Kearns-Sayre syndrome presenting with fanconi syndrome: a case report

Introduction

Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder characterized by a clinical trial of cardiac conduction anomalies, progressive external ophthalmoplegia with ptosis, and pigmentary retinopathy, typically presenting before 20 years of age. KSS arises from spontaneous heteroplasmic large-scale mitochondrial deoxyribonucleic acid (mtDNA) deletions, ranging from 1.1 to 10 kb, which occur at the germ cell level during embryonic development (1). Proximal renal tubulopathy is the most frequently reported renal manifestation. This report describes a case of a girl with a 7,521-bp deletion mutation in mtDNA who initially presented with proximal renal tubulopathy. Additional clinical manifestations included ptosis, growth retardation, type 1 diabetes mellitus, third-degree atrioventricular block, and abnormalities in the brain and skeletal muscle. These findings ultimately led to the diagnosis of KSS associated with Fanconi syndrome. We present this case in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-138/rc).

Case presentation

A 10-year-old girl was diagnosed with Fanconi syndrome at three years of age following the onset of lower extremity weakness. Routine blood chemistry at the time of diagnosis revealed hyperchloremia, hypokalemia, and metabolic acidosis. Electromyography (EMG) findings revealed the presence of myogenic damage. Symptomatic treatment resulted in clinical improvement.

At five years of age, growth retardation was observed, with an annual height increase of approximately 1 cm. By eight years of age, bilateral eyelid drooping had developed. Physical examination findings revealed suspicious ptosis, though diurnal fluctuation was not pronounced, as symptoms did not significantly improve in the morning or worsen in the evening. A fatigue test yielded a positive result. The patient’s fasting blood glucose levels and electrocardiogram findings were within normal limits at that time, based on these clinical findings, a diagnosis of ocular myasthenia gravis was considered, and treatment with steroids and tacrolimus was initiated. However, ptosis symptoms did not improve despite immunosuppressive therapy, while subsequent clinical course revealed this to be a misdiagnosis and tacrolimus was discontinuous.

At 10 years of age, the patient developed lower extremity edema, diarrhea. During the hospitalization, the patient developed progressive dyspnea and worsening lower extremity edema. Laboratory evaluation revealed an elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of 964 pg/mL, consistent with a diagnosis of heart failure. An electrocardiogram revealed the presence of third-degree atrioventricular block, which is shown in Figure 1. Echocardiography revealed a left ventricular ejection fraction (LVEF) of 41%. The patient was found to have markedly elevated fasting blood glucose (39.6 mmol/L) and glycosylated hemoglobin (HbA1c 10%) with significantly low C-peptide levels (0.12 ng/mL), accompanied by positive serum and urine ketones. A diagnosis of type 1 diabetes and third-degree atrioventricular block was established. Insulin therapy was initiated for glycemic management, and a pacemaker was implanted for cardiac conduction abnormalities, subsequently, the patient’s heart failure demonstrated improvement with resolution of edema. The patient was subsequently admitted to the hospital for further evaluation.

Figure 1 The electrocardiogram revealed the presence of third-degree atrioventricular block before the pacemaker was implanted.

At the time of admission, the patient’s height was 112.5 cm [less than 3 standard deviation (SD)], and weight was 17 kg (less than 3 SD). Clinical examination revealed severe bilateral ptosis, reduced eye fissures (approximately 4 mm), and restricted ocular motility in all directions. Laboratory test results included a pH of 7.37, PCO₂ of 17 mmHg, base excess (BE) of −7.3 mmol/L, lactate of 1.8 mmol/L, uric acid (UA) of 139 µmol/L, phosphate (P) of 1.61–2.44 mmol/L, Ca of 2.38 mmol/L, parathyroid hormone (PTH) of 16 pg/mL, albumin (Alb) of 37 g/L, serum creatinine (sCr) of 61 µmol/L, and cystatin C of 1.28 mg/L [estimated glomerular filtration rate (eGFR): 67 mL/min/1.73 m²]. The blood folic acid level was within the normal range.

Urinalysis findings were consistent with generalized proximal tubule dysfunction, characterized by low-molecular-weight proteinuria and increased urinary calcium (0.26 mmol/24 h·kg), uP (1.19 mmol/24 h·kg), calcium-to-creatinine ratio (0.605 mg/mg), P/Cr (2.12 mg/mg), and urinary β2 microglobulin (6.6 mg/L; reference range: 0–0.2 mg/L), and urinary α1 microglobulin (36.6 mg/L; reference range: 0–12.0 mg/L). Ultrasound of the urinary tract revealed small kidney stones. Radiographic evaluation demonstrated osteopenia. Pure tone audiometry revealed high-frequency hearing loss. However, retinal abnormalities and cognitive dysfunction were not observed.

Cerebrospinal fluid analysis revealed an elevated protein concentration (2.2 g/L) and a reduced level of folic acid (27.2 nmol/L; reference range: 40.0–120.0 nmol/L). Echocardiography revealed a LVEF of 67%. EMG of the upper limb and ocular muscles demonstrated myopathic involvement, with no abnormalities detected on nerve conduction studies (NCV) or repetitive nerve stimulation (RNS). Brain computed tomography (CT) demonstrated widening of the cerebral sulci and narrowing of the brain gyri. A muscle biopsy revealed the presence of broken red fibers, while electron microscopy revealed an increased number of mitochondria, some exhibiting a disc-shaped morphology, with lattice-like inclusion bodies in certain mitochondria.

As shown in Figures 2,3, exome sequencing identified a heterozygous DNA2 gene variant (c.865C>T, p.R286X), which is suspected to be associated with mitochondrial DNA cleavage. mtDNA sequencing revealed a 7,521-bp deletion mutation from nucleotide position 7,974 to 15,494, which is shown in Figure 4. Thus, the patient was considered KSS.

Figure 2 Electron microscopy of the patient’s muscle biopsy sample, showing mitochondrial abnormalities.

Figure 3 Electron microscopy of the patient’s muscle biopsy sample, illustrating ragged red fibers and mitochondrial clustering.

Figure 4 7,521-bp deletion mutation from the nucleotide position 7,974 to 15,494.

Treatment was started and included coenzyme Q10, idebenone, vitamin C, levocarnitine, and folic acid were administered to nourish the mitochondria. Following treatment, ptosis symptoms diminished. Parental reports of resolved diplopia correlated with normalized ductions on examination. However, owing to the patient’s geographically isolated setting, acquiring high-resolution orbital images was not practicable. Additionally, glycemic control was achieved, with blood glucose levels remaining within the normal range (fasting plasma glucose: 4.7–6.5 mmol/L; postprandial glucose: 5.7–7.1 mmol/L), with HbA1c of 5.4%, eliminating the need for insulin therapy.

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 Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s guardians 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

This report describes a pediatric patient presenting with proximal renal tubulopathy, ptosis, edema, diarrhea, and third-degree atrioventricular block. Clinical and laboratory investigations revealed multiple systemic abnormalities, such as Fanconi syndrome, type I diabetes, high-frequency hearing loss, osteopenia, and myopathy (2). The multisystem involvement in this case suggested the possibility of an underlying neurometabolic disorder.

KSS is a mitochondrial disorder characterized by specific genetic deletions and typically manifests before 20 years of age with a range of clinical features, including progressive external ophthalmoplegia and pigmentary retinopathy. Additional findings may include cerebellar syndrome, cerebrospinal fluid protein levels exceeding 100 mg/dL, and cardiac conduction abnormalities (3). Notably, proximal renal tubular acidosis represents a primary renal manifestation of KSS, reflecting the high metabolic demands of proximal tubular cells in contrast to their limited capacity for anaerobic ATP production. A decrease in ATP production inevitably leads to reduced activity of the sodium-potassium ATPase, subsequently resulting in a decline in transcellular transport mechanisms for glucose, amino acids, and electrolytes (4-6). This renal tubulopathy often precedes the onset of broader systemic manifestations in mitochondrial disorders, highlighting its potential utility as an early diagnostic marker (5).

The concurrent presence of Fanconi syndrome and osteopenia in individuals with KSS underscores the systemic nature of the disorder, which is partly attributed to excessive renal excretion of essential minerals and impaired vitamin D metabolism (2). A literature search conducted using PubMed, ScienceDirect, and Google Scholar identified no prior reports, as of December 30, 2024, describing KSS initially presenting with Fanconi syndrome. Existing case reports provide insights into the progressive and heterogeneous manifestations of KSS. Mihai et al. described an 18-year-old male initially presenting with Fanconi syndrome and ptosis, who later developed broader neuromuscular and endocrine complications despite a delayed diagnosis of KSS (7). Similarly, Tzoufi et al. reported a case of a 5-year-old who exhibited myopathy, Addison’s disease, and Fanconi syndrome before ultimately receiving a diagnosis of KSS (8). Additionally, Rheuban et al. described a case of a 13-year-old female who initially experienced recurrent syncopal episodes beginning at three years of age. Over time, she developed hypomagnesemia, developmental delays, ptosis, and muscle weakness, leading to a diagnosis of KSS. However, the hypomagnesemia observed in this case may not be solely attributable to KSS, as renal tubular dysfunction may have contributed to the electrolyte disturbance (9). These cases suggest that renal tubular acidosis may serve as an early indicator of mitochondrial disorders in adolescence. Notably, none of the previously reported cases initially presented with Fanconi syndrome. In contrast to prior literature emphasizing central nervous system (CNS) or endocrine dysfunction in KSS (10), our case demonstrates that renal manifestations may precede typical symptoms, suggesting broader organ susceptibility in mitochondrial disorders.

The present case represents the first documented instance of KSS manifesting initially with clinical features resembling Fanconi syndrome. Multisystem involvement was observed, including the endocrine, cardiovascular, central nervous, and auditory systems. This case highlights the importance of recognizing Fanconi syndrome as a potential early presentation of mitochondrial disease in pediatric patients and emphasizes the necessity of continuous monitoring and comprehensive evaluation. Renal tubular dysfunction may serve as a critical early indicator of such complex disorders, necessitating a proactive and systematic approach to diagnosis and management. In this case report, the patient presented with edema, which resolved following the implantation of a pacemaker, accompanied by improvement in heart failure. The edema was considered secondary to heart failure. Although the patient exhibited manifestations of renal insufficiency, the serum Alb levels were largely within the normal range, ruling out nephrotic syndrome as the cause of the edema.

Implementing these measures is essential for managing the complex clinical trajectory associated with KSS and facilitating timely and appropriate medical intervention. A previous study has documented cases in which mitochondrial diseases initially presented with renal disorders, such as proteinuria, particularly in instances of primary coenzyme Q10 deficiency (11). Due to the complexity of these disorders, it is essential to maintain a high index of suspicion for mitochondrial-related conditions, particularly in pediatric patients with early-onset renal disease, defined as onset before 3 years of age (12). Furthermore, the presence of concurrent neurological symptoms necessitates a comprehensive diagnostic evaluation. When clinically indicated, detailed assessments for hereditary metabolic disorders should be conducted. These investigations may include measurements of blood and urine lactate and pyruvate levels, as well as mtDNA analysis, all of which provide critical insights into the underlying metabolic abnormalities.

Genetic analysis identified a pathogenic variant in DNA2 (p.R286X), a nuclear gene involved in DNA repair and linked to mtDNA instability. DNA2 mutations have been implicated in progressive external ophthalmoplegia (13). KSS typically arises from sporadic, single large-scale mtDNA deletions and rarely reported in nuclear gene variants. Thus, whether this DNA2 variant directly contributes to the KSS-like phenotype in our patient remains uncertain.

As part of the treatment approach, a mitochondrial-targeted therapeutic regimen was administered, consisting of coenzyme Q10, idebenone, vitamin C, levocarnitine, and folic acid. Following this intervention, notable clinical improvements were observed, including a reduction in ptosis and enhanced blood glucose regulation. While the efficacy of multivitamin and cofactor therapy in optimizing clinical outcomes for KSS and other mitochondrial disorders remains a subject of ongoing investigation, existing literature suggests that folic acid supplementation may contribute to the improvement of white matter abnormalities in individuals with KSS (14,15). These findings support the potential role of multivitamin and cofactor therapy in managing associated clinical manifestations; however, continued monitoring of long-term clinical outcomes remains essential. However, certain mitochondrial disorders exhibit poor response to nutritional mitochondrial therapy. Additionally, individuals with mitochondrial disorders are prone to clinical deterioration following infections (14). Therefore, patient education should emphasize stringent hygiene practices and preventive measures to mitigate infection risks.

Conclusions

MtDNA mutations are potential etiological factors in Fanconi syndrome. In children exhibiting Fanconi syndrome with systemic features (e.g., ptosis), KSS—a mitochondrial disorder—must be included in the differential diagnosis. This underscores the importance of genetic evaluation in atypical presentations to identify underlying mitochondrial pathologies.

Acknowledgments

We would like to acknowledge the hard and dedicated work of all the staff that implemented the intervention and evaluation components of the study.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-138/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-138/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-138/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 Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient guardians 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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