Nephrotic Syndrome, Type 2

Alternative Names

  • NPHS2
  • Nephrotic Syndrome, Steroid-Resistant, Autosomal Recessive
  • SRN1
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WHO-ICD-10 version:2010

Diseases of the genitourinary system

Glomerular diseases

OMIM Number

600995

Mode of Inheritance

Autosomal recessive heterogeneity

Gene Map Locus

1q25.2

Description

Steroid-resistant nephrotic syndrome is a chronic, progressive glomerular disorder that occurs in 10% of cases with nephritic syndromes. It is characterized by severe proteinurea, edema, low levels of proteins in the blood, high levels of fats in the blood, a tendency for increased blood clotting, and a greater susceptibility to infection. Both males and females are equally affected. The disease affects people at any age, but it is more common in children between the ages of 18 months and four years. Morbidity and mortality are associated with persistent edema, hypertension, hyperlipidemia, thrombosis and infection. The incidence rate is estimated to be 20:100,000 live births worldwide. The physician relays on physical examination, and blood and urine tests to diagnose nephritic syndrome.

Molecular Genetics

Steroid-resistant nephrotic syndrome is transmitted as an autosomal recessive trait. A gene located on the chromosome 1q25-q31 region known as nephrosis 2, idiopathic, steroid-resistant (NPHS2) or podocin was identified as the causative gene in this type of nephritic syndrome. NPHS2 gene encodes a protein called podocin which is an integral membrane protein. To date, more than 50 mutations have been identified in the NPHS2 gene that cause steroid resistant nephritic syndrome.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
600995.1United Arab EmiratesUnknown Congenital nephrotic syndromeNM_014625.4:c.779T>AHomozygousAutosomal, RecessiveAl-Gazali and Ali, 2010
600995.2United Arab EmiratesUnknown Congenital nephrotic syndromeNM_014625.4:c.779T>AHomozygousAutosomal, RecessiveAl-Gazali and Ali, 2010
600995.3LebanonUnknown Nephrotic syndrome; Global developmental...NM_014625.4:c.538G>AHeterozygousAutosomal, DominantJalkh et al. 2019

Other Reports

Egypt

Bakr et al. (2008) studied the spectrum of NPHS2 mutations in 16 Egyptian children with non familial steroid-resistant nephrotic syndrome (SRNS). NPHS2 mutations were evident in four patients (25%) who were bearing four novel mutations including two frame shift mutations (p.R238fs and p.P45fs) and two missense mutations (p.I136L and p.F216Y). There were no phenotypic or histological characteristics of patients bearing NPHS2 mutations, apart from the earlier onset of the disease, compared to those who were not bearing mutations.

Kuwait

Zaki et al. (1989) studied a series of 55 Arab children (35 boys and 20 girls) diagnosed with primary nephrotic syndrome during a period of five years (1981-1985) in Kuwait. Based on this sample, the annual incidence of primary nephrotic syndrome in Kuwait was calculated to be 7.2 and 6.0 per 100,000 Arab children below the ages of 10 and 12-years, respectively. Nine of these patients turned out to be steroid resistant. In these nine patients, histopathological study of the renal biopsies identified five cases of membranoproliferative nephritis, three cases of focal segmental glomerulosclerosis, and one case of membranous nephropathy. Zaki et al. (1989) concluded that the incidence of this disease seemed to be higher among Arab children than in Western countries.

Oman

Ahmed et al. (2002) reported an 11-year old girl who was diagnosed with nephrotic syndrome six months earlier, as she presented with anasarca and massive protienuria, which initially responded to steroids, but needed immuno-suppressants as she became steroid-resistant after four months. This time she was admitted with anasarca, hypertension and hyponatremia (113 mmol/l), which was slowly corrected. However, by the sixth day, she continued to be hyponatremic (110mmol/l). Therefore, more than 20 meq/L of sodium was enthusiastically administered. Within two days of this, she developed central pontine myelinolysis, as she was found to be mute, quadriplegic with bilateral extensor plantar response, and having cranial nerve palsies (bilateral seventh, tenth and twelfth nerves). The clinical localization was at mid pontine level; this diagnosis being reached by the metabolic background, accidental overcorrection of hyponatremia, clinical signs, and after exclusion of structural defects by MRI and CT scan of the brain. She was managed conservatively and showed recovery after five days with complete recovery on the tenth day. After two weeks, a repeat MRI brain was normal and she was discharged with no residual sequel.

Al-Gazali and Ali (2010), reported three Omani families living in the United Arab Emirates with congenital nephrosis, a homozygous missense mutation (c.779T4A) in the NPHS2 gene has been identified in two affected families, which results in a valine to glutamic acid (p.V260E) substitution.

[Al-Gazali L, Ali BR. Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE). Hum Mutat. 2010; 31(5):505-20.]

Qatar

ElTohami and Akl (1989) studied 62 children (mean age: 5.5 years) with primary nephrotic syndrome. Of these, seven (11.2%) were initially found to be steroid resistant, while the others were steroid responsive. Six of the steroid resistant cases were found, upon renal biopsy, to show focal glomerulosclerosis (3), minimal change disease (2), or membranoproliferative glomerulonephritis (1). Of the 55 patients initially found to be steroid responsive, three became steroid resistant later; two of them were having minimal change disease. In addition, another two had a frequently relapsing course, followed by becoming steroid resistant. Upon follow-up, all patients with minimal change disease were doing well, while two of the three patients with glomerulosclerosis had reached end stage renal disease. Akl and Hamad (1994) presented an overview of all pediatric renal patients seen in Qatar from 1982-1992. Of the total of 1753 children seen, 139 were diagnosed with Nephrotic Syndrome. Only a minority (11.3%) were steroid resistant, of which three families were found to be affected with malignant focal glomerulosclerosis, which led to end stage renal disease in infancy. Children in all three families had consanguineous parents.

Saudi Arabia

In 2003, Kari reported the spectrum of membranoproliferative glomerulonephritis in eight Arab patients from Saudi Arabia with membranoproliferative glomerulonephritis type I and type II. The mean age of the patients at presentation was 2.4 +/- 1.2 years. All patients presented with a steroid resistant nephrotic syndrome. None had macroscopic hematuria. However 5 (62.5%) were hypertensive at presentation. The mean follow-up between presentation and last visit was 1.1 +/- 0.7 years; range 0.1-2. Three patients were siblings and their parents were second-degree cousins. Another patient had a brother who had a renal failure following steroid resistant nephrotic syndrome (SRNS), but the histological cause of his SRNS was not known.

Almost six years later, Kari et al. (2009) reviewed the records of children who presented with primary Steroid Resistant Nephrotic Syndrome at a single centre in Saudi Arabia between 2002 and 2007. Excluding cases of congenital nephrotic syndrome, lupus, and sickle cell disease, 36 children (25 girls, 11 boys; mean age 4.3 years) were included in the study. Half the children were Saudi, and of the remaining, another four were Arabs. All patients had 4+ proteinuria on dialysis, and mean serum albumin was 15.6 g/L. Elevated creatinine levels were seen in five children, while three had low serum complement. The most common underlying histopathology was found to be focal and segmental glomerulosclerosis (39%), followed by IgM nephropathy (28%), mesengioproliferative glomerulonephritis (17%), MCD, and C1q nephropathy (8% each), and IgA nephropathy (3%).

Tunisia

Mbarek et al. (2011) analyzed 24 children belonging to 13 families with SRNS manifesting with various ages of onset for mutations in the NPHS1, NPHS2, PLCE1, LAMB2, and the relevant exons 8 and 9 of the WT1 genes. They detected 10 pathogenic mutations in seven families (three with NPHS1 mutations; two with LAMB2 mutations, a single family with an NPHS2 mutation, and another family with a mutation in WT1). Five of the detected mutations were novel; IVS9+2 T>C and p.D616G in NPHS1; p.E371fsX16 in NPHS2, and p.E705X and p.D1151fsX23 in LAMB2. Nine of 24 patients failed to be categorized by mutational analysis.

United Arab Emirates

[See also: Oman > Al-Gazali et al., 2010].

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