Prenatal Diagnosis of Renal Cysts and Diabetes Syndrome (RCAD): A Case Report

Introduction

Renal cysts and diabetes syndrome (RCAD, OMIM #137920) is a multisystem disorder caused by heterozygous variants or whole-gene deletions in the hepatocyte nuclear factor-1β (HNF1B) gene, located on chromosome 17q12. HNF1B encodes a transcription factor essential for the embryonic development of kidneys, pancreas, liver, and the genitourinary tract. RCAD typically follows an autosomal-dominant inheritance pattern, although up to 50% of cases arise de novo [1–3].

The syndrome is characterized by variable expressivity and incomplete penetrance, often manifesting as prenatal bilateral hyperechogenic or cystic kidneys, early-onset diabetes mellitus (commonly MODY5), and genitourinary malformations [1,4,5]. Renal anomalies range from multicystic dysplasia to hypoplasia or agenesis, and can present as oligohydramnios in utero [6,7]. Diabetes, when present, usually develops in adolescence or early adulthood, and is typically insulin-requiring due to pancreatic hypoplasia or dysfunction [1,3,8].

HNF1B mutations are among the most common monogenic causes of congenital anomalies of the kidney and urinary tract (CAKUT), accounting for 5–15% of cases and up to 30% of those with bilateral renal cystic disease [6,9]. Given this prevalence, RCAD should be considered in the prenatal differential diagnosis of cystic or echogenic fetal kidneys, particularly when associated with a family history of renal disease or diabetes [3,6,10].

The clinical implications of diagnosing RCAD prenatally are substantial. Genetic confirmation enables risk stratification, long-term follow-up planning, and family counselling. Given the possibility of asymptomatic parental carriers, targeted parental testing is recommended to establish inheritance patterns and recurrence risk [1,3,11]. However, the marked phenotypic variability of HNF1B-associated disease can complicate counselling: a positive prenatal genetic result does not predict the exact outcome, as 17q12 copy-number variants have variable presentations and incomplete penetrance, posing challenges for prenatal management.

Here, we present a prenatal case of RCAD caused by a 17q12 microdeletion, notable for its severe fetal presentation and the uncommon complication of intrauterine demise. This case report highlights the importance of recognizing HNF1B mutations in utero and discusses the challenges in management and genetic counselling when confronted with the end of the RCAD phenotypic spectrum.

Case Report

CLINICAL FINDINGS:

Prenatal ultrasonography revealed bilaterally enlarged, polycystic, hyperechogenic kidneys accompanied by severe oligohydramnios, a small visible urinary bladder, a single measurable amniotic fluid pocket (approximately 1.0×1.5 cm), and a posteriorly located low-lying placenta. These findings raised suspicion of a cystic kidney disease. Differential diagnoses at this stage included autosomal recessive polycystic kidney disease (ARPKD), autosomal-dominant polycystic kidney disease (ADPKD), chromosomal conditions (eg, Meckel–Gruber syndrome or trisomy 13), and a possible HNF1B-related cystic renal disorder (RCAD). Due to severe oligohydramnios and the need for cytogenetic evaluation, the patient underwent a two-step procedure: transabdominal amnioinfusion to facilitate fetal anatomical assessment, followed by amniocentesis for cytogenetic testing.

DIAGNOSTIC ASSESSMENT AND THERAPEUTIC INTERVENTION:

Under local anesthesia, an 18G needle was inserted into the identified amniotic pocket, and 200 mL of warmed 0.9% sodium chloride solution was slowly infused to restore a normal amniotic fluid volume. The procedure was interrupted prematurely due to the onset of abdominal pain. Amniocentesis was rescheduled for the following day, during which 20 mL of clear amniotic fluid was successfully aspirated and sent for cytogenetic analysis. The patient was discharged home in stable condition the same day.

Five days after the invasive procedures, the patient re-presented with clinical suspicion of premature rupture of membranes. Upon admission, laboratory investigations revealed markedly elevated inflammatory markers: leukocytosis (20.37×10³/μL) and C-reactive protein (CRP, 170 mg/L), with further increases over the subsequent hours (leukocytes, 23.36×10³/μL; CRP, 187 mg/L). Empirical broad-spectrum antimicrobial therapy was initiated, including oral azithromycin (1.0 g), intravenous cefuroxime (2.0 g), clindamycin (0.9 g), and fluconazole (2.0 g). Due to intrauterine infection and the associated risk of maternal sepsis, the patient was qualified for termination of pregnancy. Twenty-two hours after admission, intrauterine fetal death occurred, followed by spontaneous expulsion of a male fetus with no signs of life. Over the subsequent days, inflammatory markers gradually decreased (leukocytes 4.73×10³/μL; CRP 66.1 mg/L). The patient was discharged on post-procedure day 4 in good general condition.

Cytogenetic evaluation of the amniotic fluid was performed using a whole-genome oligonucleotide microarray (CytoSure Constitutional v3, 8x60K, Oxford Gene Technology; GRCh37/hg19), with an average resolution of 120 kb. Additional genetic material was preserved for potential future testing. The analysis revealed a male karyotype with an interstitial deletion on the long arm of chromosome 17 at region 17q12, measuring approximately 1.4 Mb (arr[GRCh37] 17q12(34,850,785_36,248,926)x1). The deletion encompassed the critical region associated with renal cysts and diabetes (RCAD) syndrome (OMIM 137920; ORPHA 93111), including 15 protein-coding genes.

FOLLOW-UP AND OUTCOMES:

The 17q12 microdeletion identified in this fetus is known for variable expressivity and incomplete penetrance. The often-cited penetrance estimate of ~34.4% derives from postnatal cohorts modelled by Rosenfeld et al and primarily reflects mild-to-moderate phenotypes; therefore, it should not be extrapolated to severe or lethal outcomes [12]. Contemporary resources (ClinGen and DECIPHER) consistently emphasize broad phenotypic variability in the recurrent 17q12 deletion (including CAKUT, MODY5, and neurodevelopmental/psychiatric features). Recent prenatal series likewise report renal findings as predominant and suggest that extreme outcomes are rare, implying that the presentation in our case may lie at the far end of the spectrum.

Genetic counselling was recommended. Targeted parental testing using multiplex ligation-dependent probe amplification (MLPA, P297) was advised to establish whether the deletion occurred de novo or was inherited. Despite counselling, the parents did not undergo the recommended genetic testing, limiting the ability to define the inheritance pattern and recurrence risk definitively. The father’s early-onset diabetes (strongly suggestive of an HNF1B-related etiology) suggests that the 17q12 deletion was likely paternally inherited, in which case the recurrence risk in future pregnancies would be 50%. If, instead, this variant occurred de novo in the fetus, the recurrence risk would be low.

Maternal follow-up included an abdominal ultrasound that identified a solitary renal cyst measuring 4.9 cm. It was also noted that the father of the fetus had a medical history of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes that may be associated with mutations in the HNF1B gene, one of the genes located within the deleted 17q12 region. This history raised suspicion that the father may be an asymptomatic carrier of the 17q12 deletion, although this remains unconfirmed due to the parents’ refusal of testing.

The patient recovered without complications. Laboratory markers of infection normalized, and no adverse events or sequelae were observed during hospitalization. Intervention tolerability was assessed clinically; no signs of maternal intolerance to the procedures or ongoing symptoms were reported at discharge. The pregnancy outcome was unfavorable, and follow-up was limited due to the absence of further parental genetic evaluation. Nevertheless, the findings contribute to the prenatal phenotype spectrum of RCAD syndrome and highlight the importance of multidisciplinary assessment in cases of suspected monogenic renal disease.

Discussion

This case illustrates the classical features of renal cysts and diabetes (RCAD) syndrome, which result from a 17q12 microdeletion encompassing the HNF1B gene. The fetus presented with bilateral polycystic, hyperechogenic kidneys and severe oligohydramnios, which are hallmark prenatal findings in HNF1B-associated disease [13,14]. RCAD is an autosomal dominant, multisystem disorder with highly variable expressivity. In some individuals, especially those with large deletions of the HNF1B region, the condition manifests in utero as congenital kidney malformations and functional renal impairment, as seen in our patient. In others, the phenotype may be milder, with early-onset diabetes mellitus, solitary renal cysts, or even subclinical findings [15]. Up to 50% of RCAD cases result from de novo mutations, and penetrance is incomplete (~34% in 1 cohort), meaning that an unaffected parent can carry the pathogenic variant [12,16].

Notably, our case represents an extreme phenotype on this spectrum. The combination of early, bilateral cystic kidney disease and ensuing fetal demise (secondary to anhydramnios and infection) is exceedingly rare in RCAD pregnancies. The prenatal presentation of bilateral enlarged echogenic kidneys with severe oligohydramnios necessitates distinguishing RCAD from other cystic kidney diseases. The 2 primary differentials are autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD). ARPKD, caused by PKHD1 mutations, classically presents in the perinatal period with massively enlarged, symmetrically echogenic kidneys and poor cortico-medullary differentiation. Oligohydramnios is common in ARPKD due to early renal insufficiency, often leading to neonatal mortality. Importantly, ARPKD is a recessive disorder – parents are usually asymptomatic carriers, although the newborn may have severe disease. Hepatic fibrosis is a hallmark of ARPKD in infants who survive, but this is absent in RCAD [17–19]. In our case, there was no evidence of hepatic enlargement or fibrosis on fetal imaging, and the family history (maternal renal cyst and paternal diabetes) was more suggestive of an HNF1B-related disorder.

ADPKD, typically due to PKD1/PKD2 mutations, usually manifests later in life; however, early-onset (in utero or neonatal) ADPKD occurs in rare cases. Such cases of ADPKD can produce a prenatal ultrasound picture of enlarged cystic kidneys that may be indistinguishable from ARPKD or HNF1B-related cystic dysplasia. A key distinguishing feature is the family history: ADPKD is dominant, so 1 parent often has adult polycystic kidney disease. If fetal cystic kidneys are noted, imaging of the parents’ kidneys can be very informative. In our scenario, the mother had a renal cyst, and the father, despite having diabetes, was not known to have kidney cysts or impairment. Moreover, the presence of diabetes in the father aligned more with an HNF1B mutation (MODY5) than with ADPKD. Genetic testing ultimately confirmed HNF1B deletion, definitively distinguishing RCAD from these other entities. This highlights the importance of genetic analysis for accurate diagnosis when cystic kidney diseases present with overlapping prenatal imaging findings [12,20].

Importantly, the underlying genetic mechanisms in RCAD, ADPKD, and ARPKD have direct implications for the selection and effectiveness of prenatal diagnostic tests. RCAD is typically caused by a 17q12 microdeletion involving the HNF1B gene, which is often detectable by chromosomal microarray analysis (CMA/aCGH). This makes RCAD uniquely identifiable among cystic kidney diseases by detecting copy number variants. In contrast, ADPKD and ARPKD are usually caused by point mutations or small insertions/deletions in the PKD1/PKD2 and PKHD1 genes, respectively – alterations that aCGH cannot detect. These conditions, therefore, require targeted molecular testing, either via Sanger sequencing (when a familial variant is known) or via next-generation sequencing (NGS) panels that cover relevant cystic kidney genes.

As such, aCGH is an appropriate first-tier diagnostic tool in cases where RCAD is suspected, particularly when prenatal ultrasound reveals hyperechogenic kidneys in the absence of a family history suggestive of ADPKD or ARPKD. If aCGH yields noninformative results and cystic kidney disease remains a concern, comprehensive molecular testing, including NGS, is essential to identify the point mutations responsible for ADPKD and ARPKD.

From a genetic counselling perspective, prenatal detection of a 17q12 deletion enables individualized counselling and risk assessment. As previously discussed, there is a significant likelihood of a hereditary component, with 1 parent potentially harboring the same mutation or a milder deletion. In our case, the father’s history of early-onset diabetes raises a strong suspicion of a pathogenic HNF1B variant. Although parental testing via MLPA for the 17q12 deletion was offered to clarify inheritance and recurrence risk, the family declined, leaving some uncertainty. In general, if a parent is confirmed to carry the HNF1B mutation or deletion, the recurrence risk in future pregnancies is 50%. Conversely, if the variant is de novo, the risk is low, although germline mosaicism remains a rare possibility. This information is critical for reproductive planning and underscores the need to consider screening of at-risk relatives. Moreover, a prenatal diagnosis of RCAD creates an opportunity for multidisciplinary care planning. While the pregnancy in our case could not be continued, the case illustrates the importance of collaboration among obstetricians, clinical geneticists, pediatric nephrologists, and neonatologists.

Had the fetus survived to a viable gestational age, aggressive perinatal management would have been required. Early involvement of pediatric nephrology and endocrinology would be crucial, given the potential need for neonatal renal support (dialysis) and monitoring for pancreatic insufficiency or neonatal diabetes. Infants born with little or no renal function require prompt dialysis after birth and eventual kidney transplantation for long-term survival. Unlike ARPKD, RCAD is not typically associated with congenital hepatic fibrosis; however, transient elevations in liver enzymes have been reported in some neonatal cases. Long-term follow-up for surviving infants is essential to monitor and manage the development of MODY5 diabetes or other extrarenal manifestations as the child grows.

Conclusions

This case report expands the prenatal spectrum of HNF1B-associated RCAD syndrome and highlights the importance of considering monogenic causes in fetuses with cystic kidney disease. Distinguishing RCAD from ADPKD and ARPKD based on imaging alone is challenging; however, careful evaluation of the family history and comprehensive genetic testing can lead to a definitive diagnosis. Early identification enables informed decision-making, individualized perinatal management, and appropriate counselling on prognosis and recurrence risk. Continued case reporting and research are essential to improving our understanding of the phenotypic variability associated with 17q12 deletions and optimizing prenatal care for affected pregnancies. Ultimately, maintaining a high index of suspicion and using a proactive diagnostic approach are key to effective management of fetal cystic kidney disease.