Familial tumoral calcinosis

Introduction

Tumoral calcinosis (TC) is a rare condition characterised by progressive, ectopic, periarticular deposits of calcium. These tumour-like growths often infiltrate muscle and tendon, usually presenting as multiple masses or as a painless, solitary mass. They are typically found at large joints such as the shoulders, elbows or hips and less frequently at the foot, leg, knee and hand. ¹ TC can manifest in three separate clinical settings: (1) familial tumoral calcinosis (FTC), (2) dialysis dependent patients with renal disease, and (3) idiopathic sporadic cases with no evidence of related abnormalities. ²

Our case report and discussion will focus on FTC. FTC is an autosomal recessive metabolic disorder generally observed in patients within the first two decades of life. They tend to have multiple areas of calcification. A positive family history is encountered in 30–40% ³ of cases and there is a significantly higher incidence in those of sub-Saharan African descent. ¹ Diagnosis is achieved by a combination of a high index of suspicion, raised serum phosphate and the histopathology of the specimens. Typically, histopathology samples confirm the presence of epithelioid elements and multinucleated giant cells surrounding calcium granules. ¹ Treatment currently combines surgical excision with the medical management of underlying metabolic derangements. Complications and recurrence are common and complete resolution of lesions is rare. ⁴ There are no clinical guidelines, leaving clinicians without a clear direction when treating patients.

Our case report introduces two Sudanese siblings from consanguineous parents who presented with simultaneous recurrent multiple soft tissue swellings. We will highlight the main features of FTC and show that clinical guidance on the investigation, treatment and genetic screening of FTC is needed.

Case report

The Sudanese children in the following report are siblings. They are the offspring of a consanguineous marriage between first cousins.

In February 2009, a 7-year-old girl of Sudanese origin presented with bilateral subscapular swellings (Figure 1(a)). They were not associated with any pain or limitation of movement. Both masses were well rounded, soft, cystic and slightly mobile, stretching to a diameter of 10.5 cm. A chest X-ray (Figure 1(b)), ultrasound and CT (Figure 1(c)) were performed. All imaging identified the abnormal masses in the subscapular regions. All routine investigations were normal except for a slightly high Vitamin D 1, 25 = 56 pg/ml. Serum phosphate (key diagnostic marker in FTC) was not measured. On April 2009, the patient underwent surgery for removal of the masses. During surgery, both masses were found to lie beneath the muscles and complete excision was not possible due to the infiltration of the muscle. During dissection, the masses ruptured discharging a creamy, yellow substance. The histopathology revealed the diagnosis of TC. Two months post surgery both swellings recurred. Figure 2 demonstrates the recurrence of the mass beneath the patient’s previous surgical incision (Figure 2(a)) accompanied by a corresponding chest x-ray (Figure 2(b)). OPEN IN VIEWER

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Figure 2.

(a) The patient in June 2009, swelling has recurred. The scar from previous surgery to remove the mass is visible. (b) X-ray demonstrating recurrence of the mass on the right side.

In January 2009, a 10-year-old boy of Sudanese origin, sibling of the patient in Case 1, presented with a painless right subscapular swelling that was cystic and mobile. A chest X-ray (Figure 3) and ultrasound were performed. Both images showed a bright abnormal mass in the subscapular region. All routine investigations were normal. Serum phosphate was not measured. Two months later in April 2009, the subscapular mass was surgically removed, histopathology revealed the diagnosis of TC. OPEN IN VIEWER

In May 2009, one month post surgery the subscapular swelling recurred, accompanied by a new swelling in the right elbow region. The swelling in the right elbow disappeared gradually but a new swelling appeared in the left elbow one month later in June. Furthermore, in 2010, a new swelling appeared on the right hip.

Discussion

FTC is a rare autosomal recessive disorder caused by progressive deposition of amorphous calcium salts and calcium hydroxyapatite crystals in soft tissues, typically around large joints. ⁵ The masses are classically slow growing and can become very large in size. ⁴ The siblings described illustrate the typically aetiology of FTC but also demonstrate the lack of guidance for the identification, diagnosis and management of the condition.

FTC is a condition that demonstrates extensive phenotypic and genetic heterogeneity.^6,7 Some patients have an unrelenting, incessant course while others experience dormant periods. ⁵ There are two main types of FTC based on serum phosphate status; patients presenting as either hyperphosphatemic (HFTC) or normophosphatemic (NFTC). ⁷ The less common NFTC, characterized by the absence of metabolic abnormalities, was found to be associated with the absence of functional SAMD9, a putative tumour suppressor and anti-inflammatory protein. ⁶ HFTC, is more common and results from the mutation of one of three genes; fibroblast growth factor-23 (FGF23), ⁷ FGF23 co-receptor , α-Klotho (αKL) ⁷ and FGF23-glycosylating enzyme (GALNT3). ⁷

The kidneys’ ability to excrete excess phosphorus from the body depends on FGF23. ⁸ Defective FGF-23 synthesis or action can lead to increased renal tubular phosphate reabsorption leading to hyperphosphatemia and severe ectopic calcifications in soft tissues. ⁸

Identification of FTC from other dystrophic or hypercalcemia causes of periarticular calcification is a vital first step to successful treatment. Treatment is currently a combination of surgical excision and medical management of the underlying metabolic abnormality. ⁵ Surgical excisions of the FTC lesions are well documented in the literature. Excision is successful in infants. Beyond this stage, recurrent lesions are a frequent complication of incomplete excision and typically grow more rapidly than the initial lesion. ⁴ Several cases have also reported postoperative complications such as prolonged drainage, delayed wound healing, sinus tract formation and secondary infection. ⁴ Indeed, the lesion’s nature can promote infection, as the calcium deposits may act as a site for bacterial seeding. One case report described the superinfection of a lesion that recurred seven years post excision, leading to sepsis and death of the patient. ⁴ Due to the frequency of recurrence and complications, surgical excision is often limited to patients with significant disability or deformity. ⁴ Furthermore, as seen in the case described, new lesions may occur in the same patient at other sites, if the underlying cause is not treated. Consequently, medical management should be a priority in the treatment of HFTC.

Due to the rarity of HFTC, there is a limited evidence base to inform the best practice for the medical management of the condition. Controlled trials are lacking and all available information on management of the condition is based on case reports or case series. ¹⁰ HFTC treatment plans often involve managing the abnormal biochemical profile of the patient to counteract the consequences of inadequate FGF23 action, allowing gradual resolution of the lesions. ¹⁰ Treatment is targeted at lowering intestinal absorption of phosphate, using both dietary phosphate restriction and oral phosphate-binding agents such as aluminium hydroxide and sevalemer. ¹⁰ Phosphate depletion has proved to have variable success.^1,4,9,10 Several cases have described the use of phosphate binders in combination with therapies to increase renal phosphate excretion to augment the effect on phosphate balance. Acetazolamide, a carbonic anhydrase inhibitor, is commonly combined with phosphate binders and has demonstrated some success in reducing the size of a lesion in one case and preventing recurrence of a lesion in another case. ¹⁰ It has been shown that radiation and steroid therapy are not effective against TC. ¹⁰ Medical management remains the best option for management of FTC as it tackles the underlying metabolic abnormalities.

Conclusion

FTC is a rare condition that can have devastating effects on patients including disability, a strict lifestyle change and potentially numerous surgical procedures. The condition is currently difficult to cure and manage, but with the discovery of FGF-23 as the factor responsible for the HFTC type of FTC and advances in medical genetics, there is hope for better treatment and screening options for patients in the future. ⁸

Learning points

Genetic tests need to be carried out so that appropriate management could be given.