How HHRH Affects the Body: Bone and Kidney Symptoms

Because Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) is so rare, its symptoms can vary widely from person to person—even among siblings with the exact same genetic mutations ^[1]. The disease primarily affects two systems: the skeleton (bones) and the renal system (kidneys).

Clinical expression is highly variable. In one large literature review of genetically confirmed cases, some patients presented with symptoms in both systems, while others presented with primarily bone issues or primarily kidney issues. A small percentage of individuals with two pathogenic variants may even appear outwardly asymptomatic, highlighting the need for thorough biochemical and imaging evaluation ^[2].

Skeletal Symptoms: The Impact on Bones

The skeletal symptoms of HHRH are caused by low phosphate levels in the blood (hypophosphatemia). Without enough phosphate, the body cannot properly “mineralize” or harden new bone tissue.

In Children (Rickets):

• Leg Bowing: This is often the most visible sign. As a child begins to walk, their soft bones may curve outward (genu varum) or inward (genu valgum or “knock-knees”) ^[3][4].
• Growth Issues: Children with HHRH often have short stature or a slowing of their growth rate compared to other children their age ^[5].
• Bone Pain and Weakness: Patients might experience dull, aching pain in their legs or hips, or develop a “waddling” gait due to muscle weakness ^[2][3].
• Widened Joints: Unusual widening may be seen at the wrists or ankles, which are areas of active bone growth ^[5].

In Adults (Osteomalacia):

• Bone Softening: If undiagnosed until adulthood, or if inadequately treated, the condition is called osteomalacia. It can cause persistent bone pain and a higher risk of fractures ^[6].
• Low Bone Density: Adults may develop osteopenia or osteoporosis (thinning of the bones) earlier than expected ^[7][8].

Renal Symptoms: The Impact on Kidneys

While the bones suffer from a lack of minerals, the kidneys must filter an excess of calcium. This hypercalciuria is a major risk factor for kidney complications.

• Hypercalciuria (High Urine Calcium): This is found in nearly all patients with the full disease ^[9].
• Nephrolithiasis (Kidney Stones): Many people with HHRH will develop kidney stones, which can cause intense pain, blood in the urine, and infections ^[9].
• Nephrocalcinosis: This occurs when calcium deposits form directly inside the kidney tissue itself. In some specialized study cohorts, a majority of patients showed some level of renal calcification, though individual risk varies based on age, treatment, and genetics ^[7].
• Chronic Kidney Disease (CKD): While less common, the long-term buildup of calcium and recurrent stones can lead to permanent kidney scarring and a decline in kidney function over time ^[10].

The “Carrier” Experience: What Parents Should Know

HHRH is a recessive disease, meaning most parents are “carriers” (heterozygous) who have only one mutated copy of the SLC34A3 gene. For a long time, carriers were thought to be completely unaffected. However, research has shown that carriers can experience their own, usually milder, set of symptoms ^[11][8].

In family-based studies, a significant subset of carriers (roughly a third in some cohorts) demonstrated higher-than-normal levels of calcium in their urine. This means that:

• Kidney Stones: Carriers appear to have an increased risk of developing kidney stones compared to the general population ^[9][7].
• Bone Health: Some carriers may have slightly lower bone mineral density, though they rarely develop the severe bowing seen in children with the full disease ^[7][12].

Because of these risks, it is important for parents and siblings who are carriers to undergo individualized screening. A nephrologist or genetic counselor can help determine if a carrier needs urine calcium screening or bone density monitoring, based on their personal symptoms and family history ^[7].