Which genetic disorders are associated with hypercalciuria (elevated urinary calcium)?

Genetic Disorders Associated with Elevated Urinary Calcium

Bartter syndrome types 1 and 2 are the primary genetic disorders characterized by hypercalciuria with nephrocalcinosis, while several other monogenic conditions including Dent's disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), familial hypomagnesemia with hypercalciuria, and disorders involving SLC34A1/SLC34A3 mutations also present with elevated urinary calcium. 1, 2

Primary Genetic Disorders with Hypercalciuria

Bartter Syndrome Subtypes

Bartter syndrome type 1 (BS1) and type 2 (BS2) are autosomal recessive disorders that characteristically present with hypercalciuria and nephrocalcinosis developing after 1-2 months of life. 1 These subtypes involve mutations in:

• BS1: SLC12A1 gene (encoding NKCC2 transporter) 1
• BS2: KCNJ1 gene (encoding ROMK/Kir1.1 channel) 1

Bartter syndrome type 3 (BS3) typically presents with normocalciuria, though hypercalciuria may occur in some cases. Interestingly, hypocalciuria has also been reported in BS3 patients who mimic Gitelman syndrome phenotype. 1

Bartter syndrome type 4 (BS4) usually demonstrates normocalciuria, though hypercalciuria can occur. This subtype involves mutations in BSND (encoding barttin) or combined CLCNKA and CLCNKB mutations. 1

Transient Bartter syndrome type 5 (BS5) may show hypercalciuria, but nephrocalcinosis is rare. 1

Dent's Disease

Dent's disease is an X-linked disorder caused by mutations in the CLC-5 chloride/proton antiporter gene, characterized by the triad of:

• Low molecular weight proteinuria
• Hypercalciuria
• Nephrolithiasis 2, 3

This disorder resembles Fanconi syndrome with impaired proximal tubular reabsorption. 4

Autosomal Dominant Hypocalcemic Hypercalciuria (ADHH)

ADHH results from activating mutations of the calcium-sensing receptor (CaSR), a G protein-coupled receptor. 2, 3 These gain-of-function mutations cause the receptor to be overly sensitive to calcium, leading to:

• Hypocalcemia
• Inappropriately low PTH
• Hypercalciuria 5

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC)

FHHNC is caused by mutations in paracellin-1 (CLDN16), a claudin family tight junction protein. 2, 3 This disorder specifically affects paracellular cation transport in the thick ascending limb, resulting in:

• Urinary magnesium wasting
• Hypercalciuria
• Nephrocalcinosis
• Progressive renal failure 4

Hypophosphatemic Hypercalciuric Nephrolithiasis

This disorder involves mutations in the type 2c sodium-phosphate cotransporter (NPT2c/SLC34A3) gene, presenting with:

• Hypophosphatemia
• Hypercalciuria
• Rickets (in some cases) 2, 3

SLC34A1-Related Disorders

Heterozygous variants in SLC34A1 (encoding the type 2a sodium-phosphate cotransporter) are associated with mild idiopathic infantile hypercalcemia (IIH). 6 In a cohort of children with mild IIH:

• 55% had genetic variants identified
• The majority carried heterozygous SLC34A1 or SLC34A3 variants
• Patients demonstrated elevated 1,25(OH)₂D levels, low-normal PTH, and hypercalciuria
• 55% developed renal calcification 6

Diagnostic Approach

Initial Evaluation

When hypercalciuria is identified, the following assessment should be performed 1:

Medical history evaluation:

• Polyhydramnios and premature birth (suggests antenatal Bartter syndrome)
• Growth failure and failure to thrive
• Recurrent vomiting and fever
• Family history of kidney stones or metabolic disorders

Biochemical parameters:

• Serum electrolytes (sodium, chloride, potassium, calcium, magnesium)
• Acid-base status
• Renin and aldosterone levels
• Creatinine and fractional excretion of chloride
• Urinary calcium-creatinine ratio
• 25(OH)D and 1,25(OH)₂D levels (for IIH evaluation) 6

Imaging:

• Renal ultrasound to detect nephrocalcinosis and kidney stones 1

Genetic Testing Indications

Genetic testing with gene panel analysis should be offered in the following scenarios 1:

• Children and young adults ≤25 years with nephrolithiasis 1
• Adults >25 years with suspected inherited or metabolic disorders 1
• Recurrent stone formers (≥2 episodes), bilateral disease, or strong family history 1
• Clinical suspicion of Bartter syndrome based on biochemical findings 1

The analytical sensitivity for Bartter syndrome genetic testing is 90-100%, with clinical sensitivity of approximately 75% in children but only 12.5% in adults. 1

Clinical Pitfalls and Caveats

Overlapping phenotypes can complicate diagnosis. BS3 patients may mimic Gitelman syndrome with hypocalciuria rather than hypercalciuria, requiring genetic confirmation. 1

Large gene rearrangements, particularly in CLCNKB, require confirmation by independent methods such as multiplex ligation-dependent probe amplification, as next-generation sequencing alone may be insufficient. 1

Genetic counseling should be offered to all families with confirmed genetic diagnoses, including cascade screening of relatives. This is particularly important for identifying heterozygous female carriers in families with MAGED2 mutations (BS5). 1

Hypercalciuria is familial in more than 35% of nephrolithiasis patients, emphasizing the importance of family history assessment. 2, 3