Extensive multiple calcinosis cutis in seronegative limited cutaneous scleroderma (CREST variant): A case report

Abstract

BACKGROUND

Calcinosis cutis is a recognized manifestation of limited cutaneous systemic sclerosis (CREST syndrome), but extensive multifocal involvement of large joints and the trunk is rare. Diagnosis may be particularly challenging in patients with negative systemic sclerosis-specific autoantibodies.

CASE SUMMARY

A 59-year-old woman with extensive calcinosis cutis in the prepatellar region, elbows, and trunk, accompanied by Raynaud’s phenomenon. Despite persistently negative autoimmune serology results, a seronegative CREST variant was diagnosed based on calcinosis, Raynaud’s phenomenon, and clinically diagnosed sclerodactyly, together with histopathological evidence of chronic inflammation and fibrosis after excluding other differential diagnoses. Surgical excision of the prepatellar lesion resulted in complete resolution without recurrence. Histopathological examination revealed aggregated lymphocytes and fibrosis surrounding the calcified tissue, consistent with an autoimmune process.

CONCLUSION

CREST syndrome should not be excluded despite negative serology. Surgical excision may benefit symptomatic extensive calcinosis cutis.

Key Words: Calcinosis cutis; Surgical excision; Scleroderma; Seronegative CREST variant; Case report

Core Tip: This case describes a seronegative CREST variant presenting with widespread calcinosis cutis involving the prepatellar region, both elbows, and trunk, accompanied by Raynaud’s phenomenon and clinically diagnosed sclerodactyly. Surgical excision of the symptomatic lesions provided clinical resolution and enabled histopathological assessment demonstrating chronic lymphocytic inflammation and fibrosis. Negative autoimmune serology alone should not exclude limited cutaneous systemic sclerosis when characteristic clinical manifestations are present.

INTRODUCTION

Calcinosis cutis is a rare chronic condition characterized by the deposition of calcium phosphate crystals in the skin and subcutaneous tissue, commonly affecting the fingers, forearms, and elbows[1,2]. It is frequently associated with autoimmune connective tissue diseases[3]. However, its etiology can vary, and differential diagnosis is often challenging owing to its diverse clinical manifestations.

CREST syndrome, a limited form of scleroderma, is diagnosed when at least three of the following five clinical features are present: Calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. Among these, calcinosis cutis is considered a key element[4]. The presence of characteristic autoimmune antibodies supports this diagnosis, because seronegative CREST syndrome is rare[5].

This case report discusses a seronegative CREST variant. We observed multiple extensive calcinosis cutis lesions at uncommon locations, leading to chronic ulceration with a draining sinus in the prepatellar region of the right knee.

CASE PRESENTATION

Chief complaints

A 59-year-old Asian woman presented to the outpatient department with a right knee draining sinus that had developed over the past two weeks.

History of present illness

Six years earlier, coin-sized plaques appeared in front of her right knee patella and subsequently enlarged to the size of the palm. Similar manifestations were observed in the anterior superior iliac spine (ASIS) and in both elbows. The patient reported multiple previous consultations at other hospitals where, according to her statements, laboratory tests showed no abnormalities. Initially, the patient was painless, which led physicians to recommend monitoring. However, the recent onset of pain and a draining sinus prompted her to opt for surgical removal of the mass. Additionally, she reported multiple ulcerations and tenderness in both elbows.

History of past illness

She had a history of hypertension but no other known medical conditions.

Personal and family history

Her medical history included intermittent color changes and fingertip pain during cold weather. The patient had no relevant family history.

Physical examination

Physical examination revealed hard, palpable masses at multiple locations corresponding to the patient's complaints (Figure 1A and B). Physical examination revealed thickened and waxy skin of the hands, which was clinically diagnosed as sclerodactyly and documented in the medical record (Figure 1C) Telangiectasia and nailfold capillary abnormalities were not observed. The patient reported no symptoms suggestive of esophageal dysmotility; however, formal evaluation using esophageal manometry or barium esophagography was not performed. No rash or muscle weakness was detected.

Figure 1 Gross photographs of skin lesions in a 59-year-old woman. Multiple calcinosis cutis observed. A: Right knee; white arrow indicates skin ulceration with draining serous discharge; B: Right elbow; C: Left hand showing clinically diagnosed sclerodactyly, with thickened, waxy skin.

Laboratory examinations

Considering the common association between calcinosis cutis and autoimmune conditions or metabolic disorders, laboratory tests were performed. Hemoglobin levels at 10.4 g/dL, white blood cell count at 4.84 × 10³/dL with a normal differential count, C-reactive protein at 0.08 mg/dL, and serum calcium and phosphorus levels were 8.6 mg/dL and 3.4 mg/dL, respectively, which were within the normal ranges. Renal function was preserved, with a blood urea nitrogen level of 15 mg/dL, serum creatinine level of 0.57 mg/dL, and estimated glomerular filtration rate of 108.94 mL/minute/1.73 m². Intact parathyroid hormone and 25-hydroxyvitamin D levels were 39 pg/mL and 31 ng/mL, respectively, and were within the normal reference ranges. There was no laboratory evidence of hyperparathyroidism, renal dysfunction, or a clinically significant calcium–phosphate metabolism disorder. Tests for autoimmune antibodies, including anti-Scl-70, antinuclear, anticentromere, and anti-RNA polymerase III antibodies, were negative.

Imaging examinations

Preoperative plain radiographs revealed multiple large-sized calcinosis cutis lesions at the prepatellar aspect of the right knee, adjacent to the olecranon of both elbows, and at the level of the right anterior superior iliac spine (Figure 2)[3].

Figure 2 Preoperative simple radiographs displaying multiple, large-sized calcinosis cutis at various unusual locations, with no evidence of malignancy or infectious conditions detected. A and B: Anteroposterior and lateral views of the right knee, respectively; C and D: Lateral views of the right and left elbows, respectively; E and F: Pelvic inlet view and right oblique view, respectively.

FINAL DIAGNOSIS

Despite negative laboratory findings for all three systemic sclerosis (SSc)-specific autoantibodies, she exhibited three characteristic clinical features—calcinosis, Raynaud’s phenomenon, and clinically diagnosed sclerodactyly—which fulfilled the clinical threshold for a CREST variant.

TREATMENT

The patient had not previously received systemic medical treatment at other medical clinics specifically targeting calcinosis. Because of the large size of the lesions and the presence of pain, chronic ulceration, and a draining sinus, surgical excision was selected to achieve rapid symptom relief, wound control, and histopathological diagnosis.

The patient underwent excisional biopsies of the right knee, both elbows, and right ASIS area. During surgery, careful dissection was performed between the thinned skin and the subcutaneous calcified tissue (Figure 3A and B). After en bloc resection of the lesions, the specimens were sent to the pathology department. Histopathological examination revealed aggregated lymphocytes and fibrosis surrounding massive calcifications, suggestive of an autoimmune response (Figure 3C).

Figure 3 Excisional biopsy procedure. A: Careful dissection was performed between the thinned skin tissue and subcutaneous calcified tissue. B: The extracted calcified tissue. C: Permanent biopsy analysis under an optical microscope (200× magnification, hematoxylin and eosin stain) revealed aggregated lymphocytes and fibrosis around the massive calcification, suggestive of an autoimmune response.

OUTCOME AND FOLLOW-UP

Postoperative wound surveillance was conducted for two weeks. The patient was discharged two weeks after complete suture removal. Although focal necrosis was observed at the wound margin, the wound had spontaneously healed at the four-week postoperative follow-up (Figure 4).

Figure 4 Surgical wound at two weeks postoperative, showing total stitch removal despite focal skin necrosis at the wound margin. The wound spontaneously healed by the four-week postoperative follow-up visit.

DISCUSSION

The most distinctive feature of this case was the presence of multiple extensive calcinosis cutis lesions involving the prepatellar, olecranon, and trunk regions in the absence of detectable autoimmune antibodies. Calcinosis cutis is a well-recognized component of limited cutaneous SSc[4,6], and typically develops in pressure-prone or trauma-exposed areas, such as the digits, elbows, and knees. Digital involvement is the most frequent, whereas prepatellar, truncal, or generalized distributions are unusual or rare[1,6,7]. Marrani et al[8] described an ANA-positive but SSc-specific antibody-negative patient with a calcified trophic plaque on the lateral thigh, suspected to represent localized scleroderma. Zalewski et al[6] described calcinosis cutis as the initial manifestation of limited scleroderma, with serological markers becoming positive several years after the onset of calcinosis. These reports suggest that seronegative or initially seronegative presentations of SSc do occur, although extensive multifocal calcinosis involving atypical sites remains exceptionally uncommon. Therefore, the widespread and atypical distribution observed in this patient represents an uncommon manifestation of seronegative limited SSc, sometimes referred to as an early or incomplete form of CREST syndrome.

The differential diagnosis includes dermatomyositis, idiopathic calcinosis cutis, and metastatic calcification[9]. In this case, dermatomyositis was excluded because the patient had no muscle weakness, elevated serum creatine kinase levels, or electromyographic abnormalities. Idiopathic calcinosis cutis typically presents as localized, isolated deposits; however, this patient had multiple extensive lesions with lymphocytic infiltration and fibrosis on histopathology, suggesting an autoimmune etiology. Metastatic calcification was excluded since serum calcium and phosphorus levels, renal function, intact parathyroid hormone, and 25-hydroxyvitamin D levels showed no evidence of a clinically significant metabolic disorder. These findings supported the diagnosis of a seronegative variant of limited SSc[10]. Antibody-negative CREST syndrome within the spectrum of SSc is uncommon, because antinuclear antibodies are found in up to 80% to 90% of patients with SSc[2,5,10]. Therefore, this case emphasizes that SSc should not be ruled out solely based on negative serology and that detailed clinical and histopathologic correlation remains essential for accurate diagnosis[5,6,8].

Treatment of SSc-associated calcinosis remains challenging. Medical treatments, including diltiazem, colchicine, bisphosphonates, minocycline, sodium thiosulfate, and rituximab, have been reported, but their effects are inconsistent, particularly for large established deposits[5,7,11]. Therefore, surgical excision may be considered for accessible lesions causing severe pain, recurrent ulceration or infection, persistent drainage, functional impairment, or threatened skin integrity[7,11]. In the present case, surgery was selected because of the large lesion size, pain, chronic ulceration, and persistent drainage, which required rapid symptom and wound control.

A strength of this report lies in the integration of clinical, radiological, and histopathological data to support the diagnosis in a seronegative context. However, several limitations should be acknowledged. First, molecular or genetic analyses were not performed, which may have provided deeper insights into the pathogenesis of antibody-negative CREST syndrome. In addition, although sclerodactyly was clinically diagnosed and documented, quantitative assessment using the modified Rodnan skin score, skin biopsy, or imaging-based evaluation of skin thickness was not performed. Furthermore, objective evaluation of esophageal dysmotility was not performed; however, the absence of relevant symptoms made clinically significant esophageal involvement unlikely.

CONCLUSION

This case highlights that CREST syndrome should not be excluded despite negative serology. Surgical excision may be an effective treatment option for symptomatic extensive calcinosis cutis causing pain, ulceration, or persistent drainage.

ACKNOWLEDGEMENTS

We thank Professor Ji Yeoun Lee, Department of Dermatology, and Professor Jon Soo Kim, Department of Pediatrics and the Rare Disease Clinic, for their valuable consultation on this case.