Calcinosis Cutis

Calcinosis cutis is a term used to describe a group of disorders in which calcium deposits form in the skin. Virchow initially described calcinosis cutis in 1855. Calcinosis cutis is classified into 4 major types according to etiology: dystrophic, metastatic, iatrogenic, and idiopathic. A few rare types have been variably classified as dystrophic or idiopathic. These include calcinosis cutis circumscripta, calcinosis cutis universalis, tumoral calcinosis, and transplant-associated calcinosis cutis. ^[1]

In all cases of calcinosis cutis, insoluble compounds of calcium are deposited within the skin due to local and/or systemic factors. These calcium salts consist primarily of hydroxyapatite crystals or amorphous calcium phosphate. The pathogenesis of calcinosis cutis is not completely understood and a variety of factors allow for different clinical scenarios to occur.

Metabolic and physical factors are pivotal in the development of most cases of calcinosis. Ectopic calcification can occur in the setting of hypercalcemia and/or hyperphosphatemia when the calcium-phosphate product exceeds 70 mg²/dL², without preceding tissue damage. These elevated extracellular levels may result in increased intracellular levels, calcium-phosphate nucleation, and crystalline precipitation. Alternatively, damaged tissue may allow an influx of calcium ions leading to an elevated intracellular calcium level and subsequent crystalline precipitation. Tissue damage also may result in denatured proteins that preferentially bind phosphate. Calcium then reacts with bound phosphate ions leading to precipitation of calcium phosphate.

Disorders of calcinosis cutis may be categorized according to the type of calcification process, ie, dystrophic, metastatic, idiopathic, and iatrogenic.

Dystrophic calcification occurs in the setting of normal serum calcium and phosphate levels. The primary abnormality is damaged, inflamed, neoplastic, or necrotic skin. Tissue damage may be from mechanical, chemical, infectious, or other insults.

Localized tissue damage

Extraosseal calcification can occur in the setting of many local and destructive processes, including burns, arthropod bites, acne lesions, varicose veins, and rhabdomyolysis, among others.

Infections

Necrotic tissue produced by an infectious process may subsequently become calcified. Some infectious granulomas produce 1,25-vitamin D. Infections that may result in calcinosis cutis include onchocerciasis, cysticercosis, histoplasmosis, cryptococcosis, and intrauterine herpes simplex.

Tumors

Benign and malignant tumors may develop calcification. Pilomatrixoma, or calcifying epithelioma of Malherbe, is the most common tumor that becomes calcified. Epithelial cysts and syringomas also have a significant tendency to calcify. Foci of calcification commonly are seen in histologic sections of basal cell carcinomas. In rare cases, melanocytic nevi, malignant melanoma, atypical fibroxanthoma, hemangioma, pyogenic granuloma, seborrheic keratoses, neurilemomas, and trichoepitheliomas show foci of calcification.

Generalized tissue damage

Connective tissue diseases

Examples are dermatomyositis ^{[2, 3]} ; lupus erythematosus ^{[4, 5, 6, 7]} ; systemic sclerosis; and calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, telangiectasias (CREST) syndrome.

In dermatomyositis, calcification occurs 3 times more commonly in juvenile dermatomyositis than the adult-onset form and may be seen in 30-40% of patients. In the setting of dermatomyositis, calcinosis cutis is associated with longer disease duration, fingertip ulcers, and NXP-2 autoantibodies. There is a negative association with transcriptional intermediary factor 1-γ antibodies. ^[8] Typically, calcification is accentuated over joints, sparing the digits. Aggressive corticosteroid therapy decreases the incidence of calcification.

In lupus erythematosus, calcification is rare and usually an insignificant incidental radiologic finding. Calcification occurs most frequently with long-standing systemic disease, and though calcification may develop in lesions of lupus profundus, it usually is not associated with panniculitis. However, an associated myositis may be present. Lesions characteristically are on the extremities.

Regarding scleroderma, systemic scleroderma and CREST syndrome are related diseases frequently associated with the late development of tissue calcification.

Panniculitis

Subcutaneous fat necrosis of the newborn typically affects full- or post-term newborns within the first few days to weeks of life. Necrosis of subcutaneous tissues, predominantly on the shoulders and buttocks, results in nodules and plaques that may become calcified. The cause is unknown. Possible inciting events are obstetric trauma, maternal pre-eclampsia or diabetes, or neonatal hypothermia or hypoxia. Pancreatitis or pancreatic malignancy may result in inflammation of the panniculus. The combination of fatty acids released by damaged fat cells and calcium may lead to calcium salt formation.

Inherited disorders

Examples are Ehlers-Danlos syndrome, Werner syndrome, pseudoxanthoma elasticum, and Rothmund-Thompson syndrome.

Ehlers-Danlos syndrome is a group of inherited disorders of collagen metabolism. Individuals with Ehlers-Danlos type I may develop calcification in healing surgical scars and subcutaneous nodules.

Werner syndrome is an inherited disorder of premature aging. Soft tissue calcification may involve the ligaments, tendons, synovia, vasculature, and/or subcutaneous tissue.

Pseudoxanthoma elasticum is a disorder of abnormal elastic fibers. Calcification occurs in the elastic fibers causing rupture. Late in the disease, collagen fibers may become calcified.

In Rothmund-Thomson syndrome, small, yellow papules of calcification may be numerous on the extremities.

Metastatic calcification

Metastatic calcification arises in the setting of abnormal calcium or phosphate metabolism and is generally associated with hypercalcemia and/or hyperphosphatemia.

Primary or secondary hyperparathyroidism

In primary hyperparathyroidism, the parathyroid glands become hyperplastic and autonomously overproduce parathyroid hormone. Secondary hyperparathyroidism is a functional response to hypocalcemia. The causes of hypocalcemia may be numerous, but the most common cause is chronic renal failure.

Paraneoplastic hypercalcemia

Hypercalcemia may occur as part of a malignancy syndrome due to bony metastases or the production of an abnormal hormone that directly affects calcium and bone metabolism.

Destructive bone disease

Malignancy and other conditions, such as Paget disease, may induce enough bone destruction to cause hypercalcemia.

Milk-alkali syndrome

Uncommon today, this syndrome is caused by excessive consumption of sodium bicarbonate and calcium-containing compounds. The result is a metabolic alkalosis with hypercalcemia, hyperphosphatemia, nephrocalcinosis, and renal failure.

Excessive vitamin D

Overconsumption of vitamin D may increase GI calcium absorption, as well as renal calcium reabsorption, giving rise to hypercalcemia. This mechanism is relatively uncommon.

Sarcoidosis

The sarcoidal granuloma may overproduce 1,25-vitamin D, with subsequent hypercalcemia and an elevated calcium-phosphate product.

Chronic renal failure

This is the most common setting in which metastatic calcification occurs. Chronic renal failure affects many factors in calcium metabolism. Hyperphosphatemia due to decreased renal clearance occurs relatively early. Hypocalcemia is the direct result of this hyperphosphatemia and worsened by vitamin D deficiency due to renal failure. As a compensatory measure, excessive parathyroid hormone is produced. This augmentation results in increased calcium and phosphate mobilization; an elevated solubility product; and, subsequently, the formation and precipitation of calcium salts.

Calciphylaxis

This is a poorly understood, highly morbid process that most commonly affects patients with end-stage renal disease. Calcification occurs in the intima of the blood vessels and subcutaneous tissue. Microthrombi formation is a frequent finding. The exact mechanism remains unknown, but the most common unifying disorders are renal failure, hypercalcemia, hyperphosphatemia, and hyperparathyroidism.

Idiopathic calcinosis cutis

Idiopathic calcinosis cutis occurs in the absence of known tissue injury or systemic metabolic defect.

Idiopathic calcinosis of scrotum, penis, or vulva

Calcification may occur after trauma, or it may occur in the absence of known tissue injury. Calcinosis cutis of the penis may also result from calcification of an epidermal cyst.

Milia-like idiopathic calcinosis cutis ^{[9, 10, 11, 12]}

Many cases have been associated with Down syndrome and/or syringoma formation. Lesions are usually multiple and occur on the trunk, limbs, and face. The etiology remains controversial, but some evidence of calcium deposition in the sweat glands is present.

Subepidermal calcified nodule

These lesions usually develop in early childhood and are typically solitary, though multiple lesions can also be present. The nodules most commonly occur on the face, though they may occur anywhere. The pathogenesis is unknown, but the lesions may be due to calcification of components of adnexal structures.

Tumoral calcinosis

This may be caused by an error in renal phosphate metabolism resulting in hyperphosphatemia. General characteristics of the calcified nodules are a large size, a juxta-articular location, progressive enlargement, a tendency to recur after surgical removal, and the ability to encase the adjacent normal structures. The most common locations of calcification are the hip, elbow, scapula, foot, leg, knee, and hand. Tumoral calcinosis is often familial, and the hereditary pattern suggests that it is an autosomal recessive trait. Vitamin D deficiency may also be associated with hyperphosphatemia.

Calcinosis cutis circumscripta and calcinosis universalis

These forms are rare and may be due to altered ground substances. Calcinosis cutis circumscripta generally occurs earlier and tends to involve the extremities, whereas calcinosis universalis occurs later and is usually more widespread. Both have been associated with trauma, foreign body reaction, and (on occasion) scleroderma.

Transplant-associated calcinosis cutis ^{[13, 14, 15]}

In addition to calciphylaxis, numerous cases of calcinosis cutis have been described in transplant recipients. Although calcinosis cutis appears to be most common after renal transplantation, it is also described in liver, heart, and lung transplantation. The etiology of this calcification is unknown. Perhaps patients are infused with large numbers of blood products containing citrate and calcium that create an environment that favors calcification. The role of other factors remains to be elucidated.

Iatrogenic calcinosis

Iatrogenic calcinosis cutis arises secondary to a treatment or procedure. ^{[16, 17, 18, 19]}

Parenteral administration of calcium or phosphate

The intravenous administration of solutions containing calcium or phosphate may cause the precipitation of calcium salts and lead to calcification.

Parental inorganic phosphate

This has been implicated.

Tumor lysis syndrome

Cutaneous calcification associated with tumor lysis syndrome is due to several factors, including chemotherapy-induced tissue damage with resultant hyperphosphatemia, hypocalcemia, hyperuricemia, and the potential for acute renal failure. Hypocalcemia frequently requires parenteral calcium use, increasing the possibility of tissue calcification.

Repeated heel sticks in the newborn

Calcium salt deposition may occur in newborns at sites of repeated heel sticks.

Prolonged use of calcium-containing electrode paste

Prolonged placement of electrode pastes containing calcium on abraded skin in diagnostic procedures such as electroencephalography, electromyography, or brainstem auditory evoked potential testing may result in calcium deposition at the placement site.

Frequency

Dystrophic calcinosis cutis is most common. Specific incidence and frequency data are unavailable.

Race

Tumoral calcinosis is more common in blacks of South African heritage.

Sex

No sex predilection is documented.

Age

Subepidermal calcified nodules are more common in children. Calcinosis cutis circumscripta tends to arise in the second half of life. Calcinosis cutis universalis occurs in the second decade of life. Tumoral calcinosis usually arises in the first or second decade of life.

The prognosis is determined by that of any underlying disease. Calcinosis cutis alone usually is benign. Severe complications are infrequent. When present, morbidity is related to the size and location of the calcification.

Lesions may become painful, limit mobility of an adjacent joint, or compress adjacent neural structures. Ulceration and secondary infection may occur. Vascular calcification may result in ischemia and necrosis of the affected organ.

Patients should be educated about the underlying disease processes and natural history of their specific disorder.