OVERVIEW

What is Congenital and Infantile Nephrotic Syndrome?

Congenital nephrotic syndrome (CNS) refers to nephrotic syndrome present at birth or occurring within the first 3 months of life. Nephrotic syndrome that develops later (between 3 months and 1 year of age) is termed infantile nephrotic syndrome.

The main symptoms of this condition include proteinuria, edema, and hypoalbuminemia. Its occurrence is closely linked to genetic mutations, and genetic testing is strongly recommended upon diagnosis. Despite aggressive renal protection, symptomatic support, and nutritional therapy, the prognosis for these children remains poor. Some may require dialysis or kidney transplantation.

Is Congenital and Infantile Nephrotic Syndrome Common?

It has a slightly higher incidence in specific ethnic groups. For example, Finns have a relatively higher prevalence of CNS caused by NPHS1 gene mutations, approximately 1 in 10,000. Overall, it is a rare disease.

SYMPTOMS

What are the clinical manifestations of congenital and infantile nephrotic syndrome?

• Similar to other nephrotic syndromes. Main manifestations include massive proteinuria, hypoalbuminemia, edema, etc. However, hematuria is not obvious.

• Due to conditions like hypoalbuminemia, bacterial infections and thrombotic events are more likely to occur.

• Hypothyroidism is also relatively common due to the urinary loss of thyroxine-binding protein.

• Massive proteinuria and hypoalbuminemia are difficult to control, making early-onset uremia more likely.

CAUSES

How many single genes are currently known to be associated with nephrotic syndrome?

Currently, 52 single genes are known to be associated with nephrotic syndrome, including 44 recessive genes and 8 dominant genes. The response to hormone and immunosuppressive therapy is generally poor in these single-gene-related nephrotic syndromes.

What is the correlation between age and the occurrence of single-gene-related nephrotic syndrome?

The younger the age of a nephrotic syndrome patient, the more likely it is caused by a single-gene mutation. The frequency of single-gene-related nephrotic syndrome based on age is as follows:

• 0–3 months: 69%;
• 4–12 months: 50%;
• 13 months to 6 years: 25%;
• 7–12 years: 18%.

What are the causes of congenital and infantile nephrotic syndrome?

• Gene mutations: Pathogenic mutations most commonly occur in patients who develop symptoms within 3 months after birth:

  • NPHS1 gene: Causes Finnish-type congenital nephrotic syndrome.

  • NPHS2 gene.

  • NPHS3 (PLCE1) gene.

  • WT1 gene: Causes Denys-Drash syndrome.

  • LAMB2 gene: Causes Pierson syndrome.

  • Among patients who develop symptoms after 1 year of age, NPHS2 gene mutations are the most common. WT1 gene mutations exhibit a biphasic distribution, with the first peak at 4–12 months and the second peak after 18 years of age.

  • Other genetic factors: Other genetic disorders can also lead to nephrotic syndrome, such as coenzyme Q10-related genes (mitochondrial disorders), Galloway-Mowat syndrome, nail-patella syndrome, congenital disorders of glycosylation, etc. However, these are not the primary genetic causes of congenital and infantile nephrotic syndrome.

• Infectious and toxic factors:

  • Congenital syphilis: Histological examination typically shows a mixed pattern of membranous nephropathy and mesangial proliferation. Penicillin treatment can alleviate both syphilis and renal abnormalities.

  • Congenital toxoplasmosis: Histological examination usually reveals mesangial proliferation with or without focal segmental glomerulosclerosis. Treatment for toxoplasmosis or steroid therapy often improves proteinuria.

  • Mercury exposure.

DIAGNOSIS

Is genetic testing necessary for congenital and infantile nephrotic syndrome? What other tests are needed besides this?

Once massive proteinuria and hypoalbuminemia are present, nephrotic syndrome can be diagnosed. Then, possible underlying causes should be investigated.

It is recommended that infants under 1 year of age with nephrotic syndrome should routinely undergo monogenic testing. Non-monogenic potential causes, such as syphilis or mercury exposure, should also be ruled out.

TREATMENT

Which department should be consulted for congenital and infantile nephrotic syndrome?

Currently, pediatricians primarily handle diagnosis and treatment in China. Consultation with a pediatric nephrology specialist is usually recommended.

How should congenital and infantile nephrotic syndrome be treated?

• Identifying the cause is crucial. For example, monogenic disorders involving coenzyme Q10 can be treated with oral coenzyme Q10 at a dosage of 15–30 mg per kilogram of body weight daily.

• Since the condition is often resistant to steroids and immunosuppressants, these treatments are not recommended.

• For hypoalbuminemia, administer albumin and immunoglobulins.

• Adopt a low-salt, high-protein, and vitamin-rich diet.

• If hypothyroidism is present, supplement with thyroid hormone.

• Implement targeted measures to prevent infections and thrombosis.

• Some studies suggest that angiotensin-converting enzyme inhibitors combined with indomethacin may be beneficial, though this may not suit all patients. Therefore, a trial can be attempted while monitoring urine protein levels and kidney function.

• Some patients have WT1 mutations, which is a Wilms tumor suppressor gene. Mutations can lead to the triad of nephropathy, male pseudohermaphroditism, and Wilms tumor (Denys-Drash syndrome). Thus, all patients should undergo thorough renal ultrasound examinations to screen for nephroblastoma.

Do patients with congenital and infantile nephrotic syndrome require nephrectomy or kidney transplantation? Under what circumstances is transplantation needed?

If conservative medical treatment fails to control hypoalbuminemia, leading to recurrent infections or growth retardation, bilateral nephrectomy should be performed early rather than waiting for uremia to develop before transplantation.

After bilateral nephrectomy, prompt hemodialysis is necessary, with kidney transplantation typically performed once the patient reaches 8–9 kg in weight. However, some patients may experience a recurrence of nephrotic syndrome post-transplant.

Notably, a minority of patients with NPHS2 gene mutations have a relatively better prognosis and may progress to uremia later or not at all.

DIET & LIFESTYLE

What should children with congenital and infantile nephrotic syndrome pay attention to in daily life?

Due to hypoalbuminemia, they are prone to infections and thrombosis. Therefore, active vaccination and attention to hand hygiene are necessary.

PREVENTION

Can Congenital and Infantile Nephrotic Syndrome Be Prevented? Can It Be Screened Through Prenatal Checkups?

Congenital and infantile nephrotic syndrome cannot be prevented.

Finnish-type congenital nephrotic syndrome caused by NPHS1 gene mutations leads to proteinuria during the fetal stage. Testing may reveal a more than 10-fold increase in amniotic fluid alpha-fetoprotein (AFP) concentration. However, elevated amniotic fluid AFP does not necessarily indicate this disease. Relying solely on amniotic fluid AFP testing to suspect the condition often results in misdiagnosis, leading to unnecessary termination of healthy pregnancies.

To reduce misdiagnosis, genetic testing should be conducted in individuals with a clear family history, and amniotic fluid AFP testing should be performed only in high-risk populations, thereby minimizing prenatal misdiagnosis.

Currently, other congenital or infantile nephrotic syndromes cannot be screened prenatally.