hypophosphatemic nephrolithiasis/osteoporosis

Hypophosphatemic Nephrolithiasis/Osteoporosis: A Rare Kidney Disease

Hypophosphatemic nephrolithiasis/osteoporosis is a rare genetic kidney disease characterized by the formation of renal calcium stones or bone demineralization [5]. This condition is caused by defects in the SLC34A1 gene, which codes for a protein responsible for phosphate reabsorption in the kidneys [7].

The clinical features of hypophosphatemic nephrolithiasis/osteoporosis include:

• Abnormality of metabolism/homeostasis: Hypophosphatemia (low phosphate levels) and hyperphosphaturia (excessive phosphate loss in urine)
• Abnormality of the genitourinary system: Hypercalciuria (excessive calcium loss in urine), nephrolithiasis (formation of kidney stones), and osteoporosis (bone demineralization)
• Increased excretion of phosphates in the urine
• Presence of calculi (stones) in the kidneys

This condition is often inherited in an autosomal dominant pattern, meaning that a single copy of the mutated gene is sufficient to cause the disease [8]. The symptoms can vary in severity and may include kidney stones, bone pain, and osteoporosis.

References:

• [5] - A disease characterized by decreased renal phosphate absorption, renal phosphate wasting, hypophosphatemia, hyperphosphaturia, hypercalciuria, nephrolithiasis...
• [7] - Defects in SLC34A1 are the cause of hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1; MIM:612286), disease characterised by decreased renal...
• [8] - A number sign (#) is used with this entry because hypophosphatemic nephrolithiasis/osteoporosis-2 (NPHLOP2) is caused by heterozygous mutation in the SLC9A3R1...

Hypophosphatemic Nephrolithiasis/Osteoporosis Signs and Symptoms

Hypophosphatemic nephrolithiasis/osteoporosis is a rare genetic disorder characterized by phosphate loss in the kidneys, leading to kidney stones (nephrolithiasis) and osteoporosis. The signs and symptoms of this condition can vary from person to person but often include:

• Kidney Stones: Recurrent formation of kidney stones due to hypercalciuria (excessive calcium in the urine)
• Osteoporosis: Weakening of bones, leading to increased risk of fractures
• Muscle Weakness: Muscle weakness and fatigue are common symptoms, especially in adults [5]
• Bone Pain: Bone pain and tenderness, particularly in the hips, knees, and spine
• Gait Abnormalities: Gait abnormalities due to bone deformities and muscle weakness
• Weakness: Generalized weakness and fatigue [6]
• Rhabdomyolysis: In severe cases, hypophosphatemia can lead to rhabdomyolysis (muscle breakdown)
• Altered Mental Status: Disorientation, seizures, and altered mental status in severe cases of acute hypophosphatemia [4]

Additionally, some individuals with hereditary hypophosphatemic rickets may experience:

• Premature Fusion of Skull Bones: Premature fusion of the skull bones (craniosynostosis)
• Dental Abnormalities: Dental abnormalities and delayed tooth eruption

It's essential to note that not everyone with hypophosphatemic nephrolithiasis/osteoporosis will exhibit all these symptoms, and their severity can vary widely among individuals.

Diagnostic Tests for Hypophosphatemic Nephrolithiasis/Osteoporosis

Hypophosphatemic nephrolithiasis/osteoporosis is a rare genetic disorder characterized by low phosphate levels in the blood, kidney stones, and osteoporosis. Diagnostic tests are essential to confirm the diagnosis and rule out other conditions with similar symptoms.

Clinical Genetic Tests

1. Exome-based NextGen sequencing with CNV analysis: This is a comprehensive test that analyzes the entire genome for mutations associated with hypophosphatemic nephrolithiasis/osteoporosis [4].
2. PGxome testing: This test is offered by PreventionGenetics and is specifically designed to detect mutations in the NPT2a gene, which is associated with hereditary hypophosphatemic rickets with hypercalciuria [2].

Laboratory Tests

1. Serum phosphate studies: Measuring serum phosphate levels can help confirm low phosphate levels in the blood.
2. Serum calcium and magnesium studies: These tests can help identify high calcium levels, which are often associated with hypophosphatemic nephrolithiasis/osteoporosis [7].

Genetic Panels

1. Invitae Nephrolithiasis Panel: This panel analyzes genes associated with nephrolithiasis and can be used to diagnose hypophosphatemic nephrolithiasis/osteoporosis [5].
2. 13-gene panel for hypophosphatemic rickets: This panel is specifically designed to detect mutations in the NPT2a gene and is ideal for patients with a clinical suspicion of hypophosphatemic rickets [9].

Other Tests

1. Imaging studies: Imaging tests such as X-rays, CT scans, or MRI can help identify kidney stones or osteoporosis.
2. Bone density testing: Measuring bone density using DEXA scans can help diagnose osteoporosis.

It's essential to note that a definitive diagnosis of hypophosphatemic nephrolithiasis/osteoporosis can only be achieved through genetic testing [10]. A comprehensive diagnostic approach, including clinical genetic tests and laboratory tests, is necessary to confirm the diagnosis and rule out other conditions with similar symptoms.

Treatment Options for Hypophosphatemic Nephrolithiasis/Osteoporosis

Hypophosphatemic nephrolithiasis/osteoporosis is a condition characterized by low phosphate levels in the blood, leading to kidney stones and osteoporosis. While there are various treatment options available, the primary goal of therapy is to correct hypophosphatemia and prevent further complications.

Phosphate Supplementation

The conventional treatment for hypophosphatemic nephrolithiasis/osteoporosis involves long-term phosphorous supplementation [4]. This can be achieved through oral phosphate salts or vitamin D metabolites/analogues as replacement therapy, with a goal of correcting hypophosphatemia and preventing further complications [2].

Bisphosphonates

Bisphosphonates are another treatment option for hypophosphatemic nephrolithiasis/osteoporosis. These medications can help reduce bone resorption and increase bone density, thereby reducing the risk of osteoporotic fractures [8][9]. However, their effectiveness in treating hypophosphatemia-related kidney stones is less clear.

Vitamin D Analogues

Vitamin D analogues, such as calcitriol or paricalcitol, may also be used to treat hypophosphatemic nephrolithiasis/osteoporosis. These medications can help increase calcium absorption and reduce the risk of osteoporotic fractures [5].

Burosumab (Crysvita)

In 2018, the US Food & Drug Administration approved burosumab (Crysvita) for the treatment of X-linked hypophosphatemia (XLH), a genetic disorder that can cause hypophosphatemic nephrolithiasis/osteoporosis [6]. While this medication is specifically designed to treat XLH, it may also be effective in treating other forms of hypophosphatemic nephrolithiasis/osteoporosis.

Current Treatment Guidelines

The current treatment guidelines for hypophosphatemic nephrolithiasis/osteoporosis emphasize the importance of correcting hypophosphatemia through phosphorous supplementation and vitamin D analogue therapy [7]. However, further research is needed to determine the most effective treatment strategies for this condition.

References:

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The differential diagnosis for hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1) is a crucial aspect of diagnosing this rare genetic disorder. According to medical literature, the differential diagnosis includes other forms of inherited hypophosphatemia such as X-linked hypophosphatemia, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and hereditary hypophosphatemic rickets with hypercalciuria [1].

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare genetic disorder caused by heterozygous point mutations at amino acid residues 176 or 179 in fibroblast growth factor 23 (FGF23), and KLOTHO gene. It presents with similar clinical features to NPHLOP1, including hypophosphatemia, nephrolithiasis, and osteoporosis [2].

Other conditions that may be considered in the differential diagnosis of NPHLOP1 include hereditary hypophosphatemic rickets with hypercalciuria, which is an autosomal recessive disorder characterized by decreased renal phosphate reabsorption and increased urinary excretion of calcium [3]. Additionally, X-linked hypophosphatemia, autosomal recessive hypophosphatemic rickets, and other forms of inherited hypophosphatemia may also be considered in the differential diagnosis [4].

It is essential to note that a comprehensive evaluation, including laboratory tests and imaging studies, can help narrow down the differential diagnosis and guide further management. A detailed review of the patient's medical history, physical examination findings, and laboratory results can aid in distinguishing NPHLOP1 from other similar conditions.

References:

[1] Defects in SLC34A1 are the cause of hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1; MIM. 145980) [10]

[2] Autosomal dominant hypophosphatemic rickets has a similar clinical phenotype but, unlike NPHLOP1, it is caused by mutations in the FGF23 gene [11]

[3] In patients who have hereditary hypophosphatemic rickets with hypercalciuria, an autosomal recessive disorder, no mutation in the coding region of the NPT2a gene has been found [13]

[4] The differential diagnosis can be narrowed down substantially using relatively few, readily available laboratory tests (Fig. 2) [11]