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A rare, genetic, renal ciliopathy characterized by reduced ability of the kidneys to concentrate solutes, chronic tubulointerstitial nephritis, cystic renal disease and progression to end stage renal disease (ESRD). The three clinical subtypes are characterized by the age of onset of ESRD which includes infantile, juvenile and late onset.
ORPHA:655Classification level: Disorder
The prevalence is unknown; however, at birth it is estimated at 1: 80,000 in Finland. Nephronophthisis (NPHP) is responsible for 2.4 to 15% of ESRD in children.
Three main forms have been described. Juvenile NPHP, the most frequent form, progresses to end-stage renal failure at median age of 13 and is responsible for 15% of cases of childhood ESRD. Infantile NPHP can present in utero with oligohydramnios sequence or postnatally with reduced kidney function and progresses to ESRD before age 3. Late-onset NPHP is a rare form of the disease and presents clinical and histological signs similar to the juvenile form but with ESRD occurring later (median age of 19 years). The typical clinical symptoms include polyuria, polydipsia with regular fluid intake, impaired sodium reabsorption that cause hypovolemia and hyponatremia, anemia and growth delay. Renal ultrasonography in early stages is normal or shows unspecific changes with increased renal echogenicity, with advancing kidney disease poor cortico-medullary differentiation is described; corticomedullary cysts are present in the 70% of patients. Renal histopathology in NPHP is characterized by the triad of tubular cysts, tubular basement membrane disruption, and interstitial fibrosis with interstitial cell infiltration. Retinal degeneration is the most frequent extrarenal findings (10%), cerebellar vermis aplasia, liver fibrosis and skeletal defects could be also present. Extrarenal phenotypes are distinct but they overlap in some syndromic forms of NPHP (such as Joubert syndrome, Senior-Loken syndrome, Meckel-Gruber syndrome).
To date, mutations in 14 genes have been identified in affected individuals. The majority of these genes encode for ciliary proteins that cluster to distinct subcellular localizations. The NPHP1 gene, that encodes for nephrocystin-1, is deleted or mutated in 25% of juvenile NPHP. Mutations in the gene INVS (9q31.1), coding for inversin, is frequently responsible for infantile NPHP. Mutations in NPHP3 (3q22.1), NPHP4 (1p36.31), NEK8 (17q11.2) genes give rise to late-onset nephronophthisis, however these genes are associated also with the Senior-Loken syndrome and Meckel-Gruber syndrome and predispose to multiorgan polycystic disease.
The diagnosis is suggested by clinical features and confirmed by genetic testing.
Differential diagnosis includes early onset autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease and congenital anomalies of kidney and urinary tract (CAKUT). Furthermore, juvenile NPHP forms part of a spectrum of NPHP-related ciliopathies which includes Joubert syndrome, Senior-Loken syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome and Skeletal Ciliopathies (Oral-facial-digital syndrome, Cranioectodermal dysplasia, Short-rib thoracic dysplasia). The infantile form should also be distinguished from renal hypodysplasia.
Once the pathogenic variants have been identified in an affected family member, prenatal testing or preimplantation genetic diagnosis can be considered.
The pattern of inheritance is autosomal recessive, with homozygous or compound heterozygous mutations possible. The parents are obligate heterozygotes (carriers) and are asymptomatic with no risk of developing the disorder. Each sib of an affected individual has a 50% risk of being an asymptomatic carrier, 25% to be affected, and 25% to be unaffected and not a carrier. Offspring of an affected individual will be obligate carriers.
Management and treatment
The management is supportive to maintain fluid and metabolic balance including: correction of water and electrolyte imbalances; anemia treatment, and proteinuria treatment if necessary. For the ESRD management, dialysis or renal transplantation are necessary.
The prognosis is dependent on the age of ESRD onset. Despite the risk of complications, transplant outcomes are excellent with no recurrence of tubular injury.