Tumoral Calcinosis: Symptoms, Types, Causes and Treatment

Tumoral calcinosis is a rare and often misunderstood condition marked by abnormal calcium deposits in the soft tissues, usually near large joints. While its name may sound intimidating, understanding its symptoms, underlying types, causes, and available treatments can empower patients and their families to navigate this challenging disease. This comprehensive article aims to clarify the complexities surrounding tumoral calcinosis, drawing on recent research and clinical observations.

Symptoms of Tumoral Calcinosis

Tumoral calcinosis can present in subtle or dramatic ways, often making diagnosis challenging. Awareness of its symptoms is crucial for early recognition and effective management. The condition typically affects soft tissues near joints, leading to a variety of local and, less frequently, systemic complaints.

Symptom	Description	Frequency/Notes	Source(s)
Pain	Localized, sometimes severe	Most common symptom	1 2 4 5
Swelling	Periarticular, firm or hard mass	Often found near large joints	1 3 5 9
Impaired Mobility	Stiffness, reduced range of motion	Can be disabling	1 2 4 5
Numbness	Due to nerve compression	Less common	1 4
Fever	Systemic symptom, usually with inflammation	Rare, but reported	5 19
Asymptomatic	Incidental findings	Possible in some cases	1 3 9

Table 1: Key Symptoms

Pain and Swelling: The Hallmarks

Pain is the most commonly reported symptom, often associated with swelling or the presence of a hard, sometimes lobulated mass near a joint. These masses tend to develop gradually and can cause discomfort, especially when they press against nerves or tissues. The hip, shoulder, knee, hand, and wrist are the most frequently involved sites, but any large joint can be affected 1 3 5 9.

Impaired Mobility and Joint Dysfunction

As the calcified masses grow, they may restrict joint movement, leading to stiffness or even severe impairment. This is particularly true when the deposits are large or located in functionally critical areas like the hip or shoulder 2 4. In some cases, the condition leads to complete loss of joint motion, which can significantly limit daily activities.

Nerve Compression and Neurological Symptoms

Although less common, tumoral calcinosis can compress nearby nerves, causing numbness, tingling, or even weakness in the affected limb. These neurological symptoms are more likely when the calcifications are extensive or encase neurovascular bundles 4.

Systemic Manifestations

Fever is a rare but reported symptom, usually in the setting of significant inflammation or secondary infection of the calcified mass 5 19. General malaise and fatigue may accompany systemic inflammation but are not primary features.

Asymptomatic Cases

Not all patients experience pain or functional loss. In some, tumoral calcinosis is discovered incidentally during imaging for unrelated reasons or presents as a painless mass 1 3 9.

Types of Tumoral Calcinosis

Understanding the different types of tumoral calcinosis is critical, as the underlying type often dictates not only the cause but also the approach to treatment. Classification is based on clinical features, laboratory findings, and, increasingly, genetic understanding.

Type	Defining Features	Biochemical Profile	Source(s)
Primary Hyperphosphatemic	Familial, large periarticular masses, early onset	Elevated phosphate	8 10 11 12 13 14 15 18 19
Primary Normophosphatemic	Idiopathic, sporadic, periarticular masses	Normal phosphate	1 8 10
Secondary	Associated with systemic disease (e.g., CKD)	Variable; often hyperphosphatemia	2 4 5 8 10

Table 2: Types of Tumoral Calcinosis

Primary Hyperphosphatemic Tumoral Calcinosis

This form is typically familial, inherited in an autosomal recessive manner, and characterized by early onset of large, sometimes multiple, periarticular calcified masses. Laboratory findings consistently show elevated serum phosphate levels (hyperphosphatemia), with normal or elevated calcium and vitamin D 8 10 11 12 13 14 15 18 19. Mutations in genes responsible for phosphate regulation (GALNT3, FGF23, KL) are often identified. This type is sometimes referred to as hyperphosphatemic familial tumoral calcinosis (HFTC).

Primary Normophosphatemic Tumoral Calcinosis

This rarer subtype presents with similar masses but without abnormalities in serum phosphate levels. It is often sporadic but can have a familial component, with mutations such as those in the SAMD9 gene suggested in some cases 1 8 10. The age of onset is usually later, and the prognosis varies.

Secondary Tumoral Calcinosis

Secondary tumoral calcinosis arises as a complication of other systemic conditions, most notably chronic kidney disease (CKD) and hyperparathyroidism, which lead to disturbances in calcium and phosphate metabolism 2 4 5 8 10. It can also be seen in patients on long-term dialysis. This form is clinically similar to the primary types but is differentiated by the underlying cause and biochemical abnormalities.

Causes of Tumoral Calcinosis

The causes of tumoral calcinosis are diverse and reflect the underlying type of the disease. They range from genetic mutations affecting phosphate regulation to acquired systemic disorders.

Cause	Mechanism/Pathway	Type(s) Affected	Source(s)
GALNT3 Mutation	Disrupts FGF23 glycosylation, ↑ phosphate	Primary hyperphosphatemic	11 18 19
FGF23 Mutation	Reduces FGF23 activity, ↑ phosphate	Primary hyperphosphatemic	12 14 15 18
KL (Klotho) Mutation	Impairs FGF23 signaling, ↑ phosphate	Primary hyperphosphatemic	13 18
SAMD9 Mutation	Unclear, familial normophosphatemic variant	Primary normophosphatemic	1 8
Renal Failure	Phosphate retention, secondary hyperparathyroidism	Secondary	2 4 5 8 10
Autoimmune (Acquired)	FGF23 resistance/deficiency	Primary hyperphosphatemic	18

Table 3: Main Causes of Tumoral Calcinosis

Genetic Causes

GALNT3, FGF23, and KL Mutations

In familial (primary hyperphosphatemic) tumoral calcinosis, the most well-established causes are mutations in the GALNT3 gene (responsible for FGF23 glycosylation), FGF23 gene (encoding the hormone that regulates phosphate excretion), and KL (Klotho, a co-receptor for FGF23) 11 12 13 14 15 18 19. These mutations disrupt normal phosphate homeostasis by:

• Reducing FGF23 function or expression, leading to decreased phosphate excretion by the kidneys.
• Increasing serum phosphate levels, which in turn precipitate with calcium to form hydroxyapatite deposits in soft tissues.

SAMD9 Mutation

A familial, normophosphatemic form of tumoral calcinosis has been associated with mutations in the SAMD9 gene, though the precise pathogenic mechanisms remain unclear 1 8.

Acquired/Secondary Causes

Chronic Kidney Disease and Secondary Hyperparathyroidism

Secondary tumoral calcinosis most often occurs in patients with chronic renal failure. The kidneys’ inability to excrete phosphate leads to hyperphosphatemia, and secondary or tertiary hyperparathyroidism may further disrupt calcium-phosphate balance, culminating in ectopic calcification 2 4 5 8 10.

Autoimmune and Other Mechanisms

Rarely, an acquired, autoimmune-mediated resistance to FGF23 has been reported, mimicking the genetic forms 18.

The Pathophysiological Cascade

Regardless of the underlying cause, the end result is an elevated calcium-phosphate product in the blood, favoring the deposition of insoluble calcium phosphate crystals in periarticular soft tissues 10 18. Local injury or microtrauma may trigger or exacerbate the process 10.

Treatment of Tumoral Calcinosis

Managing tumoral calcinosis requires a tailored approach based on the underlying type, the severity of symptoms, and the presence of complications. While some cases respond well to conservative measures, others demand surgical intervention or novel therapies.

Approach	Key Features	Indication/Notes	Source(s)
Surgical Excision	Removal of calcified masses	Primary; refractory or large lesions	1 3 4 8 16
Phosphate Binders	Lower serum phosphate (dietary, medication)	Hyperphosphatemic, secondary	5 8 16 18 19
Dietary Phosphate Restriction	Reduce phosphate intake	Hyperphosphatemic, secondary	8 16 18
Parathyroidectomy	Surgical removal of parathyroid glands	Severe secondary hyperparathyroidism	8
Sodium Thiosulfate	Local/IV treatment to dissolve deposits	Selected refractory/large lesions	17
Steroid/Anti-inflammatory	Symptom control, inflammation	Inflammatory flares	2 19
Aspiration/Injection	Drain fluid, inject steroids	Symptom relief, especially bursitis	2

Table 4: Treatment Approaches

Surgical Management

Surgical excision remains the mainstay for symptomatic or disabling tumoral calcinosis, particularly for large, superficial, or functionally limiting lesions 1 3 4 8 16. When complete removal is possible, recurrence rates are low in normophosphatemic disease. However, in hyperphosphatemic or secondary forms, recurrence is common unless biochemical abnormalities are corrected.

Medical Management

Phosphate Lowering

For hyperphosphatemic tumoral calcinosis (familial or secondary), controlling serum phosphate is critical. This can involve:

• Phosphate binders (oral agents that reduce intestinal phosphate absorption) 5 8 16 18 19
• Dietary phosphate restriction 8 16 18
• Acetazolamide (promotes renal phosphate excretion in some cases) 8

These interventions can reduce lesion size and prevent recurrence.

Parathyroidectomy

In patients with secondary tumoral calcinosis due to chronic kidney disease and uncontrolled secondary or tertiary hyperparathyroidism, partial or total parathyroidectomy may be necessary to control phosphate and calcium levels 8.

Sodium Thiosulfate

Intralesional or intravenous sodium thiosulfate has shown promise in reducing the size and symptoms of calcified masses, particularly in patients who are not surgical candidates or have diffuse disease 17. Local injections may offer a non-surgical alternative for large or deep lesions.

Management of Inflammation and Pain

Anti-inflammatory agents, including corticosteroids, and targeted therapies (such as anti-interleukin-1 agents), can help control inflammatory flares, though they do not halt calcinosis progression 2 19.

Aspiration and Local Therapies

In cases with cystic lesions or bursitis, aspiration of calcific fluid and injection of local anesthetic and steroids can provide temporary symptom relief 2.

Prognosis and Recurrence

Recurrence is common if the underlying metabolic abnormality is not addressed—especially in familial hyperphosphatemic and secondary types 8 16. In normophosphatemic and surgically treated cases, outcomes are generally better 1.

Conclusion

Tumoral calcinosis is a rare but potentially disabling disorder resulting from abnormal calcium-phosphate deposition in soft tissues. Recognizing its symptoms, understanding its diverse types and causes, and applying a tailored treatment strategy are essential for optimal patient care.

Key points:

• Symptoms include pain, swelling, impaired mobility, nerve compression, and occasionally fever or asymptomatic masses 1 2 3 4 5.
• Types: Primary hyperphosphatemic (familial/genetic), primary normophosphatemic (idiopathic), and secondary (acquired, often due to CKD) 8 10 11 12 13 14 15 18 19.
• Causes: Genetic mutations (GALNT3, FGF23, KL, SAMD9), chronic kidney disease, autoimmune mechanisms 1 2 4 5 8 10 11 12 13 14 15 18 19.
• Treatment: Varies by type; includes surgical excision, phosphate-lowering strategies, parathyroidectomy, sodium thiosulfate, anti-inflammatory medications, and local therapies 1 2 3 4 5 8 16 17 18 19.

Early diagnosis and individualized treatment—often requiring collaboration between surgeons, nephrologists, endocrinologists, and geneticists—are vital for improving outcomes and quality of life in those affected by tumoral calcinosis.