| #609049 | ||||||||||||||||||||||||||||||||||||||||||
| PIERSON SYNDROME | ||||||||||||||||||||||||||||||||||||||||||
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| MICROCORIA-CONGENITAL NEPHROTIC SYNDROME | ||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because Pierson syndrome is caused by homozygous or compound heterozygous mutation in the gene encoding laminin beta-2 (LAMB2; 150325) on chromosome 3p21. | ||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||
| Pierson syndrome is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss (summary by Zenker et al., 2004). Mutations in the LAMB2 gene also cause nephrotic syndrome type 5 with or without mild ocular anomalies (NPHS5; 614199). | ||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||
| Pierson et al. (1963) reported 2 sisters with congenital nephrotic syndrome and peculiar eye abnormalities. The renal disorder manifested in the newborn period with severe nephrotic syndrome followed by early-onset end-stage renal disease; both sisters died in the first 2 weeks of life. Ocular features included extreme nonreactive narrowing of the pupils (microcoria) due to aplasia or atrophy of the dilatator pupillae muscle. Postmortem examination showed a complex maldevelopment of the eye with lens abnormalities, atrophy of the ciliary muscle, corneal changes, and retinal changes. Zenker et al. (2004) reported 2 unrelated families, 1 Turkish and 1 Arabic, with congenital nephrotic syndrome and distinct ocular anomalies. The parents in both families were consanguineous. Eleven children from the 2 families presented with a similar course of renal disease starting with nephrotic syndrome and renal failure prenatally or immediately after birth, and resulting in death before the age of 2 months. Kidney histopathology showed diffuse mesangial sclerosis. Clinically obvious eye abnormalities were recognized in 6 of the 8 patients in whom sufficient clinical data were available. Ocular anomalies included enlarged or large-appearing corneas, suggesting buphthalmos in some cases, and extremely narrow, nonreactive pupils. Pathologic examination of the eyes of 2 aborted fetuses revealed a more complex ocular malformation including posterior lenticonus as well as anomalies of cornea and retina. Zenker et al. (2004) suggested that the first report of this association was provided by Pierson et al. (1963) and that other possible reports included those of Beale et al. (1979), Schneller et al. (1983), Nielsen and Steffensen (1990), Glastre et al. (1990), and Braga et al. (1989). Zenker et al. (2004) considered the disorder to be distinct from diffuse renal mesangial sclerosis with ocular abnormalities (249660) because the latter has later onset of nephrotic syndrome and different ocular changes. Wuhl et al. (2007) reported 4 unrelated patients with Pierson syndrome who survived until the ages of 1.3 to 4.8 years due to chronic renal dialysis. Three patients had a severe phenotype associated with complete lack of LAMB2 expression. They all showed showed marked global psychomotor retardation with absence of any receptive or expressive language skills up to age 19 months, severe visual impairment with apparent blindness, and severe muscular hypotonia. The fourth patient had a milder phenotype with regard to ocular features and renal disease, normal development, no neurologic abnormalities, and absence of muscle hypotonia, suggesting that she had residual protein function. Wuhl et al. (2007) concluded that severe primary neurodevelopmental deficits should be considered a part of Pierson syndrome in the presence of biallelic functional null LAMB2 mutations. | ||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||
| In patients from 5 unrelated families with Pierson syndrome, Zenker et al. (2004) identified homozygous or compound heterozygous mutations of the LAMB2 gene (see 150325.0001-150325.0003). Most disease-associated alleles were truncating mutations. The respective LAMB2 mutations led to loss of laminin beta-2 expression in kidney and other tissues studied. In control samples, ocular laminin beta-2 expression was strongest in the intraocular muscles, corresponding well to the characteristic hypoplasia of ciliary and pupillary muscles observed in Pierson syndrome patients. In the unaffected mother and paternal aunt of the original sibs reported by Pierson et al. (1963), Zenker et al. (2005) identified heterozygous mutations in the LAMB2 gene (150325.0004 and 150325.0005, respectively). The findings provided evidence that the 2 affected sibs were compound heterozygous for the 2 mutations. | ||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | ||||||||||||||||||||||||||||||||||||||||||
| Hasselbacher et al. (2006) stated that homozygosity or compound heterozygosity for LAMB2 mutations conferring complete loss of function (e.g., truncating mutations) appear to be associated consistently with the typical features of Pierson syndrome, including neonatal renal failure, severe ocular abnormalities, and neurologic impairment in long-term survivors, whereas patients with nontruncating (missense) LAMB2 mutations may display variable phenotypes ranging from a milder variant of Pierson syndrome to isolated congenital nephrotic syndrome. | ||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||
| S-laminin/laminin beta-2, a homolog of the much more widely distributed laminin B1/beta-1 chain (150240), is a major component of adult renal glomerular basement membrane (GBM). Immature GBM carries beta-1, which is replaced by beta-2 as development proceeds. Noakes et al. (1995) used homologous recombination to generate mice that carry a null mutation in the laminin beta-2 gene and documented defects in the maturation of their neuromuscular junctions. Focusing on kidneys in a separate study, Noakes et al. (1995) showed that the mice compensate for renal beta-2 deficiency by forming a GBM that contains laminin beta-1. The mutant GBM is structurally intact, but glomerular ultrafiltration is impaired. The defects resemble, in several respects, those seen in human minimal change nephrotic syndrome (MCNS), a glomerular disorder of unknown etiology that is most common in children. The mutant mice develop massive proteinuria. The GBM contains normal complements of several collagenous and noncollagenous glycoproteins. These results supported the idea that laminin beta chains are functionally distinct although they assemble to form similar structures. Laminin beta-2 deficient mice may provide a model for human congenital or idiopathic nephrotic syndromes and can be excluded as the cause of Finnish congenital nephrotic syndrome (256300) because that disorder maps to chromosome 19. No glomerular phenotype has been noted in animal or humans with mutations in 2 other laminin genes: alpha-2 (dy/dy dystrophic mice) or gamma-2 (human junctional epidermolysis bullosa); see 226700. In Lamb2-null mice, a model of Pierson syndrome, Jarad et al. (2006) observed ectopic deposition of several laminins and mislocalization of anionic sites in the GBM, suggesting that the Lamb2 -/- GBM is severely disorganized although ultrastructurally intact. Albuminuria was detectable shortly after birth in Lamb2-null mice and preceded podocyte foot process effacement and loss of slit diaphragms by at least 7 days. GBM permeability to ferritin was markedly elevated in Lamb2-null mice, even before widespread foot process effacement, and increased ferritin permeability was not seen in nephrotic Cd2ap (604241)-null mice, which have a primary podocyte defect. Jarad et al. (2006) concluded that the GBM serves as a barrier to protein in vivo and that the glomerular slit diaphragm alone is not sufficient to prevent the passage of albumin into the urinary space. | ||||||||||||||||||||||||||||||||||||||||||
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