Maturity-onset diabetes of the young due to HNF1β variants (HNF1β-MODY): a 2-year follow-up study of six patients from a single diabetes center
-
Handan Jiang
,
Xiufeng Huang
Abstract
Objectives
Summarize the clinical phenotypes and genotypic characteristics of Chinese pediatric patients with maturity-onset diabetes of the young due to HNF1β variants (HNF1β-MODY).
Methods
Retrospective analysis of clinical characteristics, blood biochemical indexes, and genetic testing data was conducted on six children diagnosed with HNF1β-MODY followed in a single institution in Wenzhou from July 2020 to July 2024.
Results
Among the six children, three males and three females with a median age of diabetes onset at 12.3, four presented with pancreatic dysplasia. Extra-pancreatic manifestations included renal structural abnormalities(6/6), hypomagnesemia(6/6), hyperuricemia(4/6), elevated liver enzymes(4/6), hyperlipidemia(3/6), and genital tract malformation(1/6). Genetic testing identified a heterozygous HNF1β exon: 1–9 deletion in one patient, while the other five 17q12 microdeletions. Four children started insulin therapy at diagnosis, demonstrating no progressive decline in insulin secretion function and well-maintained insulin dependency. Six children received oral magnesium supplementation, and blood magnesium levels persisted at the lower limit of normal, without neuromuscular complications. Combined therapy with urinary alkalinizing agents and uricosuric drugs in three patients effectively maintained the serum urate levels, without observed progression. Hepatoprotective therapy decreased liver enzymes in two cases.
Conclusions
The clinical phenotype of HNF1β-MODY encompasses early-onset diabetes mellitus, pancreatic dysplasia, kidney disease, liver dysfunction, and genitourinary tract malformations, with refractory hypomagnesemia and hyperuricemia representing pathognomonic features. Early genetic confirmation can facilitate timely insulin initiation, guide targeted correction of electrolyte imbalances and metabolic disorders, and trigger proactive multi-organ monitoring for disease evolution.
Acknowledgments
We would like to thank all the patients as well as their parents for their consents to participate in the study.
-
Research ethics: The study protocol was in strict accordance with the tenets of the Declaration of Helsinki and has gained approval from the Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University (LCKY2020-64) by March 20, 2022.
-
Informed consent: Informed consent was obtained from all individuals included in this study, or their legal guardians or wards.
-
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. HJ conceptualized and designed the study. HJ and HW recruited patients and recorded clinical data. HJ and XH analyzed the data and wrote the manuscript. XS and YL gave constructive suggestions on the manuscript. The authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Use of Large Language Models, AI and Machine Learning Tools: None declared.
-
Conflict of interest: The authors state no conflict of interest.
-
Research funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
-
Data availability: The original data presented in the study are included in this article. Further inquiries can be directed to the corresponding author.
References
1. McDonald, TJ, Ellard, S. Maturity onset diabetes of the young: identification and diagnosis. Ann Clin Biochem 2013;50:403–15. https://doi.org/10.1177/0004563213483458.Suche in Google Scholar PubMed
2. Firdous, P, Nissar, K, Ali, S, Ganai, BA, Shabir, U, Hassan, T, et al.. Genetic testing of maturity-onset diabetes of the young: current status and future perspectives. Front Endocrinol (Lausanne) 2018;9:253. https://doi.org/10.3389/fendo.2018.00253.Suche in Google Scholar PubMed PubMed Central
3. Horikawa, Y, Iwasaki, N, Hara, M, Furuta, H, Hinokio, Y, Cockburn, BN, et al.. Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet 1997;17:384–5. https://doi.org/10.1038/ng1297-384.Suche in Google Scholar PubMed
4. Clissold, RL, Hamilton, AJ, Hattersley, AT, Ellard, S, Bingham, C: HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. Nat Rev Nephrol 2015, 11:102-12.doi.org/https://doi.org/10.1038/nrneph.2014.232.Suche in Google Scholar PubMed
5. Dubois-Laforgue, D, Cornu, E, Saint-Martin, C, Coste, J, Bellanne-Chantelot, C, Timsit, J. Response to comment on Dubois-Laforgue et al. Diabetes, associated clinical spectrum, long-term prognosis, and genotype/phenotype correlations in 201 adult patients with hepatocyte nuclear factor 1B (HNF1B) molecular defects. Diabetes Care 2017;40:1436–43. https://doi.org/10.2337/dci17-0048.Suche in Google Scholar PubMed
6. Nagano, C, Morisada, N, Nozu, K, Kamei, K, Tanaka, R, Kanda, S, et al.. Clinical characteristics of HNF1B-related disorders in a Japanese population. Clin Exp Nephrol 2019;23:1119–29. https://doi.org/10.1007/s10157-019-01747-0.Suche in Google Scholar PubMed
7. Laffargue, F, Bourthoumieu, S, Llanas, B, Baudouin, V, Lahoche, A, Morin, D, et al.. Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome. Arch Dis Child 2015;100:259–64. https://doi.org/10.1136/archdischild-2014-306810.Suche in Google Scholar PubMed
8. Stiles, CE, Thuraisingham, R, Bockenhauer, D, Platts, L, Kumar, AV, Korbonits, M. De novo HNF1 homeobox B mutation as a cause for chronic, treatment-resistant hypomagnesaemia. Endocrinol Diabetes Metab Case Rep 2018;2018. https://doi.org/10.1530/EDM-17-0120.Suche in Google Scholar PubMed PubMed Central
9. Rasmussen, M, Vestergaard, EM, Graakjaer, J, Petkov, Y, Bache, I, Fagerberg, C, et al.. 17q12 deletion and duplication syndrome in Denmark – a clinical cohort of 38 patients and review of the literature. Am J Med Genet A 2016;170:2934–42. https://doi.org/10.1002/ajmg.a.37848.Suche in Google Scholar PubMed
10. Mitchel, MW, Moreno-De-Luca, D, Myers, SM, Levy, RV, Turner, S, Ledbetter, DH, et al.. 17q12 recurrent deletion syndrome. In: Adam, MP, Feldman, J, Mirzaa, GM, Pagon, RA, Wallace, SE, Bean, LJH, et al.., editors. GeneReviews (R). Seattle (WA); 1993.Suche in Google Scholar
11. Wu, HX, Li, L, Zhang, H, Tang, J, Zhang, MB, Tang, HN, et al.. Accurate diagnosis and heterogeneity analysis of a 17q12 deletion syndrome family with adulthood diabetes onset and complex clinical phenotypes. Endocrine 2021;73:37–46. https://doi.org/10.1007/s12020-021-02682-5.Suche in Google Scholar PubMed
12. Ge, S, Yang, M, Cui, Y, Wu, J, Xu, L, Dong, J, et al.. The clinical characteristics and gene mutations of maturity-onset diabetes of the young type 5 in sixty-one patients. Front Endocrinol (Lausanne) 2022;13:911526. https://doi.org/10.3389/fendo.2022.911526.Suche in Google Scholar PubMed PubMed Central
13. Haldorsen, IS, Vesterhus, M, Raeder, H, Jensen, DK, Sovik, O, Molven, A, et al.. Lack of pancreatic body and tail in HNF1B mutation carriers. Diabet Med 2008;25:782–7. https://doi.org/10.1111/j.1464-5491.2008.02460.x.Suche in Google Scholar PubMed
14. Kumar, R, Vyas, K, Agrahari, N, Kundu, J, Jaiswal, G. Complete agenesis of the dorsal pancreas: case report with imaging findings and review of the literature. Malawi Med J 2015;27:73–4. https://doi.org/10.4314/mmj.v27i2.9.Suche in Google Scholar PubMed PubMed Central
15. Ohara, Y, Okada, Y, Yamada, T, Sugawara, K, Kanatani, M, Fukuoka, H, et al.. Phenotypic differences and similarities of monozygotic twins with maturity-onset diabetes of the young type 5. J Diabetes Investig 2019;10:1112–5. https://doi.org/10.1111/jdi.13004.Suche in Google Scholar PubMed PubMed Central
16. Clissold, RL, Fulford, J, Hudson, M, Shields, BM, McDonald, TJ, Ellard, S, et al.. Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal disease and can be symptomatic. Clin Kidney J 2018;11:453–8. https://doi.org/10.1093/ckj/sfx150.Suche in Google Scholar PubMed PubMed Central
17. Mateus, JC, Rivera, C, O’Meara, M, Valenzuela, A, Lizcano, F. Maturity-onset diabetes of the young type 5 a MULTISYSTEMIC disease: a CASE report of a novel mutation in the HNF1B gene and literature review. Clin Diabetes Endocrinol 2020;6:16. https://doi.org/10.1186/s40842-020-00103-6.Suche in Google Scholar PubMed PubMed Central
18. Herlin, MK, Petersen, MB, Brannstrom, M. Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome: a comprehensive update. Orphanet J Rare Dis 2020;15:214. https://doi.org/10.1186/s13023-020-01491-9.Suche in Google Scholar PubMed PubMed Central
19. Ledig, S, Brucker, S, Barresi, G, Schomburg, J, Rall, K, Wieacker, P. Frame shift mutation of LHX1 is associated with mayer-rokitansky-kuster-hauser (MRKH) syndrome. Hum Reprod 2012;27:2872–5. https://doi.org/10.1093/humrep/des206.Suche in Google Scholar PubMed
20. Thomson, E, Tran, M, Robevska, G, Ayers, K, van der Bergen, J, Gopalakrishnan Bhaskaran, P, et al.. Functional genomics analysis identifies loss of HNF1B function as a cause of mayer-rokitansky-kuster-hauser syndrome. Hum Mol Genet 2023;32:1032–47. https://doi.org/10.1093/hmg/ddac262.Suche in Google Scholar PubMed PubMed Central
21. KKumar, A, Hollar, L, McGill, JB, Thaker, PH, Salam, M. MODY5 and serous ovarian carcinoma in 17q12 recurrent deletion syndrome. AACE Clin Case Rep 2023;9:112–5. https://doi.org/10.1016/j.aace.2023.04.008.Suche in Google Scholar PubMed PubMed Central
22. Costello, I, Nowotschin, S, Sun, X, Mould, AW, Hadjantonakis, AK, Bikoff, EK, et al.. Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development. Genes Dev 2015;29:2108–22. https://doi.org/10.1101/gad.268979.115.Suche in Google Scholar PubMed PubMed Central
23. BBedont, JL, LeGates, TA, Slat, EA, Byerly, MS, Wang, H, Hu, J, et al.. Lhx1 controls terminal differentiation and circadian function of the suprachiasmatic nucleus. Cell Rep 2014;7:609–22. https://doi.org/10.1016/j.celrep.2014.03.060.Suche in Google Scholar PubMed PubMed Central
24. KKasperaviciute, D, Catarino, CB, Chinthapalli, K, Clayton, LM, Thom, M, Martinian, L, et al.. Uncovering genomic causes of co-morbidity in epilepsy: gene-driven phenotypic characterization of rare microdeletions. PLoS One 2011;6:e23182. https://doi.org/10.1371/journal.pone.0023182.Suche in Google Scholar PubMed PubMed Central
25. Palumbo, P, Antona, V, Palumbo, O, Piccione, M, Nardello, R, Fontana, A, et al.. Variable phenotype in 17q12 microdeletions: clinical and molecular characterization of a new case. Gene 2014;538:373–8. https://doi.org/10.1016/j.gene.2014.01.050.Suche in Google Scholar PubMed
26. Luo, Y, Dai, Z, Li, L, Shan, X, Wu, C. Hepatocyte nuclear factor 1beta maturity-onset diabetes of the young in a Chinese child presenting with hyperglycemic hyperosmolar state. Acta Diabetol 2017;54:969–73. https://doi.org/10.1007/s00592-017-1007-9.Suche in Google Scholar PubMed
27. Tritto, V, Bettinaglio, P, Mangano, E, Cesaretti, C, Marasca, F, Castronovo, C, et al.. Genetic/epigenetic effects in NF1 microdeletion syndrome: beyond the haploinsufficiency, looking at the contribution of not deleted genes. Hum Genet 2024;143:775–95. https://doi.org/10.1007/s00439-024-02683-0.Suche in Google Scholar PubMed PubMed Central
© 2025 Walter de Gruyter GmbH, Berlin/Boston
