Hereditary focal segmental glomerulosclerosis associated with an <i>LMX1B</i> mutation in the absence of extrarenal manifestations

Dae Kyu Kim; Geon Woo Kim; Kyung Hwan Jeong; Hyeon Seok Hwang; Ji-Youn Sung; Jin Sug Kim

doi:10.23876/j.krcp.25.028

Mutations in LMX1B cause nail-patella syndrome (NPS), an autosomal dominant disorder, characterized by nail dysplasia, skeletal abnormality, and renal dysplasia [1]. The common phenotypic features of NPS include nail dysplasia; reduced flexion of the interphalangeal joints, elbows, and knees; patellar abnormalities; and, in some cases, nephropathy. Renal involvement is observed in 30% to 50% of affected individuals, typically manifesting as hematuria and proteinuria, with occasional progression to nephrotic syndrome. End-stage kidney disease (ESKD) develops in approximately 5% to 10% of patients with NPS [2,3].

Based on the established clinical features of NPS, some patients exhibit isolated nephropathy without conspicuous orthopedic symptoms. Recent genetic studies indicate that specific missense mutations in LMX1B can result in isolated nephropathy without apparent orthopedic symptoms [4,5]. We report a case of LMX1B-associated nephropathy with focal segmental glomerulosclerosis (FSGS) on light microscopy and myeloid/zebra body deposition on electron microscopy, without orthopedic abnormalities. This study was approved by the Institutional Review Board of Kyung Hee University Hospital (No. KHUH 2023-12-040).

A 52-year-old female was admitted for persistent foamy urine for eight months. She had hypertension and dyslipidemia, treated with an angiotensin II receptor blocker and statin. Physical examination revealed grade 1 pretibial pitting edema, with no other significant findings. There was no history of recent infections or use of health supplements in the past 6 months. Initial laboratory tests showed a normal serum creatinine level of 0.95 mg/dL (reference range, 0.51–0.95 mg/dL). Urinalysis revealed significant proteinuria, with a urine protein-to-creatinine ratio of 4.6 g/g, along with microscopic hematuria (2–4 red blood cells per high-power field). Additional serological tests for vasculitis and infectious diseases were negative. To determine the underlying cause of the proteinuria and microscopic hematuria, a percutaneous kidney biopsy was performed. Light microscopy revealed mostly normal glomeruli, with segmental glomerulosclerosis in one of 11 glomeruli and global glomerulosclerosis in two of 11 glomeruli (Fig. 1A). Mild interstitial inflammatory cell infiltration and tubular dysplasia were observed, along with tuft adhesions in a representative glomerulus on periodic acid–Schiff–silver stain (Fig. 1B). Electron microscopy showed foot process effacement in the glomerular epithelium without basement membrane abnormalities (Fig. 1C) and revealed myelin figures and zebra bodies within podocytes (Fig. 1D).

The presence of unusual myeloid and zebra bodies within podocytes raises the possibility of an underlying genetic disorder, including Fabry disease. Accordingly, genetic analysis was performed to identify potential pathogenic variants. Genomic DNA was extracted from the buccal swab sample for further analysis. Gene analysis identified a heterozygous NM_001174147.2:c.737G>A (p.Arg246Gln) variant of the LMX1B gene (Fig. 2A, B). Given the possibility of NPS, a thorough reevaluation of the musculoskeletal system was conducted during the physical examination. However, no specific orthopedic, gastrointestinal, or genitourinary abnormalities were identified. A review of the patient’s family history revealed a familial predisposition to renal disease. Her father was undergoing hemodialysis for ESKD of unknown etiology, her younger brother was receiving treatment for FSGS, and her daughter had undergone a kidney transplant due to ESKD caused by FSGS (Fig. 2C).

Genetic testing and kidney biopsy confirmed LMX1B mutation-associated FSGS without extrarenal involvement. The patient was treated with an angiotensin II receptor blocker and a sodium-glucose cotransporter-2 inhibitor. After six months, renal function remained normal, and the urine protein-to-creatinine ratio decreased to 2.0 g/g.

Mutations in genes implicated in the syndromic forms of the disease can cause isolated FSGS. Proactively pursuing genetic testing in patients with clinical indicators of glomerulonephritis, particularly hematuria and proteinuria, is crucial for future medical practice. This approach provides a significant advantage for predicting and managing renal dysfunction across family lines. Had our case been concluded based solely on tissue examination without additional genetic testing, identifying the LMX1B mutation and uncovering the family history would not have been possible. Implementing a proactive approach to genetic screening has the potential to transform the management of renal diseases, highlighting the need for stronger integration of genetic testing into the diagnostic and treatment protocols for glomerulonephritis.

In conclusion, we report a case of FSGS associated with an LMX1B mutation. The presence of myeloid and zebra bodies within podocytes on electron microscopy may serve as a diagnostic clue for LMX1B-associated nephropathy. Furthermore, isolated FSGS can result from mutations in genes implicated in syndromic forms of the disease, highlighting the importance of incorporating these genes into the diagnostic evaluation of FSGS.

Notes

Conflicts of interest

All authors have no conflicts of interest to declare.

Data sharing statement

The data presented in this study are available from the corresponding author upon reasonable request.

Authors’ contributions

Conceptualization: JSK

Data curation: DKK, GWK

Investigation: GWK

Methodology: KHJ, HSH

Visualization: JSK, JYS

Writing–original draft: DKK, GWK, JSK

Writing–review & editing: KHJ, HSH, JYS

All authors have read and approved the final manuscript.

Figure 1.

Kidney biopsy findings.

(A) Light microscopy representative glomerulus stained by hematoxylin-eosin (×400). Focal segmental glomerulosclerosis was observed in one glomerulus with mild interstitial inflammatory cell infiltration. (B) Periodic acid–Schiff–silver stain (×400). Tuft adhesion observed in a glomerulus. (C) Electron microscopy of a glomerulus (×2,500). Foot process effacement in the glomerular epithelium without pathologic abnormality in the basement membrane. (D) Electron microscopy of a glomerulus (×10,000). Unusually, some myelin figures and zebra bodies were observed inside the podocyte.

Figure 2.

Genetic test results of the patient.

(A) Identification of c.737G>A, a heterozygous variant in LMX1B (NM_001174147.2). (B) Sequence chromatograms showing c.737G>A, a heterozygous variant in LMX1B (NM_001174147.2). (C) Family pedigree of the patient. Individuals diagnosed with focal segmental glomerulosclerosis are represented in black, unaffected family members in white, and those with kidney disease but without genetic evaluation in gray. Individual I-1 is undergoing hemodialysis, II-3 is receiving treatment for chronic kidney disease, and III-1 has undergone kidney transplantation. Individual II-4 has not yet undergone evaluation.

References

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