To the editor,

Kabuki syndrome is a genetic disorder characterized by distinctive facial features and a wide range of clinical symptoms [1,2]. Recent studies have suggested an association between increased incidence of diabetes and Kabuki syndrome [2,3]. However, only a few reports of patients with both Kabuki syndrome and concomitant diabetes are available [4-6].

To date, no cases of diabetes caused by HNF1B mutations have been reported in Korean patients with Kabuki syndrome. Here, we report the case of a Korean patient with Kabuki syndrome who presented with diabetes.

A 12-year-old female patient presented with typical hyperglycemic symptoms (polydipsia, polyuria, polyphagia, and 12% weight loss) for three weeks before visiting our hospital. At the time of visit, the patient was 149.5 cm (standard deviation score [SDS], -0.70) tall and weighed 32 kg (SDS, -1.38). The patient's previous weight was 37 kg (SDS, -0.70). She had no relevant medical history and had no family history of diabetes. She was born at a birth weight of 1,900 g after 34 weeks without perinatal problems. Her mother had no history of gestational diabetes.

Upon admission, laboratory tests revealed a serum glucose level of 642 mg/dL (reference range, 70–100 mg/dL) and an hemoglobin A1c level of 15.5% (reference range, 4.0%–6.0%). Urinalysis showed ketones 2+ and glucose 3+. Venous blood gas analysis revealed a pH of 7.19 (reference range, 7.32–7.42), bicarbonate level of 9 (reference range, 19–25), and a base deficit of 17. Moreover, initial laboratory tests also demonstrated elevated blood urea nitrogen/creatinine levels at 26.6 (reference range, 9.0–23.0) mg/dL/1.92 (reference range, 0.55–1.02) mg/dL, suggesting acute kidney injury, possibly caused by prerenal dehydration. Based on these findings, the patient was diagnosed with moderate diabetic ketoacidosis (DKA) and immediately started on conventional treatment for DKA and fluid therapy. In the subsequent test results, plasma C-peptide was 0.43 (reference range, 1.07–3.51) ng/mL, plasma insulin was 4.3 (reference range, 1.7–12.5) μU/mL. Islet cell auto-antibodies, insulin auto-antibodies, and glutamic acid decarboxylase antibodies were negative. Although her renal function initially improved with fluid therapy, azotemia recurred after fluid therapy was discontinued. To investigate other possible causes, a renal ultrasound was performed, which revealed bilaterally small kidneys.

Next-generation sequencing revealed a heterozygous variant (NM_000458.4: c.511T>C: p.Trp171Arg) in HNF1B. This variant was considered likely pathogenic in accordance with the PM1, PM2, PM5, and PP3 criteria according to the American College of Medical Genetics and Genomics (ACMG) guidelines [7] (Fig. 1, Table 1). This finding, in combination with the clinical presentation of diabetes and renal anomalies, supported a diagnosis of maturity-onset diabetes of the young type 5 (MODY5). In addition, another heterozygous variant was identified in the KMT2D gene (NM_ 003482.4: c.15460C>T; p.Arg5154Trp), suggesting the possibility of overlapping syndromic features (Fig. 1, Table 1). On physical examination, the patient exhibited characteristic features consistent with Kabuki syndrome, including prominent ears, large arched eyebrows, eversion of the lower lateral eyelids, and other distinct facial features. Two cases of the same mutation were reported in the Clinvar database, and both of those patients were also diagnosed with Kabuki syndrome. Compared with age-matched children, our patient also showed mild intellectual disability. This KMT2D variant was also classified as likely pathogenic according to ACMG guidelines based on the PM2, PM5, PP4, and PP5 criteria [7]. Considering these clinical and genetic findings, the patient was diagnosed with both MODY5 and Kabuki syndrome [8]. She is currently being treated with insulin therapy.

HNF1B heterozygous mutations are the most common monogenic cause of developmental renal disease such as renal cysts, single kidneys and renal hypoplasia. This mutation can cause other symptoms beyond renal problems, such as pancreatic hypoplasia, genital tract malformations, abnormal liver function, hypomagnesaemia, hyperuricaemia, and early-onset gout [9]. Our patient, who developed diabetes along with persistent renal function impairment, underwent genetic testing, which identified mutations in both the HNF1B and KMT2D genes. To our knowledge, this is the first reported case of a Korean patient being diagnosed with both MODY5 and Kabuki syndrome. Additionally, bilateral small kidneys observed in our patient, and are likely due to the combined effects of HNF1B and KMT2D mutations, suggesting that the clinical presentation results from the interaction of these genetic alterations [8,10]. Parental genetic testing was not conducted as the parents declined participation. Therefore, the origin of the patient's mutation remains unknown, which represents a limitation of our study.

Kabuki syndrome is typically associated with increased risk of type 2 diabetes due to insulin resistance [11]. However, in cases such as ours, wherein other gene mutations are present, insulin-dependent diabetes is also a possible diagnosis [4,12]. Furthermore, it suggests that the genetic spectrum of syndromes with overlapping features is expanding, emphasizing the need for comprehensive genetic evaluation. Lastly, this case highlights the crucial role of molecular diagnostics in guiding personalized treatment strategies.