Congenital Nephrotic Syndrome

Congenital Nephrotic Syndrome

Shanthi S. Balani

Sarah J. Kizilbash


Nephrotic syndrome is a heterogeneous group of disorders classically characterized by a triad of massive proteinuria, hypoalbuminemia, and edema. Based on the age of onset, it has been classified into three types: congenital nephrotic syndrome (CNS) manifesting in utero to 3 months of age, infantile nephrotic syndrome presenting between 3 months to 1 year of age, and childhood nephrotic syndrome occurring after 1 year of age.

This distinction is based on clinical observations of a more severe course in children with CNS. They have a worse prognosis and rapidly progress to end-stage kidney disease. Since the identification of NPHS1 mutation in 1998, a growing number of genetic defects involving the glomerular filtration barrier (GFB) have surfaced, revolutionizing our understanding of CNS pathogenesis. Although the genetic defects may manifest at any age without a clear genotype-phenotype correlation, this distinction helps guide the evaluation and management of CNS.1


Urinary losses of macromolecules, specifically albumin, caused by the dysfunction of the GFB is central to the pathophysiology of CNS. The GFB is composed of three interacting complex layers: the glomerular fenestrated endothelium, the glomerular basement membrane (GBM), and the podocytes with their interdigitating foot processes interconnected by slit diaphragms. Maintaining the integrity of slit diaphragm, which is a highly specialized intercellular junction between podocytes, is crucial for maintaining the size and charge selectivity of the GFB.2,3 Most genes implicated in CNS encode proteins related to the podocytes and slit diaphragms (Figure 7.1). Understanding the genetics has helped unravel the central role of GFB and podocytes in the pathogenesis of nephrotic syndrome.


Genetic defects are the most common cause of GFB dysfunction. Some of these defects present as syndromes including characteristic extrarenal manifestations. A monogenic cause is reported in 69% of children with CNS and 50% of children with infantile forms of nephrotic syndrome. Although CNS has been linked to more than 55 genes (Table 7.1), mutations in five genes account for >80% of the cases: NPHS1 (39%-61%), NPHS2 (15%-39%), LAMB2 (2%-4%), WT1 (˜2%), or PLCE1 (˜2%).4,5

NPHS1 (Nephrin)

NPHS1 encodes nephrin, which is the principal component of the slit diaphragm and is integral for its functioning. It is an immunoglobulin superfamily
transmembrane protein that forms heterodimers essential for connecting adjacent foot processes and regulating podocyte polarity. It also transduces phosphorylation-mediated signals that play a role in actin polymerization.6

NPHS1 mutation was first identified in Finnish families in 1998. It is the most prevalent cause of CNS. The Fin-major (p.L41fsX91—frameshift and stop codon mutation in exon 2) and Fin-minor (p.R1109X—nonsense mutation in exon 26) account for 78% and 16% of the mutated alleles, respectively, among Finnish patients.7 More than 200 different NPHS1 mutations have been identified thus far and involve all 29 exons of NPHS1.8

NPHS2 (Podocin)

NPHS2 encodes for podocin, a transmembrane protein that functions on the podocyte’s cytoplasmic side and serves as a vital connection between the slit diaphragm and the podocyte cytoskeleton. It recruits nephrin to the slit diaphragm and therefore plays a vital role in stabilizing nephrin to actin cytoskeleton. More than 100 different mutations in NPHS2 have been described. They are typically associated with milder phenotypes and are more commonly responsible for childhood-onset steroid-resistant nephrotic syndrome. However, severe mutations causing complete loss of function may cause CNS.6

LAMB2 (Laminin β2)

Laminins are matrix proteins that are found in GBM. They act as the fundamental framework for GBM and play a function in cell adhesion. LAMB2 encodes Laminin β2, a principal component of Laminin-521 (α5, β2, and γ1), the most important β2 laminin isoform and is specifically expressed in the GBM. It is also expressed in some other sites, like intraocular muscles, and is responsible for the phenotype of Pierson syndrome (Table 7.2).6

PLCE1 (PLCε1) (Phospholipase Cε1)

PLCε1 catalyzes the hydrolysis of phosphoinositides to generate two second messengers—inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). These second messengers play an important role in signaling and initiating intracellular pathways of cell growth and differentiation. PLCε1 is abundantly expressed in embryonic glomeruli and is essential for their development. Its absence causes glomerular growth to halt at the capillary loop stage, with a significant reduction in nephrin and podocin expression. In mature glomeruli, it plays a role in cell junction and signaling events.6

WT1 (Wilms Tumor Suppressor Gene)

WT1 is a transcription factor that binds to the DNA and regulates the expression of several genes. This tumor suppressor gene is crucial for gonadal and kidney development in utero, where it is widely expressed and later localized to podocytes of mature kidneys and plays a role in podocyte stabilization.


Secondary CNS may be caused by congenital infections (Table 7.3). However, the possibility of a genetic mutation should be considered if proteinuria persists despite infection treatment.24 CNS has been reported in the setting of cytomegalovirus (CMV) infection where genetic mutations were discovered when patients failed to respond to anti-CMV therapy.25,26

Other rare causes of secondary CNS include maternal lupus, mercury poisoning, and fetomaternal antineutral endopeptidase alloimmunization.29


Depending on the extent of proteinuria, CNS encompasses a spectrum of clinical phenotypes ranging from minimal symptoms to critical illness with significant anasarca and hemodynamic instability. Additional clinical features of CNS may vary depending on the underlying cause. Table 7.3 presents clinical characteristics of common mutations and congenital infections associated with CNS.

Apr 18, 2023 | Posted by in NEPHROLOGY | Comments Off on Congenital Nephrotic Syndrome
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