The Biology and Genetics of HHRH: Understanding the Labs

Understanding how Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) works is essential because it is managed very differently from other forms of rickets. While most types of rickets are caused by a lack of nutritional vitamin D or an overabundance of a hormone called FGF23, HHRH is caused by impaired phosphate reabsorption in the renal tubule of the kidneys ^[1][2].

The Biological “Cascade”

The root of HHRH lies in the SLC34A3 gene. This gene provides instructions for making a protein called NPT2c, which acts like a gatekeeper in the kidneys ^[1][3]. Normally, this gatekeeper grabs phosphate from the urine and pulls it back into the blood.

In HHRH, these gatekeepers are broken or missing. This triggers a specific chain reaction:

1. Phosphate Wasting: Because the NPT2c gatekeepers aren’t working, phosphate is lost into the urine ^[2].
2. Low Blood Phosphate: As phosphate is lost, the blood levels drop (hypophosphatemia). This deprives the bones of the mineral they need to stay hard ^[2][4].
3. The Active Vitamin D Surge: In response to low phosphate, the kidneys go into overdrive and produce high levels of active vitamin D (1,25-dihydroxyvitamin D or calcitriol). Note that this is different from nutritional vitamin D stores (25-hydroxyvitamin D) ^[5][2].
4. Increased Gut Absorption: High levels of active vitamin D cause the gut to absorb extra calcium from food. At the same time, levels of Parathyroid Hormone (PTH)—which normally helps the kidneys hold onto calcium—often drop to lower levels ^[2].
5. Hypercalciuria: With extra calcium entering the blood and lower PTH, the kidneys excrete the excess calcium into the urine (hypercalciuria). This is what creates the risk for kidney stones and calcium deposits (nephrocalcinosis) ^[2][4].

HHRH vs. XLH: Why the Difference Matters

It is very common for patients with HHRH to be initially misdiagnosed with X-Linked Hypophosphatemia (XLH), the most common form of hereditary rickets ^[6]. However, treating HHRH like XLH can be dangerous.

In XLH, a hormone called FGF23 is too high, which suppresses active vitamin D production. In contrast, HHRH is FGF23-independent—the hormone is usually inappropriately low or normal because the body is trying (and failing) to fix the phosphate leak on its own ^[2][6].

Important Note: Giving prescription active vitamin D (calcitriol/alfacalcidol) to a patient with HHRH—which is standard for XLH—can cause their urine calcium levels to rise even further, potentially increasing kidney risk ^[2][8].

The Diagnostic Evaluation

To confirm a diagnosis of HHRH and distinguish it from other conditions, your specialist will look at a combined biochemical, clinical, and genetic picture rather than a single result. Ideally, baseline lab samples are taken before starting treatments to get an accurate picture, but never stop or delay prescribed medications without explicit specialist instructions, as doing so can worsen bone disease.

Tests a specialist may use:

• Serum Phosphate: Expect this to be low ^[1].
• Serum Calcium: Often normal, but can sometimes be slightly elevated ^[10].
• PTH (Parathyroid Hormone): Should be in the low-normal range or suppressed ^[2].
• 1,25-dihydroxyvitamin D (Active Vitamin D): This is usually elevated ^[5].
• 25-hydroxyvitamin D (Nutritional Vitamin D): Checked to ensure there isn’t a standard vitamin D deficiency.
• FGF23: Often checked to rule out XLH; it should be inappropriately low for the degree of hypophosphatemia ^[2].
• Spot Urine Calcium/Creatinine Ratio or 24-Hour Urine Calcium: Measured to check for hypercalciuria; interpreted using age-appropriate ranges ^[2].
• TmP/GFR: A calculation based on paired blood and urine tests that estimates how much phosphate the kidneys are failing to reabsorb ^[6].

Confirming with Genetic Testing

The definitive way to confirm HHRH is by finding biallelic pathogenic or likely pathogenic variants in the SLC34A3 gene ^[11].

HHRH is an autosomal recessive condition, meaning a patient needs two mutated copies (one from each parent) to show full symptoms ^[12]. Genetic testing might show:

• Homozygous Variants: Two identical pathogenic variants ^[11].
• Compound Heterozygous Variants: Two different pathogenic variants in the same gene ^[12].

If a test only finds a “Variant of Uncertain Significance” (VUS) or only one mutation, it does not confirm HHRH. Further clinical evaluation, parental testing, copy-number analysis, or checking for phenocopies (look-alike diseases) will be necessary. People with a single verified mutation are carriers and may still have an increased risk for kidney stones later in life ^[11][13].