A Case of a Novel HNF1B Gene Mutation (c.316C>T) and the Renal and Extra-Renal Manifestations of HNF1B Nephropathy

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Neonatal Med. 2025;32(2):90-96

Publication date (electronic) : 2025 November 30

doi : https://doi.org/10.5385/nm.2025.32.2.90

Ji Yoo Kim, MD¹, Malak Abdulaziz Almoneef, MD¹, Hoi Kyung Koo, MD¹, Yong Sung Choi, MD, PhD¹, Young Joo Lee, MD, PhD^,2

¹Department of Pediatrics, Kyung Hee University Medical Center, College of Medicine, Kyung Hee University, Seoul, Korea

²Department of Obstetrics and Gynecology, Kyung Hee University Medical Center, College of Medicine, Kyung Hee University, Seoul, Korea

Correspondence to: Young Joo Lee, MD, PhD Department of Obstetrics and Gynecology, Kyung Hee University Medical Center, College of Medicine, Kyung Hee University, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea Tel: +82-2-958-8836 Fax: +82-2-958-8328 E-mail: intro4med@naver.com

Received 2025 April 16; Revised 2025 September 11; Accepted 2025 November 11.

Abstract

INTRODUCTION

Hepatocyte nuclear factor 1-beta (HNF1B), located on chromosome 17q12 [1], plays an important role in the embryonic development of various organs, including the kidneys, pancreas, liver, and genital tract [2-5].

Since the first report of an HNF1B mutation in a Japanese family in 1997, more than 200 pathogenic variants, including missense, nonsense, splicing, deletion, and insertion mutations, have been identified [5,6]. Although HNF1B mutations are usually inherited in an autosomal dominant manner, nearly 50% of cases arise de novo [7]. Biallelic mutations are considered embryonically lethal and often result in spontaneous abortion, whereas monoallelic mutations are associated with a wide spectrum of disorders, as previously described [8,9].

The HNF1B gene comprises four functional domains: (1) the dimerization domain (amino acid residues 1-31), which is located on the N-terminal region, and is responsible for protein dimer formation; (2) the Pit-Oct-Unc (POU)-specific DNAbinding domain (POU_S, residues 88-180), involved in DNA recognition and binding; (3) the POU-homeodomain DNAbinding domain (POU_H, residues 229-319); and (4) the transactivation domain (residues 319-557), located on the C-terminal region, that mediates coactivator binding and transcriptional regulation [10-12]. Among these, the POU_S and POU_H domains have been identified as hotspots for pathogenic variants13). Here, we report a novel nonsense mutation (c.316C>T) in the POU_S domain of HNF1B.

CASE REPORT

A female infant was delivered via cesarean section at 36 weeks and 0 days of gestation because of preterm labor. Her birth weight was 2,955 g (78th percentile), and length was 48 cm (73rd percentile). The mother received two doses of intramuscular betamethasone (12 mg each) within 2 days before delivery. There were no remarkable perinatal events, and the infant’s Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. Although her general condition was stable at birth, she was admitted to the neonatal intensive care unit (NICU) for evaluation of prematurity, oligohydramnios, and prenatal renal anomalies.

A 30-year-old primigravida with an unremarkable medical history had a normal pregnancy course until 20 weeks of gestation, when a detailed fetal ultrasound at a local clinic revealed a suspected multicystic dysplastic right kidney. The patient was then referred to our hospital for further evaluation. The patient had no family history of renal disease. Targeted prenatal ultrasonography at 20 weeks and 4 days of gestation revealed right renal enlargement with multiple hypoechoic cystic structures (Figure 1). The amniotic fluid index (AFI) was 16.3 cm, which was within the normal range, and no other structural anomalies were identified. Chromosomal analysis was recommended; however, the mother declined further evaluation. At 33 weeks of gestation, follow-up ultrasonography demonstrated progression of the cystic changes, with enlargement of the right kidney to 6.7 cm (Figure 2A). The left kidney was also enlarged to 5.6 cm with hypoechoic parenchyma and loss of the normal medullary pyramid pattern (Figure 2B). The AFI decreased to 9.7 cm.

Figure 1.

Prenatal ultrasonography at 20 weeks and 4 days of gestation demonstrating enlargement of the right kidney with a hypoechoic cystic lesion (arrows).

Figure 2.

Prenatal ultrasonography at 33 weeks of gestation. (A) The cystic hypoechoic lesion of the right kidney had increased in size, and the kidney was enlarged to 6.7 cm. (B) The left kidney was also enlarged to 5.6 cm, with hypoechoic parenchymal changes and absence of normal medullary pyramid structures.

In the NICU, the infant exhibited stable vital signs, including normal blood pressure. The urine output was 3.9 mL/kg/hr and the urine volume accounted for approximately 70% to 80% of the total fluid intake. Ultrasonography performed on day 5 after birth (Figure 3) revealed bilateral renal enlargement. The right kidney contained multiple cysts up to 2.89 cm in diameter, whereas the left kidney contained several smaller cysts (<1 cm) with increased parenchymal echogenicity and loss of corticomedullary differentiation. Mild pelviectasis was noted; however, the ureteropelvic junction could not be clearly assessed.

Figure 3.

Postnatal ultrasonography on day 5 showing bilateral kidney enlargement. (A, B) The right kidney contained multiple cysts of variable size, the largest measuring 2.89 cm, (C, D) whereas the left kidney demonstrated multiple cysts smaller than 1 cm with increased echogenicity and loss of corticomedullary differentiation. Mild pelvic dilatation was noted, although the ureteropelvic junction could not be clearly identified.

During the NICU stay, liver enzyme levels remained within normal limits. Serum magnesium levels ranged from 2.0 to 2.4 mg/dL (reference range, 1.5 to 2.3 mg/dL), indicating normomagnesemia. Serum uric acid levels (reference range, 2.0 to 6.0 mg/dL) were 5.5 mg/dL on the first day of life, peaked at 8.6 mg/dL on the second day, and returned to normal values after day 5. Blood urea nitrogen values remained normal (3 to 12 mg/dL), whereas serum creatinine increased from 0.58 mg/dL on day 1 to 1.70 mg/dL on day 2 and gradually rose to 3.05 mg/dL by day 7. Urinalysis using a urine collection bag showed mild proteinuria (1+ on day 1, trace on day 2), trace occult blood and 0–1 red blood cell/high power field on microscopic examination. Brain ultrasonography and echocardiography performed on day three revealed no abnormalities.

In our patient, antenatal ultrasonography strongly suggested polycystic kidney disease; however, the mother declined further chromosomal evaluations (amniocentesis and microarray). Next-generation sequencing (NGS) was performed after birth to identify the genetic basis of the cystic renal disease, and revealed a likely pathogenic heterozygous variant in the HNF1B gene (c.316C>T). This variant was predicted to introduce a premature stop codon at amino acid 106, resulting in early termination (Figure 4). Because parental genetic testing was not conducted, the possibility of de novo mutations could not be confirmed. The infant was transferred to another NICU on day 8 of life for renal biopsy and further assessment, although subsequent biopsy and imaging data were unavailable. The patient subsequently underwent temporary nephrostomy for external urinary drainage. The patient continues to be followed up at the outpatient clinic of another hospital for the possibility of progression to stage 5 chronic kidney disease, and remains alive at 3 years of age.

Figure 4.

Genetic analysis by next-generation sequencing (NGS) identifying a likely pathogenic heterozygous variant in the hepatocyte nuclear factor 1-beta (HNF1B) gene (c.316C>T), predicted to result in a premature stop codon at amino acid position 106. Abbreviations: POU_S, Pit-Oct-Unc (POU)-specific DNA-binding domain; POU_H, POU-homeodomain DNA-binding domain.

At the corrected age of 8 months, the patient’s height and weight were 66.8 cm (20.5th percentile) and 7.6 kg (35.6th percentile), respectively. At the corrected age of 14 months, her height was 73 cm (5th percentile) and weight was 8.4 kg (13.5th percentile), findings consistent with the overall appropriate growth for age. However, during the national infant health screening, a detailed developmental assessment was recommended. The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) test was performed at the corrected age of 14 months and 9 days. The results showed a cognitive composite score of 85 (equivalent to 11 months), a language composite score of 86 (receptive, 9 months; expressive, 13 months), and a motor composite score of 85 (fine motor, 13 months; gross motor, 11 months). The social-emotional score was 105 and the adaptive behavior score was 86, indicating developmental delay risks in all domains except the socialemotional area. The patient has been undergoing continuous physical and speech therapy.

DISCUSSION

This report presents the case of a pediatric patient carrying a novel nonsense variant (c.316C>T) in the POU_S domain of the HNF1B gene and reviews both the renal and extra-renal manifestations of HNF1B nephropathy.

Renal phenotypes associated with HNF1B nephropathy include renal cysts, glomerular tuft dysplasia, primitive tubules, irregular collecting systems, oligomeganephronia, dilated renal pelvises, abnormal calyces, small or single kidneys, and horseshoe kidneys. Extra-renal features may include maturityonset diabetes of the young type 5 (MODY5), elevated liver enzymes, hyperuricemia, hypomagnesemia, pancreatic anomalies, and a variety of genital tract malformations such as vaginal aplasia, rudimentary or bicornuate uterus, cryptorchidism, epididymal cysts, and vas deferens atresia [4,7,11,14]. Recently, neurodevelopmental features including intellectual disability, learning disorders, developmental delay, autism spectrum disorder, attention-deficit/hyperactivity disorder, and epilepsy have also been recognized (Table 1) [15]. The clinical features that help differentiate HNF1B nephropathy from other neonatal cystic kidney diseases are summarized in Table 2.

Table 1.

Clinical Manifestations of HNF1B-Related Disease [7,11,15]

Table 2.

Differential Diagnosis of Neonatal Cystic Kidney Diseases [3,4,7]

The patient exhibited multiple renal features including polycystic kidneys, renal enlargement, increased echogenicity, loss of corticomedullary differentiation, and pelviectasis. Extra-renal findings were limited to transient hyperuricemia without hypomagnesemia or liver enzyme elevation, although such abnormalities may develop later in life. MODY5 was not observed, which is consistent with its typical onset during adolescence or early adulthood due to pancreatic hypoplasia [7]. The developmental delay identified on the Bayley-III assessment aligns with the literature, indicating an association between HNF1B mutations and neurodevelopmental impairment [15].

The HNF1B gene, located on chromosome 17q12, typically follows an autosomal dominant inheritance pattern, although nearly half of all the cases are caused by de novo mutations [7]. HNF1B consists of four functional domains: the dimerization, POU_S, POU_H, and transactivation domains [11,12], with pathogenic variants most frequently found in the POU_S and POU_H domains, both of which play essential roles in DNA binding [13].

Genotype-phenotype correlations were previously unclear, with a wide range of clinical manifestations, even among family members carrying the same variants [16]. However, a recent study by Buffin-Meyer et al. [12] involving 536 European patients demonstrated that the variants in the POU_S domain were significantly associated with a faster progression to stage 3 end-stage renal disease compared with the variants in the POU_H or transactivation domains (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.06 to 0.37; P<0.001; and HR, 0.25; 95% CI, 0.11 to 0.57; P=0.001, respectively). No significant inter-domain differences were observed for hypomagnesemia or hyperglycemia, while hyperuricemia was significantly less frequent in patients with POU_H variants than in those with POU_S variants (HR, 0.30; 95% CI, 0.11 to 0.79; P=0.018) [12]. These findings support the notion that POU_S domain disruption accelerates renal function decline in HNF1B-associated nephropathy, and may explain the rapidly progressing course observed in our patient, who exhibited bilateral renal cysts, nephromegaly, and early loss of corticomedullary differentiation in infancy. Pediatric data from a German multicenter registry also indicate that although most children show slow disease progression, a subset with very early onset (<2 years) may rapidly progress to end-stage renal disease. The clinical course may differ according to domain-specific effects, variant types, and additional genetic or epigenetic modifiers. With the presence of a truncating POU_S variant in this case, the patient may belong to a higher-risk group for accelerated decline, emphasizing the need for long-term renal monitoring and early intervention [14].

In this case, the nonsense variant (c.316C>T) identified in the POU_S domain of the HNF1B gene is predicted to have introduced a premature termination codon at amino acid position 106, resulting in the clinical manifestations observed in the patient, including bilateral renal cysts, transient hyperuricemia, and an increased risk of developmental delay. The well-known nonsense variant of HNF1B, p.Arg177Ter (R177X), produces a truncated 176-amino acid protein that fails to activate normal target gene expression, resulting in a loss of function [17,18].

Therefore, the clinical presentation observed in this patient suggests that the p.Gln106Ter variant resulting from the c.316C>T mutation also represents a loss-of-function mutation, implying that reduced levels of functional HNF1B protein (haploinsufficiency) underlie the disease mechanism. This highlights the broad phenotypic variability associated with HNF1B mutations and underscores the significant impact of nonsense variants in the POU_S domain on renal development and function. This emphasizes the importance of ongoing neurodevelopmental monitoring of patients with HNF1B mutations.

Given the wide phenotypic and temporal variability of HNF1B-associated nephropathy compared with other cystic renal disorders, timely diagnosis is challenging. Therefore, early genetic testing, such as NGS, is essential when renal or extrarenal manifestations are observed. Early recognition not only improves the prognostic assessment of renal function but also enables systematic monitoring and management of laboratory abnormalities and neurodevelopmental impairments.

This case report describes a child with a novel nonsense mutation (c.316C>T) in the POU_S domain of HNF1B and illustrates the wide range of renal and extra-renal manifestations that can result from HNF1B mutations. As such broad phenotypic variability can delay diagnosis, the present case highlights the importance of early genetic testing. Additional studies with a larger number of patients are required to better define the phenotypic spectra and age-at-onset patterns according to the location of mutations within HNF1B.

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