The incidence of CNF is estimated to be 1.2 per 10,000 births in Finland (1093), but is considerably less frequent in other countries (e.g. 1:50,000 in North Americans) (1094a). CNF should be suspected if there is a history of CNF in a sibling, hydrops fetalis or edema of the placenta, i.e., placental weight greater than 25% of BW, or an elevated AFP or total protein concentration in the amniotic fluid. Because the disease begins in utero in all patients, an increased AFP (more than 10 SD above the mean amniotic fluid concentration during the second trimester) is a reliable indicator of the disease (1093).

CNF is an autosomal recessive disorder caused mainly by mutations in the nephrin gene (NPHS1), mapped to chromosome 19q13.1, which encodes nephrin, a putative transmembrane protein belonging to the immunoglobulin superfamily of adhesion molecules (1095). In Finnish families, four main CNF haplotype categories have been observed (1096). Analysis of nonFinnish families suggests that most patients with CNF share the same disease locus (1097).

The natural history of the disease is based on experience before the availability of renal transplantation in young patients (1093,1096,1097,1098,1099,1100,1101). The mean GA was 36.6 ± 1.8 weeks (mean ± SD), and 42% of the infants were premature (less than 37 weeks of GA). Many infants were small for GA, especially those with a GA at or above 37 weeks. In some patients, the typical signs of nephrotic syndrome (i.e., edema, proteinuria, hypoalbuminemia) did not develop until the third month of life. The disease was resistant to steroids or cytotoxic medications (1098). Complications included severe failure to thrive and ascites in all patients, severe bacterial infections in 85%, hypothyroidism, pyloric stenosis in 12%, and thrombotic events in 10% (1098). An increase in Pcr or BUN was observed in 20% of the patients, but none had frank uremia. One-half of the patients died by 6 months of life, and all of them by 4 years.

The proteinuria, initially very selective, i.e., almost entirely albumin as a result of increased permeability of the glomerulus only for small proteins, increases progressively and becomes nonselective, corresponding to increased sieving coefficient and to tubular damage (1101). Blood chemistry is significant for low serum albumin concentration and total thyroxine concentration (as a result of urine loss of thyroxine-binding globulin) (1102), a normal or mildly elevated Pcr, and hyperlipidemia. Ultrasonography shows enlarged kidneys, increased echogenicity of the renal cortex, decreased differentiation between cortex and medulla and poor visualization of the pyramids (1103). Tubular dilations may be misinterpreted as other causes of cystic disease, including autosomal recessive PKD (1104).

The diagnosis of CNF can be confirmed by linkage analysis or by renal biopsy. The latter shows irregularities of the glomerular basement membrane and thinning of the lamina densa (1105), followed by fusion of the epithelial cell foot processes, all of which are similar to the findings in minimal-change, steroid-sensitive nephrotic syndrome. On light microscopy, changes include obliteration of capillary loops and glomerular hyalinization, and dilated tubules from both proximal and distal origin (microcystic disease).

Infants with CNF require intensive management, which includes repetitive administration of albumin and diuretics for ascites, thyroxin, anticoagulation, oral and parenteral hyperalimentation, and the treatment of multiple complications (1098). Chronic renal insufficiency develops between 6 and 23 months of age. As a consequence, most patients eventually receive dialysis while waiting for transplantation. Aggressive therapy, including bilateral nephrectomy (performed in one series at a mean age of 1.2 years) and peritoneal dialysis until transplantation when the infant reaches about 10 kg, allows normal growth and development, a patient survival rate of 97%, and a graft survival rate of 94%, 81% and 81% at 1, 3, and 5 years after transplant (1106). Recently, conservative management of CNF with captopril and indomethacin, sometimes in combination with unilateral nephrectomy, has been described to significantly improve plasma albumin concentration, reduce the need for albumin infusion and duration of hospitalization, maintain normal growth and allow delay of dialysis, and transplantation for at least three years (1107).

The second most common cause of congenital nephrotic syndrome is diffuse mesangial sclerosis (DMS), which appears to represent a heterogenous group of disorders (1100). The onset varies between the second trimester of gestation and 33 months of age. In contrast to CNF, CRF develops rapidly in these patients and is the major cause of death in the absence of dialysis and renal transplantation. Renal venous thrombosis is a frequent complication. In most families, DMS is transmitted as an autosomal recessive trait. Histologic examination of the glomeruli shows mesangial cells embedded in a periodic acid-Schiff-positive and silver-positive fibrillar network occluding the capillaries. Tubular changes are similar to those seen in CNF, and interstitial fibrosis is more pronounced than in CNF. Patients with DMS present with proteinuria (with or without nephrotic syndrome), sometimes hematuria, often arterial hypertension, and progressive CRF leading to ESRD within a few months to 2 years from the onset.

In some infants, DMS is part of Denys-Drash syndrome, which also includes ambiguous genitalia—most often male pseudohermaphroditism, i.e., 46XY karyotype—and Wilms tumor (1108). Denys-Drash syndrome is associated with mutations of the Wilms tumor suppressor gene (WT1) (1109). In these patients, the WT1 expression is abnormal and is associated with increased expression of PAX2 gene, which encodes a transcription factor normally expressed early during development. Increased expression of PAX2 is associated with podocyte hyperplasia (1110). Several patients have presented with incomplete forms of Denys-Drash syndrome (i.e., only two of the three signs of the triad) (1108). DMS is also common in Galloway-Mowat syndrome, an autosomal recessive disorder that includes microcephaly, abnormal gyral pattern, developmental delay, and nephrotic syndrome. Renal pathology in this syndrome may show diffuse mesangial sclerosis, focal segmental sclerosis, mesangial proliferation, or basement membrane and tubular anomalies (1111,1112). In a consanguineous family with previously
affected siblings, prenatal diagnosis may be suggested by demonstration of enlarged hyperechogenic kidneys with amniotic fluid at the upper limit of normal and normal amniotic fluid concentration of AFP (1113).