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More than 20 podocyte monogenic mutations have been identified as the cause of genetic focal segmental glomerulosclerosis (FSGS). The main alterations described are located in the NPHS1 and NPHS2 genes that code for nephrin and podocin, respectively.
Among other variants, mutations have been reported in the gene that encodes INF-2 (inverted formin 2), especially in family groups carrying Charcot-Marie-Tooth Syndrome (CMT). In contrast, de novo mutations are less frequent. INF-2 is relevant to actin cytoskeleton remodeling.
We present a case report of a patient with a history of sensory-motor neuropathy and proteinuria, whose diagnosis was challenging as she had no previous family history.
A 16-year-old woman with a history of bilateral pes cavus and sensory-motor polyneuropathy was diagnosed at age 9. At that time, a CMT genetic study was performed, which was negative—no significant family history.
At 15 years old, she consulted for pustular skin lesions without response to antibiotic treatment; she had no edema. Laboratory: serum creatinine 0.9 mg/dL, urine protein-creatinine ratio 8.8 g/g, serum albumin 2.7 g/dL. Immunological study: ANA 1/1280, Anti-DNA negative, C3/C4 normal and Anti-DFS70: 163 (strong positive).
Kidney biopsy: Class IIIa focal lupus glomerulonephritis. Global glomerular sclerosis was 62%, and segmental sclerosis was 7%. Immunofluorescence: trace IgG, C1q 1+, C3 1-2+.
She started hydroxychloroquine, mycophenolate, and prednisone, evolving with anasarca at 3 months. Urine analysis: proteins 500 mg/dL, red blood cells 2-5 per field, leukocytes 2-5 per field. 24-hour proteinuria: 6.7 g, serum albumin 2.4 g/dL, serum creatinine 1.4 mg/dL, Anti-DNA negative, C3: 71 mg/dL (normal range 90-180 mg/dL) and C4: 21.5 mg/dL (normal range 10-40 mg/dL).
Due to deterioration of renal function and proteinuria, Rituximab was administered without clinical or laboratory response.
Due to the absence of response, the previous renal biopsy was re-evaluated, which concludes focal segmental glomerulosclerosis. In addition, a genetic evaluation is requested that requires an extended renal genetic panel that was positive for an autosomal dominant pathogenic mutation in INF2, which is associated with Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis. A genetic study in both parents turned out negative for this mutation.
We present a case of a patient with a genetic study that documented a de novo mutation of the INF2 gene, requested in the context of sensory-motor neuropathy and proteinuria, without response to treatment.
Given the phenotype with associated neurological manifestation, it is essential to rule out genetic etiologies of FSGS despite the absence of family history.