The extent of parathyroidectomy for HRPT2-related hyperparathyroidism

We read with interest the paper by Sarquis et al,1 who reported the results of parathyroidectomy for familial hyperparathyroidism in 3 kindreds with germline HRPT2 mutations. They suggested a more aggressive operative approach because of multiglandular involvement, high recurrence and persistence rate, difficult reoperations, and risk of parathyroid malignancies. In 2007 we published a similar experience concerning 12 patients from 3 kindreds with germline HRPT2 mutations, but our conclusions were different.2 We agree that the clinical course of familial isolated hyperparathyroidism (FIHP) (when associated with HRPT2 mutations) may be similar to HPT jaw tumor syndrome (JT); for this reason we suggest that these conditions may be named “HRPT2-related hyperparathyroidism” according to genetic criteria instead of clinical ones; the same jaw tumor—a distinctive feature of HPT-JT syndrome—is relatively rare in this setting (only one case both in Sarquis and in our experience). Different from Sarquis and colleagues, we observed single gland involvement in all patients; recurrent hyperparathyroidism after limited parathyroidectomy occurred only in 3 patients after a disease-free interval of 5, 9, and 27 years. All of these patients were cured again by a limited parathyroidectomy; parathyroid carcinoma occurred only in 1 patient. These reports are concordant with the literature that reports a synchronous single-gland involvement in 84% of patients (range, 67–100%), recurrent hyperparathyroidism in 22% (after a mean disease-free interval of 11.1 years) and parathyroid malignancies in 18%.2 Furthermore, we first demonstrated single gland involvement by immunohistochemistry, and showed a strong parafibromin expression in biopsies from normal appearing glands and a loss of parafibromin staining in adenoma from the same patient. The loss of parafibromin immunostaining is a distinct marker of the disease, but it cannot be considered a predictive factor of malignancy in this setting, differently from sporadic hyperparathyroidism. For these reasons, we maintain that systematic subtotal parathyroidectomy might represent an overtreatment. Under these assumptions, should subtotal parathyroidectomy be proposed also in healthy carriers of the mutated gene, in an attempt to prevent the occurrence of parathyroid malignancies? Is the morbidity associated with subtotal parathyroidectomy justified for a disease with incomplete penetrance? Furthermore, even subtotal parathyroidectomy might not prevent recurrences; we found an affected supernumerary and ectopic gland at carotid bifurcation; Sarquis and colleagues found pulmonary metastases from parathyroid carcinoma, but the primary tumor was never identified although five surgical procedures were attempted. For these reasons we maintain that limited parathyroidectomy is an adequate treatment of patients with HRPT2-related hyperparathyroidism, especially when preoperative imaging techniques localize concordantly a single affected gland (60% in our study). Furthermore, an accurate preoperative localization showing a single gland could allow focused, minimally invasive parathyroidectomy, in the same setting of sporadic HPT, with the potential advantage of a lesser risk of hypoparathyroidism and minimal tissue trauma, facilitating reoperations in case of recurrent hyperparathyroidism. Regular surveillance of individuals with germline HRPT2 mutations may allow earlier detection of hyperparathyroidism, earlier operative management and, possibly, prevention or cure of parathyroid carcinoma.