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Calcinosis cutis: Etiology and patient evaluation

Calcinosis cutis: Etiology and patient evaluation
Literature review current through: May 2024.
This topic last updated: Mar 14, 2023.

INTRODUCTION — Calcinosis cutis is a descriptive term for the deposition of insoluble calcium salts in the cutaneous and subcutaneous tissue. Based upon the etiology of calcium deposition, there are five subtypes of calcinosis cutis: dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis (table 1).

Dystrophic calcinosis cutis – Dystrophic calcinosis cutis results from local tissue damage. Systemic calcium metabolism is normal.

Metastatic calcinosis cutis – Metastatic calcinosis cutis results from abnormal calcium or phosphate metabolism, leading to the precipitation of calcium in skin and subcutaneous tissue.

Idiopathic calcinosis cutis – Idiopathic calcinosis cutis is the occurrence of calcinosis cutis without any underlying tissue damage or metabolic disorder.

Iatrogenic calcinosis cutis – Iatrogenic calcinosis cutis is the deposition of calcium salts in the skin as a side effect of medical intervention for other disease processes.

Calciphylaxis – Calciphylaxis demonstrates calcification of the small and medium-sized blood vessels, particularly of the dermis or subcutaneous tissue. This is thought to occur from disturbances in calcium and phosphate metabolism; often, hyperparathyroidism is present [1].

Patients with the first four subtypes of calcinosis cutis may present with skin-colored, white-yellow, or erythematous firm papules, nodules, or plaques that may exhibit ulceration or extrusion of chalky white material (picture 1A-F). In calciphylaxis, the primary involvement of the vasculature typically leads to painful violaceous nodules or plaques, retiform purpura, and ulceration (picture 2A). Calcinosis may also be evident only as a histologic or radiologic finding (image 1A-B).

The etiologies, clinical manifestations, and evaluation of calcinosis cutis will be reviewed here. Information on the management of calcinosis cutis and greater detail on the calciphylaxis subtype are provided separately. (See "Calcinosis cutis: Management" and "Calciphylaxis (calcific uremic arteriolopathy)".)

SUBTYPES — The various subtypes of calcinosis cutis (dystrophic calcinosis cutis, metastatic calcinosis cutis, idiopathic calcinosis cutis, iatrogenic calcinosis cutis, and calciphylaxis) are associated with particular inciting factors and physical features.

Dystrophic calcinosis cutis — Dystrophic calcinosis cutis is the result of deposition of insoluble calcium salts into previously damaged tissue despite normal serum calcium and phosphorous levels. Tissue damage, in the way of structural damage, hypovascularity, or tissue hypoxia [2], promotes an increased intracellular calcium influx, leading to mineralization of the tissue [3].

Dystrophic calcification is the most common type of calcinosis cutis. The clinical presentation ranges in severity from an incidental finding on radiographic imaging to subcutaneous nodules or plaques [2], which can be associated with pain or functional impairment (picture 1A-D). In particular, exophytic or ulcerated areas of involvement can lead to prominent discomfort, and dystrophic calcification located over joints can become painful and may interfere with daily activities through secondary muscle atrophy or joint contractures [2]. A retrospective study from a tertiary referral center found that 69 percent of 78 patients with dystrophic calcinosis cutis reported associated pain [4]. Local inflammation also may be present, mimicking infection [2].

Associated disorders — Dystrophic calcinosis cutis occurs most frequently in patients with underlying autoimmune connective tissue diseases. However, dystrophic calcinosis can also occur in patients with panniculitis, porphyria cutanea tarda, genodermatoses, cutaneous neoplasms [5], localized trauma, or infection [4]. The underlying disorder influences the clinical manifestations.

Autoimmune connective tissue disease — Dystrophic calcinosis cutis secondary to autoimmune connective tissue disease most often occurs in patients with systemic sclerosis or dermatomyositis. Involvement in other autoimmune connective tissue diseases is infrequent:

Systemic sclerosis – Dystrophic calcinosis cutis develops in approximately 25 percent of patients with systemic sclerosis, particularly in those with the limited variant [6] or CREST (calcification, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome (image 1A-B). The calcium deposits are composed of calcium hydroxyapatite crystals and most frequently form at sites of recurrent microtrauma. The most frequently involved sites are the feet and hands (particularly fingers), followed by the extremities (excluding hands and feet) [4]. Occasionally, calcinosis involves the trunk or head [4]. As the calcified deposits enlarge, they may ulcerate or become exophytic, exuding a chalky white-yellow material. Calcinosis cutis may be more prominent in patients with anticentromere antibodies than in other patients with systemic sclerosis [2]. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

Calcinosis universalis, a rare presentation, has occurred in patients with scleroderma [7]. Calcinosis universalis presents with extensive areas of cutaneous calcification (essentially the formation of an "exoskeleton") and significant functional impairment. The etiology is calcium salt deposition along fascial planes of skin and muscle [5].

Dermatomyositis – Calcinosis cutis is more common in juvenile dermatomyositis (44 to 70 percent) than classic dermatomyositis (11 to 20 percent) [5,8]. Juvenile dermatomyositis also demonstrates a more rapid onset after the initial diagnosis. In a retrospective study that included 11 patients with juvenile dermatomyositis and 11 patients with classic dermatomyositis, the time to onset averaged 2.9 years in juvenile disease versus 7.8 years in classic dermatomyositis [4]. Calcinosis cutis can be the presenting feature in juvenile dermatomyositis [9]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Epidemiology, pathogenesis, and clinical manifestations".)

In both children and adults with dermatomyositis, the classic location for calcinosis cutis tends to be extremities, primarily elbows, knees, shoulders, and buttocks [5]. The distribution favors sites of repeated trauma. Calcium deposits may be intracutaneous, subcutaneous, fascial, or intramuscular and can be painful. The deep, intramuscular, or fascial forms may limit joint motion [2].

Disease on the head is rare, but is more likely to occur in juvenile dermatomyositis than any of the other autoimmune connective tissue diseases [4]. Also rare, but more common in juvenile dermatomyositis than other connective tissue diseases, is calcinosis universalis [5], presenting as an extensive exoskeleton or as a lacy, reticular radiographic pattern on imaging [2].

In a cross-sectional study (n = 126), fingertip ulcerations and longer disease duration were strongly associated with the development of calcinosis cutis in adults with dermatomyositis [8]. Additionally, development of antibodies to NXP-2 was associated with calcinosis. Transcriptional intermediary factor 1-gamma antibodies were protective. Availability of NXP-2 and transcriptional intermediary factor 1-gamma antibody tests is limited to research settings. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

Systemic lupus erythematosus – Calcinosis cutis is less common in systemic lupus erythematosus (SLE) than in systemic sclerosis and dermatomyositis. It is most often asymptomatic and generally discovered as an incidental radiographic finding. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

The most frequent sites for SLE-associated calcinosis cutis are the buttocks and extremities [5]. Calcification most often occurs in long-standing disease. In a retrospective study that included two patients with SLE-associated calcinosis cutis, the average time to onset of calcinosis cutis after the diagnosis of SLE was 21.5 years [4].

Patients with lupus panniculitis, a form of lupus erythematosus that primarily affects subcutaneous fat, may develop calcinosis cutis (see 'Panniculitis' below). Calcinosis cutis is a rare complication of subacute cutaneous lupus erythematosus or discoid lupus erythematosus [10].

Other connective tissue disease – Though rare, calcinosis cutis is also reported to occur with overlap connective tissue disease, undifferentiated connective tissue disease, and mixed connective tissue disease. It has also been described in patients with polymyositis and rheumatoid arthritis, but in these rare reports is limited to the extremities [4]. (See "Undifferentiated systemic rheumatic (connective tissue) disease and overlap syndromes".)

Panniculitis — Various forms of panniculitis, particularly lobular panniculitis variants (inflammation primarily affecting subcutaneous fat lobules), may demonstrate dystrophic calcification due to underlying fat necrosis (see "Panniculitis: Recognition and diagnosis"):

Pancreatic panniculitis – Pancreatic panniculitis occurs in patients with underlying pancreatic disease, usually pancreatitis or pancreatic adenocarcinoma, and most likely stems from the pancreatic enzymes causing subcutaneous fat to dissolve. Enzymatic necrosis frees up fatty acids, and calcium soaps are formed when free fatty acids bind to calcium.

Clinically, painful erythematous subcutaneous nodules, sometimes with ulceration and classically described as draining an "oily" substance, appear on the pretibial areas (picture 3 and figure 1) [5]. Histopathologically, fat necrosis (ghost-like fat cells) is seen intermixed with basophilic deposits of calcium [5].

Subcutaneous fat necrosis of the newborn – Subcutaneous fat necrosis of the newborn is a form of lobular panniculitis that, as the name suggests, presents as erythematous nodules and plaques during the first few weeks of life (picture 4). This panniculitis is most commonly seen over the cheeks, back, buttocks, and extremities, and is largely asymptomatic in otherwise healthy neonates. A small proportion of skin lesions develop dystrophic calcinosis and there is an associated risk for symptomatic hypercalcemia [5]. (See "Subcutaneous fat necrosis of the newborn".)

Lupus panniculitis – Lupus panniculitis (or lupus profundus) is a variant of lupus erythematosus that may occur in the presence or absence of systemic lupus erythematosus. A lobular panniculitis develops, leading to nodules classically seen on the head, proximal extremities, and trunk (picture 5A-B). As with other forms of dystrophic calcinosis cutis, these firm subcutaneous nodules can ulcerate. Histologically, calcification can be seen focally within the lobular panniculitis, as well as intravascularly. (See "Overview of cutaneous lupus erythematosus", section on 'Lupus profundus (lupus panniculitis)'.)

Porphyria cutanea tarda — Porphyria cutanea tarda (PCT) is a metabolic disorder that presents with blistering and skin fragility in sites of sun-exposed skin, hypertrichosis, hyperpigmentation, and sclerodermoid changes (picture 6A-B). Dystrophic calcification can occur within the sclerodermoid changes, often manifesting as firm plaques that may exhibit ulceration or transepidermal elimination of calcium [11]. Calcification is most often localized to the preauricular area, scalp, neck, and dorsal hands [5]. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

Most patients with PCT do not develop dystrophic calcification. In a series of 40 patients with PCT, dystrophic calcification with ulceration developed in only 3 patients (8 percent) [12].

Genodermatoses — Dystrophic calcinosis cutis is a common finding in some inherited cutaneous disorders, notably pseudoxanthoma elasticum (PXE), Werner syndrome, and Ehlers-Danlos syndromes:

Pseudoxanthoma elasticum – Pseudoxanthoma elasticum (PXE) is an autosomal recessive inherited disorder with a mutation of the adenosine triphosphate-binding cassette subfamily C member 6 on chromosome 16. The genetic defect leads to calcification of elastic fibers causing rupture of the altered fibers, which is subsequently responsible for adverse effects seen in the skin, cardiovascular system, eyes, and gastrointestinal tract [1]. Patients with PXE most often present with cutaneous findings, namely yellowish papules in flexor surfaces (neck, axillae, popliteal and antecubital fossae, groin) (picture 7A-B). (See "Pseudoxanthoma elasticum".)

In most cases of PXE, calcification is only evident histologically. Clinically evident calcinosis cutis, which may manifest as papules or nodules extruding calcium, is rare [13]. On biopsy, fragmented, calcified elastic fibers can be visualized microscopically. These classic histologic findings of PXE can also be demonstrated in systemic lupus erythematosus, idiopathic hypercalcemia with secondary calcinosis cutis, juvenile Paget disease of the bone, exposure to saltpeter, necrobiosis lipoidica, L-tryptophan-induced eosinophilia-myalgia syndrome, and beta-thalassemia [14].

Werner syndrome – Werner syndrome is an autosomal recessively inherited mutation in the WRN gene, which encodes the RecQ-type DNA helicase. This mutation leads to premature aging and scleroderma-like skin changes [1]. Soft tissue calcification (usually involving the Achilles tendon and knee or elbow tendons) was identified in 12 of 24 patients with Werner syndrome in one series [15]. Pain and ulceration may develop at sites of subcutaneous calcification [16]. Calcification also affects vasculature, ligaments, tendons, and synovia [1].

Ehlers-Danlos syndromes – Ehlers-Danlos syndromes are a group of inherited disorders of collagen metabolism, each with skin hyperextensibility, joint hypermobility, and tissue fragility. The variants are inherited in either an autosomal dominant or autosomal recessive pattern [17]. Vascular, cardiac, skeletal, ocular, and gastrointestinal abnormalities may occur, depending on the specific mutation [5]. If calcification occurs, it is observed in the form of calcified spheroids, as focal subcutaneous calcification, or in existing molluscoid pseudotumors (plaques or papules of cutaneous herniations within scarred/traumatized skin) [1]. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".)

Cutaneous neoplasms — Both benign and malignant cutaneous neoplasms may exhibit microscopic calcification. The most common cutaneous neoplasms to exhibit calcification are pilomatricomas. Pilar cysts also frequently have calcification:

Pilomatricoma – Pilomatricomas (also referred to as pilomatrixoma, trichomatricoma, or calcifying epitheliomas of Malherbe) are benign neoplasms of the follicular matrix clinically presenting as firm, solitary papules or nodules, often with a faintly blue hue (picture 8A-B). These benign neoplasms are most common in childhood but can be found in adulthood. Pilomatricomas are most frequently located on the head and upper trunk. Ossification is also present, usually in the surrounding stroma [5]. (See "Cutaneous adnexal tumors", section on 'Pilomatricoma'.)

Pilar cyst – Pilar, or trichilemmal, cysts are a very common cutaneous type of cyst seen on the scalp (picture 9). Pilar cysts exhibit focal microscopic calcification approximately 25 percent of the time. (See "Overview of benign lesions of the skin", section on 'Pilar (trichilemmal) cysts'.)

Other neoplasms – Other cutaneous neoplasms that may demonstrate calcification are desmoplastic trichoepitheliomas, chondroid syringomas, basal cell carcinomas, and melanocytic nevi [5].

Trauma — Dystrophic calcification can occur in most forms of localized cutaneous trauma. Calcification has been reported in scarring due to burns, trauma, surgery, and within keloids [5]. This calcification often occurs many years after the injury and most often manifests as firm, whitish papules or subcutaneous nodules [1].

Infection — Tissue injury from some cutaneous infections may cause dystrophic calcinosis cutis:

Onchocerciasis – Onchocerciasis, or river blindness, is a filarial infestation that manifests as subcutaneous nodules (onchocercomas) that over time can calcify (picture 10). Onchocercomas are one of the initial features of infection and develop most commonly over bony prominences, particularly on the upper body. These nodules are composed of the parasite Onchocerca volvulus and fibrous tissue surrounding the worms. It is in older lesions that calcification becomes a prominent part of the nodule [18]. (See "Onchocerciasis".)

Cysticercosis – Cysticercosis is a helminthic infestation associated with notable calcification. This infectious disease is most often transmitted when Taenia solium (the pork tapeworm) enters the human host during consumption of undercooked meat of a diseased animal. When the organism penetrates the human intestine, the oncosphere form will mature rapidly, forming cysts in almost any organ or tissue in the body. (See "Cysticercosis: Clinical manifestations and diagnosis".)

When the cysts degenerate (usually three to five years after the organism enters the host), intense inflammation surrounds the degenerating cysts, and thus calcification occurs. The calcified cysts are often found in the skin as small papulonodules, which are easier to palpate than visualize (picture 11) [18]. Skin, skeletal muscle, and mucous membranes are affected with the calcified cysts in 90 percent of cases; the central nervous system is less commonly affected. Diagnosis of cysticercosis can be made by radiographs demonstrating numerous calcified cysts [18].

Metastatic calcinosis cutis — In metastatic calcinosis cutis there is an underlying defect in the metabolism of calcium and/or phosphorus, resulting in precipitation of calcium salts in cutaneous or subcutaneous tissues. Calcification is also often seen in blood vessels, kidneys, lungs, and gastric mucosa.

Associated disorders — Any systemic disorder causing an elevation of serum calcium and/or phosphate levels can cause metastatic calcification. The most common underlying cause is chronic renal failure.

Chronic renal failure — Chronic renal failure leads to hyperphosphatemia through a variety of mechanisms. Diseased kidneys are inefficient at clearing phosphate from the blood, leading to an increasing serum level. This high serum phosphate leads both directly and indirectly to secondary hyperparathyroidism. Additionally, the vitamin D3 level is decreased given malfunction of the kidneys, which leads to decreased calcium absorption from the gastrointestinal tract and thus serum hypocalcemia. Hypocalcemia induces secondary hyperparathyroidism, which in turn stimulates bone reabsorption, further elevating serum levels of phosphorus and calcium. Most often in metastatic calcification associated with chronic renal disease, the serum calcium is normal but the serum phosphate level is increased. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)" and "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Metastatic calcinosis secondary to chronic renal failure usually manifests as benign nodular calcification at periarticular sites. The degree of disease tends to correlate with the level of hyperphosphatemia [5]. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)" and "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Other disorders — Metastatic calcification can also be seen in hypervitaminosis D, milk-alkali syndrome, Albright hereditary osteodystrophy (type 1a), neoplasms, and sarcoidosis [5]:

Hypervitaminosis D – Patients with hypervitaminosis D may present with weakness, lethargy, headache, nausea, and polyuria secondary to hypercalcemia and hypercalciuria. In hypervitaminosis D, calcinosis is most likely to be found in periarticular tissues [5]. (See "Overview of vitamin D", section on 'Excess'.)

Milk-alkali syndrome Milk-alkali syndrome results from excessive ingestion of calcium and absorbable alkali, leading to hypercalcemia, metabolic acidosis, and acute kidney injury. Milk-alkali syndrome-associated calcinosis may occur in ocular tissues and renal tissue and is less frequently found in periarticular tissue, subcutaneous tissue, and other tissues. (See "The milk-alkali syndrome".)

Albright hereditary osteodystrophy – Albright hereditary osteodystrophy is an epigenetically inherited mutation on the maternal allele of the GNAS gene that encodes the Gs alpha subunit. Patients have a deficiency of the end organ response to parathyroid hormone (pseudohypoparathyroidism) and, in addition to calcification of the cutaneous and subcutaneous tissues, manifest mild to moderate intellectual disability and early-onset obesity [19]. Patients with cutaneous disease typically present with symmetric cutaneous ossification [5].

Malignancy – Any neoplasm causing destruction of bone (lymphoma, leukemia, multiple myeloma, and metastatic carcinoma) can cause metastatic calcification. This will most often clinically manifest as firm, whitish papules or subcutaneous nodules.

Idiopathic calcinosis cutis — In contrast to both dystrophic and metabolic calcification, idiopathic calcinosis cutis occurs in the absence of any tissue injury or metabolic disorder.

Associated disorders — Idiopathic calcification of the scrotum, subepidermal calcified nodule, and tumoral calcinosis are examples of idiopathic calcification [5].

Idiopathic calcification of the scrotum — Scrotal calcinosis is characterized by firm, white subcutaneous nodules on the scrotum and is most often seen in otherwise healthy young men (picture 1E-F). The nodules vary in size and number, and while easily palpable, they are usually asymptomatic. Similarly, idiopathic calcification of the labia has been described in women [20] and reports of penile calcification also exist [21].

Histopathologic features are most often large, calcified nodules within the dermis with a thick, fibrous stroma and usually without any epithelial lining. In some cases, epidermal inclusion cysts, sometimes with rupture and calcified keratin, can be demonstrated, leading to debate on whether these scrotal calcifications are truly idiopathic or a result of cyst rupture [1].

Subepidermal calcified nodule — Subepidermal calcified nodule (also referred to as solitary congenital nodular calcification or Winer's nodular calcinosis) usually presents on the head (often the ear), neck, or upper extremities as a solitary, hard white papule [5]. Less commonly, multiple nodules occur. Subepidermal calcified nodules are most common in children and often congenital in nature, but can be acquired and occur at all ages [22,23]. Biopsy will reveal subepidermal calcium deposits. Frequently, subepidermal calcified nodules ulcerate and calcium deposits are eliminated transepidermally.

Tumoral calcinosis — Tumoral calcinosis is a rare disorder that most often affects otherwise healthy adolescents, manifesting as large calcium deposits surrounding major joints (hips, shoulders, elbows, and knees) [24]. Given the size of some of the deposits, these calcifications may cause significant impairment of joint function, requiring surgical correction [25]. Hyperphosphatemia is present in some patients with tumoral calcinosis, leading to questions about whether some presentations are best classified as metastatic calcification [5].

Histologic examination of tissue demonstrates a calcified, multiloculated cyst with milky, granular fluid. The cyst is classically embedded in a lining of fibrous tissue.

Iatrogenic calcinosis cutis — Iatrogenic calcinosis cutis is characterized by firm nodules within the dermis or subcutis, which is due to the rapid precipitation of calcium salts in the skin. This phenomenon most often occurs after extravasation of intravenous calcium gluconate, calcium chloride, or phosphate-containing solutions [26], and classically presents as a warm and tender swelling at the site of venipuncture [1]. Iatrogenic calcification has also been reported with calcium salt exposure from electroencephalography and electromyographic electrode compounds [3], presenting as soft yellow-white cutaneous plaques [1].

Neonates may develop calcified nodules on their heels after numerous heel venipuncture sticks during the postpartum period. The hypothesized etiology involves trauma to local tissue as well as local elevation of calcium levels [3].

Small, transient deposits of calcium have been reported in the postoperative period in patients who underwent liver and, more rarely, lung transplantation. These patients not only demonstrated cutaneous calcium deposits, but also had deposition of calcium in several internal organs (lungs, transplanted liver, colon, kidneys, adrenal glands, gastric mucosa). Postoperative metabolic abnormalities in addition to copious amounts of calcium and blood products (containing citrate) required in the operative period are the hypothesized culprit [27].

Calciphylaxis — Calciphylaxis, previously referred to as uremic gangrene syndrome, calcific uremic arteriolopathy, or calcifying panniculitis [26], is a calcific vasculopathy of small and medium-sized vessels in the dermis and subcutis that often leads to ischemic necrosis [14]. This vasculopathy may also affect visceral organs and skeletal muscle [1]. (See "Calciphylaxis (calcific uremic arteriolopathy)".)

Calciphylaxis has been considered by some sources to be a subset of metastatic calcification, given that the majority of cases present in patients with end-stage kidney disease. However, as the pathophysiology has become better understood, it is more often categorized as a distinct subtype of calcinosis cutis.

Although calciphylaxis is most common in patients with end-stage kidney disease, the condition has also been increasingly documented in patients with normal renal function. The most commonly reported "non-uremic" causes are secondary hyperparathyroidism, alcoholic liver disease, malignancy, and connective tissue disease [14,28]. Often, patients will have high serum levels of calcium and phosphate (in particular, a high serum calcium x phosphate product). However, this is not seen in all patients [29]. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Laboratory manifestations'.)

Early cutaneous manifestations of calciphylaxis are violaceous reticulated patches (retiform purpura) resembling livedo reticularis. With time the tissue often becomes necrotic, leading to bullae and subsequent ulcer formation (picture 2A-B). Calciphylaxis ulcers are classically deep, stellate, or wedge-shaped [1]. Even in the early stages, lesions are very painful [26]. Approximately 90 percent of cases affect the legs; predisposed sites are buttocks, thighs, and breast [29].

Classic histopathologic findings of calciphylaxis are calcium deposits in the medial layer of the small to medium vessels of the reticular dermis and subcutaneous fat (mural calcification). Lobular fat necrosis and a mixed inflammatory infiltrate can also be visualized. In more severe cases of calciphylaxis, extravascular calcium deposits can be seen [1].

DIAGNOSIS — The diagnosis of calcinosis cutis may be suspected based upon physical findings. Physical findings that should raise suspicion for this diagnosis of are firm papules or nodules, particularly when the papules or nodules ulcerate or extrude chalky white-yellow material. A skin biopsy of an involved area confirms the diagnosis and will demonstrate calcium in the dermis or subcutis manifesting as intensely basophilic deposits on hematoxylin and eosin-stained specimens. Calcium will stain black with performance of a von Kossa tissue stain. A foreign body reaction may surround the calcium deposits.

Calciphylaxis should be suspected in patients with retiform purpura and ulceration, particularly when occurring on the legs or fatty areas and in patients with renal failure (see 'Calciphylaxis' above). Histologic examination reveals calcium deposits within the wall of small and medium-sized blood vessels. The diagnosis of calciphylaxis is reviewed separately. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Diagnosis'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of calcinosis cutis includes several other disorders of the skin and subcutaneous tissue that exhibit firm papules or nodules or substances that may be mistaken for calcium deposits. Examples include:

Chronic tophaceous gout – Tophaceous gout is a manifestation of gout in which chronic collections of solid urate crystals (tophi) develop in the skin or subcutaneous tissue. Tophi typically present as skin-colored, white, yellow, or red firm papules or nodules on the helix of the ear or over joints (picture 12A-B). Ulceration, drainage, or extrusion of a chalky material may be present. (See "Clinical manifestations and diagnosis of gout", section on 'Tophaceous gout'.)

Milia – Milia are common, small (1 to 2 mm) epidermoid cysts that can occur in infants, children, or adults (picture 13A-B). Milia may appear spontaneously or develop at sites of resolving blisters or skin trauma. The face is a common site. Occasionally, multiple milia are a manifestation of a genetic disorder, such as hereditary trichodysplasia, oral-facial-digital syndrome type 1, Rombo syndrome, and Bazex-Dupré-Christol syndrome.

Molluscum contagiosum – Molluscum contagiosum is a cutaneous poxvirus infection that classically manifests with skin-colored or erythematous umbilicated papules (picture 14). The umbilication may contain a visible white core. Although the infection is usually easily diagnosed via recognition of these classic features, molluscum contagiosum occasionally may be confused with calcinosis cutis [30]. (See "Molluscum contagiosum".)

Osteoma cutis – Osteoma cutis is a condition in which bone formation occurs in the skin, manifesting as very firm papules or plaques (picture 15). Osteoma cutis may occur in sites of scarring (eg, acne scars), skin inflammation, or within cutaneous neoplasms, such as nevi, pilomatricomas, basal cell carcinomas, or cysts. Osteoma cutis is also a feature of several genetic diseases, including fibrodysplasia ossificans progressiva, Albright hereditary osteodystrophy, progressive osseous heterodysplasia, and plate-like osteoma cutis. A skin biopsy can confirm a diagnosis of osteoma cutis. Osteoma cutis is also visible on radiographic images.

Knowledge of the patient history and a careful physical examination is often sufficient to recognize these conditions. When necessary, a biopsy can confirm the diagnosis.

The differential diagnosis of calciphylaxis is reviewed separately. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Differential diagnosis'.)

PATIENT EVALUATION — In patients with calcinosis cutis, an evaluation to identify the subtype, etiology, and extent of calcinosis is critical. The results of this assessment influence the approach to further work-up and treatment. (See "Calcinosis cutis: Management".)

Patient history — The patient history serves to elicit clues for an underlying cause. Helpful information may include:

Age of onset

Medical history (particularly autoimmune diseases, chronic renal disease, pancreatic disorders, porphyria cutanea tarda, genetic disorders, malignancy)

History of trauma to the affected area

History of medical procedures or infusions in the affected area

Supplement use, particularly vitamin D or calcium

Travel history (in particular, risk for cysticercosis and onchocerciasis)

In addition, a review of systems should be performed to identify signs or symptoms suggestive of underlying disease.

Physical examination — A full skin examination should be performed to identify the extent of calcinosis cutis. Palpation is useful for identifying areas of involvement that are more easily felt than seen. The physical examination may also provide clues for the type of calcinosis cutis present based upon the morphology and distribution of involvement and the presence of other cutaneous and noncutaneous signs suggestive of an underlying disease. A table describing clinical features of the various types of calcinosis cutis is provided (table 1).

Radiologic studies — Calcification is easily visualized on radiographic images. Therefore, radiologic studies can be useful for determining the extent of tissue involvement and can demonstrate the depth and expansion of calcification into the subcutis.

Radiologic evaluation for calciphylaxis is reviewed separately. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Diagnosis'.)

Laboratory studies — In patients with suspected metabolic calcinosis cutis (eg, calcinosis cutis occurring in the setting of chronic renal failure) or calcinosis cutis of uncertain etiology, testing to rule out metastatic calcification should be performed. This includes the following laboratory studies:

Serum calcium

Serum phosphorus

Urinary calcium (24-hour)

Serum parathyroid hormone level

Serum vitamin D level

Other laboratory tests may be indicated in patients with calcinosis cutis based upon the suspected underlying etiology.

SUMMARY AND RECOMMENDATIONS

Calcinosis cutis is a descriptive term for the deposition of insoluble calcium salts in cutaneous or subcutaneous tissue. Calcinosis cutis can be divided into five subtypes: dystrophic calcinosis cutis, metastatic calcinosis cutis, idiopathic calcinosis cutis, iatrogenic calcinosis cutis, and calciphylaxis (table 1). (See 'Introduction' above and 'Subtypes' above.)

Dystrophic calcinosis cutis is the most common form of calcinosis cutis. Dystrophic calcinosis cutis may occur in the setting of autoimmune connective tissue disease (most common), panniculitis, porphyria cutanea tarda, select genodermatoses, cutaneous neoplasms, trauma, and infection. The autoimmune connective tissue diseases most likely to exhibit calcinosis cutis are systemic sclerosis and dermatomyositis. (See 'Dystrophic calcinosis cutis' above.)

Metastatic calcification occurs as a result of abnormal calcium or phosphate metabolism leading to precipitation of calcium in skin and subcutaneous tissue. Chronic renal failure is the most common cause of metastatic calcification. (See 'Metastatic calcinosis cutis' above.)

Idiopathic calcinosis cutis occurs in the absence of a detectable cause of tissue injury or metabolic disorder. Idiopathic calcification of the scrotum, subepidermal calcified nodule, and tumoral calcinosis are forms of idiopathic calcinosis cutis. (See 'Idiopathic calcinosis cutis' above.)

Iatrogenic calcinosis cutis is calcium deposition resulting from medical interventions. Extravasation of intravenous calcium gluconate, calcium chloride, or phosphate-containing solutions is the most common cause of iatrogenic calcinosis cutis. (See 'Iatrogenic calcinosis cutis' above.)

Cutaneous manifestations of calciphylaxis result from calcium deposition in the walls of small and medium-sized blood vessels in the skin and subcutaneous tissue. Calciphylaxis most frequently occurs in patients with end-stage kidney disease. (See 'Calciphylaxis' above.)

The clinical manifestations of calcinosis cutis vary widely. Patients may present with firm papules, nodules, or plaques that are skin-colored, white-yellow, or erythematous (picture 1A-F). Ulceration or extrusion of calcium may be present. Calciphylaxis usually presents with painful retiform purpura and ulceration. In some cases, calcinosis cutis is an incidental histologic or radiologic finding (image 1A-B). (See 'Subtypes' above.)

The diagnosis of calcinosis cutis may be suspected based upon the patient history and physical examination. A skin biopsy confirms the diagnosis. An evaluation to determine the subtype, etiology, and extent of involvement is indicated for patients with calcinosis cutis. (See 'Diagnosis' above and 'Patient evaluation' above.)

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Topic 13756 Version 10.0

References

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