Nephronophthisis 1

Alternative Names

  • NPHP1
  • Nephronophthisis, Familial Juvenile
  • NPH1

Associated Genes

Nephrocystin 1
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WHO-ICD-10 version:2010

Congenital malformations, deformations and chromosomal abnormalities

Congenital malformations of the urinary system

OMIM Number

256100

Mode of Inheritance

Autosomal recessive

Gene Map Locus

2q13

Description

Nephronophthisis (NPH) is an autosomal recessive and genetically heterogeneous disease characterized by a chronic tubulo-interstitial nephritis that progresses to terminal renal failure during the second decade (juvenile form) or before the age of 5 years (infantile form). In the juvenile form, a urine concentration defect starts during the first decade, and a progressive deterioration of renal function is observed in the following years. Kidney size may be normal, but loss of corticomedullary differentiation is often observed, and cysts occur usually after patients have progressed to end-stage renal failure. Histologic lesions are characterized by tubular basement membrane anomalies, tubular atrophy, and interstitial fibrosis. The infantile form is characterized by cortical microcysts and progression to end-stage renal failure before 5 years of age. Some children present with extrarenal symptoms: retinitis pigmentosa (Senior-Løken syndrome), mental retardation, cerebellar ataxia (Joubert syndrome), and ocular lesions.

Molecular Genetics

The NPHP1 gene, mapped to chromosome 2q13, contains at least 20 exons spanning more than 80 kb. NPHP1 encodes the nephrocystin protein with src homology domain 3 (SH3) patterns. This protein interacts with the signaling proteins p130Cas, tensin, focal adhesion kinase 2, and filamins A and B, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures especially in renal epithelial cells.

Mutations in the NPHP1 gene are responsible for the vast majority, ~85%, of the purely renal form of nephronophthisis including familial juvenile nephronophthisis type 1. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy, and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene.

Epidemiology in the Arab World

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Other Reports

Egypt

Soliman et al. (2010) studied 20 children from 17 independent Egyptian families who met the clinical and ultrasonographic criteria of nephronophthisis. All patients had an ophthalmologic examination, and magnetic resonance imaging (MRI) of the brain was carried out in children with neurological involvement. Sex distribution among the affected patients showed a slight preponderance of females (1.2:1, 11 females and 9 males). Seventy-five percent of the studied patients were the products of consanguineous marriages, the percentage of affected siblings was strikingly high (65%, 13/20 patients), and 40% (8/20 patient) had a history of sibling death due to a similar condition. Among the 20 patients, 15 (75%) presented with signs of end stage renal disease (ESRD). All patients suffered from anemia and growth retardation when they first presented for medical attention. Nineteen of the patients (95%) had a history typical of nephronophthisis, with symptoms of polydipsia, polyuria, and secondary enuresis. Four of the patients (20%) were hypertensive, with elevated blood pressure above the 95th percentile for age, gender, and height. Clinically, the patients were best categorized as presenting with isolated juvenile NPHP (65%, 13/20) and infantile NPHP (15%, 3/20). The remaining four patients (20%) were clinically categorized as Joubert syndrome-related disorder (JSRD). At the molecular level, Soliman et al. (2010) identified homozygous deletions in the NPHP1 gene in six patients from five independent families of 17 families studied (29.4%), thereby confirming the diagnosis of type 1 (juvenile) nephronophthisis.

Kuwait

Al-Eisa et al. (2004) conducted a retrospective study of all children less than 16 years of age with end-stage renal disease treated in the pediatric nephrology unit in Kuwait over a period of 8 years (January 1995 to December 2002). Of the 48 children boys comprises 52% and the overall mean age at institution of dialysis was 94.4 months. Causes of renal disease included congenital structural anomalies in 52%. Hereditary nephropathy was diagnosed in 35.4%, including primary hyperoxaluria in 10.4%, nephronophthisis in 2%, autosomal-recessive polycystic renal disease in 8%, and glomerulopathies in 14.5%. The mortality rate in the dialyzed group was 16%. Twenty-four patients received kidney transplants from, cadaveric donors in 19 cases. Al-Eisa et al. (2004) indicated that genetic factors contributed to the high incidence of end-stage renal disease, which is most likely due to the common practice of consanguineous marriages in the country.

Saudi Arabia

ElZouki et al. (1996) studied the role of thin-section (1.5-mm) computed tomography (CT) scan as an optimal imaging diagnostic technique for juvenile nephronophthisis. In three children with NPH, Elzouki et al. (1996) found that the thin-section CT scan detected cysts as small as 5 mm in diameter the medullary cysts in all patients and recommend CT scan as the investigation of choice in patients with clinical features suggestive of nephronophthisis-cystic renal medulla complex.

Al Romaih et al. (2011) studied two unrelated Saudi families with family histories of proteinuria, end stage renal disease, and different finding on kidney biopsy. The first family had two affected children born to consanguineous parents, and developed proteinuria at the age of 9 years.  They had an affected aunt with a similar problem.  The aunt and elder child underwent renal transplant.  Three children of the second family were born to consanguineous parents.  They presented to medical attention at different ages; 21, 15 and 12 years, with severe renal failure.  In both families, the diagnosis was initially thought to be focal segmental glomerulosclerosis (FSGS).  Failure to identify the underlying genetic defects in nephrotic syndrome and FSGS genes led to the use of high throughput technologies such as whole-genome SNP genotyping coupled with exome sequencing, which led to the identification of a homozygous deletion of the NPHP1gene. 

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