A KDM6 A variant in a Chinese female patient with diabetes mellitus and oligomenorrhea: a case report

Abstract

Background

Kabuki syndrome (KS) is a rare, multisystemic genetic disorder caused by mutations in either the KMT2D or KDM6A genes. It is characterized by distinctive dysmorphic facial features, intellectual disability, and a variety of congenital anomalies. Endocrine manifestations such as growth hormone deficiency, hypoglycemia, and less frequently, diabetes mellitus (DM) and menstrual irregularities, have been reported. The diagnosis of KS can be challenging due to its phenotypic variability.

Case presentation

We report a case of a 18 year-old female Han Chinese patient with KS who presented with menstrual irregularities, specifically oligomenorrhea, and a newly diagnosed non-autoimmune DM. She exhibited typical KS-related facial dysmorphism, short stature, and intellectual disability. Genetic testing confirmed a de novo mutation in the KDM6A gene (NM_021140.4:c.2177del). This case highlights the importance of recognizing uncommon endocrine presentations of KS, such as DM and menstrual disturbances, which may emerge during adolescence.

Conclusion

This case illustrates the necessity of monitoring for endocrine complications, including glycemic abnormalities and reproductive issues, in patients with KS. Early recognition and intervention in these patients may improve outcomes and quality of life. Further research is needed to elucidate the mechanisms linking KDM6A mutations to endocrine dysfunction in KS.

Introduction

Kabuki syndrome (KS) is a rare multisystem genetic disorder first described in 1981 [1]. It is primarily caused by mutations in the KMT2D gene (autosomal dominant) or the KDM6 A gene (X-linked dominant), with an estimated prevalence of 1 in 32,000 to 1 in 86,000 live births [2, 3]. The actual incidence may be higher due to diagnostic challenges and phenotypic variability.

The pathogenesis of KS involves mutations in histone-modifying genes, leading to epigenetic dysregulation, disrupted chromatin remodeling, and abnormal transcriptional activity [4, 5]. These molecular changes contribute to a broad spectrum of clinical features, which often complicates diagnosis, especially in infancy when key characteristics may not yet be apparent [3, 6].

Endocrine and metabolic abnormalities are increasingly recognized in KS, but the prevalence and mechanisms remain poorly understood. Reported endocrine manifestations include growth hormone deficiency, hypothyroidism, precocious puberty, and hyperinsulinemic hypoglycemia (HH) [7,8,9,10]. HH is thought to result from dysregulated pancreatic beta-cell development and excessive insulin secretion. Menstrual irregularities, such as delayed menarche and oligomenorrhea, have also been observed in female individuals with KS [11]. In contrast, DM is an exceedingly rare manifestation of KS. To our knowledge, this is the first reported case of diabetes in a patient with a KDM6 A mutation.

Case presentation

We report the case of an 18-year-old female Han Chinese patient who presented with DM and oligomenorrhea. Her birth weight was 3000 g, and her birth length was 50 cm, both within the normal range, with no perinatal complications such as asphyxia. The proband did not suffer any hypoglycemic episodes. At 6 years of age, intellectual disability was identified, and from age 10, her growth rate slowed. Her final height was 150 cm. She experienced menarche at the age of 14, with menstrual cycles occurring every 3–6 months thereafter.

On physical examination, the patient displayed characteristic facial dysmorphism consistent with KS: sparse lateral eyebrows, arched eyebrows, elongated palpebral fissures with eversion of the outer third of the lower eyelids, flattened nasal tip, thin upper lip with thick lower lip, and brachydactyly V. Additional findings included acanthosis nigricans on the neck, subcutaneous nodule, and intellectual disability (Fig. 1). She had Tanner stage 3 breast development, with Tanner pubic hair stage 4.

Fig. 1

Clinical characteristics of patients with KS. A Acanthosis Nigricans on the neck, B, C Brachydactyly V, D Subcutaneous nodule on the arm

Upon admission, laboratory tests confirmed the diagnosis of DM. The patient’s glycated hemoglobin (HbA1c) was 6.9%, and an oral glucose tolerance test demonstrated impaired glucose regulation and insulin resistance (Fig. 2A, B). Further evaluations, including pituitary magnetic resonance imaging (MRI), gynecological ultrasound, sex hormone levels, thyroid function, insulin-like growth factor-1 (IGF-1), adrenocorticotropic hormone (ACTH), and cortisol rhythm tests, were unremarkable (Table 1). Karyotyping revealed a normal female genotype (46, XX).

Fig. 2

Glucose and insulin levels during oral glucose tolerance test in proband. A Glucose levels during oral glucose tolerance test. B Insulin secretion during oral glucose tolerance test

Table 1 Clinical characteristics of the proband

To confirm molecular diagnosis, whole-exome sequencing was performed with the patient’s consent. Briefly, genomic DNA was extracted from peripheral blood and prepared for sequencing using standard protocols. Sequencing was conducted at a depth of 100 × using T7 sequencing technology. Bioinformatics analysis aligned sequencing data to the human reference genome (hg19) using the Burrows-Wheeler Aligner, and variants were identified using GATK. Detected variants were annotated with ANNOVAR and compared with population databases, including the 1000 Genomes Project, ExAC, and gnomAD. Variants were classified following American College of Medical Genetics and Genomics (ACMG) guidelines. A pathogenic mutation was identified in the KDM6 A gene (NM_021140.4:c.2177 del), which was validated through Sanger sequencing of parental samples, confirming its de novo origin (PVS1 + PM2_Supporting + PM6) (Fig. 3A). Additionally, analysis of diabetes-related genes identified a missense mutation in the INSR gene (NM_000208.4:c.2447 C > T). According to ACMG guidelines, this mutation was classified as a variant of uncertain significance (VUS, PM2_Supporting + PP2 + PP3_Moderate) and was inherited from the proband’s phenotypically normal mother (Fig. 3B).

Fig. 3

Schematic of the validation results by Sanger sequencing of KDM6 A and INSR variants in the proband and her parents. Above: proband. Middle: proband’s father. Below: proband’s mother. A Sanger sequencing results of the frameshift mutation (c.2177 del) in the proband. B Sanger sequencing results of the missense mutation (c.2447 C > T) in the proband and her mother

We gave lifestyle guidance and metformin intervention in the treatment of diabetes. After 1 year of treatment with metformin (1.0 g/day), the patient achieved fasting glucose levels of 5–7 mmol/L, with an HbA1c of 6.0%. Her weight increased from 50 to 55 kg. For menstrual irregularities, treatment with dydrogesterone resulted in cycles occurring every 1–2 months.The patient took medication regularly, had good compliance, and no adverse events had occurred.

Discussion

We report the case of a Chinese female patient who initially presented with DM and oligomenorrhea. Clinical examination revealed characteristic features of KS, prompting further genetic investigation with whole-exome sequencing. A pathogenic frameshift mutation in the KDM6 A gene (NM_021140.4:c.2177 del) was identified, confirming the diagnosis of KS.

In addition to its typical clinical features, such as distinctive facial dysmorphism, intellectual disability, and skeletal anomalies, KS is often associated with various endocrine and metabolic abnormalities [12]. Short stature is one of the most common endocrine features in KS, and our patient exhibited a final height of 150 cm. It is recognized as a syndromic cause of congenital hyperinsulinemic hypoglycemia (HH) [13]. HH in KS is primarily associated with KDM6 A mutations and is believed to result from impaired demethylation of histone H3 K27. This epigenetic disruption leads to dysregulated pancreatic beta-cell development and function, resulting in excessive insulin secretion [14, 15]. However, this case is notable for the presence of DM and menstrual irregularities, which are less commonly reported in KS. The initial clinical suspicion of Turner syndrome was ruled out on the basis of normal karyotype results (46, XX) and the absence of hypergonadotropic hypogonadism or ovarian/uterine dysgenesis. Moreover, Turner syndrome does not present with the characteristic dysmorphic facial features of KS, highlighting the importance of careful clinical evaluation in distinguishing between these conditions.

While HH is a well-established endocrine feature of KS, DM is rarely reported. Recent studies and case reports have suggested an association between KMT2D mutations and diabetes in patients with KS, particularly in those with obesity or insulin resistance [16]. However, this case represents the first report of diabetes in a patient with a KDM6 A mutation. The underlying mechanisms linking KDM6 A mutations to diabetes remain unclear, though the involvement of epigenetic dysregulation in pancreatic beta-cell function and insulin sensitivity warrants further investigation. In addition to the KDM6 A mutation, our patient harbored a missense variant in the INSR gene (NM_000208.4:c.2447 C > T), classified as a variant of uncertain significance. The INSR gene encodes the insulin receptor, and mutations in this gene are known to cause insulin resistance. The inheritance of this variant from the patient’s phenotypically normal mother, combined with the incomplete penetrance of INSR mutations [17], complicates its clinical interpretation. Nevertheless, this variant may partially explain the patient’s insulin resistance and hyperglycemia. Further functional studies are needed to elucidate its pathogenicity and contribution to the observed phenotype.

This case highlights the diagnostic utility of whole-exome sequencing in identifying the molecular basis of complex disorders such as KS, particularly in patients with atypical or overlapping clinical features. The identification of a KDM6 A mutation in this patient expands the clinical spectrum of KS to include DM, further emphasizing the need to monitor glucose metabolism and endocrine function in affected individuals. Additionally, the co-occurrence of the INSR variant raises the possibility of genetic interactions contributing to the patient’s phenotype, underscoring the importance of comprehensive genetic analysis in such cases.

Conclusion

We report the first case of DM in a patient with KS with a KDM6 A mutation, broadening the understanding of the endocrine and metabolic spectrum of this rare disorder. Further research is needed to clarify the mechanisms linking KDM6 A mutations to metabolic abnormalities and the role of additional genetic variants, such as the INSR mutation, in modulating the phenotypic presentation of KS. Early recognition and multidisciplinary care remain essential to optimizing outcomes for these patients.