks' gestation, ultrasound revealed that the fetus had enlargement and enhanced echo of the kidneys along with no echo of renal parenchymal tubular fissure and oligohydramnios. MRI at 22 weeks' gestation confirmed that both kidneys were enlarged with uniformly increased abnormal T2 signal and decreased DWI signal. The volume of both lungs was small, with slightly higher T2 signal. No CNV was detected in the fetus. WES revealed that the fetus has harbored compound heterozygous variants of the ETFDH gene, namely c.1285+1G＞A and c.343_344delTC, which were inherited from its father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as pathogenic (PVS1+PM2_Supporting+PS3_Supporting; PVS1+PM2_Supporting+PM3).@*CONCLUSION@#The c.1285+1G＞A and c.343_344delTC compound heterozygous variants of the ETFDH gene probably underlay the disease in this fetus. Type II C glutaric acidemia may manifest as bilateral kidney enlargement with enhanced echo and oligohydramnios. Discovery of the c.343_344delTC has enriched the spectrum of ETFDH gene variants.

[Enlarged multicystic dysplastic kidneys with oligohydramnios during infancy caused by NPHP3 gene mutation].

OBJECTIVE: To explore the clinical features and genomic abnorm ality of a fetus enlarged multicystic dysplastic kidneys with oligohydramnios caused by NPHP3 gene mutation. METHODS: The fetuse was found to have multicystic dysplastic kidneys with oligohydramnios upon ultrasonography during the second trimester. Following induced abortion, fetal tissue was collected for the extraction of DNA, chromosomal microarray analysis (CMA) and whole exome sequencing (WES). Sanger sequencing was used to verify the suspected variants in the family. RESULTS: Antenatal ultrasound examination at 19 weeks showed "polycystic" kidneys with Oligohydramnios. Delivery was by induced labour because of the critically low amniotic fluid volume. Testing of CMA was normal. WES showed a compound heterozygous mutation of c.1817G>A, p.W606X; c.432dupA, p.E145Rfs*18 mutations are novel mutations in this study. CONCLUSION: The research may further expand the NPHP3 gene mutation spectrum. Enlarged multicystic dysplastic kidneys with oligohydramnios caused by NPHP3 gene mutation at least include one or two splice site mutation, frameshift mutation or nonsense mutation foetal poor prognosis.

A multidisciplinary approach for prenatal diagnosis of FRASER SYNDROME-report of a novel variant in FRAS1.

OBJECTIVE: With this case report, we would like to highlight the importance of a multidisciplinary approach and atypical findings of congenital high airway obstruction sequence (CHAOS), anhydramnios, and renal dysgenesis in the prenatal diagnosis of Fraser syndrome (FS). CASE REPORT: A 25-year-old primigravida at 19 weeks of routine anomaly scan revealed abnormal sonographic findings such as fetal bilateral dysplastic small kidneys and gross oligohydramnios. The further detailed evaluation revealed that both fetal lungs were hyperechogenic with prominent (dilated) trachea and bronchi suggestive of CHAOS. Based on these findings, a diagnosis of FS was suspected. The couple was counseled and the pregnancy was terminated. The postmortem evaluation and novel homozygous variant in the FRAS1 gene confirmed the diagnosis of FS. CONCLUSION: The diagnosis and counseling of the patient were supported by a well-coordinated, multidisciplinary approach involving an obstetrician, a fetal medicine specialist, a medical geneticist, and a fetal pathologist.

Enlarged multicystic dysplastic kidneys with oligohydramnios during infancy caused by NPHP3 gene mutation / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical features and genomic abnorm ality of a fetus enlarged multicystic dysplastic kidneys with oligohydramnios caused by NPHP3 gene mutation.@*METHODS@#The fetuse was found to have multicystic dysplastic kidneys with oligohydramnios upon ultrasonography during the second trimester. Following induced abortion, fetal tissue was collected for the extraction of DNA, chromosomal microarray analysis (CMA) and whole exome sequencing (WES). Sanger sequencing was used to verify the suspected variants in the family.@*RESULTS@#Antenatal ultrasound examination at 19 weeks showed "polycystic" kidneys with Oligohydramnios. Delivery was by induced labour because of the critically low amniotic fluid volume. Testing of CMA was normal. WES showed a compound heterozygous mutation of c.1817G>A, p.W606X; c.432dupA, p.E145Rfs*18 mutations are novel mutations in this study.@*CONCLUSION@#The research may further expand the NPHP3 gene mutation spectrum. Enlarged multicystic dysplastic kidneys with oligohydramnios caused by NPHP3 gene mutation at least include one or two splice site mutation, frameshift mutation or nonsense mutation foetal poor prognosis.

A novel homozygous variant in REN in a family presenting with classic features of disorders involving the renin-angiotensin pathway, without renal tubular dysgenesis.

Autosomal recessively inherited pathogenic variants in genes associated with the renin-angiotensin-aldosterone system (RAAS) result in early onset oligohydramnios and clinical features of the Potter sequence, typically in association with proximal renal tubules dysgenesis. We describe two siblings and a first cousin who had severe oligohydramnios in the second trimester, and presented at birth with loose skin, wide fontanelles and sutures, and pulmonary insufficiency. Two had refractory hypotension during their brief lives and one received palliative care after birth. All were found to have a homozygous nonsense variant, REN: c.891delG; p.Tyr287*, on exome sequencing. Autopsy limited to the genitourinary system in two of the children revealed normal renal tubular histology in both. Immunoblotting confirmed diminished expression of renin within cultured skin fibroblasts. To our knowledge, this is the first identification of an association between biallelic variants in REN and oligohydramnios in the absence of renal tubular dysgenesis. Due to its role in the RAAS, it has previously been proposed that the decreased expression of REN results in hypotension, ischemia, and decreased urine production. We suggest sequencing of genes in the RAAS, including REN, should be considered in cases of severe early onset oligohydramnios, even when renal morphology and histology are normal.

LncRNA and transcriptomic analysis of fetal membrane reveal potential targets involved in oligohydramnios.

BACKGROUND: The multiple causes of oligohydramnios make it challenging to study. Long noncoding RNAs (lncRNAs) are sets of RNAs that have been proven to function in multiple biological processes. The purpose of this study is to study expression level and possible role of lncRNAs in oligohydramnios. METHODS: In this study, total RNA was isolated from fetal membranes resected from oligohydramnios pregnant women (OP) and normal amount of amniotic fluid pregnant women (Normal). LncRNA microarray was used to analyze the differentially expressed lncRNAs and mRNAs. Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to analyze the main enrichment pathways of differentially expressed mRNAs. Real-time quantitative PCR (qPCR) was used to validate the lncRNA expression level. RESULTS: LncRNA microarray analysis revealed that a total of 801 lncRNAs and 367 mRNAs were differentially expressed in OP; in these results, 638 lncRNAs and 189 mRNAs were upregulated, and 163 lncRNAs and 178 mRNAs were downregulated. Of the lncRNAs, 566 were intergenic lncRNAs, 351 were intronic antisense lncRNAs, and 300 were natural antisense lncRNAs. The differentially expressed lncRNAs were primarily located in chromosomes 2, 1, and 11. KEGG enrichment pathways revealed that the differentially expressed mRNAs were enriched in focal adhesion as well as in the signaling pathways of Ras, tumor necrosis factor (TNF), estrogen, and chemokine. The qPCR results confirmed that LINC00515 and RP11-388P9.2 were upregulated in OP. Furthermore, the constructed lncRNA-miRNA-mRNA regulatory network revealed tenascin R (TNR), cystic fibrosis transmembrane conductance regulator (CFTR), ATP-binding cassette sub-family A member 12 (ABCA12), and collagen 9A2 (COL9A2) as the candidate targets of LINC00515 and RP11-388P9.2. CONCLUSIONS: In summary, we revealed the profiles of lncRNA and mRNA in OP. These results might offer potential targets for biological prevention for pregnant women with oligohydramnios detected before delivery and provided a reliable basis for clinical biological treatment in OP.

Detection of a familial 1q21.1 microdeletion and concomitant CHD1L mutation in a fetus with oligohydramnios and bilateral renal dysplasia on prenatal ultrasound.

OBJECTIVE: We present detection of a familial 1q21.1 microdeletion and concomitant CHD1L mutation in a fetus with oligohydramnios and bilateral renal dysplasia on prenatal ultrasound. CASE REPORT: A 37-year-old, primigravid woman was referred for level II ultrasound examination at 16 weeks of gestation because of oligohydramnios. The parents were phenotypically normal, and there were no congenital malformations in the family. Prenatal ultrasound at 17 weeks of gestation revealed a fetus with fetal growth biometry equivalent to 16 weeks, oligohydramnios with an amniotic fluid index (AFI) of 1.4 cm and bilateral renal dysplasia without sonographic demonstration of bilateral renal arteries. The pregnancy was subsequently terminated, and a 137-g fetus was delivered without characteristic facial dysmorphism. Postnatal cytogenetic analysis of the umbilical cord and parental bloods revealed normal karyotypes. However, array comparative genomic hybridization (aCGH) analysis on the DNA extracted from the umbilical cord revealed a 2.038-Mb microdeletion of 1q21.1-q21.2 encompassing 11 [Online Mendelian Inheritance in Man (OMIM)] genes of PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8, GPR89B, NBPF14, TRN-GTT2-1 and NBPF20. The mother was found to carry the same microdeletion. A missense mutation of c.2353T > G, p.Ser785Ala in CHD1L was detected in the umbilical cord. The father was found to carry a heterozygous mutation of c.2353T > G, p.Ser785Ala in CHD1L. CONCLUSION: Fetuses with a 1q21.1 microdeletion and concomitant CHD1L mutation may present oligohydramnios and bilateral renal dysplasia on prenatal ultrasound.

Mosaic trisomy 22 at amniocentesis: Prenatal diagnosis and literature review.

OBJECTIVE: We present prenatal diagnosis of mosaic trisomy 22 at amniocentesis in a pregnancy with facial cleft, oligohydramnios and intrauterine growth restriction (IUGR), and we review the literature. CASE REPORT: A 37-year-old woman underwent amniocentesis at 19 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+22[9]/46,XX[9]. Array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes showed a result of arr(22) × 3 [0.8]. Prenatal ultrasound revealed fetal median facial cleft, oligohydramnios and IUGR. Repeat amniocentesis at 22 weeks of gestation using uncultured amniocytes revealed an aCGH result of arr 22q11.1q13.33 (17,397,498-51,178,264) × 2.8 compatible with 80% mosaicism for trisomy 22, and a fluorescence in situ hybridization (FISH) result of mosaic trisomy 22 with trisomy 22 in 54/100 interphase cells. The cultured amniocytes at repeat amniocentesis had a karyotype of 47,XX,+22[12]/46,XX[8]. The parental karyotypes were normal. Polymorphic DNA marker analysis confirmed a maternal origin of the extra chromosome 22. The pregnancy was terminated, and a 256-g female fetus was delivered with facial dysmorphism and median facial cleft. Cytogenetic analysis of the skin fibroblasts revealed a karyotype of 47,XX,+22[33]/46,XX[7]. CONCLUSION: Fetuses with high level mosaicism for trisomy 22 at amniocentesis may present IUGR, facial cleft and oligohydramnios on prenatal ultrasound.

Are Congenital Urinary Tract Abnormalities Linked to Maternal Methylenetetrahydrofolate Reductase Polymorphisms in Fetuses of Intentionally Terminated Pregnancies with Oligo- or Anhydramnios ?

OBJECTIVE: We aimed to evaluate fetuses of terminated pregnancies with oligo-or anhydramnios (OAH) to further investigate the association between maternal methylenetetrahydrofolate reductase (MTHFR) polymorphisms and fetal urinary tract malformations. MATERIALS AND METHODS: This retrospective study included 16 pregnancies with OAH (with normal fetal karyotype) that were intentionally terminated before 22nd gestational week. Fetal autopsy was performed in all cases. We evaluated cases for presence of DNA methylation pathway-related gene polymorphisms. RESULTS: We demonstrated that renal abnormalities and disorders exist in 75% of the cases. Pulmonary system anomalies and single umbilical artery were the most frequently observed associated abnormalities. Polymorphisms with known reduced MTHFR activity were found in 81.8% (9/11) of the cases.Association between urinary system abnormalities and polymorphisms with known reduced MTHFR activity was observed in 88.8% (8/9) of the cases. CONCLUSION: Physicians should keep in mind that polymorphisms with known reduced MTHFR activity may be associated with urinary tract abnormalities and OAH.

Danshen extract regulates the expression of aquaporin 3 in human amniotic epithelial cells.

Danshen extract has been used in the treatment of oligohydramnios, however, the mechanism of its action has not been elucidated. Previously, we demonstrated that down-regulation of AQP3 in fetal membranes may contribute to the development of oligohydramnios. In this study, we investigated the effects of Danshen extract on AQP3 expression in human amniotic epithelial cells from term pregnancies with oligohydramnios or those with those with (those with) normovolemic amniotic fluid. Human amniotic epithelial cells from the oligohydramnios group expressed a lower level of AQP3 mRNA and protein than those with normovolemia. Tweleve hour (Twelvehours) of treatment with Danshen extract, in a dose dependent manner, significantly increased the expression of AQP3 in the two groups. However, human amniotic epithelial cells from the oligohydramnios patients showed a greater sensitivity to the treatment of Danshen extract. These data provide a molecular basis for the treatment of patients with oligohydraminos.

Aquaporin 3 Expression Induced by Salvia Miltiorrhiza via ERK1/2 Signal Pathway in the Primary Human Amnion Epithelium Cells from Isolated Oligohydramnios.

Salvia miltiorrhiza is one of the most common Chinese herbal drugs, which is effective to treat oligohydramnios. In this study, the aim was to investigate how Salvia miltiorrhiza regulate aquaporin 3 expression in the human amnion epithelial cells (hAECs) with normal amniotic fluid volume or isolated oligohydramnios, whether via extracellular signal regulated kinase1/2 (ERK1/2) signal transduction pathway or not. Primary hAECs cultures from 120 patients were incubated with Salvia miltiorrhiza or/and ERK1/2 inhibitor-- U0126. Localization of aquaporin 3 was detected by immunohistochemistry and the expression of total ERK1/2, phospho-ERK1/2 (p-ERK1/2) and aquaporin 3 was detected by Western blot. The results were: (1) In hAECs with normal amniotic fluid volume, treatment with 10 µmol/L of U0126 for 6 h resulted in the optimal inhibition of p-ERK1/2 (P<0.05). However, the expression of total ERK1/2 or aquaporin 3 did not significantly change after different concentrations or time of U0126 treatment. Salvia miltiorrhiza significantly up-regulated aquaporin 3 expression, which was not affected by U0126. (2) In hAECs with isolated oligohydramnios, treatment with 5 µmol/L of U0126 for 2 h resulted in the optimal inhibition of p-ERK1/2 and the lowest expression of aquaporin 3 (P<0.05). Moreover, Salvia miltiorrhiza significantly up-regulated aquaporin 3 expression, which was obviously blocked by U0126. These results suggest that Salvia miltiorrhiza may regulate aquaporin 3 expression in hAECs. In addition, in hAECs with isolated oligohydramnios, Salvia miltiorrhiza may regulate the expression of aquaporin 3 via the ERK1/2 signal transduction pathway, which provides a novel thread to the improved treatment for isolated oligohydramnios.

Oligohydramnios sequence revisited in relationship to arthrogryposis, with distinctive skin changes.

Thirty cases of arthrogryposis associated with longstanding oligohydramnios were identified among 2,500 cases of arthrogryposis (1.2%) and were reviewed for clinical features and natural history. None had renal agenesis or renal disease. Twenty-two had a history of known rupture of membranes. Only 50% had pulmonary hypoplasia at birth and only two died (7%). Sixty percent (18/30) seemed to have their multiple congenital contractures (MCC) primarily on the basis of compression related to the longstanding oligohydramnios and responded well to physical therapy. On average they did not have intrauterine growth restriction. "Potter" facies and remarkable skin changes were present in all. An excess of males was observed in spite of the lack of genitourinary anomalies.

TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia.

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.