Congenital Nephrotic Syndrome of the Finnish Type



Congenital Nephrotic Syndrome of the Finnish Type


Helen Liapis, MD

Joseph Gaut, MD, PhD










This schematic of the slit diaphragm demonstrates the interaction between various proteins known to be mutated in different types of inherited nephrotic syndromes. Nephrin, a key component of the slit diaphragm, is mutated in patients with FN. Given nephrin’s role in slit diaphragm structure, it is not surprising that FN patients present with massive proteinuria. Podocin mutations present with similar clinical symptoms and pathologic findings of FSGS.


TERMINOLOGY


Abbreviations



  • Finnish nephropathy (FN)


Synonyms



  • Microcystic kidney disease


Definitions



  • Steroid-resistant nephrotic syndrome in neonates up to 3 months of age due to mutations in nephrin (NPHS1) gene


ETIOLOGY/PATHOGENESIS


Genetics



  • Autosomal recessive disease


  • Homozygous mutation in NPHS1



    • Maps to chromosome 19q13.1


    • Encodes protein nephrin



      • Transmembrane protein of immunoglobulin (Ig) superfamily with 8 extracellular immunoglobulin-like domains with N-glycosylated sites


      • N-glycosylation is important for protein folding, formation of slit diaphragm, and localization in GBM


      • Forms “zipper” structure of slit diaphragm described by Karnovsky


    • Over 70 mutations have been identified in Finland and elsewhere around the world


    • Fin-major



      • Frameshift mutation in chromosome 19q13.1 leading to absent slit diaphragms and no nephrin protein expression


    • Fin-minor



      • Nonsense mutations in exon 26 produce a truncated or nonfunctioning nephrin


  • Compound heterozygous NPHS1 mutations are rare



    • May present as adult onset focal segmental glomerulosclerosis (FSGS)



  • Heterozygotes with 1 normal NPHS1 allele (carriers) are normal post birth



    • In utero may have transient deficiency of nephrin during podocytogenesis


    • Can lead to false-positive α-fetoprotein (AFP) test in amniotic fluid and maternal serum


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Highest in Finland



      • 1:10,000-1:80,000 births (gene frequency 1:200)


      • Fin-major accounts for 78% of Finnish cases


      • Fin-minor accounts for 22% of Finnish cases


    • Occurs worldwide at lower frequency



      • 61% of nephrotic syndrome in first 3 months of life


    • Numerous other point mutations are described in non-Finnish patients, resulting in variable nephrin synthesis


  • Age



    • Onset < 3 months: Homozygous mutation


    • Onset 6 months to 5 years: Compound heterozygous mutation


    • Rare cases of adult onset FSGS attributed to NPHS1 mutations


Presentation



  • Massive proteinuria-nephrotic syndrome


  • Elevated AFP in amniotic fluid and maternal serum


Laboratory Tests



  • AFP elevated in maternal plasma and amniotic fluid (in utero nephrotic syndrome)


  • Antinephrin antibodies post transplant


Treatment



  • Supportive therapy


  • Transplantation once patient weight is > 8 kg



    • Patients who are transplanted have 30% rate of recurrent nephrotic syndrome



      • Not a recurrence but instead secondary to anti-nephrin antibodies


      • Plasmapheresis, cyclophosphamide, and methylprednisolone prolongs graft survival in patients with antinephrin antibodies


Prognosis



  • Mean time to ESRD = 32 months



    • Rate of progression is variable



      • Somewhat slower in females (40 months) than males (21 months)


      • Patients with Fin-major have earliest onset and most rapid course


      • Patients with Fin-minor have later onset and delayed progression


  • Many severely affected infants with FN die from infection


  • Compound heterozygotes develop ESRD later at 6-15 years of age


  • Fetal carriers of NPHS1 mutations are normal post birth

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Congenital Nephrotic Syndrome of the Finnish Type
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