INTRODUCTION — The term congenital nephrotic syndrome (CNS) refers to disease that is present at birth or within the first three months of life. Later onset, between three months and one year of age, is called infantile nephrotic syndrome. Most of these children have a genetic basis for the kidney disease and a poor outcome. The precise diagnosis of the glomerular lesion is based on clinical, laboratory, and histologic criteria.
The causes of CNS will be discussed here.
ETIOLOGY — The results of four reports indicate that variants in five different genes are responsible for more than 80 percent of CNS cases (table 1).
●NPHS2, which encodes podocin (a protein that interacts with nephrin at the slit diaphragm) and is responsible for familial focal segmental glomerulosclerosis. (See 'Congenital Nephrotic Syndrome and NPHS2 variants' below.)
●NPHS3 (PLCE1), which encodes phospholipase C epsilon (a signaling protein of many G protein-coupled receptors) and is responsible for early-onset nephrotic syndrome. (See 'Diffuse mesangial sclerosis' below.)
●WT1, which encodes the transcription tumor suppressor (a protein involved in kidney and gonad development) and is responsible for Denys-Drash syndrome. (See 'Diffuse mesangial sclerosis with Denys-Drash syndrome' below.)
NPHS2 and NPHS1 are the most commonly affected genes, accounting for approximately 95 percent of cases . Genetic causes of CNS do not respond to glucocorticoid or immunosuppressive therapy.
Nongenetic causes are often secondary and possibly curable disorders. These include infections, such as CNS induced by syphilis or toxoplasmosis, and immune disorders. (See 'Infectious causes' below and 'Immune disorders' below.)
CONGENITAL NEPHROTIC SYNDROME OF FINNISH TYPE — CNS of the Finnish type (CNF; MIM #256300) is most frequent in Finland, with initial studies suggesting an incidence of 1.2 per 10,000 births [3,4]. With prenatal screening, the incidence has fallen to 0.9 per 10,000 births . CNF has also been described in various ethnic groups throughout the world [6-8].
CNF is inherited as an autosomal recessive trait, with males and females being involved equally. There are no manifestations of the disease in heterozygous individuals.
Pathology — Light microscopic studies of kidney biopsy specimens obtained early in the course of the disease show mild mesangial hypercellularity and increased mesangial matrix in the glomeruli [6,9]. No immune deposits are detected by immunofluorescence studies. Over time, there is an increase in mesangial matrix accompanied by progressive glomerulosclerosis.
Tubulointerstitial changes are also prominent in CNF. Irregular microcystic dilatation of proximal tubules is the most striking feature (picture 1); however, this change is not specific and is not seen in all patients . Later in the course, interstitial fibrosis, lymphocytic and plasma cell infiltration, tubular atrophy, and periglomerular fibrosis develop in parallel with sclerosis of the glomeruli.
Pathogenesis — Proteinuria in CNF results from an inherited error in the structure of the glomerular capillary filter. The abnormal gene NPHS1 is localized to the long arm of chromosome 19 in both Finnish and non-Finnish families [11-15] and encodes a transmembrane protein, named nephrin, which is a member of the immunoglobulin (Ig) family of cell adhesion molecules and is phosphorylated by Src family kinases . Nephrin is specifically located at the slit diaphragm of the glomerular podocytes; this could explain the absence of slit diaphragms and foot processes in patients with CNF who have a mutant nephrin protein [17,18] and in mice with nephrin gene disruption .
In the original report, four different variants in NPHS1 were found to segregate with the disorder in affected Finnish families . However, the two most common variants, Fin-major (nt121delCT) and Fin-minor (R1109X), account for nearly 90 percent of all affected Finnish patients and are associated with severe early onset of disease [14,20,21].
More than 200 variants in NPHS1 have been reported in non-Finnish CNF patients [2,22-24]. Most of them are missense variants, many of them causing misfolding of the protein nephrin, which is retained in the endoplasmic reticulum . Some patients with certain variants have been reported to have a less severe form of the disease than Finnish patients [22,26,27].
A case report of two siblings with a milder form of CNF (ie, alternating periods of proteinuria and remission) showed that the two children were compound heterozygotes for two novel, nonconserved missense variants . Additional studies from kidney biopsy samples demonstrated expression of nephrin but with impaired function.
Clinical features — Most infants with CNF are born prematurely (35 to 38 weeks), with a low birth weight for gestational age. The placenta is enlarged, being more than 25 percent of the total birth weight. Fetal distress is common, and the cranial sutures are widely separated due to delayed ossification. Infants often have a small nose and low ears. Flexion deformities of the hips, knees, and elbows are thought to be secondary to the large placenta.
Edema is present at birth or appears during the first week of life in one-half of cases. Severe nephrotic syndrome with marked ascites is always present by three months. The proteinuria is highly selective early in the course of the disease, and hematuria is uncommon, reflecting the lack of inflammation in the glomeruli. The urinary protein losses are accompanied by profound hypoalbuminemia and severe hypogammaglobulinemia due, in part, to loss of selectivity as the disease progresses. As a result of these changes, nutritional status and statural growth are poor and affected infants are highly susceptible to bacterial infections (peritonitis, respiratory infections) and to thromboembolic complications due to the severity of the nephrotic syndrome. Hypothyroidism because of urinary losses of thyroxine-binding proteins is also common . (See "Hypercoagulability in nephrotic syndrome".)
The blood urea nitrogen and creatinine concentrations are initially normal. Kidney ultrasonography shows slightly enlarged, hyperechogenic kidneys without normal corticomedullary differentiation.
End-stage kidney disease usually occurs between three and eight years of age. Several studies, however, have reported that some NPHS1 variants are associated with end-stage kidney disease occurring after the age of 20 years [20,26,29]. As an example, a case series from New Zealand reported that Maori children with CNS have prolonged kidney survival with medical therapy, including with indomethacin and an angiotensin-converting enzyme (ACE) inhibitor . Genetic evaluation detected a common founder variant, a missense variant at codon location 2131, in all of the affected Maori children.
Treatment — The nephrotic syndrome in CNF is always resistant to glucocorticoids and immunosuppressive drugs since it is not an immunologic disease. Furthermore, these drugs may be harmful due to the already high susceptibility to infection. A retrospective study of 21 infants with CNF, for example, found that 63 verified and 62 suspected septic episodes occurred over a mean follow-up period of one year .
Standard conservative treatment includes daily or every-other-day albumin infusion; gamma globulin replacement; nutrition with a high-protein, low-salt diet; vitamin and thyroxine substitution; and prevention of infections and thrombotic complications . Dietary intake is provided by tube feeding or parenteral alimentation .
However, the rate of intercurrent complications remains high and growth and development are usually retarded. Several reported interventions to reduce protein excretion include unilateral nephrectomy  and combination therapy of an ACE inhibitor and indomethacin, which lower intraglomerular pressure and lead to a fall in protein excretion [35-37]. However, some patients may require bilateral nephrectomy in case of severe complications such as failure to thrive or thrombosis to prevent continued massive protein losses before the development of kidney failure [34-36,38].
If bilateral nephrectomy is performed, dialysis is provided until the patient reaches a weight of 8 to 9 kg. At this stage, kidney transplantation can be considered [39,40]. The European Registry for Children on Renal Replacement Therapy reported excellent five-year patient (91 percent) and graft (89 percent) survival for both Finnish and non-Finnish NPHS1 patients that was comparable with patient and graft survival for children with CAKUT (congenital anomalies of the kidney and urinary tract) .
Nephrotic syndrome can develop in the transplanted kidney. In one case series of 65 patients who received 77 kidney transplants, 23 episodes of recurrent nephrotic syndrome occurred in 13 patients with 19 grafts . All 13 affected patients had the Fin-major/Fin-major genotype, which is associated with the absence of nephrin. Eight (of 11 patients tested) had circulating antinephrin antibodies. Recurrence of disease is associated with graft loss. Plasma exchange combined with cyclophosphamide and anti-CD20 antibodies has been successful in treating recurrence of nephrosis due to antinephrin antibodies .
Antenatal diagnosis — CNF becomes manifest during early fetal life, beginning at the gestational age of 15 to 16 weeks. The initial symptom is fetal proteinuria, which leads to a more than 10-fold increase in the amniotic fluid alpha-fetoprotein (AFP) concentration. A parallel but less important increase in the maternal plasma AFP level is observed. These changes are not specific, but they may permit the antenatal diagnosis of CNF in high-risk families in which termination of the pregnancy might be considered .
However, elevated AFP levels in maternal blood and amniotic fluid can also be observed before the 20th gestational week in pregnancies in which the fetus is a healthy carrier (heterozygote) of a pathogenic NPHS1 variant. In one report, the AFP values for pregnancies in which the fetus was a healthy carrier overlapped with the elevated values in an affected fetus (homozygote) . Repeated measurement of AFP in amniotic fluid during the second trimester of pregnancy is needed to distinguish affected fetuses from carriers .
Genetic analyses diminish the risk of false-positive results in informative families . The four major haplotypes, which cover 90 percent of the CNF alleles in Finland, have been identified, resulting in a test with up to 95 percent accuracy. Commercial tests are also available to detect NPHS1 variants. Antenatal diagnosis may be possible for a fetus following trophoblast biopsy if the responsible variants have been identified in an older sibling.
CONGENITAL NEPHROTIC SYNDROME AND NPHS2 VARIANTS — NPHS2 encodes an integral membrane protein, podocin, which is found exclusively in glomerular podocytes and is the causative gene for an autosomal recessive form of familial steroid-resistant nephrotic syndrome (MIM #600995). A few patients with the typical clinical picture of CNS were found to lack NPHS1 variants:
●One study found homozygous NPHS2 variants in two of five such patients .
●These findings were confirmed in a second report that described 11 patients with two recessive NPHS2 variants who presented initially with CNS .
●Two additional cases with similar findings in terms of variants in NPHS2, but not NPHS1, were also reported in a study of 13 unrelated patients from Japan .
Although affected individuals typically present in early childhood with proteinuria , some have milder disease and present in adolescence or young adulthood. Issues related to treatment of nephrotic syndrome associated with NPHS2 variants are discussed separately. Children develop end-stage kidney disease at a mean age of 6.6 years . (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'NPHS2 gene' and "Steroid-resistant nephrotic syndrome in children: Etiology", section on 'Specific gene variants'.)
Associated features include cardiac anomalies .
Some patients also have both NPHS1 and NPHS2 variants, resulting in a triallelic abnormality (homozygous variants in one gene and a heterozygous variant in the other) [26,29,51]. These findings demonstrate the genetic heterogeneity of CNS and the absence of clear genotype/phenotype correlations.
DIFFUSE MESANGIAL SCLEROSIS — Diffuse mesangial sclerosis is another hereditary cause of CNS associated with glomerular injury and rapid progression to end-stage kidney disease. The same glomerular lesions are observed in Denys-Drash syndrome (MIM #194080), which is characterized by the combination of nephropathy, male pseudohermaphroditism, and Wilms tumor.
Pathology — The glomerular lesions are characterized in the early stages by a fibrillar increase in mesangial matrix without mesangial cell proliferation [55-57]. The capillary walls are lined by hypertrophied podocytes (picture 2). The fully developed lesion consists of the combination of thickening of the glomerular basement membranes and massive enlargement of mesangial areas, leading to reduction of the capillary lumens. The mesangial sclerosis eventually contracts the glomerular tuft into a sclerotic mass within a dilated urinary space (picture 3). There is usually a corticomedullary gradient of involvement, with the deepest glomeruli being less affected. Tubules are severely damaged, especially in the deeper cortex, where they are markedly dilated and often contain hyaline casts.
Electron microscopy reveals hypertrophic mesangial cells surrounded by an abundant mesangial matrix, which often contains collagen fibrils. The podocytes are hypertrophied and contain many vacuoles. There is also irregular effacement of foot processes with focal detachment of the epithelial cell from the glomerular basement membrane.
Immunofluorescence shows mesangial deposits of IgM, C3, and C1q in the least affected glomeruli, while deposits of IgM and C3 outline the periphery of the sclerosed glomeruli. These immune deposits are probably nonspecific, occurring in areas of previous injury.
The same glomerular lesion is observed in the Denys-Drash syndrome. As a result, all patients with diffuse mesangial sclerosis should be screened for the Denys-Drash syndrome. This consists of karyotyping in phenotypic females, looking for male pseudohermaphroditism with a 46 XY genotype, and ultrasonography in all patients, looking for Wilms tumor and abnormal gonadal development. Some investigators also suggest that an assessment for variants in the Wilms tumor predisposing gene, WT1, should be performed to help identify individuals at risk for the tumor [58,59]. As an example, among 10 patients presenting with isolated diffuse mesangial sclerosis, four had variants in the WT1 gene . (See 'Diffuse mesangial sclerosis with Denys-Drash syndrome' below.)
Pathogenesis — Diffuse mesangial sclerosis is associated with dominant pathogenic variants in WT1 (23.1 percent) and biallelic pathogenic variants in PLCE1 (17.8 percent), LAMB2 (13.6 percent), and NPHS1 (4.9 percent) .
Abnormalities in the PLCE1 gene, which encodes phospholipase C epsilon, appear to cause isolated diffuse mesangial sclerosis. In one study of 12 children from six families with the disease, homozygous truncating gene variants in PLCE1 were found in eight children . By comparison, missense variants found in two siblings were only associated with focal segmental glomerulosclerosis. A subsequent report involving a worldwide cohort of children with isolated diffuse mesangial sclerosis found truncating PCLE1 variants in 10 of 35 families . WT1 variants were detected in three families.
Phospholipase C epsilon is a member of the phospholipase family of enzymes that catalyzes the hydrolysis of polyphosphoinositides,w resulting in generation of second messengers (eg, inositol-1,4,5-triphosphate), which are involved in cell growth and differentiation. A pathogenetic role for PLCE1 in glomerular development was supported by findings of disruption of the glomerular filtration barrier and edema in a PLCE1 knockout zebrafish model.
How a PLCE1 gene defect results in changes in the glomerular nephrotic syndrome is unknown. One possible explanation is that phospholipase C epsilon interacts with GTPase-activating protein, which is known to interact with the slit diaphragm protein, nephrin. Perturbations of this normal interaction would have a downstream effect including the subsequent interaction of GTPase-activating protein with nephrin.
Clinical and laboratory features — Newborns with diffuse mesangial sclerosis appear normal at birth, with a normal birth weight and without placental enlargement, in contrast with the low birth weight and enlarged placental seen in those with CNS of the Finnish type (CNF). The nephrotic syndrome may be present at birth or even suspected in utero by the finding of an elevated plasma alpha-fetoprotein (AFP) level in the mother or the discovery of large hyperechogenic kidneys . More commonly, however, proteinuria with a bland urine sediment develops postnatally, increasing progressively during the first or the second year of life. Various types of extrarenal signs have been reported in isolated patients including nystagmus, cataract, intellectual disability, microcephaly, severe myopia, and muscular dystrophy. (See "Cataract in children".)
All children progress to end-stage kidney disease, frequently in association with hypertension. This usually occurs before age three, within a few months after the discovery of kidney manifestations .
Treatment — Diffuse mesangial sclerosis is reportedly resistant to corticosteroids and immunosuppressive drugs. In the previously mentioned report, however, there was a clinical response to cyclosporine after failing initial steroid therapy in one of the eight children with diffuse mesangial sclerosis due to a genetic variant in PLCE1 . This case is the first reported cases of successful remission in patients with CNS due to genetic defect.
The degree of proteinuria is typically less severe than in CNF, and specific supplemental therapy is usually not required.
Treatment is supportive and consists of maintenance of electrolyte and water balance and adequate nutrition, prevention and treatment of infectious complications, and management of kidney failure. Bilateral nephrectomy has been considered at the time of transplantation in patients with WT1 variants because of the theoretical risk of developing a Wilms tumor. This issue remains unresolved, although some investigators have not found Wilms tumor in the kidneys from 14 children with kidney failure . Recurrent disease does not develop in the transplant.
The combination of an angiotensin-converting enzyme (ACE) inhibitor and indomethacin therapy was used to treat one child with diffuse mesangial sclerosis . The child had a sustained clinical response and normal growth pattern and suffered no adverse effects.
DIFFUSE MESANGIAL SCLEROSIS WITH DENYS-DRASH SYNDROME — Denys-Drash syndrome (MIM #194080) refers to the triad of progressive kidney disease, male pseudohermaphroditism, and Wilms tumor [63,64]. All of the patients were infants with heavy proteinuria progressing rapidly to kidney failure. Incomplete forms of the syndrome were described, and the glomerulopathy was identified as diffuse mesangial sclerosis .
Epidemiology and genetics — A number of cases of Denys-Drash syndrome have been reported [63-67]. The Denys-Drash syndrome is usually sporadic, although occurrence in two kindreds has been reported. However, constitutional variants occur in the Wilms tumor predisposing gene, WT1 .
Wilms tumor is an embryonic kidney tumor thought to arise from aberrant mesenchymal stem cell differentiation secondary to the loss of a tumor suppressor gene or genes [69,70]. The WT1 gene lies at chromosomal position 11p13; it appears to encode a zinc finger protein, which is probably a transcription factor [71-74]. WT1 is also expressed in the gonads, suggesting that the genital abnormalities in the Denys-Drash syndrome may result from pleiotropic effects of mutations in the WT1 gene itself. This hypothesis was first confirmed in a report, which identified constitutional heterozygous variants within the WT1 gene in some individuals with the Denys-Drash syndrome .
Subsequently, variants of WT1 have been found in most patients with this syndrome. Most abnormalities are missense changes either in exon 9, which encodes for zinc finger 3 (with a mutational hot spot at an arginine residue thought to interact with the consensus deoxyribonucleic acid [DNA] sequence), in exon 8, which encodes for zinc finger 2 or their intronic junctions .
Clinical presentation — Diffuse mesangial sclerosis is a constant feature of the Denys-Drash syndrome. It is associated with the two other components of the triad in the complete form but with only one of the two in the incomplete forms.
The clinical course of the nephropathy is not different from that described above in isolated diffuse mesangial sclerosis. However, Wilms tumor may not be the first clinical manifestation of the syndrome. Thus, careful kidney ultrasonography should be performed every three months until the age of seven years, looking for nephroblastoma. The tumor may be unilateral or bilateral and is associated in a few cases with nodules of nephroblastomatosis [57,68].
Male pseudohermaphroditism, characterized by ambiguous genitalia or female phenotype with dysgenetic testis or streak gonads, is observed in all 46 XY patients. In contrast, all 46 XX children appeared to have a normal female phenotype, with normal ovaries, when the information was available. The finding of a normal male phenotype seems to exclude the diagnosis of Denys-Drash syndrome. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)
Treatment — Patients who reach end-stage kidney disease should undergo bilateral nephrectomy to prevent the development of Wilms tumor after kidney transplantation. Patients with a female phenotype and 46,XY karyotype should be considered for bilateral gonadectomy due to an increased risk of gonadoblastoma .
PIERSON SYNDROME — Pierson syndrome (MIM #609049) is a rare autosomal recessive syndrome. Characteristic findings include CNS with histologic lesions of diffuse mesangial sclerosis, ocular malformations (microcoria, abnormal lens with cataracts, and retinal abnormalities), and neurologic symptoms (hypotonia, psychomotor retardation) [78-80]. A majority of affected individuals progress to kidney failure within 12 months .
This autosomal recessive disorder is due to variants in the LAMB2 gene, which encodes laminin beta 2 [81,82]. Laminin beta 2 is abundantly expressed in the glomerular basement membrane, where it plays a role in anchoring and in the development of podocyte foot processes . LAMB2 knockout mice exhibit CNS in association with anomalies of the retina and neuromuscular junction. LAMB2 variants have also been found in patients with CNS and either no or less severe ocular abnormalities .
OTHER GENETIC CAUSES — A number of other disorders with a genetic basis are rare causes of CNS.
●Galloway-Mowat syndrome – Galloway-Mowat syndrome (MIM #251300) is characterized by microcephaly, intellectual disability, hiatus hernia, skeletal anomalies, and nephrotic syndrome . It appears to be transmitted as an autosomal recessive trait. The nephrotic syndrome presents early with a mean age of onset of three months and is usually severe and resistant to steroid therapy. Kidney biopsy reveals minimal changes or focal segmental glomerulosclerosis.
There is genetic heterogeneity of the syndrome, as illustrated by the following case reports:
•Recessive variants in the genes encoding the four subunits of the KEOPS complex (OSGEP, TP53RK, TPRKB, and LAGE3) have also been identified in 37 affected individuals from 32 families . The OSGEP and TP53RK genes appear to encode proteins involved with the actin cytoskeleton and podocyte function.
•A case report of four families identified variants in the protein's zinc-finger domain of the transcriptional regulator PRDM15 that resulted in nephrotic syndrome within the first two months of life, as well as brain anomalies, cardiac defects, and skeletal defects consistent with Galloway-Mowat syndrome .
•Homozygous splice site variants in the gene WDR4 that encodes a transfer ribonucleic acid-modifying enzyme was identified in three affected siblings of an Indian family with Galloway-Mowat syndrome .
●Mitochondrial disorders – An early-onset nephrotic syndrome has been reported in children with a coenzyme Q10 (ubiquinone) deficiency secondary to variants in genes involved in coenzyme Q10 biosynthesis (COQ2, PDSS2, COQ6, and COQ8B/ADCK4) [92-97]. Several associated symptoms suggest a mitochondrial disorder: hearing loss, nystagmus, encephalopathy, seizures, ataxia, hypotonia, developmental delay, diabetes mellitus, and elevated lactate levels. These patients may benefit from a treatment with ubiquinone (15 to 30 mg/kg per day) .
●Herlitz junctional epidermolysis bullosa – This autosomal recessive disease is characterized by recurrent blister formation as a result of structural fragility within the skin. Variants of several genes involved in collagens, integrins, or laminins biosynthesis have been reported, some of them in association with a nephrotic syndrome and focal segmental glomerulosclerosis: ITGB4, ITGA4, ITGA3, LAMB3, and CD151 [99-101].
●Nail-patella syndrome – Kidney disease varies among patients with nail-patella syndrome (MIM #161200), an autosomal dominant disorder typically caused by variants of the LMX1B gene. Proteinuria may present at any age, and a few patients will develop nephrotic syndrome and progress to end-stage kidney disease. (See "Nail-patella syndrome".)
●Other associations – CNS has been observed in case reports that have identified variants in the following genes:
•Lowe syndrome (MIM #309000) – Two cases of CNS have been reported in patients with Lowe oculo-cerebro-renal syndrome, caused by variants in the OCRL gene . (See "Dent disease (X-linked recessive nephrolithiasis)", section on 'Dent disease 2 versus Lowe syndrome'.)
•Sphingosine phosphate lyase insufficiency syndrome (MIM #617575) – Recessive variants in the SGPL1 gene have been reported to cause adrenal insufficiency with calcifications, ichthyosis, acanthosis, immunodeficiency, and CNS. Other symptoms include hypothyroidism, neurologic symptoms, and cryptorchidism [103-106].
•Nephrotic syndrome type 12 (MIM #617609) – Variants in MAGI2 have been reported in patients with CNS . MAGI2 has been shown to interact with nephrin and regulate podocyte cytoskeleton and slit diaphragm dynamics.
•Congenital disorders of glycosylation – CNS has been reported in up to 20 percent of patients with congenital disorders of glycosylation [108-110]. (See "Overview of congenital disorders of glycosylation".)
•Biallelic CRB2 variants were described in five fetuses and one child from three families with severe neurologic involvement, including ventriculomegaly and kidney involvement, including elevated alpha-foetoprotein, and kidney histology showing tubular cysts at the corticomedullary junction and effacement of the podocyte foot processes .
●Congenital syphilis – Congenital syphilis can cause membranous nephropathy [114,115]. Histologic examination often shows a mixed pattern with membranous nephropathy and mesangial proliferation. Penicillin treatment leads to the resolution of the syphilis and kidney abnormalities.
●Congenital toxoplasmosis – The nephrotic syndrome may be induced by congenital toxoplasmosis . Proteinuria may be present at birth or may develop during the first three months, in association with ocular or neurologic symptoms. Histologic examination often shows mesangial proliferation with or without focal segmental glomerulosclerosis. Treatment of toxoplasmosis or steroid therapy usually leads to remission of the proteinuria.
●Congenital cytomegalovirus infection – CNS with diffuse mesangial sclerosis has been reported in association with cytomegalovirus . The patient responded to ganciclovir therapy . (See "Congenital cytomegalovirus infection: Clinical features and diagnosis".)
●Infantile systemic lupus erythematosus has been reported in a 10-week-old boy with CNS .
●Neonatal nephrotic syndrome due to membranous nephropathy has been diagnosed antenatally in infants with mothers who have variants in the metallomembrane endopeptidase gene, which encodes the podocyte protein neutral endopeptidase (NEP) . During pregnancy, the presence of fetal NEP protein induces a maternal alloimmune response. Maternal antibody to NEP fetal protein results in fetal podocyte injury, which may lead to chronic kidney failure. The mothers' IgG response to the expression of fetal NEP determines the severity of the neonatal disease.
●Membranous nephropathy has also been reported in children under one year who had both circulating cationic bovine serum albumin (BSA) and anti-BSA antibodies . BSA was detected in the immune deposits, suggesting that the cationic BSA is pathogenic through binding to the anionic glomerular basement membrane and in situ formation of immune complexes. These observations raise the possibility that other food antigens might be involved in cases of membranous nephropathy.
DIAGNOSIS — Genetic testing is the first-choice diagnostic test because most cases of CNS are caused by genetic variants and fail to respond to immunosuppressive therapy. Screening for the NPHS1, NPHS2, WT1, and LAMB2 genes identifies underlying genetic anomalies in more than 80 percent of cases [60,122]. Kidney biopsy results may be nonspecific and may not identify the underlying etiology, especially a genetic cause.
Extrarenal manifestations can be helpful in the diagnosis, especially in syndromic cases. Neurologic examination, including brain imaging, may detect abnormal cerebral gyration or cerebellar atrophy suggestive of Galloway-Mowat syndrome, cerebellar and cerebral atrophy suggestive of CoQ10 deficiency, or ventriculomegaly in patients with CRB2 variants . Genital abnormalities in an affected male infant suggest a WT1 variant and the diagnosis of Denys-Drash syndrome. Dysmorphic features or ophthalmologic anomalies suggest a genetic cause.
●Overview – Nephrotic syndrome that presents at birth or within the first three months of life is defined as congenital nephrotic syndrome (CNS). Most children with CNS have a genetic basis for the kidney disease and a poor outcome. (See 'Introduction' above.)
●Etiology – Variants of the following genes are responsible for the majority of cases of CNS:
•NPHS2, which encodes podocin (a protein that interacts with nephrin at the slit diaphragm) and is responsible for familial steroid-resistant nephrotic syndrome. (See 'Congenital Nephrotic Syndrome and NPHS2 variants' above.)
•WT1, which encodes the transcription tumor suppressor (a protein involved in kidney and gonad development) and is responsible for Denys-Drash syndrome. (See 'Diffuse mesangial sclerosis with Denys-Drash syndrome' above.)
Other etiologies of CNS include other less common genetic disorders and secondary causes such as infections (eg, syphilis or toxoplasmosis) (table 1) or immune disorders. (See 'Other genetic causes' above and 'Nongenetic causes' above.)
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