Parathyroid Adenoma in a Young Girl with Type 3 von Willebrand Disease: Comment on “Cancers in Patients with von Willebrand Disease”

We read with great interest the manuscript entitled “Cancers in patients with von Willebrand disease: A survey from the Italian Association of hemophilia centers” written by Franchini et al.[1] These authors from Italy reported a comprehensive study of 106 von Willebrand disease (VWD) patients who were diagnosed with cancer during long-term follow-up between 1981 and 2014.[1] They detected solid cancer in 87 (82%) of these individuals, and found hematological cancer in 19 (18%). One hundred and three (97%) of the 106 patients were type 1 and 2 VWD, and only three (3%) were type 3 VWD. All three patients with type 3 VWD were females, and they were diagnosed with breast cancer, a myeloproliferative disorder, and a solid tumor, respectively. Their median age at diagnosis was 43 years. None of the three type 3 VWD patients had parathyroid adenoma. A literature search for parathyroid disorders in patients with VWD revealed only one case, a 58-year-old woman who had primary hyperparathyroidism, Marfan syndrome, and VWD.[2] We, therefore, wish to present a case of a female patient who was diagnosed with type 3 VWD in infancy, followed regularly, and who developed parathyroid adenoma during adolescence, and subsequently was successfully treated for this cancer. To our knowledge, this is the first report of parathyroid adenoma in a young girl with type 3 VWD who has presented with paresthesia and hypercalcemia.

At the time of first presentation in infancy, laboratory testing revealed von Willebrand factor (VWF) antigen (Ag) 0.01 IU/mL, VWF:RCo 0.01 IU/mL, factor VIII (FVIII) coagulant activity 0.03 IU/mL. She had been regularly treated with human VWF/FVIII concentrate (Haemate P; CSL-Behring, Marburg, Germany; two doses of 1,500 IU [50IU/kg of VWF:RCo]) for heavy menstrual bleedings, with four doses of 15 mg/kg tranexamic acid also given. At the age of 20, she was admitted to the emergency room complaining of pain in the region from her right hip to right knee. The preliminary diagnosis was bleeding into the psoas muscle. However, abdominal ultrasonography revealed no findings compatible with this, and opacities were noted in the patient's bladder. Laboratory examination revealed calcium 12.5 mg/dL (normal range: 8.2–10.6 mg/dL), phosphorus 2.9 mg/dL (2.5–4.5 mg/dL), parathyroid hormone 280 pg/mL (15–68 pg/mL), 25-hydroxy vitamin D level 27.3 ng/mL (10–50 ng/mL), spot urine calcium/creatinine 5 mg/dL (normal <0.2 mg/dL), and 24-hour urine calcium 8 mg/kg/day (normal <4 mg/kg/day). These findings were compatible with hypercalciuria. Renal and thyroid function test results were in the normal range. More detailed history-taking revealed that the patient had been experiencing numbness and tingling in her hands, as well as leg cramping, for a long time. Parathyroid/thyroid ultrasonography showed a hypoechoic, heterogeneous, solid, 12 × 7 mm nodular lesion immediately adjacent to the lower lobe of the thyroid. Color Doppler ultrasonography revealed increased vascularity in the mass. The patient was diagnosed with parathyroid adenoma. Total parathyroidectomy was performed. In a preoperative inhibitor screening, no inhibitors of FVIII and VWF:Ag could be detected by the Bethesda Method.[3] She was successfully treated with Haemate P 2000 IU before and after surgery. Further screening showed complications due to the adenoma, namely, osteoporosis of the hip and osteopenia of the vertebrae. Vitamin D supplementation was given. No recurrence was seen on her follow-up.

The hereditary bleeding disorder VWD occurs at an incidence of up to 1% in the general population.[4] The cause is usually an abnormality of the gene that controls VWF, which plays a key role in platelet-plug formation and FVIII stabilization at an injury site. VWD is classified as type 1 (partial deficiency of VWF), type 2 (functional deficiency of VWF), or type 3 (complete deficiency of VWF).[1] Patients with VWD can develop benign and malign tumor. Previous reports indicate that the age of onset and spectrum of such disorders vary widely in these individuals.[1] [5] Solid tumors and hematological cancers were found to be common in a large series of patients with VWD; however, parathyroid adenoma has not been documented to date in patients with type 3 VWD.[5] The findings in our case suggest that, when considering tumor risk in patients with VWD, physicians should be alert for unusual clinical manifestations that may not directly involve bleeding. Additionally, early diagnosis and treatment of parathyroid adenoma may be crucial to prevent hypercalcemia complications, such as nephrolithiasis, osteoporosis, and bone fractures, in these patients.[6]

Publikationsverlauf

Artikel online veröffentlicht:
02. Februar 2022

• References

• 1 Franchini M, Di Perna C, Santoro C. et al; Italian Association of Haemophilia Centres. Cancers in patients with von Willebrand disease: a survey from the Italian Association of Haemophilia Centres. Semin Thromb Hemost 2016; 42 (01) 36-41
• 2 Bednarek-Tupikowska G, Rakowska-Chort A, Adamarczuk-Janczyszyn M. [A patient with coexistence of primary hyperparathyroidism, Marfan's syndrome and von Willebrand's disease]. Przegl Lek 2008; 65 (02) 109-112
• 3 Miller CH. Monitoring of von Willebrand factor inhibitors in patients with type 3 von Willebrand disease using a quantitative assay. Haemophilia 2021; 27 (05) 823-829
• 4 Castaman G, Linari S. Obstacles to early diagnosis and treatment of inherited von Willebrand disease: current perspectives. J Blood Med 2021; 12: 165-175
• 5 Patmore S, Dhami SPS, O'Sullivan JM. Von Willebrand factor and cancer; metastasis and coagulopathies. J Thromb Haemost 2020; 18 (10) 2444-2456
• 6 Wilhelm SM, Wang TS, Ruan DT. et al. The American Association of Endocrine Surgeons' guidelines for definitive management of primary hyperparathyroidism. JAMA Surg 2016; 151 (10) 959-968