Atypical presentation of HNF1β gene mutation mimicking type 2 diabetes: Case report and literature review

Abstract

Hepatocyte nuclear factor 1β (HNF1β)-related disease is a rare autosomal dominant genetic disorder. It presents with diverse clinical phenotypes and involves multiple systems. We report a heterozygous c.544C>T mutation in the HNF1β gene identified in three members of a Han Chinese family. All patients presented with renal cysts, renal impairment, hyperuricemia, hypomagnesemia, and hyperparathyroidism. Only the proband exhibited hyperglycemia, pancreatic dysplasia, and genital malformations. The older son presented with asymptomatic elevation of liver enzymes, while the younger son had left renal hypoplasia. Whole exome sequencing revealed a nonsense mutation of HNF1β gene in the proband and his two sons (NM_000458.4: c.544C>T: p. Gln182Ter). The proband underwent renal replacement therapy for end-stage renal disease. His son received high-quality, low-protein diet combined with medication for renal protection, uric acid reduction, and hypomagnesemia correction. The older son received ursodeoxycholic acid and hepatoprotective drugs to normalize liver enzyme levels. All patients showed significant symptom improvement after treatment during the long-term follow-up. This case report highlights the multi-organ involvement, diagnostic challenges, and importance of comprehensive genetic analysis in HNF1β-related disease. Recognition of this condition can reduce unnecessary kidney biopsies and minimize misdiagnosis and missed diagnosis.

Introduction

Hepatocyte nuclear factor 1β (HNF1β) gene mutation is an autosomal dominant disorder affecting multiple organs, including the liver, intestine, pancreas, kidney, and genitourinary tract. It plays a crucial role in tissue-specific gene expression regulation. ¹ The mutation can lead to abnormal expression of target genes in affected tissues, disrupting cellular development and differentiation, impairing organ function, and causing HNF1β-related diseases. The diverse gene expression patterns explain the clinical heterogeneity of HNF1β-related diseases, making misdiagnosis or missed diagnosis common.

We report a case of a family with multi-organ involvement caused by HNF1β gene mutation. We summarize the clinical phenotypes of HNF1β-related diseases and provide a literature review to aid in the diagnosis and treatment of HNF1β-related diseases by clinicians.

Case presentation

Medical history of the proband

The proband (I-1, Figure 1(a)) was a 69-year-old Chinese male. His medical history revealed that at the age of 59, he had a fasting glucose level of 18 mmol/L, glycosylated hemoglobin of 13.1% (normal range 4.0%–6.3%), uric acid of 624 μmol/L (normal range 210–420 μmol/L), and serum creatinine (SCr) of 221 μmol/L (normal range 44–133 μmol/L). Autoimmune antibodies used to differentiate type 1 diabetes, including anti-glutamic acid decarboxylase, anti-indoleacetic acid, and anti-indoleacetic acid antibodies, were negative. A fundus examination revealed diabetic retinopathy. The patient was initially diagnosed with type 2 diabetes mellitus and diabetic nephropathy.

Figure 1.

Pedigree and mutation analysis of the family. (a) The pedigree of a Han Chinese family with HNF1β gene mutation. The proband (I-1) is indicated with an arrow. (b) Sanger sequencing confirmed a nonsense mutation of HNF1β gene in the proband (I-1) and his two sons (II-1 and II-2; NM_000458.4: c.544C>T: p. Gln182Ter). The gene locus within the red box indicates the mutation site. Normal sequencing of the proband’s wife (I-2).

During 10 years of intermittent outpatient follow-up, SCr levels progressively increased, with the estimated glomerular filtration rate declining by 2.1 mL/min/year. The current reasons for the proband’s hospitalization were lower limb weakness, dizziness, and poor appetite. Abdominal computed tomography revealed bilateral renal atrophy, renal cysts, and renal calcification. Notably, it also revealed pancreatic dysplasia, characterized by the presence of residual pancreatic tissue in the pancreatic tail with a visible main pancreatic duct (Figure 2(a) and (b)). Genital ultrasonography revealed right epididymal calcification and a left epididymal head cyst (Figure 2(c) and (d)). Laboratory tests (Table 1) showed SCr 708 μmol/L, uric acid 549 μmol/L, and parathyroid hormone 470 pg/mL (normal range 12–65). An oral glucose tolerance test indicated loss of insulin secretion. The proband was treated with renal replacement therapy, intensified insulin therapy, and correction of complications.

Figure 2.

Imaging findings in the proband and his family. Abdominal CT of the proband revealed bilateral renal cysts, renal calcium deposition (a), residual pancreatic tissue and a main pancreatic duct in the tail of the pancreas, and no display of the head, neck, and body of the pancreas (b). The proband’s genital ultrasonography revealed right epididymal calcification (c), and a left epididymal head cyst (d), cyst size 1.03 × 0.82 cm. Abdominal B-wave ultrasonography of younger son revealed multiple cysts in the liver and kidneys, left kidney dysplasia (e), and right kidney atrophy (f), left kidney size 3.7 × 2.3 × 1.1 cm, right kidney size 9.1 × 3.9 × 2.9 cm. Each arrow in the image underscores the distinctive hallmarks of the clinical phenotypes linked to HNF1B gene mutations.

Table 1.

Summary of laboratory data.

Patients	Proband (I-1)	Proband’s older son (II-1)	Proband’s younger son (II-2)	Reference ranges
BMI (kg/m2)	17.2↓	18.6	18.1↓	18.5–22.9
TP/Alb (g/L)	62.1/30.7	77.8/43.9	73.8/46.6	65.0–85.0/40.0–55.0
ALT/AST (U/L)	23/21	313↑/96↑	41/27	9–50/15–40
SCr (μmol/L)	708↑	149↑	239↑	44–133
BUN (mmol/L)	21.3↑	6.3	11.8↑	2.86–8.20
UA (μmol/L)	549↑	452↑	465↑	210–420
TC/TG (mmol/L)	3.33/0.78	4.81/2.83↑	4.32/2.25↑	3.1–5.9/0.56–1.70
Glucose (mmol/L)	10.1↑	5.13	4.87	3.89–6.11
Mg/Ca (mmol/L)	0.68↓/1.64↓	0.44↓/2.38	0.59↓/2.44	0.96–1.34/2.08–2.60
iPTH (pg/mL)	470↑	68↑	270↑	12–65
HbA1c (%)	7.1↑	5.1	5	4.0–6.3
C-peptide (ng/mL)	0.78↓	2.54	3.25	0.81–3.84
Autoantibodies	Negative	Negative	Negative	Negative
ACR (mg/g)	356.8↑	30.07↑	294.9↑	<30
HNF1β score	18↑	12↑	12↑	<8

BMI: body mass index; TP: total protein; Alb: albumin; ALT: alanine aminotransferase; AST: aspartate transaminase; SCr: serum creatinine; BUN: blood urea nitrogen; UA: uric acid; TC: total cholesterol; TG: triglyceride; Mg: magnesium; Ca: calcium; iPTH: intact parathyroid hormone; HbA1c: glycated hemoglobin; ACR: albumin-creatinine ratio; HNF1β score: hepatocyte nuclear factor 1β score.

Family lineage surveys

The proband had two sons. Following medical advice, both sons underwent comprehensive physical examination. The older son (II-1, Figure 1(a)), an unmarried 49-year-old male, had symptoms of fatigue and poor appetite. Abdominal computed tomography revealed multiple hepatic cysts, complex cysts in both kidneys, and pancreatic calcification. Laboratory tests (Table 1) showed SCr 149 μmol/L, alanine aminotransferase 313 U/L (normal range 9–50), and aspartate aminotransferase 96 U/L (normal range 15–40). The younger son (II-2, Figure 1(a)) was a married 46-year-old male with occasional fatigue symptoms. Abdominal ultrasonography revealed multiple cysts in the liver and kidneys, left kidney dysplasia, and right kidney atrophy (Figure 2(e) and (f)). Laboratory tests (Table 1) showed SCr 239 μmol/L, uric acid 465 μmol/L, and intact parathyroid hormone 270 pg/mL. The proband’s wife and two grandchildren had normal blood tests for liver function, kidney function, and a normal renal ultrasound. The proband’s parents and six siblings denied any history of diabetes or chronic kidney disease.

Laboratory and auxiliary examination findings

Based on the laboratory data and auxiliary examination findings, the proband and his sons had renal insufficiency, hyperuricemia, hypomagnesemia, hyperparathyroidism, and renal cysts. Only the proband presented with diabetes, pancreatic dysplasia, and genital lesions. The older son had elevated transaminase levels without a specific cause. The younger son also had left-sided renal dysplasia. Neither son had diabetes or impaired glucose tolerance.

The clinical manifestations in this family were heterogeneous with multi-organ involvement, leading us to suspect mutations in the HNF1β gene. In 2014, Faguer et al. ² developed the HNF1β score for rational genetic screening. This score included family history, organ involvement, prenatal conditions, electrolytes, and uric acid. A score above 8 points indicated a HNF1β mutation (sensitivity 98.1%, specificity 41.1%). The HNF1β score of the proband was 18 points, and both sons scored 12 points, raising high suspicion for HNF1β-related diseases.

Genetic testing and analysis

To explore the possible genetic causes of disease occurrence and progression, peripheral venous blood was collected from the proband and his family members after informed consent was obtained for whole exome sequencing (WES). WES was done on NovaSeq6000 platform (Illumina, San Diego, CA, USA) with 154.01 × depth of coverage and 150 bp paired end reads. FastQC software (Babraham Bioinformatics, Cambridge, UK) was used to analyze the quality control of the original sequencing data. BWA software (Wellcome Trust Sanger Institute, Cambridge, UK) (v0.7.15-r1140) was used to compare all filtered sequencing sequences (reads) to the reference genome (GRCH37/hg19), and GATK software (The Broad Institute of MIT and Harvard, Cambridge, MA, USA) was used for mutation detection. The genetic testing results revealed a nonsense mutation in the HNF1β gene (NM_000458.4: C.544C >T (p. Gln182Ter)) in the proband and his two sons. This variant met the American College of Medical Genetics and Genomics standards PVS1, PM2_Supporting, PP4, and PS4_Supporting. It is included in HGMD database (http://www.hgmd.org) and ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar), and both indicate that this variation is pathogenic. The HNF1β gene is located on chromosome 17, and the base at position 544 was changed from C to T, converting glutamine at position 182 to a termination codon.

Based on genetic testing and clinical manifestations, we confirmed the diagnosis of HNF1β-related diseases in the proband and his two sons. According to the clinical guidelines of the International Society for Diabetes in Children and Adolescents (ISPAD), ³ diabetic patients carrying pathogenic or possibly pathogenic variants of the HNF1β gene can be diagnosed as MODY5. Therefore, the proband was diagnosed with MODY5, which corrected the long-standing misdiagnosis of the proband as having type 2 diabetes and diabetic nephropathy.

Discussion

The HNF1β gene, located on the long arm of chromosome 17 (17q12), contains 9 exons and 3 functional domains and encodes the transcription factor HNF1β. To date, 549 potentially pathogenic variants have been registered in ClinVar, including 368 missense, 99 frameshift, 48 nonsense, and 34 splice-site mutations (http://www.ncbi.nlm.nih.gov/clinvar/, accessed October 9, 2025). In this case, this mutation at the c.544C>T position affects the DNA-binding domain of the HNF1β protein, resulting in complete loss of HNF1β function and its inability to serve as a transcription factor. Notably, the main pathogenic mechanisms of HNF1β-related diseases have been repeatedly confirmed by numerous large cohort studies.^2,4 Among them, chromosome fragment deletion accounts for approximately 50%–70% of cases, while point mutation accounts for 30%–50%. The observed phenotypic heterogeneity in this family, along with incomplete penetrance, poses challenges for understanding the disease.

A French study ⁵ described a 13-year-old girl with this mutation site (C.544C>T). She presented with kidney involvement and a diabetic phenotype. Our case report describes the clinical phenotype of HNF1β-related diseases in a Han Chinese family. Notably, our case elucidates clinical characteristics of MODY5 presenting in middle age with particular emphasis on the atypical phenotype of pancreatic dysplasia. Severe renal insufficiency occurred in all three affected family members, with specific differences in liver and kidney dysplasia between the two sons. MODY5 has a low incidence; HNF1β mutations account for approximately 5% of all MODY cases. ⁶ The average age of onset is below 25 years old. Studies ⁷ have shown that approximately 30% of patients have pancreatic atrophy and approximately 50% of patients develop hyperglycemia. Additionally imaging studies have shown dysgenesis of the pancreas, with over 70% of cases occurring in the pancreatic body or tail; this pattern is known as dorsal pancreatic dysplasia. In this case, the imaging findings in the proband were unique, with only a small amount of pancreatic tail tissue and main pancreatic duct present, while the pancreatic head, body, and neck were absent. This phenotype of pancreatic hypoplasia had not been previously reported in association with HNF1β gene mutations. Recent studies have shown that the homologous genes GATA6 and GATA4, as well as the HNF1β gene, are involved in the regulating pancreatic development. HNF1β gene belongs to the homeobox-containing transcription factor family, which regulates the morphological development of pancreas and the differentiation of endocrine cells. ⁸ Since most islet cells are located in the pancreatic body and tail, the proband’s residual pancreatic tail islet cells likely released sufficient insulin, which may explain why he did not develop diabetes-related manifestations during adolescence and early adulthood. After the onset of diabetes, oral hypoglycemic drugs were poorly effective, requiring long-term insulin therapy for blood glucose control. The proband’s son did not develop diabetes, and long-term follow-up is important to determine if diabetes will manifest in the future. The proband presented with epididymal cysts and multiple epididymal calcifications. In previous reports, male patients with HNF1β mutations were documented to have various genital tract malformations. The incidence of genital abnormalities in MODY5 is 13.3%, including cryptorchidism, absence of the vas deferens, azoospermia, epididymal cysts, and epididymal dysplasia. ⁹ Therefore, clinicians should consider the possibility of HNF1β gene mutation when encountering diabetes mellitus complicated with genital tract abnormalities in clinical practice.

HNF1β gene mutation can manifest as abnormal development or dysfunction of multiple organs, with renal impairment being the earliest and most common finding in HNF1β-related diseases. Studies have shown that approximately 66% of patients with HNF1β gene abnormalities had renal cysts, and 86% of patients had combined renal insufficiency.^10,11 Renal insufficiency usually presents around the age of 40 years ¹² which is consistent with the age at onset of renal insufficiency in the patients in this family. The spectrum of renal phenotypes associated with HNF1β mutations is very broad, including tubulointerstitial nephropathy, renal cystic disease, renal dysplasia, glomerular cystic nephropathy, horseshoe kidney, bilateral hydronephrosis, renal calcinosis, and nephrogenic diabetes insipidus. ¹³ The renal manifestations in this family included renal cysts, renal calcinosis, and left renal dysplasia in the younger son. Therefore, renal insufficiency onset was earliest in the younger son. In a study of 27 adults with HNF1β mutation and various renal phenotypes, the median annual estimated glomerular filtration rate decline was 2.45 mL/min/year, ⁹ consistent with the rate of renal function deterioration in our proband. HNF1β gene abnormalities can also lead to hyperuricemia and early-onset gout. Abnormal uric acid metabolism caused by HNF1β mutation was first reported in 2003, ¹⁴ which is possibly related to HNF1β’s ability to regulate transcription of the uromodulin gene encoding uric acid transport proteins. ¹⁵ All patients in this family had hyperuricemia, and received long-term febuxostat treatment to control serum uric acid levels with regular monitoring. All patients exhibited symptoms of fatigue and hypomagnesemia. The pathogenesis may involve HNF1β gene mutations that inhibit G subunit transcriptional activation, resulting in blocked magnesium ion reabsorption. ¹⁶ The proband’s sons received oral magnesium supplementation, showing significant improvement in fatigue symptoms; the proband’s hypomagnesemia improved with dialysis treatment. Additionally, all patients in this family had hyperparathyroidism. The pathogenesis involves HNF1β mutations causing the loss of the inhibition of parathyroid hormone transcription, ¹⁷ which can explain the early hyperparathyroidism in patients with HNF1β mutations.

Hepatic dysfunction occurs in 65% of patients with mutations in the HNF1β gene. ¹⁸ Patients with mild liver dysfunction usually show asymptomatic elevation of liver enzymes, especially alanine aminotransferase and γ-glutamyl transferase, while severe cases can lead to cholestatic hepatomegaly. ¹⁹ Liver-targeted HNF1β deficiency can lead to a significant reduction in intrahepatic bile ducts and interlobular arteriosclerosis, ²⁰ which is related to the loss of normal primary cilia on vascular cells. ²¹ The proband’s older son had asymptomatic liver dysfunction, with no history of alcoholism, fatty liver, or hepatotoxic drug use. Hepatitis virus markers and autoimmune liver disease-related antibodies were negative. After excluding other potential causes, we considered that the HNF1β mutation caused the liver damage. The patient was treated with ursodeoxycholic acid capsules and hepatoprotective agents to reduce the liver enzyme levels. After 3 months of follow-up, liver enzyme indices were within the normal range.

In this case, the proband and his two sons carried the same mutation, but demonstrated variable age of onset and phenotype of organ dysfunction differed. This variability may be related to microenvironmental modifying factors, random variation in HNF1β gene expression, and the influence of other synergistic genes. ²² Therefore, genetic screening for HNF1β-related diseases should be considered for patients with renal cysts, pancreatic agenesis, genital tract malformations, hyperglycemia, hypomagnesemia, or liver dysfunction.

Conclusion

This family harbored a mutation at c.544C>T in the HNF1β gene. The observed phenotypes included renal cysts, renal calcification, pancreatic dysplasia, genital malformations, liver and kidney dysfunctions, hypomagnesemia, hyperuricemia, and hyperparathyroidism. Multiple organ dysfunction is common among HNF1β-related disorders, making clinical recognition essential for diagnosis. A comprehensive understanding of the clinical phenotype of this disease can help clinicians identify HNF1β-related diseases. With the assistance of genetic testing, early diagnosis can be achieved to avoid missed diagnosis and misdiagnosis, and reduce unnecessary renal biopsies in clinical practice. However, renal biopsy may still be necessary in patients with complex kidney lesions (e.g. when immune-mediated kidney disease or malignancy cannot be excluded) for accurate diagnosis and treatment planning. Additionally, genetic testing aids in prognostic assessment, treatment optimization, and genetic counseling.