Nephrotic Syndrome, Type 1

A number sign (#) is used with this entry because nephrotic syndrome type 1 (NPHS1), also known as Finnish congenital nephrosis, is caused by homozygous or compound heterozygous mutation in the gene encoding nephrin (NPHS1; 602716) on chromosome 19q13.

Description

The nephrotic syndrome is characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. Approximately 20% of affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure (summary by Fuchshuber et al., 1996).

Nephrotic syndrome type 1 (NPHS1) is characterized by prenatal onset of massive proteinuria followed by severe steroid-resistant nephrotic syndrome apparent at birth with rapid progression to end-stage renal failure (Kestila et al., 1998).

Because of confusion in the literature regarding use of the terms 'nephrotic syndrome' and 'focal segmental glomerulosclerosis' (see NOMENCLATURE section), these disorders in OMIM are classified as NPHS or FSGS according to how they were first designated in the literature.

Genetic Heterogeneity of Nephrotic Syndrome and Focal Segmental Glomerulosclerosis

Nephrotic syndrome and FSGS are genetically heterogeneous disorders representing a spectrum of hereditary renal diseases. See also NPHS2 (600995), caused by mutation in the podocin gene (604766); NPHS3 (610725), caused by mutation in the PLCE1 gene (608414); NPHS4 (256370), caused by mutation in the WT1 gene (607102); NPHS5 (614199), caused by mutation in the LAMB2 gene (150325); NPHS6 (614196), caused by mutation in the PTPRO gene (600579); NPHS7 (615008), caused by mutation in the DGKE gene (601440); NPHS8 (615244), caused by mutation in the ARHGDIA gene (601925); NPHS9 (615573), caused by mutation in the COQ8B gene (615567); NPHS10 (615861), caused by mutation in the EMP2 gene (602334); NPHS11 (616730), caused by mutation in the NUP107 gene (607617); NPHS12 (616892), caused by mutation in the NUP93 gene (614351); NPHS13 (616893), caused by mutation in the NUP205 gene (614352); NPHS14 (617575), caused by mutation in the SGPL1 gene (603729); NPHS15 (617609), caused by mutation in the MAGI2 gene (606382); NPHS16 (617783), caused by mutation in the KANK2 gene (614610), NPHS17 (618176), caused by mutation in the NUP85 gene (170285); NPHS18 (618177), caused by mutation in the NUP133 gene (607613); NPHS19 (618178), caused by mutation in the NUP160 gene (607614); and NPHS20 (301028), caused by mutation in the TBC1D8B gene (301027).

FSGS1 (603278) is caused by mutation in the ACTN4 gene (604638) and FSGS2 (603965) by mutation in the TRPC6 gene (603652). FSGS3 (607832) is associated with variation in the CD2AP gene (604241). FSGS4 (612551) has been mapped to chromosome 22q12, and FSGS5 (613237) is caused by mutation in the INF2 gene (610982).

Clinical Features

Ongre (1961) described sibs with nephrosis starting in the neonatal period associated with cystic-like dilation of renal tubules.

In a review of Finnish congenital nephrosis, Tryggvason et al. (2006) noted that affected persons have massive proteinuria in utero and the nephrotic syndrome develops soon after birth. Affected children are usually born prematurely, and the weight of the placenta is almost invariably more than 25% of the weight of the child at birth. Hypoalbuminemia, hyperlipidemia, abdominal distention, and edema appear soon after birth. Electron microscopic studies of the kidney show effacement of the podocytes, a narrow slit, and absence of the slit diaphragm. The disorder is lethal; immunosuppressive therapy does not induce a remission. Successful kidney transplant is curative, although there is a risk of recurrence of nephrotic syndrome after transplantation. At least half the patients with recurrence have circulating antinephrin antibodies, which probably have a pathogenic role in the recurrence.

Clinical Variability

Kitamura et al. (2007) reported a Japanese brother and sister, aged 11 years and 4 years, respectively, who had nephrotic syndrome in infancy and achieved partial remission without immunosuppressive therapy, with only mild relapsing proteinuria associated with upper respiratory infections thereafter. The sibs had normal growth, and renal function was preserved in both. Renal biopsies from the brother at ages 2 months and 5 years showed minimal-change histology; electron microscopy revealed diffuse podocyte foot process effacement with no other significant ultrastructural abnormalities. Immunohistochemical staining of the biopsy specimen showed nephrin and podocin in a continuous linear pattern along the glomerular capillary loops with an intensity comparable to control tissue, suggesting that foot process integrity was fairly well preserved. Genetic analysis identified compound heterozygosity for missense mutations in the nephrin gene (602716.0008 and 602716.0009).

Other Features

Twelve percent of 41 infants with congenital nephrotic syndrome described by Mahan et al. (1984) presented with pyloric stenosis.

Grahame-Smith et al. (1988) described twins with Finnish congenital nephrosis. One twin was stillborn; the second presented with a diagnosis of pyloric stenosis.

Inheritance

Nephrotic syndrome type 1 is an autosomal recessive disorder (Kestila et al., 1998).

Diagnosis

Prenatal Diagnosis

Seppala et al. (1976) demonstrated that this disorder can be diagnosed antenatally by elevated levels of alpha-fetoprotein (AFP; 104150) in amniotic fluid.

Morris et al. (1995) described congenital Finnish nephrosis in 2 of 3 successive pregnancies of a nonconsanguineous couple with no known Finnish ancestry. They confirmed the usefulness of amniotic fluid alpha-fetoprotein determination in the prenatal diagnosis, since the fetus loses large amounts of AFP in the urine due to kidney damage.

Clinical Management

NPHS1 is a form of steroid-resistant nephrotic syndrome. Mahan et al. (1984) found that steroids or cytotoxic drugs, alone or in combination, were without benefit in 41 patients with congenital nephrotic syndrome. Intensive medical therapy to control bacterial infections, combined with renal transplantation, was judged to offer a good opportunity for survival with an acceptable quality of life for infants with congenital nephrotic syndrome.

Pathogenesis

Using radioimmunoassay methods, Risteli et al. (1982) found an accumulation of type IV collagen in the renal cortex in renal biopsies from patients with congenital nephrotic syndrome. The accumulation of the collagen was out of proportion to another basement membrane protein, laminin. They interpreted this to mean that metabolism of type IV collagen is disturbed in this disorder. The normal barrier to penetration of the renal glomerular basement membrane by anionic plasma proteins depends in part on the existence of negatively charged sites within the membrane (Cotran and Rennke, 1983).

Vernier et al. (1983) found that normal subjects had anionic sites distributed at regular intervals in the lamina rara externa, with a frequency of 23.8 sites per 1,000 nm length of membrane, whereas 5 patients with congenital nephrosis had 8.9 sites. An in vitro histochemical technique was used in these studies. Vernier et al. (1983) concluded that the basic defect in congenital nephrosis is failure of heparan sulfate-rich anionic sites to develop in the lamina rara externa of the glomerular basement membrane.

Tryggvason et al. (2006) stated that Finnish congenital nephrosis is caused by the absence of functional nephrin, which leads to the absence or malfunction of the slit diaphragm and loss of the size-selective slit filter.

Mapping

Kestila et al. (1994) assigned the locus for congenital nephrotic syndrome of the Finnish type (symbolized CNF by them) to 19q12-q13.1 on the basis of linkage analyses in 17 Finnish families. Although Dressler and Douglass (1992) had shown in transgenic mice that deregulation of the Pax2 gene (167409) resulted in severe kidney abnormalities resembling those found in patients with Finnish nephrosis, Kestila et al. (1994) showed that the disorder in these patients is not linked to the PAX2 gene locus on chromosome 10.

Olsen et al. (1996) assembled a 1-Mb cosmid contig and restriction map spanning the candidate region for NPHS1 on chromosome 19q13.1.

Mannikko et al. (1996) applied haplotype analysis to several non-Finnish CNF families to determine whether the same genetic locus is involved in these families as in Finnish families. The results indicated linkage to the 19q13.1 region. It was also observed that, in most cases, alleles typically found on CNF chromosomes of Finnish families were also found on CNF chromosomes of non-Finnish families from North America and Europe.

Population Genetics

Nephrotic syndrome type 1 has a relatively high frequency in Finland (Norio et al., 1964), where the incidence is about 1 in 8,000 (Norio, 1980). A large series of cases was collected by Hallman and Hjelt (1959) in Finland and by Vernier et al. (1957) and Worthen et al. (1959) in Minnesota, where many persons of Finnish extraction live. Worthen et al. (1959) were impressed with the high frequency of maternal toxemia in these cases.

Nine of 41 patients (22%) with congenital nephrotic syndrome studied by Mahan et al. (1984) in Minneapolis, Minnesota, were shown to have Finnish ancestry.

Bolk et al. (1999) observed a high incidence of NPHS1 in the Old Order Mennonites in Lancaster County, Pennsylvania. They identified 26 cases, dating from the 1950s. All but 1 of the cases occurred in a subgroup known as the Groffdale Conference Mennonites, formed as a result of a schism in the Weaverland Conference Mennonites in 1927. Bolk et al. (1999) estimated the frequency to be about 1 per 500 live births, giving an incidence 20 times greater than that observed in Finland and predicting that approximately 8% of Groffdale Mennonites are carriers of the NPHS1-causing allele. There was no known Finnish ancestry.

Molecular Genetics

By use of positional cloning strategies, Kestila et al. (1998) isolated the gene responsible for NPHS1 and identified pathogenic mutations in Finnish patients with congenital nephrosis. The most common Finnish mutation was a deletion of 2 nucleotides in exon 2 (602716.0001), resulting in a frameshift and a truncated protein. The predicted nephrin protein belongs to the immunoglobulin family of cell adhesion molecules and is specifically expressed in renal glomeruli.

Bolk et al. (1999) confirmed the role of nephrin in NPHS1, showed that a major mutation (602716.0005) was shared by families with nephrosis that are in the Groffdale Conference, and showed that this mutation was most likely of recent origin, uncovered by inbreeding and amplified by genetic drift. The data suggested that the major Mennonite mutation probably predated the split from the Weaverland Conference, since 1 proband in the previous group was a double heterozygote with 1 copy of the major nephrin mutation and a second novel mutation (602716.0006), possibly contributed through a non-Mennonite lineage. Puffenberger (2003) published data on the surname distribution in the Weaverland and Groffdale Mennonite groups indicating appreciable differences.

Frishberg et al. (2007) identified homozygosity or compound heterozygosity for 3 novel mutations in the NPHS1 gene in 12 children with congenital nephrotic syndrome living in a village near Jerusalem. All were descendants of 1 Muslim family with high inbreeding.

Associations Pending Confirmation

For discussion of a possible association between nephrotic syndrome and variation in the XPO5 gene, see 607845.0001.

For discussion of a possible association between nephrotic syndrome and variation in the FAT1 gene, see 600976.0001.

For discussion of a possible association between nephrotic syndrome and variation in the KANK1 gene, see 607704.0002.

For discussion of a possible association between nephrotic syndrome and variation in the KANK4 gene, see 614612.0001.

Nomenclature

In the literature, use of the clinical term 'nephrotic syndrome' (NPHS) and the pathologic term 'focal segmental glomerulosclerosis' (FSGS) to refer to the same disease entity has generated confusion in the naming and classification of similar disorders. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature. It is important to recognize that FSGS is a histologic pattern of renal injury: some patients with FSGS on biopsy have nephrotic syndrome, whereas others have only mild proteinuria. NPHS and FSGS represent a spectrum of hereditary renal diseases of the podocyte (see reviews by Pollak, 2002; Meyrier, 2005; Caridi et al., 2010; Hildebrandt, 2010).

History

Finnish congenital nephrosis is only one of many disorders, numbering more than 30, that are absent or infrequent elsewhere and exist in the Finnish population, sometimes at high carrier frequencies. Conversely, recessive autosomal diseases common in other European populations, such as cystic fibrosis (219700), phenylketonuria (261600), or galactosemia (230400), are rare or absent in Finland. Sajantila et al. (1996) noted that single mutations embedded in chromosomal regions exhibiting linkage disequilibrium have been demonstrated in the case of several of these 'Finnish' genetic disorders. In contrast, outside Finland, the rare cases of these disorders are usually due to several different mutations. Furthermore, many of the disorders occur in locally restricted areas in Finland. Sajantila et al. (1996) found that Y-chromosomal haplotypes in several European populations revealed an almost monomorphic pattern in the Finns, whereas Y-chromosomal diversity was significantly higher in other populations. Furthermore, analyses of nucleotide positions in the mitochondrial control region that evolves slowly showed a decrease in genetic diversity in Finns. Thus, relatively few men and women contributed to the genetic lineages that today survive in the Finnish population. This is likely to have caused the 'Finnish disease heritage,' i.e., the occurrence of several genetic diseases in the Finnish population that are rare elsewhere. A preliminary analysis of the mitochondrial mutations that had accumulated subsequent to the bottleneck suggested that it occurred about 4,000 years ago, presumably when populations using agriculture and animal husbandry arrived in Finland. The results suggested that genetic founder effects have played a role also in the biologic history of Estonians and the Basques.

Fournier et al. (1963) observed a family in which 4 of 5 children had clinical and/or autopsy evidence of pulmonary stenosis and congenital nephrotic syndrome (see 265600). Zunin and Soave (1964) observed nephrosis in association with nephroblastoma in 2 sibs. In one of them, removal of the tumor was accompanied by amelioration of the nephrotic syndrome.