Congenital and infantile nephrotic syndrome

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 renal disease and a poor outcome. The precise diagnosis of the glomerular lesion is based on clinical, laboratory, and histological criteria.

The causes of congenital and infantile nephrotic syndrome will be discussed here.

ETIOLOGY — The results of four reports indicate that mutations in five different genes are responsible for more than 80 percent of congenital nephrotic syndrome (CNS) cases (table 1).

●NPHS1, which encodes nephrin (a key component of the podocyte slit diaphragm) and is responsible for the Finnish-type congenital nephrotic syndrome. (See 'Congenital Nephrotic Syndrome of Finnish type' below.)

●NPHS2, which encodes podocin (a protein that interacts with nephrin at the slit diaphragm) and is responsible for familial focal segmental glomerulosclerosis (FSGS). (See 'Congenital Nephrotic Syndrome and NPHS2 mutations' 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 the Denys-Drash syndrome. (See 'Diffuse mesangial sclerosis with Drash syndrome' below.)

●LAMB2, which encodes laminin beta 2 (a component of the glomerular basement membrane) and is responsible for the Pierson syndrome with diffuse mesangial sclerosis [1]. (See 'Pierson syndrome' below.)

NPHS2 and NPHS1 were the most commonly affected gene, accounting for approximately 95 percent of cases [2]. Genetic causes of CNS do not respond to glucocorticoid or immunosuppressive therapy.

Nongenetic causes are often secondary and possibly curable disorders. These include idiopathic NS, infections, such as CNS induced by syphilis or toxoplasmosis, and toxins such as mercury exposure. (See 'Infectious causes' below and 'Other disorders' below.)

CONGENITAL NEPHROTIC SYNDROME OF FINNISH TYPE — Congenital nephrotic syndrome (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 [5]. 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 renal 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 [10]. 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 family of cell adhesion molecules and is phosphorylated by Src family kinases [16]. 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 [19].

In the original report, four different mutations in this gene were found to segregate with the disorder in affected Finnish families [14]. However, the two most common mutations, 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].

In another study, 32 novel mutations in the nephrin gene were discovered in patients elsewhere in Europe and North America, but no abnormalities were found in seven affected individuals (including the 5' flanking region) [12]. These patients may have mutations elsewhere in the promoter or in intron areas, or in a gene encoding another protein that interacts with nephrin [22]. (See "Focal segmental glomerulosclerosis: Epidemiology, classification, clinical features, and diagnosis".)

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 mutations [23]. Additional studies from renal 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 [24]. (See "Hypercoagulability in nephrotic syndrome".)

The blood urea nitrogen and creatinine concentrations are initially normal. Renal ultrasonography shows enlarged, hyperechogenic kidneys without normal corticomedullary differentiation.

End-stage kidney disease (ESKD) usually occurs between three and eight years of age. Several studies, however, have reported that some NPHS1 mutations are associated with ESKD occurring after the age of 20 years [20,25,26]. As an example, a case series from New Zealand reported that Maori children with CNS have prolonged renal survival with medical therapy, including with indomethacin and angiotensin converting enzyme inhibitor [27]. Genetic evaluation detected a common founder mutation, a missense mutation 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 this 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 [28].

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 by parenteral alimentation [29].

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 [30] and combination therapy of an angiotensin-converting enzyme inhibitor and indomethacin, which lower intraglomerular pressure and lead to a fall in protein excretion [31-33] 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 renal failure [30-32,34].

If nephrectomy is performed, dialysis is provided until the patient reaches a weight of 8 to 9 kg. At this stage, renal transplantation can be considered [35,36]. The European Registry for Children on Renal Replacement Therapy (ESPN/ERA-EDA) reported excellent five-year patient (91 percent) and graft (89 percent) survival for both Finnish and non-Finnish NPHS1 patients that was comparable to patient and graft survival for children with CAKUT (congenital anomalies of the kidney and urinary tract) [37].

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 [38]. 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 [39].

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 [40].

However, false-positive results do occur, often leading to abortion of healthy fetuses. In one study of 21 pregnancies that had been terminated because of increased AFP levels in amniotic fluid, only 12 fetuses were homozygous for nephrin gene mutations as determined by DNA sequencing [41]. The remaining nine were heterozygous carriers and would therefore not have developed CNF. The kidneys of both groups had a similar reduction in podocyte foot processes and slit pores.

Genetic linkage and haplotype analyses may diminish the risk of false-positive results in informative families [42]. 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 mutations. Antenatal diagnosis may be possible for a fetus following trophoblast biopsy if the responsible mutation has been identified in an older sibling.

CONGENITAL NEPHROTIC SYNDROME AND NPHS2 MUTATIONS — 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 focal segmental glomerulosclerosis (FSGS) MIM #604766. A few patients with the typical clinical picture of congenital nephrotic syndrome (CNS) were found to lack NPHS1 mutations:

●One study found homozygous NPHS2 variants in two of five such patients [25].

●These findings were confirmed in a second report that described 11 patients with two recessive NPHS2 variants who presented initially with congenital nephrotic syndrome [26].

●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 [43].

Although affected individuals typically present in early childhood with proteinuria [44], some have milder disease and present in adolescence or young adulthood. Issues related to treatment of FSGS associated with NPHS2 mutations are discussed separately. Children develop end-stage renal disease (ESRD) at a mean age of 6.6 years [2]. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'NPHS2 gene' and "Steroid-resistant idiopathic nephrotic syndrome in children: Etiology", section on 'Specific gene variants'.)

Associated features include cardiac anomalies [45].

Some patients also have both NPHS1 and NPHS2 mutations, resulting in a triallelic abnormality (homozygous mutations in one gene and a heterozygous mutation in the other) [25,26,46]. These findings demonstrate the genetic heterogeneity of congenital nephrotic syndrome and the absence of clear genotype/phenotype correlations.

DIFFUSE MESANGIAL SCLEROSIS — Diffuse mesangial sclerosis is a second hereditary cause of infantile nephrotic syndrome associated with glomerular injury and rapid progression to end-stage renal disease (ESRD). The same glomerular lesions are observed in the Denys-Drash syndrome MIM #194080, which is characterized by the combination of nephropathy, male pseudohermaphroditism, and Wilms' tumor.

Diffuse mesangial sclerosis is seen exclusively in infancy [6,47-51] and appears to be transmitted in some families as an autosomal recessive trait [52].

Pathology — The glomerular lesions are characterized in the early stages by a fibrillar increase in mesangial matrix without mesangial cell proliferation [50-52]. 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 immunoglobulin M (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 mutations in the Wilms' tumor predisposing gene, WT1, should be performed to help identify individuals at risk for the tumor [53,54]. As an example, among 10 patients presenting with isolated diffuse mesangial sclerosis, four had mutations in the WT1 gene [54]. (See 'Diffuse mesangial sclerosis with Drash syndrome' below.)

Pathogenesis — 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 mutations in PLCE1 were found in eight children [1]. By comparison, missense mutations found in two siblings were only associated with focal segmental changes. A subsequent report involving a worldwide cohort of children with isolated diffuse mesangial sclerosis found truncating PCLE1 mutations in 10 of 35 families [55]. WT1 mutations were detected in three families.

Phospholipase C epsilon is a member of the phospholipase family of enzymes that catalyzes the hydrolysis of polyphosphoinositides 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 — As opposed to the congenital nephrotic syndrome of the Finnish type (CNF), children with diffuse mesangial sclerosis appear normal at birth, with a normal birth weight and without placental enlargement. 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 [56]. 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 ESRD, frequently in association with hypertension. This usually occurs before age three, within a few months after the discovery of renal symptoms [51].

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 mutation in PLCE1 [1]. This case is the first reported cases of successful remission in patients with congenital nephrotic syndrome 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 renal failure. Bilateral nephrectomy has been considered at the time of transplantation 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 renal failure [51]. Recurrent disease does not develop in the transplant.

The combination of an angiotensin converting enzyme inhibitor and indomethacin therapy was used to treat one child with diffuse mesangial sclerosis [34]. The child had a sustained clinical response, normal growth pattern, and suffered no adverse effects.

DIFFUSE MESANGIAL SCLEROSIS WITH DRASH SYNDROME — Denys and Drash first reported the triad of progressive renal disease, male pseudohermaphroditism, and Wilms' tumor [57,58]. All of the patients were infants with heavy proteinuria progressing rapidly to renal failure. Incomplete forms of the syndrome were described and the glomerulopathy was identified as diffuse mesangial sclerosis [59].

Epidemiology and genetics — A number of cases of Denys-Drash syndrome have been reported [57-61]. The Denys-Drash syndrome is usually sporadic, although occurrence in two kindreds has been reported. However, constitutional mutations occur in the Wilms' tumor predisposing gene, WT1 [62].

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 [63,64]. The WT1 gene lies at chromosomal position 11p13; it appears to encode a zinc finger protein, which is probably a transcription factor [65-68]. 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 mutations within the WT1 gene in some individuals with the Denys-Drash syndrome [69].

Subsequently, mutations 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 DNA sequence), in exon 8, which encodes for zinc finger 2 or their intronic junctions [70].

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 renal ultrasonography should be performed, looking for nephroblastoma, in any patient found to have diffuse mesangial sclerosis. The tumor may be unilateral or bilateral and is associated in a few cases with nodules of nephroblastomatosis [52,62].

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 ESKD should undergo bilateral nephrectomy in order to prevent the development of Wilms tumor after renal transplantation. Patients with a female phenotype and 46,XY karyotype should be considered for bilateral gonadectomy due to an increased risk of gonadoblastoma [71].

PIERSON SYNDROME — Pierson syndrome (also referred to as microcoria-congenital nephrosis syndrome, MIM #609049) is a rare autosomal recessive syndrome. Characteristic findings include congenital nephrotic syndrome (CNS) with histologic lesions of diffuse mesangial sclerosis, ocular malformations (microcoria, abnormal lens with cataracts, and retinal abnormalities), and neurologic symptoms (hypotonia, psychomotor retardation) [72-75]. This autosomal recessive disorder is due to mutations in the LAMB2 gene, which encodes laminin beta 2 [72,73]. 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 [76]. LAMB2 knockout mice exhibit CNS in association with anomalies of the retina and neuromuscular junction. LAMB2 mutations have also been found in patients with CNS and either no or less severe ocular abnormalities [77].

OTHER GENETIC CAUSES — A number of other disorders with a genetic basis are rare causes of congenital or infantile nephrotic syndrome.

●Galloway-Mowat syndrome – Galloway-Mowat syndrome is characterized by microcephaly, intellectual disability, hiatus hernia, skeletal anomalies, and the nephrotic syndrome [78]. 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. Renal biopsy reveals minimal changes or focal segmental glomerulosclerosis (FSGS).

There is genetic heterogeneity of the syndrome as illustrated by the following case reports:

•Loss-of-function mutations of the WDR73 gene have been reported in six families with Galloway-Mowat syndrome from two cohorts of unrelated patients [79,80].

•Recessive mutations in the genes (OSGEP, TP53RK, TPRKB, and LAGE3) encoding the four subunits of the KEOPS complex have also been identified in 37 affected individuals from 32 families [81]. The OSGEP and TP53RK genes appear to encode proteins involved with the actin cytoskeleton and podocyte function.

•A case report of four families with findings consistent with Galloway-Mowat syndrome identified a NUP133 mutation [82]. NUP133 encodes nucleoporin, a subunit of the nuclear pore complex.

•A case report of four families identified mutations in the protein's zinc-finger (ZNF) 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 [83].

●Mitochondrial disorders – An early-onset nephrotic syndrome has been reported in children with a coenzyme Q10 (ubiquinone) deficiency secondary to mutations in genes involved in coenzyme Q10 biosynthesis (COQ2, PDSS2, COQ6, ADCK4) [84-89]. Several associated symptoms suggest a mitochondrial disorder: hearing loss, nystagmus, encephalopathy, seizures, ataxia, hypotonia, developmental delay, diabetes mellitus, 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. Mutations of several genes involved in collagens, integrins, or laminins biosynthesis have been reported, some of them in association with a nephrotic syndrome and FSGS: ITGB4 encoding integrin b4, ITGA4 encoding integrin a3, ITGA3 encoding the integrin alpha3 subunit, LAMB3 encoding laminin-5, and CD151 [90-92].

●Nail-patella syndrome – Renal disease varies amongst patients with nail-patella syndrome MIM #161200, which is an autosomal dominant disorder typically caused by mutations of the LMX1B gene. Proteinuria may present at any age and a few patients will develop nephrotic syndrome and progress to end-stage renal disease. (See "Nail-patella syndrome".)

●CNS and infantile NS have been observed in case reports that have identified mutations 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 mutation in the OCRL gene [93]. (See "Dent disease (X-linked recessive nephrolithiasis)", section on 'Dent disease 2 versus Lowe syndrome'.)

•Sphingosine-1-phosphate lyase (SGPL1) gene MIM #603729 – Recessive mutations in the SGPL1 gene have been reported to cause adrenal insufficiency with calcifications, ichthyosis, acanthosis, immunodeficiency and congenital nephrotic syndrome (CNS). Other symptoms include hypothyroidism, neurological symptoms, and cryptorchidism [94-97].

•Membrane-associated guanylate kinase (MAG) gene (MIM #602625) – Mutations in MAGI2 (MAG, WW and PDZ domain-containing 2) have been reported in patients with CNS [98]. MAGI2 has been shown to interact with nephrin and regulate podocyte cytoskeleton and slit diaphragm dynamics.

•Congenital disorders of glycosylation (CDG) – CNS has been reported in up to 20 percent of patients with congenital disorders of glycosylation (CDG) [99-101].

•Biallelic CRB2 variants were described in five fetuses and one child from three families with severe neurological involvement, including ventriculomegaly and renal involvement, including elevated alpha-foetoprotein, and renal histology showing tubular cysts at the corticomedullary junction and effacement of the podocyte foot processes [102].

•CNS has been reported in single case reports of type I carbohydrate-deficient glycoprotein syndrome [103], and a patient with ARHGDIA gene mutation [104].

NONGENETIC CAUSES

Idiopathic nephrotic syndrome — Idiopathic nephrosis rarely occurs at birth, more commonly presenting during the first year of life. All the morphological variants of idiopathic nephrotic syndrome seen in older children can occur at this time including minimal change disease, diffuse mesangial proliferation, and focal segmental glomerulosclerosis (FSGS).

Establishing the diagnosis of one of these disorders may be important clinically, since steroid-responsiveness with a favorable course can be seen [8,105]. However, most affected infants are resistant to therapy and many progress to end-stage renal disease (ESRD).

Infectious causes

●Congenital syphilis – Congenital syphilis can cause membranous nephropathy [106,107]. Histological examination often shows a mixed pattern with membranous nephropathy and mesangial proliferation. Penicillin treatment leads to the resolution of the syphilis and the renal abnormalities.

●Congenital toxoplasmosis – The nephrotic syndrome may be induced by congenital toxoplasmosis [108]. Proteinuria may be present at birth or may develop during the first three months, in association with ocular or neurologic symptoms. Histological examination often shows mesangial proliferation with or without FSGS. Treatment of toxoplasmosis or steroid therapy usually leads to remission of the proteinuria.

●Other organisms – Congenital or infantile nephrotic syndrome has been reported in association with cytomegalovirus, rubeola virus, and human immunodeficiency virus (HIV) [109].

Other disorders

●Mercury exposure.

●Infantile systemic lupus erythematosus has been reported in a 10-week-old boy with nephrotic syndrome [110].

●Neonatal nephrotic syndrome due to membranous nephropathy has been diagnosed antenatally in infants with mothers who have mutations in the metallomembrane endopeptidase gene, which encodes the podocyte protein neutral endopeptidase (NEP) [111]. 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 renal failure. The mothers' immunoglobulin G (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 [112]. BSA was detected in the immune deposits, suggesting the cationic BSA is pathogenic through binding to the anionic GBM 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 and should be performed before starting any treatment because most cases of congenital and infantile nephrotic syndrome are caused by genetic mutations and fail to respond to immunosuppressive therapy. Screening for NPHS1, NPHS2, WT1, and LAMB2 genes uncovers underlying genetic anomalies in more than 80 percent of cases [113,114]. Renal 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 mutations [113]. Genital abnormalities in an affected male infant suggest a WT1 mutation and the diagnosis of Denys-Drash syndrome. Dysmorphic features or ophthalmological anomalies suggest a genetic cause.

SUMMARY

●Nephrotic syndrome that presents at birth or within the first three months of life is defined as congenital nephrotic syndrome (CNS). Later onset, between three months and one year of age, is called infantile nephrotic syndrome. Most children with congenital or infantile nephrotic syndrome have a genetic basis for the renal disease and a poor outcome.

●Mutations of the following genes are responsible for the majority of cases of congenital and infantile nephrotic syndrome:

•NPHS1, which encodes nephrin (a key component of the podocyte slit diaphragm) and is responsible for the Finnish-type congenital nephrotic syndrome. (See 'Congenital Nephrotic Syndrome of Finnish type' above.)

•NPHS2, which encodes podocin (a protein that interacts with nephrin at the slit diaphragm) and is responsible for familial focal segmental glomerulosclerosis (FSGS). (See 'Congenital Nephrotic Syndrome and NPHS2 mutations' above.)

•WT1, which encodes the transcription tumor suppressor (a protein involved in kidney and gonad development) and is responsible for the Denys-Drash syndrome. (See 'Diffuse mesangial sclerosis with Drash syndrome' above.)

●Other etiologies of congenital or infantile nephrotic syndrome include other less common genetic disorders, idiopathic nephrotic syndrome, and secondary causes such as infections (eg, syphilis or toxoplasmosis) (table 1), toxins such as mercury exposure. (See 'Other genetic causes' above and 'Nongenetic causes' above.)

●Because most cases of congenital and infantile nephrotic syndrome are caused by genetic mutations and fail to respond to immunosuppressive therapy, we suggest genetic screening be performed to confirm the underlying diagnosis before starting immunosuppressive treatment (Grade 2C).