Rare Genetic Syndrome Unmasked at 31 After Diabetes, Gout, and Hypogonadism

A 31-year-old farmer from Yunnan Province, China, arrived at an endocrinology ward in November 2023 with a blood glucose of 20.0 mmol/L, an acutely swollen and painful right ankle, and a working diagnosis of mitochondrial diabetes. Two weeks earlier he had developed extreme thirst of roughly three liters daily, polyuria with nocturia, dizziness, and nausea. Ten days before admission his ankle had turned red, swollen, and painful, and local treatment for presumed gout had brought little relief.

KBG syndrome is a rare autosomal dominant disorder caused by loss-of-function variants in the ANKRD11 gene at chromosome 16q24.3, or by microdeletions of that same region. First described in 1975 and defined molecularly in 2011, it is classically recognized in children through macrodontia of the permanent upper central incisors, seen in 85 to 95 percent of patients, along with hearing impairment in 25 to 31 percent, postnatal short stature, skeletal anomalies, and variable intellectual disability. The encoded protein is a chromatin-associated coregulator essential for craniofacial, dental, skeletal, and neural development. The literature is overwhelmingly pediatric: the largest series of 340 patients centers on early life, and adult internal-medicine presentations are scarcely described.

This patient’s cardinal features had been present for decades. Bilateral cryptorchidism had been surgically repaired at age four, sensorineural hearing loss was identified at six, and he had worn hearing aids ever since. Recurrent gouty arthritis had troubled him for more than ten years, beginning around age 21, self-managed irregularly with allopurinol, sodium bicarbonate, and diclofenac. School performance had been average, and his family described long-standing social-communication difficulties, though no formal neurodevelopmental diagnosis had been established. His parents were unaffected, while a grandfather and an uncle had type 2 diabetes.

On examination, the striking findings assembled themselves into a recognizable pattern: macrodontia of the upper central incisors, mild kyphoscoliosis, brachydactyly with fifth-finger clinodactyly, bilateral gynecomastia, sparse axillary hair, and small, soft testes measuring 6 mL on the left and 8 mL on the right. He was of average build at 168 cm and 70 kg, with central adiposity and a waist-to-hip ratio of 0.96. His right ankle was warm, swollen, and tender with limited movement.

Laboratory work sharpened the picture. A 75-g oral glucose tolerance test showed fasting and 2-hour glucose of 8.34 and 22.1 mmol/L, with insulin and C-peptide peaking late at 3 hours, indicating insulin resistance with delayed secretion rather than absolute deficiency. HbA1c was 6.8 percent, and all five islet autoantibodies were negative. Serum urate had been 576.5 μmol/L eleven days earlier but measured 325 μmol/L on admission, probably reflecting his intermittent allopurinol use. A 24-hour urine collection, completed before any in-hospital urate-lowering therapy, contained 2,480 μmol of uric acid, at the lower end of the reference range, consistent with relatively low excretion rather than overproduction. Testosterone was repeatedly borderline-low across three measurements at 2.43 to 2.77 ng/mL, while gonadotropins were not persistently elevated, and sex hormone-binding globulin was markedly low at 5.47 nmol/L.

The admitting suspicion of maternally inherited diabetes and deafness was reasonable, since diabetes with sensorineural deafness is that condition’s textbook pairing. Three observations argued against it: his deafness was congenital rather than progressive, his family history of diabetes was paternal, and his congenital anomalies exceeded what mitochondrial disease explains. Careful physical examination proved decisive, redirecting the work-up toward a syndromic disorder. Trio whole-exome sequencing of the patient and both parents, confirmed by Sanger sequencing, identified a heterozygous ANKRD11 frameshift variant, c.1903_1907del, p.Lys635Glnfs*26, absent from both parents and therefore de novo. Under American College of Medical Genetics and Genomics criteria the variant was classified as pathogenic: it was absent from the gnomAD population database, previously reported as pathogenic in unrelated patients with KBG syndrome, and predicted to trigger nonsense-mediated mRNA decay. Full-length mitochondrial genome sequencing found no pathogenic variant, and the karyotype was 46,XY.

The diagnostic assessment was equally careful on the metabolic side. Type 1 diabetes was excluded by negative autoantibodies and preserved, delayed-peak C-peptide despite admission ketonuria. Common type 2 diabetes with central adiposity and insulin resistance best fit the data, and the monoarticular ankle arthritis with prior hyperuricemia and a prompt response to anti-inflammatory therapy was diagnosed as a gout flare. He was treated with intravenous methylprednisolone and etoricoxib for the flare, then febuxostat, colchicine, atorvastatin, and liraglutide, and discharged on 23 November 2023 free of joint pain. The molecular diagnosis arrived seven weeks later.

Over 33 months of follow-up, glycemic control was excellent, with glycated hemoglobin between 4.5 and 5.3 percent across eight reviews, and thyroid function normalized spontaneously by March 2026. Serum urate, in contrast, remained markedly elevated at nearly every routine measurement, with values including 637, 643, 574, 619, 538, 587, 567, 693, 569, and 513 μmol/L despite prescribed febuxostat, advised dose up-titration, and benzbromarone added in April 2025. The single in-range reading of 427 μmol/L was drawn during a flare readmission, when serum urate characteristically falls. In July 2025 his only gout flare of the interval required readmission; dual-energy CT showed large knee effusions without definite urate crystal deposition, synovial fluid culture was sterile, and crystal microscopy was not performed. Adherence was documented to be poor, with prolonged self-initiated treatment gaps, and by March 2026 he reported having stopped all medications for approximately six months.

The ten-year gout history, preceding diabetes by a decade, is the report’s most provocative feature. The authors note that attributing the hyperuricemia to diabetic insulin resistance would be backwards, since gout came first. Yet they present the association cautiously: the persistence of severe hyperuricemia is plausibly explained by conventional confounding factors, including central adiposity, insulin resistance, steatotic liver disease, dyslipidemia, suboptimal dose titration, and documented poor adherence, rather than by the ANKRD11 variant itself, although intrinsically severe hyperuricemia cannot be excluded. Gout was not reported in either of two recent adult KBG cohorts, one physician-reported series of 36 molecularly confirmed adults and a literature review of 154 further patients, nor in the large pediatric-focused series. A population-level hint exists: in an epigenome-wide association study of serum urate, ANKRD11 was implicated by urate-associated CpG sites and showed reduced renal expression in a humanized mouse model of hyperuricemia, though such differences may lie downstream rather than upstream. The authors frame the conjunction as a single observation generating a hypothesis, not evidence of an expanded phenotype.

The case carries broader lessons. In a patient- and caregiver-reported survey of 91 adults with KBG syndrome, nearly half of respondents with a known diagnosis age had been diagnosed at 18 years or older, suggesting such delay is common rather than exceptional. Diabetes with deafness is not automatically mitochondrial disease, and in atypical diabetes, careful attention to teeth and hands may be more informative than an expanded autoantibody panel. The authors also emphasize restraint elsewhere: low free T3 with low TSH and normal free T4 during an acute gout flare reflected non-thyroidal illness rather than central hypothyroidism, and low serum cortisol with normal urinary free cortisol was read as an acute-illness artifact. The report’s limitations are explicit: it describes a single patient in whom causality cannot be established, urinary creatinine was not measured so fractional urate excretion could not be calculated, pituitary imaging and dynamic gonadal testing were unavailable, and blood-based mitochondrial sequencing cannot exclude tissue-specific heteroplasmy. Whether KBG syndrome adds independent metabolic risk cannot be answered from one case, but the authors suggest that metabolic surveillance of adults with the syndrome may be worthwhile, and that deliberate attention to dental, skeletal, and developmental clues can shorten a long diagnostic odyssey.

Subject of Research: A case report of KBG syndrome diagnosed in adulthood through diabetes, gout, and hypogonadism

Article Title: Case Report: KBG syndrome in an adult presenting with diabetes, gout, and hypogonadism

Article References: Shi, W., Xie, Z., Liu, C., Kong, D., & Chen, N. (2026). Case Report: KBG syndrome in an adult presenting with diabetes, gout, and hypogonadism. Frontiers in Endocrinology, 17, Article 1986666. https://doi.org/10.3389/fendo.2026.1986666

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1986666

Keywords: KBG syndrome, ANKRD11, diabetes, gout, hypogonadism, whole-exome sequencing, macrodontia, hyperuricemia, genetics, endocrinology, rare disease, case report