| Abstract|| |
The congenital nephrotic syndrome (CNS) is an uncommon disorder with onset of the nephrotic syndrome usually in the first three months of life. Several different diseases may cause the syndrome. These may be inherited, sporadic, acquired or part of a general malformation syndrome. The clinical course is marked by failure to thrive, recurrent life threatening bacterial infections, and early death from sepsis and/or uremia. A characteristic phenotype may be seen in children with CNS. The majority of reported cases of CNS are of the Finnish type (CNF). Although the role of the glomerular basement membrane has been emphasized as the barrier for retaining plasma proteins, recent studies have clearly shown that the slit diaphragm is the structure most likely to be the barrier in the glomerular capillary wall. The gene (NPHS1) was shown to encode a novel protein that was termed nephrin, due to its specific location in the kidney filter barrier, where it seems to form a highly organized filter structure. Nephrin is a transmembrane protein that probably forms the main building block of an isoporous zipper-like slit diaphragm filter structure. Defects in nephrin lead to the abnormal or absent slit diaphragm resulting in massive proteinuria and renal failure
Keywords: Nephrotic, Renal failure, Congenital, Glomerulopathy, Genes.
|How to cite this article:|
Hamed RM. Congenital Nephrotic Syndrome. Saudi J Kidney Dis Transpl 2003;14:328-35
| Introduction|| |
The congenital nephrotic syndrome (CNS) is an uncommon disorder. The designation CNS identifies infants with onset of the nephrotic syndrome usually in the first three months of life, and is characterized by heavy proteinuria, hypoproteinemia, hyperlipidemia, and edema. Although uncommon, it continues to be a diagnostic and therapeutic challenge for the pediatrician. Several different diseases may cause the syndrome. These may be inherited, sporadic, acquired or part of a general malformation syndrome. Affected fetuses are commonly born prematurely and small for dates. ,
The clinical course is marked by failure to thrive, recurrent life threatening bacterial infection, and early death from sepsis and/ or uremia. Loss of thyroid binding globulin in the urine may result in neonatal hypothyroidism requiring thyroxin replacement.  A characteristic phenotype may be seen in children with CNS. Facial features may include small mouth, tented upper lip, small nose, and fullness of the cheeks giving a 'jowly' appearance.  Accurate diagnosis is essential for genetic counseling, prenatal diagnosis, and treatment.
The majority of reported cases of CNS came initially from Finland, and those children were identified as having congenital nephrotic syndrome of the Finnish type (CNF). Similar cases of CNF have now been reported from many other countries and racial backgrounds.  The placenta is usually larger than normal and often weighs more than 25% of the baby's birth weight in CNF.
Other less frequent forms of CNS include diffuse mesangial sclerosis (DMS), minimal change nephrotic syndrome (MCNS), mesangial proliferative glomerulonephritis (MesPGN), and focal segmental sclerosis (FSGS). These forms include the idiopathic variants of CNS.
Rare forms of CNS include Lowes' syndrome, XY gonadal dysgenesis, and the nail-patella syndrome.
| Mechanism and Genetic Basis of Proteinuria|| |
Although the role of the glomerular basement membrane has been emphasized as the barrier for retaining plasma proteins, recent studies have clearly shown that the slit diaphragm is the structure most likely to be the barrier in the glomerular capillary wall. Positional cloning of the gene for CNS was a groundbreaking result because it provided new insight into the kidney filter. The gene (NPHS1) was shown to encode a novel protein that was termed nephrin, due to its specific location in the kidney filter barrier, where it seems to form a highly organized filter structure. The NPHS1 gene is located in the chromosomal region 19 q 13.1 and consists of 29 exons. Nephrin is a transmembrane protein that probably forms the main building block of an isoporous zipper-like slit diaphragm filter structure. Defects in nephrin lead to the abnormal or absent slit diaphragm resulting massive proteinuria and renal failure. More than 60 mutations have been reported in the nephrin region in patients with CNF worldwide.  In the Finnish population, two nonsense mutations account for over 94% of all mutations found in Finland.
CNF in non-Finnish families also maps to 19q13.1. , Most mutations found in nonFinnish patients are missense mutations, but they include also nonsense and splice site mutations, as well as deletions and insertions.,Recent evidence suggests that mitochondrial dysfunction also is a characteristic feature of the glomeruli in CNF and suggests a critical role for mitochondria in maintaining the glomerular permeability barrier.
| Types of the Congenital Nephrotic Syndrome|| |
A. Heritable Disorders
1. The Finnish Type (CNF)
The majority of reported cases of CNS belong to CNF. CNF is an autosomal recessive condition, and is the predominant cause of massive proteinuria in the first three months of life; most of them were initially reported from Finland - hence the name. The incidence of this disease has been estimated to be 12.2 cases per 100,000 births in Finland, but much lower rates occur in other parts of the world. Nearly all infants are born prematurely (typically between 35 and 38 weeks) and they are small for date. The placenta is remarkably larger than normal, and signs of fetal asphyxia are common. There is proteinuria at birth, beginning in utero, but edema develops later. About half the infants with CNF develop marked edema and ascites within the first 2 weeks of life. There is hypoalbuminemia and hyperlipidemia comparable to features of the nephrotic syndrome in the older age groups.
The histology of CNF depends on the stage of the disease. The most striking feature by light microscopy is a diffuse cystic dilatation of the proximal tubules, though cases without dilatation have been reported.  Early in the course of the disease, the mature glomeruli typically show minimal abnormalities; mild mesangial hypercellularity and increased amount of the mesangial matrix. Immature glomeruli are commonly seen, with palisade of epithelial cell nuclei around a small glomerular tuft within a dilated urinary space. There are no glomerular deposits of immunoglobulin or complement. Extensive fusion of epithelial cell foot processes is seen by electron microscopy. The glomerular changes progress to result in obliteration of the capillary loops and glomerular hyalinization, combined with tubular atrophy and interstitial fibrosis.
The strikingly uniform course of this type of nephrosis is associated with a dismal prognosis and a progressive decline in the renal function, frequent infections, failure to thrive, and usually death in the first years of life from sepsis or uremia. Nowadays, supportive therapy with improved nutritional management, specific antibiotics and reduction of edema may prolong survival. However, if renal transplantation is not performed, these patients usually die of renal failure before 3-4 years of age. 
These children have very low IgG, often below 2% of normal infant values, but treatment with parenteral immunoglobulin preparations is useless because of rapid renal loss. There is no definitive therapy for the renal disease during the first year of life, and no response to corticosteroids or immunosuppressive drugs, which in any case would increase the risk of sepsis. There are few controversial reports in the literature on the usefulness of angiotensin-converting enzyme inhibitors, and non-steroidal anti-inflammatory drugs in CNF. ,,
Peritoneal dialysis is feasible and safe in these patients. The major challenges presented by continuous peritoneal dialysis therapy, however, include avoidance of peritonitis, volume control and the maintenance of optimal nutrition. 
Renal transplantation gives unacceptably low survival rates during the early course of the disease  . Care should be taken to eliminate risk factors for hypercoagulablilty and infections prior to transplantation. The North American Pediatric Renal Transplant Cooperative Study Report on the allograft survival according to primary diagnosis suggested that CNS carried the highest risk of graft failure.  Vascular thrombosis and death with a functioning graft were more frequent in patients with CNS compared to patients with other primary diseases.  The nephrotic syndrome may recur in the transplanted kidney. , Transplantation introduces a neoantigen inducing production of autoantibodies, which may be pathogenic for perturbation of the function of glomerular filtration barrier. Post-transplant nephrosis can occur immediately, but may be responsive to steroids and cyclophosphamide. 
2. Diffuse Mesangial Sclerosis (DMS)
DMS is inherited in autosomal recessive manner. It may occur also as an isolated DMS, and may be observed in the context of Denys-Drash syndrome due to WT1 mutation. This is a rare condition with onset of proteinuria and progressive renal insufficiency at any time in the first year of life. ,,, The reported children have been born at term, with normal placenta and birth weight. The disease progresses rapidly. Patients develop terminal renal failure and die before the third year of life. , Morphologically all the glomeruli are affected. They show obliteration of the capillaries with fibrosis but without hypercellularity. This gives a contracted appearance to the glomerular tuft. The urinary space is often slightly dilated. The cortical tubules are atrophic, with occasional cystic dilatations that contain pertinacious and hyaline casts. Interstitial fibrosis with a scanty number of lymphocytes is present.
Like CNF, DMS is resistant to all therapeutic attempts. Even with progressive supportive therapy, almost none of these children with neonatal onset are kept alive long enough to be candidates for renal transplantation.
3. Familial Focal Segmental Glomerulosclerosis (FFSGS)
Only few cases of CNS have been classified as FFSGS in the literature. Familial forms of FFSGS that exhibit autosomal dominant or recessive patterns of inheritance have been described and are highly heterogeneous. Microscopically, there are focal segmental sclerotic areas with or without mesangial cellular proliferation. There are local adhesions to the Bowman's capsule. Epithelial crescents and focal global sclerosis are sometimes seen.  The lesions commence in the inner part of the cortex. Microcysts are not found, but tubular atrophy and interstitial fibrosis are present. Ultrastructurally, there is nearly complete obliteration of the epithelial foot processes.
Unlike acquired (idiopathic) FSGS, FFSGS does not recur in transplanted kidneys.  Familial FSGS can also be seen as a component of non-renal-limited familial syndromes. Recently, homozygosity for a mutation in Beta-4-integrin was reported in an infant with epidermolysis bullosa and congenital FSGS with nephrotic proteinuria. 
B. Acquired (Secondary) CNS.
Several secondary causes of CNS have been identified, although the number of cases is small in each category. Secondary forms include congenital infections (such as syphilis, toxoplasmosis, and cytomegalo virus), ,, mercury intoxication, and systemic lupus erythematosus.
In Congenital Syphilis, , the renal lesions represent either a mesangial proliferative glomerulonephritis or a membranous glomerulopathy, in which thickening of the basement membrane is the major abnormality. Both light and electron microscopy reveal subepithelial deposits, and these are identified as IgG and fibrin by immunofluorescent studies.
In Congenital Toxoplasmosis, the glomeruli exhibit glomerulosclerosis.  The earliest lesion consists of a thickening of the capillary walls. This process progresses so that the lumen is gradually obliterated. Simultaneously, fibrosis develops in the capillary tuft. All the changes are segmental. Immunofluorescent studies are negative for IgG, IgA, and IgM, but positive for small amounts of fibrinogen. By electron microscopy, extensive foot process adhesions are seen, together with electron deposits subendothelially and in the mesangium. Some studies revealed that these changes were minimized after treatment with prednisone, pyrimethamine and sulphadiazine.
In Cytomegalovirus Infection, light microscopy shows marked dilatation of the proximal tubules, moderate hypercellularity of the glomeruli, occasional hyalinized glomeruli, thickening of the glomerular capsule and a moderate degree of interstitial inflammatory reaction.
In Mercury Intoxication, light microscopy reveals no abnormalities in the glomeruli.
C. Congenital Nephrosis Associated with Other Syndromes
- Tricho-rhino-phalangeal syndrome type II ( Langer-Giedion syndrome More Details). 
- 46XY gonadal dysgenesis.  Reports of CNS and XY Gonadal dysgenesis in phenotypic females without genital ambiguity are extremely rare in the literature.
- Denys-Drash syndrome , is a triad of nephropathy, male pseudohermaphroditism, and Wilms tumor. Patients with XY gonadal dysgenesis and renal disease have been reported with or without Wilms tumor. The genital malformations in XY gonadal dysgenesis are various. The external genitalia are often ambiguous.
- Lipoprotein glomerulopathy. 
- Epidermolysis bullosa. 
- Diffuse mesangial sclerosis and bilateral cataract 
- Nail-Patella Syndrome (Hereditary OnychOsteodysplasia)  is an autosomal-dominant disease characterized by dystrophic nails, absence of one or both patellas, and an assortment of other skeletal abnormalities.
- Lowe's Syndrome (Oculo-Cerebro-Renal Syndrome) is a sex-linked recessive disease, characterized by congenital glaucoma, cataracts, growth retardation, mental deficiency, hypotonia, metabolic acidosis, generalized aminoa-ciduria, proteinuria, and rickets.  The metabolic abnormalities agree with the pathological changes in the kidney. It usually takes from a few months to a year to develop the characteristic renal symptoms and lesions, and they can be demonstrated in only a few before the age of three months. The renal lesions may be in the form of severe generalized and global glomerular changes of mesangial cellular proliferation, and a slightly increased amount of mesangial matrix.
D. Sporadic CNS of Childhood Type
a. Minimal change nephrotic syndrome (MCNS). The histology of MCNS is the same regardless of time of onset and shows adherence of the foot processes of podocytes on electron microscopy. Infants with MCNS can have a steroidresponsive or steroid-resistant disease. Unlike infants with other types of CNS, those with minimal changes may benefit from medical treatment; however the prognosis of these infants does not seem as good as the older children.
b. Mesangial proliferative glomerulonephritis (MesPGN). In infants, light microscopy shows prominent diffuse mesangial cellular proliferation and more or less increased amounts of mesangial matrix without segmental sclerosis. These changes including adherence of the foot processes of podocytes, are also seen by electron microscopy. Infants with MesPGN may be steroid-responsive but are more likely to be steroid-resistant.
c. Sporadic (non-familial) Focal Segmental Glomerulosclerosis (FSGS). Few cases of CNS have been reported as this type in the literature. 
| Discussion|| |
Although uncommon, CNS continues to be a diagnostic and therapeutic challenge for the pediatrician. The nephritic syndrome presenting in children before the age of three months has been described well in the literature, but an adequate classification is often impossible on the basis of the histological descriptions or illustrations. Even a clearly reported diagnosis can be questioned. CNS with minimal changes, non-responsive to treatment, is such an example. If light microscopy alone is used, focal glomerulonephritis of proliferative types may be overlooked by sampling error, especially if the biopsy contained few glomeruli; and unless a large biopsy was obtained it can be nearly impossible to exclude focal segmental sclerosis, because the characteristic glomerular changes tend to be located in the inner cortex, which the biopsy may miss. In this latter case, immunofluorescent and ultrastructural studies are often of no use.
A correct diagnosis is important for prognosis, therapy, and genetic counseling. A good representative renal biopsy is essential. On the whole, all forms of CNS except the secondary ones have very poor prognosis. With secondary CNS, there is the possibility of specific treatment for the underlying disease, which may lead to regression of the renal lesions. Thus, penicillin is used in syphilis, pyrimethamine and sulfadiazine in toxoplasmosis, and dimercaprol in mercury intoxication. In all the other forms of CNS, only MCNS should be treated with steroids, and such therapy should be avoided or used with caution in some other types such as MesPGN.
The mode of inheritance has been established in several of the cases described, making genetic counseling easier. Prenatal diagnosis as has been shown in Finland may be helpful. CNS can be diagnosed prenatally by determining the Alfa fetoprotein concentration in the amniotic fluid. The concentration is increased in CNF as early as the 15 th week of gestation, and the best time for prenatal diagnosis should be between the 15 th and the 18 th week of gestation. More recently,
the use of mutation analysis of NPHS1 gene to confirm the Alpha-fetoprotein results in prenatal diagnosis in the fetal carriers of nephrin gene mutations has been emphasized. 
Infection is a major problem in children with CNS. Clinically, a high degree of suspicion for septic infections is warranted. Many of these patients are at risk of serious bacterial infections. , Some investigators have recommended the use of prophylactic antibiotics such as penicillin. Antibiotic therapy should be started promptly on suspicion of infection and should cover for gram-negative and gram-positive bacteria. Huttunen reported that one-third of all CNF children born in Finland from 1965 to 1973 died of infections.  Recent studies reported an excellent response to antibiotic therapy in these patients.  The prophylactic use of immunoglobulins is not indicated. The infused immunoglobulin is rapidly lost into the urine, and the commercial immunoglobulin preparations contain low IgG titers against bacteria mainly responsible for the septic episodes.
Other serious complications such as thrombosis of the inferior vana cava and/or the renal veins have been reported in association with CNS. This is a consequence of the nephrotic state, ,3 and may lead to serious sequelae.
The management depends on the type of nephrosis. In infants with CNF, the goal of all therapeutic decisions should be eventual renal transplantation, which is currently the only curative therapy. This is however distant from reality in the developing or under developed countries because of cost considerations in treating these patients and the technical difficulties of transplantation. The goals of medical therapy are to provide good nutrition, to control edema by parenteral protein supplementation, and to prevent infections and thrombosis. Few medical centers advocate unilateral nephrectomy or percutaneous renal ablation. Most institutions now recommend early bilateral nephrectomy in CNF patients, followed by dialysis, adequate nutritional support, and transplantation. 
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Radi MA Hamed
Department of Pediatrics, Jordan University Hospital, P.O.Box 13046, Amman