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A rare primary glomerular disease characterized by the association of congenital nephrotic syndrome, early onset renal failure and ocular anomalies with microcoria and severe neurodevelopment deficits.
ORPHA:2670Classification level: Disorder
Less than 70 cases have been described in the literature to date.
Presentation is typically with congenital microcoria and heavy proteinuria. Proteinuria is usually nephrotic range, at or shortly after birth and progresses rapidly to early onset renal failure. The histological finding is usually diffuse mesangial sclerosis characterized by small and condensed appearance of glomerulus in which mesangial region shows some collagenous tissue. Ocular anomalies are usually bilateral but may vary in severity which include microcoria, iris hypoplasia, posterior embryotoxon, megalo- or microcornea, cataract, lenticonus, persistent fetal vasculature, retinal detachment, glaucoma, and phthisis bulbi. Neurological manifestations include severe global development delay, marked muscle hypotonia, movement disorders, and blindness. It should be noted that some cases with this disease show mild phenotypes of late onset proteinuria without ocular or neurological abnormalities.
Mutations in the LAMB2 gene (3p21) encoding laminin beta 2 have been identified. Laminin beta 2 is expressed in the glomerular basement membrane, at the neuromuscular junctions, as well as in the intraocular muscles, lens and retina.
Early onset severe proteinuria accompanied by ocular anomalies are rare. Therefore, in typical cases, it is relatively easy to suspect this disease. Lowe syndrome (proteinuria, mostly low molecular weight protein, and congenital cataract) or renal-coloboma syndrome (due to PAX2 gene pathogenic variants) can be candidates for differential diagnosis.
Prenatal diagnosis is difficult, but sometimes may be suspected on hyperechogenic kidneys and oligohydramnios. Only genetic testing allows early and reliable prenatal diagnosis. Prenatal diagnosis may be offered to families in which the disease-causing mutation has already been identified in affected siblings.
The disease is transmitted as an autosomal recessive trait. Where both parents are unaffected carriers of the disease, there is a 25% risk of transmission to offspring. Carrier testing of healthy family members is possible where the mutation has been identified in a family with at least one affected member.
Management and treatment
There is no specific treatment available. Since protein loss is limited, nephrectomy to prevent protein loss to urine is rarely needed. Angiotensin converting enzyme (ACE) inhibitors could help reduce urine protein loss and can delay the progression to end-stage kidney disease (ESKD) due to their renal protective effects. Renal replacement therapies including kidney transplantation are successfully employed. To date, there is no-evidence of disease-recurrence reported in the grafts after kidney transplantation. Careful ophthalmological follow up is required for the care of retinal detachment.
The kidney prognosis is severe with most patients progressing towards renal failure within the first year of life. Visual prognosis is generally poor: visual acuity ranges from no light perception to 20/200. Mild to severe intellectual disability is always observed. Survival into adult is reported with renal replacement therapies.
A summary on this disease is available in Deutsch (2007) Italiano (2007) Português (2007) Español (2020) Français (2020) Nederlands (2020) Japanese (2020, pdf)
Disease review articles
- Review article
- Español (2014) - An Pediatr Contin
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