Congenital nephrotic syndrome

According to Reynolds (2019), the first to describe congenital nephrotic syndrome (CNS) were Gautier and Miville, who wrote about this disease as early as 1942.

According to Höltta (2020), it was first described by Niilo Hallman in 1956. In 1966, Reijo Norio was the first to describe autosomal recessive inheritance (Hölttä 2020).

As early as the mid-1980s, intensive medical therapy followed by kidney transplantation was established as the treatment of choice for severely ill infants (Hölttä 2020).

CNS is defined as a triad of proteinuria > 200 mg/mmol creatinine, hypoalbuminemia and edema occurring within the first three months of life (Reynolds 2019).

Congenital nephrotic syndrome is a special form of nephrotic syndrome alongside congenital and infantile nephrotic syndrome. It is only possible to differentiate between the two diseases based on the age of onset (Dötsch 2017).

Congenital nephrotic syndrome is largely a hereditary disease that is predominantly inherited in an autosomal recessive manner. It is caused by a mutation of the NPHS1 gene (19q13), which codes for nephrin (Herold 2021). The gene locus is located on chromosome 19q12 (Geiger 2003). The disease belongs to the group of focal segmented glomerulosclerosis, also known as FSGS (Herold 2021).

The so-called Finnish type (mutation of the NPHS1 gene) of congenital nephrotic syndrome is the most common, named after the fact that it occurs most frequently in Finland (Geiger 2003). According to the latest findings, the Finnish form can be inherited both autosomal dominant and autosomal recessive (Jain 2023).

Other forms include:

• Diffuse mesangial sclerosis
• Focal segmental glomerulosclerosis
• Membranous glomerulopathy
• Minimal change disease (Reynolds 2019).

The incidence of congenital nephrotic syndrome of the Finnish type is 0.5 - 1:100,000 worldwide, but 1:10,000 in Finland (Manski 2024).

The main cause is mutations of the NPHS1 gene (Manski 2024).

In rarer cases, maternal alloimmune diseases or congenital infections can also cause the disease (Boyer 2021).

The genetic defect primarily affects the protein nephrin. This is of great importance for the structure of the slit diaphragm (Keller 2002).

In the Finnish type, the primary defect is due to a loss of protein in the kidney (Jain 2023).

The proteinuria leads to:

• albuminuria
• edema
• hypoalbuminemia
• Hyperlipidemia
• Increased platelet aggregation
• Loss of minerals and vitamins with malnutrition and increased risk of infection
• Loss of thyroid-binding globulin in the urine with the occurrence of hypothyroidism (Jain 2023)

Congenital nephrotic syndrome manifests itself up to the 3rd month of life (Dötsch 2017). If it manifests later, it is referred to as infantile nephrotic syndrome. Both syndromes are caused by different diseases:

• Diffuse mesangial sclerosis
• Congenital nephrotic syndrome of the Finnish type
• Congenital syphilis, toxoplasmosis, rubella, HIV, cytomegaly
• Idiopathic nephrotic syndrome
• Galloway syndrome
• Mercury intoxication (Keller 2010).

• The main feature of the disease is a significant leakage of plasma proteins (AbuMaziad 2021).
• The infants are usually born between the 35th and 38th week of pregnancy and develop oedema in the first week postpartum due to the high proteinuria (Keller 2010).
• In the further course, terminal renal insufficiency develops between the 3rd and 8th year of life (Keller 2010).

There are additional symptoms such as:

• Poor nutritional status
• Hypothyroidism
• Thromboembolic complications
• Hypogammaglobulinemia (Keller 2010).

The diagnosis can be made intrauterine, but at the latest before the 3rd month of life (AbuMaziad 2021). In > 85% of those affected, the disease can be diagnosed through genetic screening. The invasive kidney biopsy previously used for diagnosis is therefore rarely necessary nowadays (Boyer 2021).

In congenital nephrotic syndrome of the Finnish type, abnormalities such as an enlarged placenta and a high concentration of alpha-1 fetoprotein due to the fetus's high proteinuria are already apparent intrauterine. The children are usually born prematurely (Geiger 2003).

The rapid onset of edema postpartum is striking. A kidney biopsy is recommended in unclear cases (Manski 2024).

Sonography

Sonography shows a clear enlargement of the kidneys, which have an increased echogenicity compared to the liver (Hofmann 2005).

Histopathologically, a distinction is made between five different types:

• Finnish type (most common)
• Diffuse mesangial sclerosis
• Focal segmental glomerulosclerosis
• Membranous glomerulopathy
• Minimal change disease (Reynolds 2019).

Histologically detectable may be:

• mesangial glomerulopathy
• progressive glomerulosclerosis with proportionate tubulointerstitial changes
• no immune deposits
• microcystic dilation in the area of the proximal tubules
• lymphoplasmacellular infiltrates
• tubular atrophy
• periglomerular fibrosis
• glomerulosclerosis (Geiger 2003).

In the Finnish type, there is irregular microcystic dilatation of the proximal tubule, whereas the glomeruli are usually normal or exhibit mesangial hypercellularity and matrix expansion (Jain 2023).

- Congenital and infantile nephrotic syndrome (this typically only manifests after the third month of life [Herold 2018]).

The affected patients are prone to:

• Hemodynamic disturbances
• thromboses
• infections
• Growth disorders
• Renal failure (Boyer 2021)

It is advisable to refer children with CNS to a specialized paediatric nephrology unit as soon as possible (Boyer 2021).

Congenital nephrotic syndrome of the Finnish type is typically characterized by resistance to steroid therapy (Geiger 2003). Immunosuppressants are also ineffective (Manski 2024).

The treatment consists of:

• Good nutrition
• Albumin infusions
• Unilateral or bilateral nephrectomy may be required for severe proteinuria
• Drug therapy for the edema
• Kidney transplantation or dialysis (Manski 2024)

ACE inhibitors and indomethacin can be used to reduce protein excretion via the kidneys (Jain 2023).

Hypothyroidism, if present, should be started with 6.25 to 12.5 mcg and then adjusted to the TSH value (Jain 2023).

Acetylsalicylic acid or dipyridamole are recommended for anticoagulation (Jain 2023).

According to a Finnish study, the average survival time in the years 1965 - 1973 was only 7.6 months. Later, an aggressive treatment regimen with early nephrectomy, transplantation and dialysis was used. As a result, over 90% of children treated in this way showed similar overall survival rates to other transplanted children (Boyer 2021). The graft survival rate is >. 80 % (Jain 2023).

The prognosis of a CNS caused by infection, on the other hand, is good (Jain 2023)

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