Case 2 -

Congenital Nephrotic Syndrome David Witte Children's Hospital Medical Center Cincinnati, OH

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Clinical History A 2665-gram female infant was delivered vaginally at 36 weeks of gestation to a 24 year-old gravida IV para II Caucasian mother and her 41 year-old African American father. Prenatal care had been sporadic, but maternal laboratory values were normal. The family history was negative for any inheritable disorders and there was no history of renal or ophthalmologic problems. The pregnancy was remarkable for an abnormal fetal ultrasound at 28 weeks which revealed large, hyperechoic kidneys. At the 36 week visit, another ultrasound showed a decreased bio-physical profile (5/10) and a decreased amniotic fluid index, prompting induction of labor. Delivery was uneventful with Apgar scores of 7 and 8 at one and five minutes, respectively. On initial newborn exam, the patient had slightly decreased muscle tone but intact reflexes. Moreover, she was found to have bilateral microcoria, ie.- pinpoint pupils, prompting a maternal drug screen which was positive only for caffeine. No other dysmorphology was noted. On day of life 3, the patient was noted to have slight edema of her legs and left eyelid. After initially doing well, she started to feed poorly, taking only 10 milliliters per feeding. Meconium drug screen was also negative.After further inquiry revealed the abnormal prenatal ultrasound findings, a renal profile was obtained, showing hyponatremia (129 mmol/dL) and renal insufficiency (creatinine of 2.7 mg/dL). A follow-up renal ultrasound was obtained which confirmed bilaterally enlarged hyperechoic kidneys. Because of the patient's renal failure, she was transferred with a suspected diagnosis of autosomal recessive polycystic kidney disease. Laboratory evaluation after transfer showed significant proteinuria (>300 mg/dL on dipstick), hypoalbuminemia (1.5 gm/dL) and persistent renal dysfunction (creatinine of 2.9 mg/dL), leading to the diagnosis of Congenital Nephrotic Syndrome with renal failure. Abdominal and pelvic ultrasound revealed a normal liver and spleen, the aforementioned enlarged hyperechoic kidneys with loss of corticomedullary differentiation, and normal ovaries and uterus. A head ultrasound was normal, as well. CMV antigen was undetectable, and there was no other evidence of TORCH infections. High resolution chromosomal analysis showed a normal XX karyotype. Pediatric ophthalmology consultants found continued pupillary constriction despite dilating drops and persistent hyperplastic primary vitreous of the right eye. The patient was noted to be moderately hypertensive with blood pressures >120/ 80 in all four extremities, requiring multiple anti-hypertensive medications to control. She was also dependent on intravenous albumin and furosemide for edema management. An open renal biopsy was performed at 3 weeks of life. Case 2 - Figure 1 - Closeup photograph of the patients eye with microcoria (pinpoint pupil). Case 2 - Figure 2 - Photomicrograph of kidney showing extensive tubular atrophy and cystic dilatation of tubules. There is a wide range of glomerular lesions including crescent formation, sclerosis, and some immature glomeruli. Case 2 - Figure 3 - Higher magnification photomicrograph of the kidney showing hypercellular glomerulus and tubular atrophy. Case 2 - Figure 4 - Higher magnification of kidney section shown in Figure 2 showing details of glomerulus with crescent formation and a sclerotic glomerulus. Case 2 - Figure 5 - Photomicrograph of kidney section stained with Jones stain. There is one collapsed glomerulus with increased matrix surrounded by a crescent. Case 2 - Figure 6 - Electron photomicrograph of kidney which shows microvillous change, foot process effacement with patent capillary loops. Case 2 - Figure 7 - High magnification electronphotomicrograph of the kidney showing a very thin lamina densa (< 50 nm) and foot process effacement. Case 2 - Figure 8 - Electron photomicrograph of kidney showing an immature glomerulus with a capillary loop surrounded by a "corona" of prominent podocytes. Diagnosis Congenital Nephrotic Syndrome Discussion Finnish type Congenital nephritic syndrome is a rare disease characterized by the development of massive proteinuria at or shortly after birth. By definition, the designation of congenital nephrotic syndrome usually includes infants with onset of nephrotic syndrome during the first three months of life. One of the earliest classes of congenital nephrotic syndrome recognized and described was the Finnish type, which is associated with an autosomal recessive inheritance pattern. These infant's are frequently born prematurely, have high levels of alphafetoprotein, and laboratory studies reveal massive proteinuria associated with low albumin levels and hypogammaglobulinemia. The infants are very edematous and the placenta is frequently markedly enlarged. Histologic features in the kidney usually consist of dilated proximal tubules, occasionally associated with microcyst formation. Generally, the glomeruli are normal in appearance or show a slight increase in mesangial cellularity or matrix expansion. Electron microscopy studies reveal podocyte foot process fusion and occasionally evidence of collapsing glomeruli or early sclerosis. Most infants die during the first year of life from complications related to their renal disease such as sepsis. The pathogenesis in congenital nephrotic syndrome of the Finnish type has been localized to a gene defect on chromosome 19 and the NPHS-1 gene has been identified as the major gene mutation in this disorder. This gene encodes a 185 kDA transmembrane protein called nephrin. This protein has since then been localized to the slit diaphragm of the podocytes and it has been speculated that it plays an important role in ultrafiltration of the glomerular filtration barrier. More than fifty mutations have now been reported both in the Finnish and non-Finnish type of patients with congenital nephrotic syndrome, and the important role of nephrin in the function of the slit diaphragm has also been confirmed by the development of NPHS-1 knock-out mouse, which has also been found to have massive proteinuria at birth and die within the first 24 hours. Steroid-resistant idiopathic nephrotic syndrome (SRNS) Another gene mutation which has been associated with early onset nephrotic syndrome has been identified in patients that typically present in the age range between 3 months and 5 years of age, although earlier presentations have now been described. These patients have a mutation in the NPHS-2 gene, which is also inherited as an autosomal recessive trait. Typically, these patients do not respond to steroid treatment after onset of proteinuria, and progress on to end stage renal disease over a short time. The gene is localized to chromosome 1 and encodes the protein podocin. This protein is exclusively expressed in the podocytes and has been known to interact with the protein nephrin as well as interacting with CD2AP, which is an adapter protein that anchors CD2, a protein that stabilizes contacts between podocytes. Thus, podocin plays a major role in the structural integrity and function of the slit diaphragm for maintaining glomerular filtration. More than 30 different mutations have now been described in these patients and, now that it has been described in patients with congenital nephrotic syndrome, this finding confirms the genetic heterogeneity of patients presenting at birth with congenital nephrotic syndrome. Recent studies have suggested that patients with congenital nephrotic syndrome, mild mesangial cell hypercellularity, foot process fusion, and microcystic change in the proximal tubules can result from either NPHS-1 or NPHS-2 gene mutations. The clinical distinctions between patients with NPHS-1 and NPHS-2 gene mutations has now become further complicated by the recognition of patients with combined mutations in NPHS-1 and NPHS-2. Patients have now been identified with nephrotic syndrome who have a homozygous mutation in either NPHS-1 or NPHS-2 in addition to a heterozygous mutation in the alternate gene. This digenic inheritance pattern can result in three variant alleles which can alter the phenotypic expression of the disease from its classic presentation. This increasing complexity of multigenetic mutations in patients with nephrotic syndrome will require further clarification of the genotype-phenotype correlation but will add additional complexity to diagnostic genetic studies. Diffuse Mesangial Sclerosis In 1973, Habib and Boise identified diffuse mesangial sclerosis as a distinct clinical pathologic entity. Patients were characterized by the early onset of severe proteinuria and rapid progression of end stage renal failure. The typical pathologic features include diffuse dilatation of the tubules, which were frequently lined by attenuated epithelium, collapsed sclerotic avascular glomeruli, epithelial crescents, and segmental fibrinoid necrosis. Electron microscopy studies sometimes revealed effacement of foot processes, and microvillous transformation. This nephropathy is usually discovered within the first couple months of life including at birth and can be associated with male pseudohermaphroditism, and Wilms tumor, and is recognized as the Denys-Drash syndrome. Heterozygous germline mutations are observed in most patients with Denys-Drash syndrome and more than 60 mutations have been reported in the WT1 gene, which encodes a transcription factor. WT1 is strongly expressed during embryogenesis but in the mature kidney, wt1 expression persists only in podocytes and epithelial cells of Bowman's capsule. Pierson Syndrome Although the above described gene mutations have been identified in patients with various forms of congenital nephrotic syndrome, this group still does not account for all the patients with congenital nephrotic syndrome and in fact a definite complete classification of congenital nephrotic syndrome has not yet been established. Recently two families including eleven affected offspring were described with a new autosomal recessive clinical entity which included severe congenital nephrotic syndrome, diffuse mesangial sclerosis and distinct eye abnormalities characterized by microcoria. This condition was first described by Pierson et al. in 1963, and the molecular basis for this newly identified group with congenital nephrotic syndrome has only recently been reported. Genetic mapping in these two families identified a candidate gene in the region on chromosome 3p. These studies further determined that these patients were either homozygous or compound heterozygous mutations of LAMB2 which resulted in loss of laminin beta 2 expression in the kidney and other tissues involved. Laminin beta 2 is known to be abundantly expressed in the glomerular basement membrane where it is believed to play a key role in anchoring as well as differentiation of podocyte foot processes. Previously LAMB2 knock-out mice had been reported which exhibited congenital nephrosis associated with anomalies of the retina and neuromuscular junctions. The results of these studies suggest that human laminin beta 2 deficiency is consistently and specifically associated with Pierson syndrome. The glomerular basement membrane is a highly cross-linked macromolecular meshwork composed of specific extracellular matrix proteins including type IV collagen, laminins, nidogen and heparan sulfate proteoglycans. Mutations in genes coding for structural glomerular basement membrane proteins such as collagen type IV has been associated with Alport's syndrome which results in a disruption of the normal GMB structure. In general, congenital nephrotic syndrome patients have an increased glomerular permeability and seem to be generally associated with defects more in the structure and function of the podocyte foot processes. Laminin is a basement membrane glycoprotein which is a heterotrimer with alpha, beta and gamma chains held together in a triple stranded alpha helical coiled-coil structure. Basic diverse biological functions including the promotion of cell adhesion, growth, migration and differentiation. Based on the finding from these reports, the date appears to clearly indicate that Pierson syndrome is caused by absence or a severe quantitative reduction of laminin beta 2 expression rather than a dysfunctional protein. In conclusion, this newborn infant who presented with severe congenital nephrotic syndrome associated with abnormalities of the eye, is an example of Pierson syndrome which is a direct result of a deficiency in laminin beta 2 in the glomerular basement membrane. References Papez KE, Smoyer WE. Recent advances in congenital nephrotic syndrome [Nephrology]. Current Opinion in Pediatrics 2004; 16(2):165-170. Kohshnoodi J, Tryggvason K. Congenital nephrotic syndromes. Current Opinion in Genetics & Development 2001;11:322-327. Zenker M, Pierson M, Jonveaux P, Reis A. Demonstration of two novel LAMB2 mutations in the original Person syndrome family reported 42 years ago. Letter. American Journal of Medical Genetics, Part A. 2005;138(1):73-74. 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