The Landscape of HNF1B Deficiency: A Syndrome Not Yet Fully Explored

Abstract

The hepatocyte nuclear factor 1β (HNF1B) gene is involved in the development of specialized epithelia of several organs during the early and late phases of embryogenesis, performing its function mainly by regulating the cell cycle and apoptosis pathways. The first pathogenic variant of HNF1B (namely, R177X) was reported in 1997 and is associated with the maturity-onset diabetes of the young. Since then, more than 230 different HNF1B variants have been reported, revealing a multifaceted syndrome with complex and heterogenous genetic, pathologic, and clinical profiles, mainly affecting the pediatric population. The pancreas and kidneys are the most frequently affected organs, resulting in diabetes, renal cysts, and a decrease in renal function, leading, in 2001, to the definition of HNF1B deficiency syndrome, including renal cysts and diabetes. However, several other organs and systems have since emerged as being affected by HNF1B defect, while diabetes and renal cysts are not always present. Especially, liver involvement has generally been overlooked but recently emerged as particularly relevant (mostly showing chronically elevated liver enzymes) and with a putative relation with tumor development, thus requiring a more granular analysis. Nowadays, HNF1B-associated disease has been recognized as a clinical entity with a broader and more variable multisystem phenotype, but the reasons for the phenotypic heterogeneity are still poorly understood. In this review, we aimed to describe the multifaceted nature of HNF1B deficiency in the pediatric and adult populations: we analyzed the genetic, phenotypic, and clinical features of this complex and misdiagnosed syndrome, covering the most frequent, unusual, and recently identified traits.

Potential Causal Association between C-Reactive Protein Levels in Age-Related Macular Degeneration: A Two-Sample Mendelian Randomization Study

“…HNF1B primarily regulates the pathways involved in cell cycle progression and apoptosis. A defect in this gene causes maturity-onset diabetes in young people, as well as causing other cancers [76]. APCS or SAP (serum amyloid protein) is produced in the liver, is associated with inflammation, and has a characteristic pentameric organization like CRP.…”

The Phenotypic Variability Associated with Hepatocyte Nuclear Factor 1B Genetic Defects Poses Challenges in Both Diagnosis and Therapy

“…Genetic anomalies associated with HNF1B include single-nucleotide variations, small indels, and whole gene deletions [3]. To date, over 230 distinct HNF1B variants have been documented [4]. The most common genetic alteration (around 50% of patients) is a complete gene deletion, in the context of 17q12 chromosomal microdeletion, which also includes at least 14 other genes [4].…”

“…To date, over 230 distinct HNF1B variants have been documented [4]. The most common genetic alteration (around 50% of patients) is a complete gene deletion, in the context of 17q12 chromosomal microdeletion, which also includes at least 14 other genes [4]. This genetic diversity results in heterogeneous clinical presentations, giving rise to a spectrum of manifestations such as multicystic and/or dysplastic kidney disease, maturity-onset diabetes of the young (MODY), genital tract abnormalities, pancreatic atrophy, and aberrant liver function tests [5].…”

“…Hypomagnesemia and hypokalemia are seen in 62% and 46% of mutation carriers, respectively [6]. However, the presence of diabetes or renal cysts is not universal [4].…”

Special Issue—Diabetes Mellitus: Current Research and Future Perspectives

“…Testing this gene allowed the authors to identify two previously unknown mutations and diverse clinical presentations of HNF1B-related MODY. Multiple extra-pancreatic organ systems could be involved in some forms of MODY, and in HNF1B-related forms kidney involvement was the most frequent extra-pancreatic manifestation [ 1 ]. In previous studies, HNF1B mutations in people screened for diabetes and defects of the urogenital tract affected 3 subjects among 210 with MODY [ 2 ].…”