Nephrotic Syndrome: Congenital / Infantile

Congenital: Presents in 1^st 3 months after birth

Infantile: Presents between 4-12 months of age

Associated with prematurity, low birthweight, enlarged placental size (>25% of birthweight), +/- dysmorphic features (small, snub nose)

May see large echogenic kidneys on pre/postnatal ultrasound

Histology: variable

• Finnish-type (NPHS1): microcystic dilations of proximal tubule with immature, sclerosed glomeruli

• Diffuse mesangial sclerosis seen in some cases (e.g., PLCE1)

Likely to have an identifiable genetic mutation

More than 40 genes associated with nephrotic syndrome

• 4 most common genes: NPHS1, NPHS2, WT1, LAMB2

  • 66-85% of congenital NS and up to 40% of infantile NS

Protein encoded: Wilms tumor 1

Mutations

• Vast majority of mutations occur in exon 8 or 9 of chromosome 11.

• Mutations in exons 8 or 9 of WT1 are associated with Denys-Drash syndrome (DDS).

  • DDS: Nephropathy, genital abnormalities (classically male pseudohermaphroditism), increased risk (90%) for Wilms tumor

  • Affected males usually infertile, but may have incomplete penetrance

  • Usually NS develops at 1-2 years of age, can be as early as birth

• Splice site mutations result in Frasier syndrome

  • Later onset than DDS, most commonly presents after 12 months of age

  • Frasier syndrome: FSGS, gonadal dysgenesis/male pseudohermaphroditism, increased risk of gonadal tumor)

Pathogenesis

• One mutation produces nephropathy, gonadal dysgenesis

  • Abnormal product of the mutant copy interferes with function of normal WT1 gene product, leads to persistence of undifferentiated tissue (mesenchyme) in developing kidney

• Two mutations results in Wims tumor

  • Causes uncontrolled cell growth in the kidney

Inheritance: AD or de novo

• Most cases are sporadic

• Parents should be assessed for carrier status

Protein encoded: Nephrin

• "This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine."

Inheritance: autosomal recessive (Cr 19q13.1)

• Congenital Nephrotic Syndrome of the Finnish Type (CNF)

• In Finland, NPHS1 has 2 common mutations, called Fin-major (frameshift and stop codon in exon 2) and Fin-minor (nonsense mutation in exon 26), that result in truncated proteins

  • These mutations are rare outside of Finland; over 200 disease-causing mutations have been identified

Epidemiology:

• Prevalence was as high as 1 in 2,600 in Finland but this has been reduced with screening

• There is a high incidence reported among the Old Order Mennonites in Lancaster County, PA

• Most commonly presents in newborns/infants as congenital nephrotic syndrome (CNS)

  • Some "milder" mutations can cause disease that presents in older children or adults

Screening:

• Maternal serum α-fetoprotein (AFP) measurement at 15 to 18 weeks’ gestation (thought to be from fetal urinary protein leakage) has been effectively used to screen for nephrotic syndrome caused by NPHS1 mutations in the Finnish population.

  • AFP >5x median is considered likely congenital NS (assuming no neurological/other abnormality on US)

  • AFP 2-5x median “high risk” for congenital NS, but can also be seen in heterozygous carriers, so genetic testing preferred method

• Genetic testing of Finnish mothers for NPHS1 carrier status is being used more often

Protein encoded: Podocin

Inheritance: autosomal recessive

Protein encoded: Laminin beta 2

Inheritance: autosomal recessive

Phenotype: associated with eye defects (micro-otia)

Protein encoded: Phospholipase C Epsilon 1

Inheritance: autosomal recessive

Phenotype: diffuse mesangial sclerosis most common pathology on renal biopsy

Epidemiology: rare cause of congenital NS, but causes up to ~8% of infantile NS

Treatment: some patients have been reported to respond to steroids or calcineurin inhibitors

Proteins encoded: members of the coenzyme Q10 biosynthesis pathway

• COQ2: Para-hydroxybenzoate-polyprenyl transferase

• COQ6: Coenzyme Q6, monooxygenase

• PDSS2: Decaprenyl-diphosphate synthase subunit 2

• ADCK4: AARF domain containing kinase 4

Inheritance: autosomal recessive

Phenotype: may present with extrarenal features (sensorineural deafness, seizures, ataxia)

Treatment: may respond to treatment, coenzyme Q10 supplementation