Nephrotic Syndrome, Type 3

A number sign (#) is used with this entry because this form of hereditary renal disease, referred to here as nephrotic syndrome type 3 (NPHS3), is caused by homozygous or compound heterozygous mutation in the PLCE1 gene (608414) on chromosome 10q23.

Description

Nephrotic syndrome, a malfunction of the glomerular filter, is characterized clinically by proteinuria, edema, and end-stage renal disease (ESRD). Renal histopathology may show diffuse mesangial sclerosis (DMS) or focal segmental glomerulosclerosis (FSGS) (Hinkes et al., 2006).

Most patients with NPHS3 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen (Gbadegesin et al., 2008).

For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome and FSGS, see NPHS1 (256300).

Clinical Features

Hinkes et al. (2006) described 14 patients from 7 unrelated families with nephrotic syndrome. Five families were of Turkish origin and consanguineous, 1 was of Israeli origin and consanguineous, and the last was of Turkish and Russian origin with unknown consanguinity. The age at onset ranged from 2 months to 4 years, except for 1 child who had onset at age 8.5 years, and ESRD occurred within several months. One child had ESRD as early as 5 months of age. Most patients showed steroid resistance, but 1 had steroid-sensitive disease and another had favorable response to cyclophosphamide. Others were not treated. None had extrarenal manifestations. Renal biopsies of most patients showed diffuse mesangial sclerosis, although biopsies from 2 sibs with a slightly later age at onset and less rapid progression showed focal segmental glomerulosclerosis.

Gbadegesin et al. (2008) reported 7 patients from 6 families with genetically confirmed NPHS3. They were ascertained from a larger group of patients on the basis of having early-onset proteinuria, edema, and hypoalbuminemia associated with diffuse mesangial sclerosis on renal biopsy, resulting in rapid progression to end-stage renal failure. None of the patients in this report who were treated responded to steroid therapy.

Boyer et al. (2010) reported 18 patients from 12 families with NPHS3 confirmed by genetic analysis. Renal biopsies showed FSGS in 6 and DMS in 5; 1 family did not have biopsy results. Age at onset was reported as ranging from 3 months to 5 years, but most with later onset had already reach end-stage renal disease, suggesting that the disorder had been present for some time. Age at end-stage renal disease was always before age 7 years, and as early as 8 months. All patients had steroid-resistant disease. Three sporadic patients with similar clinical characteristics were also identified. The patients were of multiple ethnic origins, including Moroccan, Pakistani, French, Turkish, Bosnian, Serbian, and Greek.

Inheritance

Consanguinity and affected sibs in the families segregating nephrotic syndrome reported by Hinkes et al. (2006) indicated autosomal recessive inheritance.

Clinical Management

Most patients with NPHS3 do not respond to steroid treatment (Hinkes et al., 2006; Gbadegesin et al., 2008) and are thus classified as having steroid nonresponsive nephrotic syndrome. However, Hinkes (2008) emphasized the finding of Hinkes et al. (2006) who reported 2 patients with genetically confirmed NPHS3 who did show a sustained response to steroid treatment. Both had homozygous truncating mutations in the PLCE1 gene and onset of nephrotic syndrome at ages 2 and 12 months, respectively. An Israeli child, treated with cyclosporin A for 2.5 years, was free of proteinuria at age 13 years. A Turkish patient responded to an 8-month course of steroid therapy and had normal serum albumin and creatinine and a near-normal protein/creatinine ratio at age 6 years. Hinkes (2008) noted that these were the first examples of complete therapeutic response patients with a severe form of hereditary nephrotic syndrome.

Mapping

Hinkes et al. (2006) generated whole-genome haplotype data for 26 consanguineous families with idiopathic nephrotic syndrome, 22 with 1 affected child and 4 with 2 affected children, all of whom were negative for mutations in the nephrin (NPHS1; 602716), podocin (NPHS2; 604766), WT1 (607102), and laminin-beta-2 (LAMB2; 150325) genes. Parametric multipoint analysis of the 4 multiplex families yielded a maximum lod score of 5.1 on chromosome 10q23.32-q24.1, defining a new gene locus for nephrotic syndrome that the authors designated NPHS3. Haplotype analysis revealed a continuous segment of homozygosity in 3 of the multiplex families and 2 of the simplex families; microsatellite analysis of these 5 families delimited a 4.0-Mb critical region between markers A1717632 and A1715598. Candidate genes in the region included PLCE1 (608414), which was found to have 10- to 11-fold higher expression in glomeruli compared with renal cortex or medulla and approximately 6-fold higher expression in podocyte-containing glomeruli compared with podocyte-depleted glomeruli.

Molecular Genetics

Hinkes et al. (2006) analyzed the PLCE1 gene in 7 consanguineous kindreds with early-onset nephrotic syndrome and homozygosity for microsatellites at the NPHS3 locus on chromosome 10q23.32-q24.1 and identified 7 different homozygous mutations. All 12 affected individuals from 6 kindreds with truncating mutations (608414.0001-608414.0006, respectively) presented with proteinuria by age 4 and developed gross proteinuria and edema; 9 of the 12 progressed to end-stage renal disease by 5 years of age. Renal histopathology was performed in 8 individuals with truncating mutations and all had diffuse mesangial sclerosis. In contrast, renal biopsy in the 2 sibs with a homozygous missense mutation (608414.0007) showed focal segmental glomerulosclerosis; in these patients, the onset of proteinuria was comparatively late (8.8 years and 2.0 years, respectively), as was the age of onset for ESRD (12.0 years and 4.0 years, respectively).

Including the patients reported by Hinkes et al. (2006), Gbadegesin et al. (2008) found homozygous PLCE1 mutations in 10 (28.6%) of 35 families with NPHS3 and diffuse mesangial sclerosis. Three (8.5%) of the families had mutations in the WT1 gene (see NPHS4, 256370).

Boyer et al. (2010) identified homozygous or compound heterozygous mutations in the PLCE1 gene (see, e.g., 608414.0008-608414.0010) in affected individuals from 12 (18%) of 68 families with early-onset steroid-resistant nephrotic syndrome and 3 (7%) of 44 patients with sporadic disease. Among the 12 families, renal biopsy showed FSGS in 6 and DMS in 5; 1 family had no biopsy results. Among the whole cohort, PLCE1 mutations were found in 12% of families with FSGS and 50% of families with DMS. There were no apparent genotype/phenotype correlations, but patients with DMS had a worse prognosis compared to those with FSGS. However, 3 unrelated individuals who were not affected were found to carry homozygous mutations that caused disease in their respective families, suggesting that additional factors are necessary to disease to occur.

Nomenclature

In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the pathologic terms 'focal segmental glomerulosclerosis' (FSGS) and 'diffuse mesangial sclerosis' have often been used to refer to the same disease entity. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature.