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Congenital nephrotic syndrome, Finnish type
A rare congenital nephrotic syndrome characterized by massive protein loss and marked edema manifesting in utero or during the first 3 months of life.
ORPHA:839Classification level: Disorder
This type of nephrotic syndrome is more frequent in Finland with a prevalence of 1/8,200 births. The disease is observed in various ethnic groups worldwide but the prevalence is unknown.
Affected children show massive proteinuria and edema starting in utero (fetal hydrops). Children usually have low birth weight and are born prematurely; the weight of the placenta constitutes more than 25% of the birth weight. Severe nephrotic syndrome develops soon after birth; typical features include hypoalbuminemia, hyperlipidemia, hypothyreosis, abdominal distension and edema with associated failure to thrive, increased susceptibility to thromboembolic events and severe infections. Histologically, microcystic dilatations of the tubules are seen whereas glomeruli are only slightly modified initially, with variable mesangial cell hypercellularity and/or endocapillary hypercellularity. Electron microscopy shows glomerular effacement of the podocytes.
The disease is caused by recessive mutations in the NPHS1 gene (19q13). NPHS1 encodes for Nephrin, a zipper-like protein, which is essential for the porous structure of the glomerular slit diaphragm. To date more than 200 NPHS1 mutations have been detected but two of them have a particular high frequency in affected Finnish children, one is a two base pair deletion in exon 2 resulting in a truncated protein (Fin-major) and the other is a nonsense mutation in exon 26 (Fin minor). These two mutations are observed in 94% of Finnish patients but are quite rare outside Finland.
The diagnosis is suspected on clinical grounds and confirmed by genetic analysis.
Differential diagnoses include other forms of early onset nephrotic syndrome, including Denys Drash syndrome, Pierson syndrome, Galloway Mowat syndrome, Schimke immuno-osseous dysplasia and congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization.
Antenatal proteinuria results in an up to 10-fold increase in alpha-fetoprotein concentrations as early as in the 15th week of gestation, with a parallel but smaller rise in the maternal serum level. However, heterozygous mutations in the NPHS1 gene can also lead to increased levels of alpha-fetoprotein, leading to misdiagnosis. Reliable antenatal diagnosis is achieved by gene analysis on a trophoblastic sample.
The pattern of disease transmission is autosomal recessive. The risk of recurrence in siblings of an affected individual is 25%.
Management and treatment
The nephrotic syndrome does not respond to any immunosuppressive therapy and treatment is largely symptomatic, comprising frequent albumin infusions, protein-rich diet, anti-proteinuric pharmacotherapy with RAS (renin-angiotensin system) inhibitors and indomethacin, anticoagulation, thyroid hormone supplementation and aggressive treatment of infections. In case of failure to thrive despite these measures, uni- or bilateral nephrectomy may be necessary to stop the massive protein loss.
With adequate supportive care, most children survive long-term but develop end-stage kidney disease requiring renal replacement therapy within the first 2-3 years of life. Five-year patient and graft survival after transplantation is around 90%, similar as in infants with other causes of end-stage kidney disease. Post-transplant disease recurrence is limited to patients who are homozygous for the Fin major mutation, who have a 30% risk to develop de novo glomerulonephritis due to circulating anti-nephrin antibodies.