Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma-a case report and review.

Introduction: 24-Hydroxylase, encoded by the CYP24A1 gene, is a crucial enzyme involved in the catabolism of vitamin D. Loss-of-function mutations in CYP24A1 result in PTH-independent hypercalcaemia with high levels of 1,25(OH)2D3. The variety of clinical manifestations depends on age, and underlying genetic predisposition mutations can lead to fatal infantile hypercalcaemia among neonates, whereas adult symptoms are usually mild. Aim of the study: We report a rare case of an adult with primary hyperparathyroidism and loss-of-function mutations in the CYP24A1 gene and a review of similar cases. Case presentation: We report the case of a 58-year-old woman diagnosed initially with primary hyperparathyroidism. Preoperatively, the suspected mass adjoining the upper pole of the left lobe of the thyroid gland was found via ultrasonography and confirmed by 99mTc scintigraphy and biopsy as the parathyroid gland. The patient underwent parathyroidectomy (a histopathology report revealed parathyroid adenoma), which led to normocalcaemia. After 10 months, vitamin D supplementation was introduced due to deficiency, and the calcium level remained within the reference range. Two years later, biochemical tests showed recurrence of hypercalcaemia with suppressed parathyroid hormone levels and elevated 1,25(OH)2D3 concentrations. Further investigation excluded the most common causes of PTH-independent hypercalcaemia, such as granulomatous disease, malignancy, and vitamin D intoxication. Subsequently, vitamin D metabolites were measured using LC-MS/MS, which revealed high levels of 25(OH)D3, low levels of 24,25(OH)2D3 and elevated 25(OH)2D3/24,25(OH)2D3 ratios, suggesting a defect in vitamin D catabolism. Molecular analysis of the CYP24A1 gene using the NGS technique revealed two pathogenic variants: p.(Arg396Trp) and p.(Glu143del) (rs114368325 and rs777676129, respectively). Conclusions: The diagnostic process for hypercalcaemia becomes complicated when multiple causes of hypercalcaemia coexist. The measurement of vitamin D metabolites using LC-MS/MS may help to identify carriers of CYP24A1 mutations. Subsequent molecular testing may contribute to establishing the exact frequency of pathogenic variants of the CYP24A1 gene and introducing personalized treatment.

Parathyroid carcinoma during pregnancy: a novel pathogenic CDC73 mutation - a case report.

BACKGROUND: Parathyroid carcinoma is an uncommon cause of PTH-dependent hypercalcemia. Only a handful of cases have been reported of parathyroid carcinoma during pregnancy. CASE PRESENTATION: Twenty-four - Year - old female presented with proximal myopathy was found to have hypercalcemia. Her serum corrected total calcium was - 15 mg/dl (8.5 - 10.3), serum phosphate - 2.3 mg/dl (2.5 - 4.5), intact PTH - 118 pg/ml (20 - 80), Vitamin D - 15 ng/ml and Urine Ca/Cr ratio - 2.1 (0.1 - 0.2). Her CECT-neck revealed a well-defined mass lesion posterior to the right lobe of the thyroid - 2.6 cm × 2.5 cm × 2.9 cm in size. She was started on vitamin D supplementation, and she underwent right lower focal parathyroidectomy. Her PTH levels normalized following surgery. Her histology revealed an atypical parathyroid adenoma. She was treated with calcium and vitamin D. Her follow up was uneventful. One year following initial surgery the patient became pregnant and at 16 weeks of POA, the patient presented with a rapidly enhancing neck mass for one week duration. Her biochemical investigations were suggestive of a recurrence of primary hyperparathyroidism. Her ultrasound scan of the neck revealed a well-defined discreate hypoechoic nodule, superior to the thyroid isthmus which was confirmed by a non-contrast MRI scan of the neck. She underwent an uncomplicated second trimester parathyroid tumour excision with normalization of post op PTH. Her histology revealed a parathyroid carcinoma with vascular and capsular invasion. Her genetic studies revealed a novel frameshift mutation of the CDC73 gene. She was treated with calcium and vitamin D supplementation and closely followed up with ionized calcium and PTH levels which were normal throughout the pregnancy. She had an uncomplicated caesarean section at a POA of 37 weeks. Currently she is twelve weeks post-partum, in remission of disease. CONCLUSION: This case shows the importance of stringent follow up of atypical parathyroid adenoma patients, the benefit of second trimester surgery in management of hypercalcemia due to parathyroid carcinoma during pregnancy and the importance of identifying the novel CDC73 gene mutation.

Parathyroid carcinoma: Single centre experience.

OBJECTIVE: Parathyroid Carcinoma is a rare malignant neoplasm, accounting for less than 1% of primary hyperparathyroidism cases. Parathyroid carcinomas are characterized by markedly elevated levels of PTH, severe hypercalcemia and established target organ damage. The authors report the experience of a single centre regarding the management and outcome of patients with parathyroid carcinomas and revise relevant literature. DESIGN: Retrospective review of all patients with parathyroid carcinoma evaluated at a tertiary oncologic centre from 1991 until 2021. RESULTS: Seventeen patients were identified (10 males), with a mean age at diagnosis of 53 ± 16 years and a median follow-up of 16.5 years. Most patients presented with hypercalcemia (n = 15), with a mean serum calcium concentration of 13.5 mg/dl (9.6-16.5) and mean PTH of 1173 pg/ml (276-2500). Hyperparathyroidism-mediated organ damage was observed in most patients (n = 16), with predominant renal (n = 12) and skeletal (n = 9) complications. En bloc surgical resection was performed in nine patients. Three patients underwent adjuvant radiotherapy. Recurrence was observed in 8 cases (47.1%) after a median of 24 months following surgery and no independent predictors of recurrence were identified. The overall survival and disease specific survival at 5-year was 88% and 94%, respectively. CDC73 mutations were present in 38.5% of analysed patients and one patient was diagnosed with MEN1. CONCLUSION: Parathyroid carcinoma is associated with a significant rate of recurrence and limited effective treatment beyond initial complete surgical resection. Therefore, preoperatively high index of suspicion is paramount to optimize patient care. This is, to our knowledge, the largest Portuguese cohort published so far.

A germline c.1546dupC MEN1 mutation in an MEN1 family: A case report.

RATIONALE: Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome with an autosomal dominant inheritance, and genetic testing for MEN1 gene is important for both affected individuals and their relatives. We present a 2-person family affected by a germline c.1546dupC MEN1 mutation, and one of them had a full-spectrum of MEN-related endocrine tumors. PATIENT CONCERNS: A female patient aged 32 years presented with jejunal ulcer perforation due to gastrinoma. DIAGNOSES: We conducted genetic analysis and extensive biochemical/radiological evaluation for detecting other endocrine tumors. Multiple pancreatic neuroendocrine tumors (NETs), prolactinoma and primary hyperparathyroidism were diagnosed, and a frame-shift mutation, NM_130799.1:c.1546dupC (p.Arg516Profs∗15), was detected. One daughter of the proband, aged 12 years, had the same mutation for MEN1. INTERVENTION: She underwent pancreatic surgery for pancreatic NETs and total parathyroidectomy for primary hyperparathyroidism. OUTCOMES: After pancreatic surgery, long-term symptoms of epigastric soreness, acid belching, sweating, and palpitation in fasting were improved. Hypercalcemia was improved after parathyroidectomy and she was supplemented with oral calcium and vitamin D. Her daughter showed normal biochemical surveillance until 15 years of age. LESSONS: We report 2 people in a family affected by MEN1 with the heterozygous germline c.1546dupC mutation, a variant that should be surveilled for early development of full-blown MEN1-associated endocrine tumors.

Microsatellite instability driven metastatic parathyroid carcinoma managed with the anti-PD1 immunotherapy, pembrolizumab.

The present case report describes a 65-year-old man with Lynch syndrome and hypercalcaemia associated with hyperparathyroidism. Parathyroid surgery confirmed the diagnosis of parathyroid carcinoma. Serum calcium and parathyroid hormone (PTH) concentrations serially increased after initial surgery. Imaging study and subsequent biopsy confirmed lung metastases with mismatch repair deficiency. Pembrolizumab was initiated achieving 60% reduction in tumour burden.

Diagnosis and management of parathyroid cancer.

Parathyroid cancer is rare, but often fatal, as preoperative identification of malignancy against the backdrop of benign parathyroid disease is challenging. Advanced genetic, laboratory and imaging techniques can help to identify parathyroid cancer. In patients with clinically suspected parathyroid cancer, malignancy of any individual lesion is established by three criteria: demonstration of metastasis, specific ultrasonographic features, and a ratio >1 for the results of third-generation:second-generation parathyroid hormone assays. Positive findings for all three criteria dictate an oncological surgical approach, as appropriate radical surgery can achieve a cure. Mutation screening pinpoints associated conditions and asymptomatic carriers. Molecular profiling of tumour cells can identify high-risk features, such as differential expression of specific micro-RNAs and proteins, and germ line mutations in CDC73, but is unsuitable for preoperative assessment owing to the potential risks associated with biopsy. A validated, histopathology-based prognostic classification can identify patients in need of close follow-up and adjuvant therapy, and should prove valuable to stratify clinical trial cohorts: low-risk patients rarely die from parathyroid cancer, even on long-term follow-up, whereas 5-year mortality in high-risk patients is around 50%. This insight has improved the approach to parathyroid cancer by enabling risk-adapted surgery and follow-up.

Parathyroid cancer.

Parathyroid cancer is an uncommon malignancy and rare cause of primary hyperparathyroidism (HPT) with a high morbidity and patient death in advanced cases usually resulting from intractable hypercalcemia. Inactivation of the HRPT2/CDC73 gene, encoding the putative tumor-suppressor protein parafibromin and discovered in the context of the hyperparathyroidism-jaw tumor (HPT-JT) syndrome, is a common, somatic event in most parathyroid cancers. Approximately 25% of patients with apparently sporadic parathyroid cancer carry germline HRPT2/CDC73 mutation. Germline DNA analysis for HRPT2/CDC73 mutation is recommended in all patients with parathyroid cancer because of the potential benefit for first-degree relatives, who should nevertheless undergo serum calcium screening. The histopathologic diagnosis of parathyroid cancer is nonspecific unless vascular, lymphatic, capsular, or soft tissue invasion is seen, or metastases are clinically evident. Immunohistochemical analysis of parathyroid tumors for loss of parafibromin expression offers promise as a diagnostic tool. En bloc tumor resection offers the highest chance of cure in patients with suspected parathyroid carcinoma. No adjuvant chemotherapy regimen has yet proven effective, and the role of local adjuvant radiotherapy is being evaluated. Metastatic disease can be palliated with surgical debulking. Medical therapy with the calcimimetic cinacalcet and bisphosphonates can ameliorate hypercalcemia in patients with inoperable disease.

[Parathyroid carcinoma]. / Le carcinome parathyroïdien.

Parathyroid carcinoma is a rare disease accounting for 1 to 5% of parathyroid neoplasms. This malignant tumour must be suspected when a severe primary hyperparathyroidism occurs with high hypercalcemia and elevated parathormon levels. At this time, a cervical mass is often palpable. Both head and neck ultrasonography and 99mTc-sestamibi scintigraphy are the best preoperative imaging tests to suspect and localize the tumour. Surgical approach with simultaneous tumorectomy and hemithyroidectomy, completed by selective neck dissection (level VI) is the treatment of choice. An elective lateral neck dissection should be performed if necessary. Tumour control should be monitored by regular measurement of calcium and parathormon levels. Local recurrence or metastasis risk is 30 to 70% and the 5 year overall survival about 50 to 80%. In case of recurrence, aggressive surgical management should be applied and adjuvant radiation therapy may be discussed.

Decreased expression of calcium-sensing receptor messenger ribonucleic acids in parathyroid adenomas.

BACKGROUND: The set point for parathyroid hormone (PTH) secretion is increased in patients with primary hyperparathyroidism, possibly because of receptor defect(s). A decreased expression of calcium receptor (CaR) messenger ribonucleic acid (mRNA) and protein and a decreased expression of the putative calcium-sensing CAS (gp330/megalin) protein have been demonstrated in parathyroid adenomas. METHODS: Expression of CAS mRNA was studied in matched pairs of adenomas and adenoma-associated biopsy specimens from normal parathyroid glands from 15 patients with sporadic primary hyperparathyroidism. Cryostat sections were hybridized with an oligonucleotide complementary to CAS mRNA, rinsed, air dried, and exposed to x-ray film for semiquantification of radioactivity. RESULTS: Expression of CAS mRNA in the adenomas was lowered significantly to 25% (median; range 9% to 80%) of that of the corresponding biopsy specimens of normal parathyroid glands. No correlation was seen between CAS mRNA in the adenoma and preoperative serum calcium levels, PTH level, or weight of the adenoma. The levels of CAS mRNA were significantly lower than those observed previously for CaR mRNA. There was no significant correlation between the levels of CAS and CaR mRNA. CONCLUSIONS: Lowered levels of receptors sensing extracellular calcium (CaR and CAS) probably contribute to the increased set point for PTH secretion in primary hyperparathyroidism.

Management of primary hyperparathyroidism in children.

Primary hyperparathyroidism is unusual in children. It is most commonly due to a solitary sporadic parathyroid adenoma, though parathyroid hyperplasia and related familial syndromes should be considered. In the case presented here, an 11-year-old boy with primary hyperparathyroidism had preoperative imaging studies that localized to the inferior aspect of the left side of the neck anteriorly, and a parathyroid adenoma was successfully resected. Screening for familial syndromes involving hyperparathyroidism should be individually considered in children with primary hyperparathyroidism. Preoperative localizing studies and the role of unilateral surgery are controversial issues in adults with primary hyperparathyroidism. Although such issues have not been addressed in children, localization and unilateral surgery proved successful in this case.