A number sign (#) is used with this entry because nephronophthisis-2 (NPHP2) is caused by homozygous or compound heterozygous mutation in the inversin gene (INVS; 243305) on chromosome 9q31.

For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100).

Gagnadoux et al. (1989) described observations taken over a 15-year period in 7 children (4 girls, 3 boys) presented within the first months of life with severe renal failure and acidosis, associated with hypertension in 5 patients and polyuria in 4. In addition, 1 patient had a severe cholestatic liver disease. In 2 families, a similarly affected sib had died previously. Four patients were referred with the clinical diagnosis of polycystic kidney disease because of moderate enlargement of kidneys, but renal imaging did not confirm this diagnosis. A renal biopsy, performed in all patients, showed similar features characterized by a diffuse chronic tubulointerstitial nephritis and particularly by the presence of microcystic dilatation of proximal tubules and Bowman space. Liver pathology was normal in 2 patients, including 1 with hepatomegaly. However, in the patient with cholestasis there was inflammatory portal fibrosis with mild duct proliferation. Progression of the renal disease was extremely rapid and all patients reached end-stage renal failure before the age of 2 years (11 to 22 months). Gagnadoux et al. (1989) suggested that this disorder represented a distinct entity both on clinical and morphologic grounds. The specific clinical features of this disease are its early onset and rapid progression to end-stage renal failure. Pathologically, it differs from later-onset nephronophthisis by the absence of medullary cysts and thickened tubular basement membranes and by the presence of cortical microcysts.

Haider et al. (1998) described a novel type of infantile nephronophthisis in an extended Bedouin family in Israel. The pedigree pattern was distinctly that of autosomal recessive inheritance. The phenotypic presentation ranged from a Potter-like syndrome to hyperechogenic kidneys, renal insufficiency, hypertension, and hyperkalemia. Affected individuals showed rapid deterioration of kidney function, leading to end-stage renal failure within 3 years. Histopathologic examination of renal tissues showed variable findings, ranging from infantile polycystic kidneys to chronic tubulointerstitial nephritis, fibrosis, and cortical microcysts. The manifestations range from prenatal fetal oliguria and oligohydramnios resulting in postnatal respiratory failure and death to postnatal onset of disease later than 30 months of age. None of the postnatally diagnosed patients had a history of either oligohydramnios or neonatal respiratory symptoms. Four of the 10 affected subjects were identified early because of family history. Prospective serial renal sonograms performed on these 4 patients showed hyperechogenic kidneys before the development of symptoms and abnormal laboratory findings. Renal sonograms of all patients showed enlarged and echogenic kidneys that lacked corticomedullary differentiation. All affected individuals developed anemia, hyperkalemic metabolic acidosis, and increased serum creatine. None of the affected subjects had polyuria, polydipsia, or associated ocular or hepatic complications.

Tory et al. (2009) reported 18 patients from 16 families with genetically confirmed NPHP2. Seven of the families had previously been reported by Otto et al. (2003). The median age at diagnosis was 11 months (range 5 to 36 months). Renal function deteriorated rapidly; end-stage renal disease was already present in half of the patients at diagnosis, and had developed in all but 2 before age 2 years. Ultrasound showed hyperechogenic kidneys in all but 1 case, cysts in 5, and variable kidney size. Nine biopsies showed infantile NPHP, with focal cystic tubule dilatation and diffuse moderate interstitial fibrosis. Thickened tubular basement membranes in this group were rare. Two biopsies were more consistent with juvenile NPHP, with severe and nearly diffuse atrophy of tubules surrounded by a thick and irregularly laminated basement membrane. Five nephrectomy specimens showed advanced chronic tubulointerstitial nephropathy with marked corticomedullary atrophy and cysts. All patients had hypertension, and there was marked medial hypertrophy of the arteries. Extrarenal renal manifestations were found in 12 of 17 patients, and included heart valve or septal defects in 5, hepatic involvement in 4, recurrent bronchial infections in 4, developmental delay in 2, and situs inversus in 2. The findings indicated that infantile and juvenile forms of NPHP are different manifestations of the same disease.

By linkage analysis in an Israeli Bedouin kindred, Haider et al. (1998) excluded the familial juvenile nephronophthisis locus (NPHP1; 256100) on 2q13 and the autosomal recessive polycystic kidney disease locus (PKHD1; 263200) on 6p21.1-p12. A homozygosity mapping strategy (Lander and Botstein, 1987) was employed to search for the locus causing infantile nephronophthisis in this kindred. Pooled DNA samples from parents and unaffected sibs and individual DNA samples from 4 affected individuals were used as PCR templates with trinucleotide- and tetranucleotide-repeat polymorphic markers. Using this approach, Haider et al. (1998) identified linkage of the clinical phenotype to markers on 9q22-q31. The disorder mapped to a 12.9-cM region flanked by markers D9S280 and GGAT3G09.

Otto et al. (2003) identified inversin as the gene mutated in NPHP2 with or without situs inversus (see, e.g., 243305.0001-243305.0002). They showed molecular interaction of inversin with nephrocystin (607100), the product of the gene mutated in NPHP1 (256100), and interaction of nephrocystin with beta-tubulin (TUBB; 191130), a main component of primary cilia. They showed that nephrocystin, inversin, and beta-tubulin colocalized to primary cilia of renal tubular cells. Furthermore, they produced a polycystic kidney disease (see 173900)-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin, and beta-tubulin connect pathogenetic aspects of NPHP to polycystic kidney disease, to primary cilia function, and to left-right axis determination.

Tory et al. (2009) identified 13 different mutations in the INVS gene (see, e.g., 243305.0003-243305.0005) in 16 (37%) of 43 families with infantile-onset nephronophthisis and end-stage renal failure by 5 years of age. The INVS mutation rate was 78% in the subgroup of patients who developed end-stage renal disease before age 2. Nine different mutations in the NPHP3 gene (608002) were found in 7 (16%) families. Overall, those with NPHP2 mutations had a faster deterioration compared to those with NPHP3 mutations, and those with NPHP3 mutations tended to have liver abnormalities.