Fin-major and Fin-minor were the first two main genetic mutations identified in Finnish newborns, however, numerous mutations have now been identified in patients all over the world from various ethnic groups. NPHS1 mutations are the most common cause of primary congenital nephrotic syndrome, accounting for 40-80% of cases. NPHS2: This gene encodes for the protein podocin. Patients with this genetic mutation develop nephrotic syndrome in the first few weeks of infancy, but can also manifest symptoms later in life. Urinary protein loss is less severe when compared with the Finnish type. Both nephrin and podocin play important roles in the structure and function of the podocyte filtration slit diaphragm and disease involvement is typically limited to the kidneys
WT1: The Wilms tumor suppressor gene regulates the expression of many genes involved in kidney and urogenital development. Mutations lead to several types of developmental syndromes, including Denys-Drash syndrome, Frasier syndrome, WAGR syndrome (Wilms tumor, aniridia, genitourinary abnormalities, and intellectual disability), and isolated nephrotic syndrome in infants. Depending on the specific syndrome, patients are at risk for Wilms and other tumors, genital abnormalities, and nephrotic syndrome. LAMβ2 (Pierson syndrome): This gene encodes for the protein laminin β2, which helps attach podocytes to the glomerular basement membrane. Patients with Pierson syndrome have eye abnormalities, including nonreactive narrowing of the pupils (microcoria), and neurologic deficits. PLCε1: Codes for the enzyme Phospholipase Cε1, which is expressed in podocytes.
Secondary Causes
Congenital infections: syphilis, cytomegalovirus, toxoplasmosis, rubella, human immunodeficiency virus (HIV), malaria, hepatitis B
Immunologic: maternal systemic lupus erythematosus

Diagnosis
An examination reveals massive fluid retention and generalized swelling. Abnormal sounds are heard when listening to the heart and lungs with a stethoscope. Blood pressure may be high. The patient may have signs of malnutrition.A urinalysis reveals large amounts of protein and sometimes small amounts of blood in the urine. Kidney function may be normal in the first weeks or months of life. Laboratory studies show low serum levels of protein (albumin) and immunoglobulins, and elevated levels of triglycerides and cholesterol. Blood work may also show thyroid and vitamin D deficiency. Kidneys on ultrasound imaging may appear enlarged and brighter (hyperechoic). The disorder can be screened during pregnancy by finding elevated levels of alpha-fetoprotein on a routine sampling of amniotic fluid.Indication for kidney biopsy remains unclear as histologic findings do no reveal the cause of congenital nephrotic syndrome, but findings may help in developing treatment strategies. Findings on light microscopy can vary from minimal change nephropathy to focal segmental glomerulosclerosis or diffuse mesanigial sclerosis. Electron microscopy shows podocyte disruption (loss of foot processes or slit diaphragm).Genetic analysis and infectious workup are needed to determine the precise cause of congenital nephrotic syndrome. Understanding the underlying cause can assist in disease management, prognosis, and genetic counseling. Treatment
Genetic forms of nephrotic syndrome are typically resistant to steroid and other immunosuppressive treatment.