Congenital Nephrotic Syndrome
Introduction to Congenital Nephrotic Syndrome
Congenital Nephrotic Syndrome (CNS) is a rare kidney disorder characterized by the presence of nephrotic syndrome within the first three months of life. It is primarily a genetic condition that affects the glomerular filtration barrier, leading to severe proteinuria, hypoalbuminemia, and edema.
Key features of CNS include:
- Onset within the first 3 months of life
- Massive proteinuria (>20 mg/m²/hour)
- Hypoalbuminemia (<2.5 g/dL)
- Edema
- Hyperlipidemia
CNS is distinct from other forms of nephrotic syndrome due to its early onset and genetic etiology, making it a challenging condition to manage in neonates and infants.
Etiology of Congenital Nephrotic Syndrome
Congenital Nephrotic Syndrome is primarily caused by genetic mutations affecting proteins crucial for the integrity of the glomerular filtration barrier. The most common genetic causes include:
- NPHS1 gene mutations (Finnish-type CNS):
- Accounts for about 40-50% of CNS cases
- Encodes nephrin, a key component of the slit diaphragm
- Autosomal recessive inheritance
- NPHS2 gene mutations:
- Encodes podocin, another essential protein in the slit diaphragm
- Can cause both congenital and infantile nephrotic syndrome
- Autosomal recessive inheritance
- WT1 gene mutations (Denys-Drash syndrome, Frasier syndrome):
- Associated with other congenital anomalies and increased risk of Wilms tumor
- Typically autosomal dominant
- LAMB2 gene mutations (Pierson syndrome):
- Affects laminin β2, a component of the glomerular basement membrane
- Often associated with ocular abnormalities
- Autosomal recessive inheritance
Less common genetic causes include mutations in PLCE1, CD2AP, and ARHGDIA genes. In rare cases, CNS can be secondary to congenital infections (e.g., cytomegalovirus, toxoplasmosis) or maternal alloimmunization to neutral endopeptidase.
Clinical Presentation of Congenital Nephrotic Syndrome
The clinical presentation of Congenital Nephrotic Syndrome typically includes:
- Prenatal findings:
- Elevated alpha-fetoprotein (AFP) in maternal serum and amniotic fluid
- Enlarged placenta (>25% of birth weight)
- Premature birth (often 35-38 weeks gestation)
- Neonatal presentation:
- Low birth weight for gestational age
- Edema, particularly periorbital and in the lower extremities
- Ascites
- Enlarged kidneys on physical examination
- Early infancy:
- Failure to thrive
- Recurrent infections due to loss of immunoglobulins
- Hypothyroidism (due to loss of thyroid-binding proteins)
- Anemia
- Vitamin D deficiency and hypocalcemia
- Associated features (depending on genetic cause):
- Microcoria and abnormal lens structure (Pierson syndrome)
- Ambiguous genitalia and/or cryptorchidism (WT1 mutations)
- Developmental delay
The severity and progression of symptoms can vary depending on the underlying genetic cause and the effectiveness of early interventions.
Diagnosis of Congenital Nephrotic Syndrome
Diagnosis of Congenital Nephrotic Syndrome involves a combination of clinical, laboratory, and genetic investigations:
- Clinical assessment:
- Detailed family history
- Physical examination for edema, ascites, and other associated features
- Laboratory tests:
- Urinalysis: Massive proteinuria (>20 mg/m²/hour or urine protein/creatinine ratio >2)
- Serum albumin: Typically <2.5 g/dL
- Lipid profile: Hyperlipidemia (elevated cholesterol and triglycerides)
- Renal function tests: Serum creatinine, blood urea nitrogen (BUN)
- Complement levels: Usually normal in genetic forms of CNS
- Thyroid function tests
- Immunoglobulin levels
- Imaging studies:
- Renal ultrasound: To assess kidney size and echogenicity
- Chest X-ray: To evaluate for pleural effusions
- Genetic testing:
- Next-generation sequencing panels for known CNS-associated genes
- Whole exome sequencing in cases without identified mutations in common genes
- Renal biopsy:
- Not always necessary for diagnosis but can be helpful in some cases
- Findings may include foot process effacement on electron microscopy
- Specific histological patterns may be seen depending on the genetic cause
- Prenatal diagnosis:
- Elevated maternal serum alpha-fetoprotein (MSAFP)
- Genetic testing of amniotic fluid or chorionic villus sampling in high-risk pregnancies
Early and accurate diagnosis is crucial for initiating appropriate management and genetic counseling for affected families.
Management of Congenital Nephrotic Syndrome
Management of Congenital Nephrotic Syndrome is complex and requires a multidisciplinary approach. The primary goals are to control symptoms, prevent complications, and optimize growth and development. Key aspects of management include:
- Nutritional support:
- High-protein diet (2-3 g/kg/day)
- Calorie supplementation to meet increased metabolic demands
- Vitamin D and calcium supplementation
- Fluid and electrolyte management:
- Regular albumin infusions (1-2 g/kg/day) to maintain serum albumin >2 g/dL
- Diuretics (e.g., furosemide) to manage edema
- Careful monitoring and replacement of electrolytes
- Anticoagulation:
- Prophylactic anticoagulation (e.g., low-dose aspirin or heparin) in severe cases to prevent thrombotic complications
- Infection prevention and management:
- Immunoglobulin replacement therapy
- Vaccinations as per schedule, including pneumococcal vaccine
- Prompt treatment of infections
- Hormonal therapy:
- Thyroid hormone replacement if hypothyroidism develops
- Growth hormone therapy to improve growth in some cases
- Angiotensin-converting enzyme (ACE) inhibitors or Angiotensin receptor blockers (ARBs):
- May be used to reduce proteinuria and slow disease progression
- Careful monitoring of renal function and potassium levels required
- Renal replacement therapy:
- Unilateral or bilateral nephrectomy may be considered to reduce protein losses
- Dialysis (usually peritoneal dialysis in infants) as a bridge to transplantation
- Renal transplantation is the definitive treatment, typically performed around 1-2 years of age or when the child reaches 8-10 kg
- Genetic counseling:
- For family planning and risk assessment in future pregnancies
Management strategies may need to be individualized based on the specific genetic cause, disease severity, and response to interventions. Close monitoring and frequent adjustments to the treatment plan are often necessary.
Prognosis of Congenital Nephrotic Syndrome
The prognosis of Congenital Nephrotic Syndrome has improved significantly with advances in management strategies and renal replacement therapy. However, it remains a challenging condition with substantial morbidity and mortality risks. Key prognostic factors include:
- Genetic etiology:
- Some genetic forms (e.g., NPHS2 mutations) may have a slightly better prognosis than others
- Certain mutations (e.g., WT1) carry additional risks such as malignancy
- Time to end-stage renal disease (ESRD):
- Most children progress to ESRD within the first few years of life
- Early and aggressive management may delay progression in some cases
- Complications:
- Infections remain a significant cause of morbidity and mortality
- Thrombotic events can lead to severe complications if not prevented or managed promptly
- Growth retardation and developmental delays are common but may improve with optimal management
- Renal transplantation outcomes:
- Generally good outcomes post-transplantation, with low recurrence risk for genetic forms of CNS
- 5-year graft survival rates are comparable to those for other causes of ESRD in children
- Long-term immunosuppression carries its own risks and requires careful monitoring
- Extra-renal manifestations:
- Some genetic forms of CNS may have associated extra-renal features that impact long-term prognosis
With optimal management and successful renal transplantation, many children with CNS can achieve good long-term outcomes. However, they require lifelong medical follow-up and may face challenges related to chronic kidney disease and its treatment. Early diagnosis, prompt initiation of appropriate therapy, and a multidisciplinary approach to care are crucial for optimizing outcomes in children with Congenital Nephrotic Syndrome.
