Why some children develop resistance to steroids is not well understood [9]. Recent studies have shown that specific genetic mutations constitute a principle mechanism for steroid resistance. Mutations of NPHS1, NPHS2, ACTN4 and WTI genes are responsible for severe forms of SRNS in childhood, progressing to end-stage renal failure [10]. Positional cloning has revealed defects in these 4 different genes as monogenic causes of SRNS in familial cases [11]. See table 1.

Table 1: Genetic mutations associated with SRNS in childhood.

GENE	TYPE OF NS
NPHS1	Recessive mutations, encoding nephrin, (OMIM No. 602716) causes congenital NS of the Finnish type.
NPHS2	Recessive mutations, encoding podocin (OMIN no. 604766), causes SRNS Type 1.
ACTN4	Mutations encoding actinin 4, (OMIN no. 604638), causes autosomal dominant form of SRNS. An additional locus for an autosomal dominant form of NS has been mapped to chromosome 11q21-q22 (OMIN no. 603965).
WT1	Mutations are associated with congenital NS and diffuse mesangial sclerosis in the Denys-Drash syndrome and Frasier syndrome.

The Denys-Drash syndrome is characterised by early onset of NS progressing rapidly to end-stage renal disease, male pseudohermaphroditism, and Wilm's tumour [12]. The Frasier syndrome is characterised by the association of male pseudohermaphroditism and progressive glomerulopathy [13,14].

Podocin mutations Podocin, a 383-amino-acid protein, is a lipid raft-associated protein at the filtration slit, which is exclusively expressed in the podocytes at the foot processes [15]. Podocin interacts with nephrin [16]. Podocin also interacts with CD2AP, an adaptor protein that anchors CD2, a protein that stabilizes contact between podocytes [17]. The podocin plays a major role in the structural integrity and function of the slit diaphragm, which is the maintenance of glomerular permselectivity. Mutations in this gene can be observed in patients with both familial and sporadic disease. In a study by Weber et al, [18] NPHS2 mutation analysis was performed in 338 children from 272 families with SRNS: 81 families had autosomal recessive (AR) SRNS, 72 patients had sporadic SRNS, and 19 diffuse mesangial sclerosis [18]. The following results were obtained:

• The detection rate of NPHS2 mutations (homozygous or compound heterozygous) for AR SRNS was 43%. The average age of onset was 58 months.
 
• For those with sporadic forms of SRNS, it was 11%. The average age of onset was 103 months.
 
• Relatively late onset of NS was observed in patients with only one pathogenetic NPHS2 mutation.

In a second large study by Ruf et al [19] direct sequencing of the NPHS2 gene was performed in 190 patients with SRNS (from 165 different families) as well as 124 patients with steroid-sensitive NS (from 120 families). The following results were obtained:

• In the SR families, 43 (26%) of 165 SRNS families had homozygous or compound heterozygous mutations in NPHS2. Of the 29 patients with such mutations treated with cyclosporin or cyclophosphamide, more experienced a complete remission.
 
• No homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families.
 
• Recurrence of FSGS in a renal transplant was noted for 7 of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only 2 of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2.

It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid therapy and have a reduced risk for recurrence of FSGS in a renal transplant. The authors further advocate that mutational analysis of NPHS2, if the patient consents, be done in parallel with the first course of standard steroid therapy in children with NS to avoid unnecessary side effects from prolonged or repeated course of steroids and cytotoxic agents. They further concluded that because patients with SRNS and homozygous or compound heterozygous mutations in NPHS2 have reduced risk for recurrence of FSGS in a renal transplant, compared to children without mutations, living related donor transplants might be considered more readily. However, given that 85% of children are steroid-sensitive and only approximately 20% of SR patients have NPHS2 mutations, screening for abnormalities at this gene locus will identify less than 5 percent of all cases [20]. Also, not all familial cases of SRNS are associated with NPHS2 mutations, suggesting that yet to be identified genes are responsible in these cases [21]. These genes may in fact be responsible for a higher proportion of sporadic SRNS.

WT1 mutations
The WT1 gene, which encodes a transcription factor, contains ten exons [21]. WT1 is strongly expressed during embryofetal life [22]. In the mature kidney, WT1 expression persists only in podocytes and epithelial cells of Bowman's capsule. Disruption of the WT1 gene in mice results in the absence of both kidneys and gonads, suggesting a crucial role of WT1 in the development of the genitourinary tract. Mutations in WT1, the Wilm's tumour suppressor gene, have been reported in children with sporadic SRNS and several forms of hereditary NS.

CD2-Associated protein
CD2AP anchors CD2 receptors of T-lymphocytes to the cytoskeleton. It is also expressed in the podocyte. It has been shown in murine studies that CD2AP and nephrin interact directly, suggesting an important role of this protein in the anchoring of nephrin to the slit diaphragm or into the signalling pathways [23]. No mutations of the CD2AP gene to date have been reported to be associated with SRNS.

HLA associations with SRNS
Several studies have failed to demonstrate any significant association of SRNS with class II antigens [24,25,26,27]. Other studies from Europe and the United States have shown an association of HLA-DR7 with the frequency of relapses in steroid sensitive NS [28,29,30,31,26]. Bakr et al [32] studied 20 Egyptian children with frequent relapses/steroid-dependant NS and 14 children with SRNS. The DRBI * 07011 allele frequency was significantly higher among patients than the 121 unrelated healthy controls (64.3% vs. 16.5%, Pc <0.001). The aetiological fraction was high at 0.57 (RR=9.6, Cl 2.9-31.7).

Clinical Presentation

The majority of patients present between 2-7 years of age. There is a preponderance of males with a ratio of males: females of 2:1. The disease is characterized by the sudden onset of oedema. Anasarca may develop with ascites, pleural and pericardial effusions. Blood pressure is usually normal but is sometimes elevated. Abdominal pain is occasionally due to complications such as peritonitis, thrombosis, or rarely pancreatitis. Sometimes the rapid development of ascites with concomitant hypovolemia leads to abdominal pain and malaise. In some patients, oedema is minimal and the nephrotic state is only discovered during routine urine analysis. Macroscopic hematuria may occur in a few cases. SRNS may also present with an infection or thrombotic complication.