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Fibronectin glomerulopathy

ORPHA84090
Synonym(s) GFND
Glomerulopathy with fibronectin deposits
Prevalence <1 / 1 000 000
Inheritance Autosomal dominant
Age of onset All ages
ICD-10
  • N07.6
OMIM
UMLS -
MeSH -
MedDRA -

Summary

Disease definition

Fibronectin glomerulopathy is a hereditary kidney disease characterized by proteinuria, type IV renal tubular acidosis, microscopic hematuria and hypertension that may lead to end-stage renal failure in the second to sixth decade of life.

Epidemiology

It is a very rare disease. The exact prevalence is unknown. Only 16 families have been described in the literature so far.

Clinical description

Fibronectin glomerulopathy may present at different ages, although mostly in adolescence or early adulthood, with typical features of a nephrotic syndrome including hypertension, which can be severe, and edema, which initially develops around the eyes and legs but with time may become generalized. Biochemical analysis shows microscopic hematuria and proteinuria with hypoalbuminemia. Patients may also present with varying degrees of renal failure that progressively worsen over several years, reaching end stage renal disease in the second to sixth decade of life.

Etiology

Clustering of the disease within families indicates a genetic origin, and segregation with disease appearance in successive generations is consistent with an autosomal dominant pattern of inheritance with age-related penetrance. In 40% of families the disease is caused by heterozygous mutations in the FN1 gene (2q34) encoding fibronectin. However, genetic heterogeneity is suspected. Whole-genome linkage analysis in a large pedigree showed another disease locus on 1q32, however no specific candidate genes has been identified so far.

Diagnostic methods

Diagnosis rests on renal biopsy. Typical findings at light microscopy are enlarged glomeruli with deposits in the mesangium and subendothelial space, with scant immunoreactivity for immunoglobulins or complement factors. Electron microscopy reveals deposits mainly located in the subendothelial space but also in the subepithelial and intramembranous spaces. Homogeneous granular deposits dominate in most cases; in some an admixture of fibrils is observed. The most striking finding is the immunoreactivity of the glomerular deposits to fibronectin. Family history is supportive of the diagnosis.

Differential diagnosis

Differential diagnosis includes other chronic non-amyloid glomerulopathies with organized deposits including mixed cryoglobulinemia, fibrillary glomerulonephritis, immunotactoid glomerulopathy, collagen type III glomerulopathy, systemic lupus erythematosus (see these terms), diabetes glomerulopathy and other non-specific collagen deposition diseases. It is difficult to discriminate fibronectin glomerulopathy from membranoproliferative glomerulonephritis (see this term) at light microscopy examination. In all cases strong immunohistochemical positivity to fibronectin is mandatory for differential diagnosis.

Genetic counseling

Genetic counseling is useful for children of affected subjects with FN1 mutations to identify carriers that are at risk of developing the disease later in life. Monitoring these subjects for proteinuria could allow early treatment with angiotensin inhibitors to delay onset of renal dysfunction.

Management and treatment

There is no specific treatment for fibronectin glomerulopathy. Treatment of symptoms can include corticosteroids, diuretics and treatment for hypertension. Antiproteinuric and renoprotective treatment with ACE inhibitors or anti-AT1R antagonists could be of help to slow renal disease progression. More advanced cases of renal failure require renal dialysis or transplantation.

Prognosis

Prognosis is uncertain, in some cases the disease follows an indolent course and in others it leads to end stage renal disease and chronic renal failure in the second to sixth decade of life.

Expert reviewer(s)

  • Dr Marina NORIS
  • Pr Giuseppe REMUZZI

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