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A rare clinical variant of hereditary nephronophthisis characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before 3 years of age.
ORPHA:93591Classification level: Subtype of disorder
The prevalence of the infantile form is unknown. This rare kidney disorder affects both male and female; there is no difference in risk between ethnic groups.
Infantile nephronophthisis can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with reduced kidney function beginning within 1 year after birth and progressing to ESRD before 3 years of age. The disease is characterized by severe hypertension, anemia, skeletal abnormalities and increased thirst and urination. Extra renal involvement may include hepatic fibrosis, recurrent bronchial infections, situs inversus and valvular or ventricular septal defects. Renal ultrasound findings include hyperechogenic kidneys with size ranging from reduced to enlarged. Histological findings include diffuse interstitial fibrosis, tubular atrophy, renal cortical microcysts, dilatation of proximal tubules and Bowman space, and absence of a thickened tubular basement membrane.
Monogenic causal mutations have been identified in several genes involved in the Inversin compartment, which is localized at the proximal segment of the cilia. The most common pathogenic variants are found in the genes INVS (9q31.1) encoding Inversin, a protein that has a role in kidney development, and NPHP3 (3q22.1) encoding nephrocystin-3. Other pathogenic variants include NEK8 (17q11.2), TTC21B (2q24.3), ZNF423 (16q12.1), and CEP83 (12q22).
The diagnosis is either by renal biopsy or genetic testing. Investigational work-up may include blood tests for anemia, electrolyte imbalances and metabolic panel, and renal or abdominal ultrasound. Involvement of other organs should be investigated and may include an eye examination, neuroimaging, and a neurological examination.
Differential diagnosis includes autosomal recessive polycystic kidney disease, early-onset autosomal dominant polycystic kidney disease, and renal hypodysplasia.
Antenatal diagnosis is possible where a pathogenic variant has been identified in a family.
Inheritance is autosomal recessive. Homozygous or compound heterozygous mutations can be present in the patient. The parents are obligate heterozygotes (carriers) for a pathogenic variation and are asymptomatic with no risk of developing the disorder. Each sib of an affected individual has 50% risk to be an asymptomatic carrier, 25% to be affected, and 25% to be unaffected and not a carrier. Doubtless the offspring of affected individuals will be obligate carriers for a nephronophthisis-related pathogenic variant.
Management and treatment
There is no specific therapy. The management is supportive to maintain fluid and metabolic balance including correction of water and electrolyte imbalances as well as anemia, hypertension and proteinuria treatment if necessary. The management of patients includes growth hormone therapy in children who meet the criteria for treatment. For the ESRD management, dialysis, and isolated kidney/combined liver-kidney transplant is necessary.
Patients progress to ESRD before the age of 3 years. Despite the risk of complications, transplant outcomes are excellent with no recurrence of tubular injury
- Clinical genetics review
- English (2016)