A 6-year-old girl with gout: a case report and another unusual presentation

Introduction

Uric acid is the final product of purine metabolism in the human body, primarily resulting from the cellular breakdown of nucleic acids and other purine-like compounds, as well as from the catabolism of purines found in food (1). The prevalence of hyperuricemia has been increasingly observed in younger individuals in recent years (2), yet the current knowledge regarding hyperuricemia and gout in pediatric patients remains limited (2). Hyperuricemia is a significant metabolic disorder among children, with positive familial history, growth and development, and obesity serving as important risk factors (3). The etiology of the disease encompasses secondary factors, hereditary disorders, and other conditions associated with hyperuricemia and gout (4,5). Treatment in children is similar to that in adults, emphasizing weight control and reduction of high purine and high fructose diet intake to ensure normal growth and development. Uric acid-lowering medications can also be safely used if necessary. Therefore, understanding the characteristics of hyperuricemia and gout in children is crucial for their prevention and treatment. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-354/rc).

Case presentation

The patient is a 6-year-old girl presenting with a swelling on the right foot little toe and the lateral side of the right dorsum, measuring approximately 0.5 cm in diameter, which was initially diagnosed as a “vascular malformation” at a local hospital in April 2023. Despite receiving sirolimus topical treatment, there was no observed improvement. Subsequently, the swelling increased to about 1.5 cm in diameters. the parents noticed an increase in the size of the swelling on the child’s foot, measuring approximately 1.5 cm in diameter in August 2023. They sought a second opinion at another hospital and received a diagnosis of “thick fluid cyst”. The family was hesitant to proceed with surgical treatment, opting instead for ongoing follow-up care for the child. The child’s foot swelling was found to have enlarged again, with a diameter of approximately 2.5 cm. The child sought medical attention at the Children’s Hospital in the provincial capital and was diagnosed with a “sebaceous cyst” in November 2023. The patient received oral antibacterial drugs and hot compresses as anti-inflammatory treatment. Over the past 2 months, this patient had complained of pain in the big toe, the parents observed a gradual increase in swelling on the child’s right foot, reaching a diameter of about 4 cm. As a result, she was unable to put on her shoes and was subsequently admitted to our department in January 2024. Upon admission, her blood pressure measured 108/66 mmHg (90^th percentile), weight was 29 kg (97^th percentile), height was 130 cm (75^th percentile), and body mass index (BMI) was calculated at 17.2 kg/m² (90^th percentile). Upon examination, a 4 cm oval broad-based swelling with a slightly reddish surface and soft texture was observed on the lateral dorsum of the right foot. There were no open wounds, active bleeding, subcutaneous petechiae on the surrounding skin, localized tenderness, tenderness to palpation, tenderness to percussion, or bony friction sensation. The rest of the systemic examination was unremarkable. This patient’s father had a history of gout, while the rest of the family history was unremarkable. This patient’s personal history revealed a consistent consumption of high-fructose beverages over the past 2 years. Laboratory tests indicated elevated serum uric acid levels (6.25 mg/dL; reference range, 2.4–5.3 mg/dL), while other parameters including urinalysis, blood glucose, blood ammonia, lactic acid, insulin, hepatic and renal function, blood lipids, cardiac enzyme profiles, electrolytes, thyroid function, blood sedimentation rate, C-reactive protein level, anti-streptococcal hemolysin “O”, rheumatoid factor presence or absence, antinuclear antibodies presence or absence , immunoglobulin levels , complement levels, T and B lymphocyte subsets counts, and arterial blood gas fraction were all within normal ranges. Ultrasonography of the urinary tract revealed no abnormalities. A superficial foot ultrasound identified a subcutaneous mass on the fifth toe and lateral aspect of the right foot, requiring further investigation. Dorsal orthogonal and oblique radiographs showed a dense nodular mass around the fifth metatarsal and phalanges of the right foot (Figure 1). Magnetic resonance imaging (MRI) of the ankle and soft tissues revealed abnormal signal foci in the subcutaneous soft tissues between the right fourth and fifth toes and the lateral aspect of the fifth metatarsal (Figure 2). Enhanced plain computed tomography (CT) scanning indicated dense metatarsal soft tissue shadows between the right fourth and fifth toes, as well as around the lateral subcutaneous soft tissue of the fifth metatarsal (Figure 3). Considering this patient’s medical history, physical examination, and auxiliary findings, a diagnosis of “primary gout in children; hyperuricemia” was made. The resection of the right foot mass resulted in a postoperative serum uric acid level of 9.6 mg/dL, and the pathology revealed extensive urate deposits and multinucleated giant cell reaction within the fibrous tissue, consistent with a diagnosis of gout (Figure 4). In order to elucidate the etiology of the disease, a comprehensive analysis was conducted on amino acid and acylcarnitine profiles of inherited metabolic diseases, urinary organic acids, and genetic testing. The results revealed no abnormalities in urinary organic acids, amino acids, and acylcarnitines. Next-generation sequencing (NGS) identified genetic variants associated with gout and hyperuricemia in this patient: ABCG2 gene: c.421C>A (rs2231142) locus; SLC2A9 gene: c.881G>A (rs3733591) locus; SLC22A12 gene: c.831-192C>A (rs893006) locus; and MTHFR gene: c.677C>T (rs1801133) locus (Figure 5). In addition to a low purine diet, this patient was prescribed oral febuxostat 10 mg/day and sodium bicarbonate tablets 0.25 g three times daily to increase uric acid excretion through increased water intake. This patient’s blood uric acid gradually decreased to 4.48 mg/dL, with subsequent normal laboratory indicators during regular outpatient follow-up, good wound healing, and no further discomfort (Figure 6). This patient has been under treatment for 1 year and continues to receive care at our outpatient clinic.

Figure 1 Dorsal view of the foot in orthogonal and oblique X-ray positions. Two dense shadows were observed surrounding the fifth metatarsal and phalanges of the right foot, indicating a multinodular mass with high density shadows. The remaining bones of the right foot, as well as the phalanges, metatarsals, and tarsal bones of the left foot, exhibited normal morphology and uniform density. Smooth joint surfaces, uniform joint spaces, and normal joint relationships were noted. The red arrows indicate presence of tophi.

Figure 2 MRI of the right ankle soft tissue. Two rounded foci of abnormal signal located between the fourth and fifth phalanges, as well as under the lateral cortex of the fifth metatarsal on the right side. These foci exhibit low signal intensity on both T1-weighted and T2-weighted images, with dimensions measuring approximately 32 mm × 26 mm and 24 mm × 21 mm, respectively. They are characterized by clear boundaries, linear segregation, and no evident bone destruction in neighboring bones. Additionally, a small amount of fluid accumulation around the lesion is observed, along with mild thickening of the adjacent synovium. The remainder of the composition within the right foot demonstrates no abnormalities in either bone or soft tissue, nor any irregularities within joint spaces. The tophi are indicated by red arrows for reference. MRI, magnetic resonance imaging.

Figure 3 CT plain and enhanced imaging of the right foot. Multiple nodular high-density shadows between the fourth and fifth phalanges, as well as subcutaneously on the lateral side of the fifth metatarsal bone. These nodules demonstrate fusion with clear borders, with the largest measuring approximately 32 mm × 26 mm in size. The enhancement scan did not show any obvious enhancement, and there was no evident bony destruction or osteophytic changes in neighboring bones. Additionally, surrounding soft tissues appeared slightly swollen. No abnormalities were observed in the remaining bone and soft tissue of the right foot, and joint relationships were normal. The monosodium urate deposits are indicated by red arrows. CT, computed tomography.

Figure 4 Pathological findings following surgical removal of mass from the right foot (staining with hematoxylin and eosin). Pathologic examination reveals the presence of urate deposits and a multinucleated giant cell reaction in the fibrous tissue. Urate deposits and multinucleated giant cells are indicated by red arrows. (A, ×50) and (C, ×100) represent the pathology of urate crystals at different magnifications; (B, ×100) and (D, ×200) represent the pathology of multinucleated macrophages at different magnifications.

Figure 5 NGS of genes related to gout. This patient was found to have risk gene variants for gout and hyperuricemia, including the following loci: ABCG2 gene c.421C>A (rs2231142), SLC2A9 gene c.881G>A (rs3733591), SLC22A12 gene c.831-192 C>A (rs893006), and MTHFR gene c.677 C>T (rs1801133). NGS, next-generation sequencing.

Figure 6 The progression of wound healing before and after treatment for tophi.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

In recent years, there has been a global increase in the prevalence of hyperuricemia in children, significantly impacting their physical and mental well-being and emerging as a major threat to public health. Hyperuricemia serves not only as an indicator of kidney damage but also as an independent risk factor for chronic kidney disease, cardiovascular and cerebrovascular diseases, and metabolic disorders. Therefore, early diagnosis and intervention for hyperuricemia and gout in children hold significant clinical importance.

Hyperuricemia and gout are two interconnected yet distinct pathological conditions. The deposition of urate crystals on the synovial membrane, followed by phagocytosis by leukocytes and release of inflammatory mediators, leads to joint swelling and pain characteristic of gout. Current research indicates varying prevalence of hyperuricemia in children and adolescents across different countries. A nationally representative subsample from the U.S. National Health and Nutrition Examination Surveys [2013–2016] reported a weighted prevalence of hyperuricemia in adolescents aged 12–19 years at 16.56% (6). In a recent cross-sectional survey utilizing data from the 7^th Korean National Health and Nutrition Examination Survey [2016–2017], it was found that the prevalence of hyperuricemia among children aged 10–18 years was 9.4% (8.4% in males and 10.5% in females) (7). The prevalence of gout has significantly risen in developed countries and coastal areas, however, data are lacking for most regions in developing countries (8). In contrast, the prevalence of hyperuricemia among children and adolescents in mainland China is as high as 23.3%, which is much higher than that in other countries. This discrepancy may be due to differences in race, obesity prevalence, dietary habits and lifestyle (3,9). Therefore, there is an urgent need to implement effective interventions to reduce the risk of hyperuricemia in Chinese adolescents. The prevalence of gout in children/adolescents is low and there is a lack of specific flow data (10). A study conducted in Taiwan investigated the clinical characteristics of gout in adolescents and found that the proportion of adolescent gout patients with a family history of gout was 1.9 times higher than that of the control group (44.3% vs. 23.8%, P<0.0001). The findings of a Chinese study revealed the presence of urate crystal deposits in adolescents experiencing symptomatic hyperuricemia, with the first metatarsophalangeal (MTP) joint and the heel bone being the most commonly affected sites, predominantly located in the soft tissues surrounding the joint (11). In addition, adolescent gouty stone patients are more likely to develop comorbidities and renal insufficiency than adult patients.

Children with hyperuricemia/gout need to take into account hereditary factors, as current research has identified a correlation between genes associated with uric acid transporter proteins such as SLC2A9 [glucose transporter 9 (GLUT-9)] and SLC22A12, which can impact the excretion of uric acid from the kidneys and subsequently elevate blood uric acid levels (12). Dysfunction of the ABCG2 gene is a known factor in the development of early-onset gout, which is the primary cause of this condition (13). SLC2A9 has also been identified in Mexican children by Rivera-Paredez et al. (14). ABCG2 is linked to the development of hyperuricemia, while other genetic disorders such as methylmalonic acidemia and Down syndrome can also lead to hyperuricemia in adolescents and children (15,16). Genetic testing of this patient revealed the presence of the following gene variants: ABCG2 gene: c.421C>A (rs2231142) locus; SLC2A9 gene: c.881G>A (rs3733591) locus; SLC22A12 gene: c.831-192C>A (rs893006) locus; MTHFR gene: variation at locus c.677C>T (rs1801133). The MTHFR gene encodes methylenetetrahydrofolate reductase, and the C677T variant is associated with decreased MTHFR activity and elevated plasma homocysteine levels, which in turn correlates with increased serum uric acid levels. Individuals with the CC genotype at rs1801133 have lower blood uric acid levels compared to those with CT or TT genotypes, indicating that the T allele at this locus is a risk factor for hyperuricemia. The protein encoded by the ABCG2 gene is expressed in the brush border of the proximal tubule of the kidney and plays a role in apical secretion of uric acid. Dysfunction of this protein can lead to hyperuricemia and gout. Research has indicated that the rs2231142 locus of the ABCG2 gene is associated with susceptibility to primary gout, with AA genotypes at this locus exhibiting reduced renal capacity for uric acid excretion and elevated blood uric acid levels compared to CA and CC genotypes. The A allele of the SLC2A9 gene is associated with elevated uric acid levels in gout patients, particularly in individuals with the AA genotype. The SLC2A9 gene encodes GLUT-9, which plays a role in uric acid reabsorption by exchanging glucose in the renal tubular epithelium. Additionally, the blood uric acid level of the AA type at locus rs733591 is significantly lower than that of the GA and GG types. Furthermore, the SLC22A12 gene encodes urate anion transporter 1 (URAT1), which is involved in the reabsorption of uric acid primarily within lumenal membranes of renal proximal tubular epithelial cells. The rs893006 locus of the SLC22A12 gene is associated with significantly lower blood uric acid levels in individuals with the AA genotype compared to those with the CA and CC genotypes. Specifically, allele C at this locus is considered a risk gene variant. This gene variant may contribute to the development of early-onset gout in affected individuals.

Gouty arthritis is uncommon in pediatric clinical practice and often misdiagnosed due to its atypical clinical presentations. The patient underwent inherited metabolic and genetic testing, which ruled out the following diseases: glucose-6-phosphatase deficiency (Von Gierke disease), hereditary fructose intolerance, UMOD gene mutations and hyperuricemic nephropathy, X-linked recessive diseases, and others. This patient was misdiagnosed because they did not exhibit typical manifestations of gouty arthritis, such as joint destruction, local signs of redness, swelling, heat, and limited limb movement. Secondly, the receiving doctor lacked sufficient knowledge of the characteristics of gouty arthritis in children, leading to an incorrect subjective judgment and a failure to conduct necessary clinical examinations. Furthermore, there is no uniform standard for defining hyperuricemia in children, which contributes to a lack of clarity among doctors regarding diagnostic criteria. The internationally accepted definition of hyperuricemia involves a non-same-day, 2-time fasting serum uric acid level >420 µmol/L (7 mg/dL) in adults on a normal purine diet, but this does not provide clear guidance for diagnosing hyperuricemia in children (17). In addition, certain studies have defined hyperuricemia in pediatric patients as serum uric acid levels >500 µmol/L at 1–12 months and >320 µmol/L at 1–10 years of age; >470 µmol/L in boys at 11–15 years of age; >350 µmol/L in girls at 11–15 years of age; and the adult standard is applied for individuals aged 15 years and older (18). The diagnostic criteria for hyperuricemia in children in Japan are determined by specific threshold values: 5.9 mg/dL for 6–8 years old (both sexes), 6.1 mg/dL for 9–11 years old (both sexes), and 7.0 mg/dL for males and 6.2 mg/dL for females aged 12–14 years old (19,20).

Therefore, it is highly practical and clinically valuable to establish criteria for elevated uric acid levels in children across different age groups. We anticipate more extensive, multi-center prospective clinical studies in this area to define the reference values for hyperuricemia in children of varying ages and better guide the clinical management of pediatric patients with hyperuricemia and gout.

Conclusions

In conclusion, hyperuricemia and gout in children currently pose a significant threat to global public health, profoundly impacting the survival and quality of life of affected children, and imposing a substantial economic burden on society and families. This case report, combined with literature review and pediatric characteristics, has allowed us to adapt flexibly and accumulate pediatric experience in order to enhance the diagnosis and treatment of primary gout in children by pediatric clinicians, as well as provide guidance for the early and accurate diagnosis and treatment of similar diseases.

Acknowledgments

Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 82271858); Guangzhou Planned Project of Science and Technology (Nos. 2024A03J1018; 2024A03J1094); The National Key Research and Development Program of China (Nos. 2022YFC2705100; 2022YFC2705103; 2022YFC2705104); Guangdong Science and Research Project of Traditional Chinese Medicine Bureau (No. 20222158); Guangdong Medical Science and Research Foundation (No. A2023160).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-354/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-354/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-354/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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