Case report: Focal segmental glomerulosclerosis in a pediatric atypical progeroid syndrome

Abstract

Atypical progeroid syndrome (APS) is a rare type of progeroid syndrome mainly caused by heterozygous missense mutations in the LMNA (MIM 150330) gene. APS has heterogeneous clinical manifestations, and its kidney manifestations, particularly in children, are rarely documented. Here, we report the first pediatric case of APS with focal segmental glomerulosclerosis (FSGS). A 10-year-old boy with progeroid features was referred to the nephrology clinic because of hyperuricemia. He had dark skin, protruding eyes, and beaked nose and was very thin, suggesting lipodystrophy. He had been treated for recurrent urinary tract infection during infancy, and liver biopsy for persisting hepatitis showed steatohepatitis. He also had hypertrophic cardiomyopathy (HCMP) with mitral and tricuspid valve regurgitation. Genetic studies were performed considering his multisystem symptoms, and he was diagnosed as having APS according to exome sequencing findings (c.898G > C, p.Asp300His of LMNA). During the first visit to the nephrology clinic, he had minimal proteinuria (urine protein/creatinine ratio of 0.23 mg/mg), which worsened during follow-up. In three years, his urine protein/creatinine ratio and N-acetyl-b-D-glucosaminidase/creatinine ratio increased to 1.52 and 18.7, respectively. The kidney biopsy result was consistent with findings of FSGS, peri-hilar type, showing segmental sclerosis of 1 (5%) glomerulus out of 21 glomeruli. An angiotensin receptor blocker was added to manage his proteinuria. This is the first pediatric report of FSGS in an APS patient with confirmed LMNA defect, who manifested progeroid features, lipodystrophy, HCMP with heart valve dysfunction, and steatohepatitis. Our case suggests that screening for proteinuric nephropathy is essential for managing APS patients since childhood.

Keywords: LMNA; TGF - β1; atypical progeroid syndrome; focal segmental glomerular sclerosis (FSGS); lipodystrophy.

Figure 1

Kidney biopsy findings. (A–B) H&E and PAS staining show segmental sclerosis at the vascular pole of the glomerulus. The patient was diagnosed as having focal segmental glomerulosclerosis, perihilar variant. (A) H&E stain, × 400, (B) PAS stain, × 400). (C) Mild endocapillary hypercellularity and glomerular enlargement was observed in other glomeruli, with a maximum diameter of 302 μm. (PAS stain, × 250). (D) Electron microscopy showing mild effacement of foot processes. (EM, × 12,000).

Figure 2

Characteristics of the patient during the follow-up. This graph shows the patient's trend of proteinuria and creatinine-based estimated glomerular filtration rate (eGFR) and cystatin C levels during the follow-up. Proteinuria is indicated using a solid line, cystatin C using a dashed line, and creatinine-based eGFR using a double line. The patient's proteinuria and kidney function waxed and waned during the follow-up, and following the administration of losartan, his proteinuria and renal function improved and remains stationary. Creatinine based eGFR (ml/min/1.73 m²), Cystatin C (mg/L), Protein/Cr (mg/mg).

Figure 3

(A) Schematic structure of the LMNA gene. The mutation of the patient is indicated with a solid line, and the locations of mutations associated with FSGS are shown in dotted lines. FSGS: focal segmental glomerular sclerosis. (B,C) The crystal structure of wild-type human lamin A coil 2B domain and a model of proposed p.Asp300His mutant. I-TASSER software and PyMol were used to model the wild-type human lamin A and the p.Asp300His mutant. The peptide chain of the human lamin A coil 2B domain (aa. 290–310 from left to right) is shown as an alpha-helical structure (green). Side chains are shown as sticks. The carbon atoms in the mutation site are highlighted in yellow and other carbons are in green. Nitrogen atoms are labeled blue, oxygen atoms are red, hydrogen atoms are white, and sulfur atoms are shown orange.