Primary Hyperoxaluria Type 3

CLINICAL DESCRIPTION

Primary hyperoxaluria type 3 (PH3) is characterized by recurring calcium oxalate stones beginning in childhood or adolescence and, on occasion, nephrocalcinosis or reduced kidney function. PH3 most often presents in childhood (median age 2 to 3 years) with signs or symptoms related to stones including hematuria, frequent urination, dysuria, blood visible in the urine, or stone-associated pain. Some individuals with PH3 do not present until adulthood, usually with stone-related symptoms or findings. Over time, frequent stones and/or nephrocalcinosis may compromise kidney function, resulting in chronic kidney disease. To date, systemic oxalosis has not been reported in PH3.

DIAGNOSIS/TESTING: The diagnosis of PH3 is established in a proband with suggestive findings and biallelic pathogenic variants in identified by molecular genetic testing.

MANAGEMENT

: There is no cure for PH3. Lifelong treatment includes medical therapy and pharmacotherapy to reduce urine supersaturation of calcium oxalate to prevent formation of stones and calcium oxalate crystals that can injure the kidney. Mainstays of treatment are high oral fluid intake (>2.5 L per m body surface area) at all times; oral administration of an inhibitor of calcium oxalate crystallization, typically potassium and/or sodium citrate; prevention of stone complications by prompt relief of urinary tract obstruction and treatment of urinary tract infections. For those who are stable: (1) annual clinical assessment of stone-related symptoms (pain); frequency of passage of urinary stones and/or gravel and urinary tract infection; adherence to high fluid intake and medication schedule; and (2) annual assessment of kidney function (serum creatinine and eGFR), measurement of plasma oxalate concentration in those with impaired renal function, 24-hour urine oxalate and supersaturation study, and renal ultrasound examination or other imaging to monitor for stone formation. More frequent assessments are required for: children under age four years, individuals with complex stone problems, and individuals with reduced kidney function. Intravascular volume contraction, delays in treatment of acute stone episodes, nephrotoxic agents, high-dose ascorbic acid, and marked dietary oxalate excess. Targeted molecular genetic testing for the familial pathogenic variants is recommended for all sibs of a proband (regardless of age and even if apparently asymptomatic) in order to identify as early as possible those who would benefit from early treatment, preventive measures, and knowledge of circumstances/agents to avoid. In the few reports available to date, pregnancy outcomes in women with PH3 appear to be similar to those in women with other genetic causes of hyperoxaluria. Nonetheless, pregnant women who have PH3 should be considered at higher risk and warrant close monitoring, given the increased risk of acute kidney injury due to hypovolemia and/or an obstructing or infected stone.

GENETIC COUNSELING

PH3 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.