Overlapping Phenotypes Associated With CYP24A1, SLC34A1, and SLC34A3 Mutations: A Cohort Study of Patients With Hypersensitivity to Vitamin D

Mutations in CYP24A1 (vitamin D 24-hydroxylase) and SLC34A1 (renal phosphate transporter NPT2a) cause autosomal recessive Infantile Hypercalcemia type 1 and 2, illustrating links between vitamin D and phosphate metabolism. Patients may present with hypercalciuria and alternate between chronic phases with normal serum calcium but inappropriately high 1,25-(OH)2D and appropriately low PTH, and acute phases with hypercalcemia with suppressed PTH. Mutations in SLC34A3 and SLC9A3R1 have been associated with phosphate wasting without hypercalcemia. The aims of this study were to evaluate the frequency of mutations in these genes in patients with a medical history suggestive of CYP24A1 mutation to search for a specific pattern. Using next generation sequencing, we screened for mutations in 185 patients with PTH levels < 20 pg/mL, hypercalcemia and/or hypercalciuria, and relatives. Twenty-eight (15%) patients harbored biallelic mutations in CYP24A1 (25) and SLC34A3 (3), mostly associated with renal disease (lithiasis, nephrocalcinosis) (86%). Hypophosphatemia was found in 7 patients with biallelic mutations in CYP24A1 and a normal phosphatemia was reported in 2 patients with biallelic mutations in SLC34A3. Rare variations in SLC34A1 and SLC34A3 were mostly of uncertain significance. Fifteen patients (8%) carried only one heterozygous mutation. Heterozygous relatives carrying SLC34A1 or SLC34A3 variation may present with biochemical changes in mineral metabolism. Two patients’ genotype may suggest digenism (heterozygous variations in different genes). No variation was found in SLC9A3R1. As no specific pattern can be found, patients with medical history suggestive of CYP24A1 mutation should benefit from SLC34A1 and SLC34A3 analysis.

Surgical outcome after focused parathyroidectomy: an experience from a tertiary care center in north India

Introduction: Focused parathyroidectomy is the gold standard treatment for primary hyperparathyroidism (PHPT) due to single gland disease with comparable success rate as that of conventional four gland exploration. It is also associated with fewer surgical complications. Despite these benefits, there is still controversy about the high recurrence following focused approach. Therefore the aim was to analyse our experience in terms of success rate of focused parathyroidectomy for PHPT. Methods: This was a retrospective analysis of 192 patients of PHPT between January 2017 and August 2020 who underwent focused parathyroidectomy without iOPTH analysis; and had a minimum follow up of six months. Demographic profile, biochemical (pre and postoperative), radiological, operative and histological detail of all patients was recorded. Parathyroidectomy was considered curative if patient maintained normal serum calcium and PTH levels six months after surgery. Persistent hyperparathyroidism was considered if hypercalcemia or high PTH levels persisted; or recurrent disease when patient had rising serum calcium and / or PTH levels six months after curative parathyroidectomy. Results: No patient had pain and wound related complications after parathyroidectomy. Two patients had voice change in the immediate postoperative period which recovered subsequently; no patient had documented vocal cord paralysis. Persistent disease was present in two patients; both required neck exploration. Four patients had recurrence of PHPT within 6 months of parathyroidectomy; all of them had hyperplasia on the final biopsy. The overall cure rate was 97.92%. Conclusion: Therefore, we recommend focused surgery for sporadic PHPT with acceptable recurrence rate and surgical complications.

Falsely Positive Parathyroid Scan in a Patient With Medullary Thyroid Cancer

Background: Technitium 99m sestamibi is a very useful method for preoperative localization in hyperparathyroidism. It have some limitations including false positivity due to thyroid pathology. We present a patient with positive Technitium 99m sestamibi uptake by a medullary thyroid cancer Case Presentation: A 67-year-old female referred to the endocrine clinic for evaluation of medullary thyroid cancer diagnosed by fine needle aspiration of left side thyroid nodule. TSH level was normal with high normal serum calcium and high PTH levels. No family history of medullary thyroid cancer, hyperparathyroidism or pheochromocytoma. Her plasma metanephrines were normal. Preoperative evaluation included a parathyroid scan with oral I-123 and Intravenous Technitium 99m sestamibi. I-123 scan showed a cold nodule in the left thyroid lobe and the subtraction images demonstrated persistent uptake of Technitium 99M sestamibi which was reported by the radiologist as a parathyroid adenoma. Repeated serum calcium was normal and intraoperative evaluation of parathyroid glands demonstrated no abnormal enlargement confirming that parathyroid scan was falsely positive secondary to medullary thyroid cancer. Conclusion: This case highlights the importance of careful interpretation of nuclear parathyroid scan results. False positive results have been reported with both benign and malignant thyroid disease including medullary thyroid cancer.

Osteitis Fibrosa Cystica: An Unusual but Still Prevalent Manifestation of Uncontrolled Secondary Hyperparathyroidism

Background: Osteitis fibrosa cystica is an uncommon complication of untreated secondary hyperparathyroidism in patients with end-stage renal disease. The characteristic bony lesions that are seen in this condition very rarely can regress after medical treatment or parathyroidectomy. Clinical Case: A 65-year-old male with PMH of Systemic Lupus Erythematous (SLE) resulting in End-Stage Renal Disease (ESRD) on peritoneal dialysis (PD) and HTN, presented to his primary care physician for evaluation of a painful, enlarging lesion in his left forearm. The patient reported no history of trauma and denied having systemic symptoms. An X-Ray of his left forearm showed a lytic lesion within the proximal neck of the ulna, with erosion of the adjacent cortex. CT of the forearm showed a very vascular soft tissue mass causing significant erosive changes of the anterior cortex in the proximal ulna. Due to the characteristics of the lesion, an underlying malignancy was suspected as a possible diagnosis. The patient had a whole-body PET CT which showed multiple scattered hypermetabolic lytic osseous lesions throughout the axial and appendicular skeleton, including a large left proximal ulnar lesion. The patient had a bone biopsy from the lesion in his left ulna which showed a giant cell proliferation in a background of fibrosis and hemosiderin, suggestive of Osteitis Fibrosa Cystica (brown tumor of hyperparathyroidism). His laboratory workup around the time of the symptoms showed a normal serum calcium (9 mg/dl), associated with a high serum phosphorus (6.2 mg/dl), low vitamin D (20 ng/ml), and an elevated PTH (900 pg/ml). The patient was started on Cinacalcet, an increased dose of phosphate binders, as well as Calcitriol and the lesions and pain disappeared. Follow up lab work showed a normal Vitamin D (34 mg/dl), normal Phosphorus (4 mg/dl), and a PTH of 199 mg/dl, with a normal serum Calcium. A surveillance PET was performed 6 months after the initial one when the lesions clinically had disappeared and it showed again the presence of the bony lesions described prior, including the one in the left ulna, but with decreased FDG uptake, as well as new lesions in the spine. To date, the patient is asymptomatic and has not noted any new painful lesions. Conclusions: Osteitis fibrosa cystica remains a rare manifestation of secondary hyperparathyroidism, which may lead to an initial impression of malignancy. This patient exhibited clinical resolution of the painful symptoms associated with osteitis fibrosa cystica following medical management, though the lytic lesions involving the axial and appendicular skeleton persisted on surveillance imaging. This case serves as a reminder of the severe manifestations of a skeletal disease that has become rare given advances in early detection of and appropriate medical management of hyperparathyroidism.

Normocalcaemic primary hyperparathyroidism: what is the role of parathyroid surgery?

Primary hyperparathyroidism (PHPT) is classically associated with both an elevated or ‘inappropriately normal’ parathyroid hormone (PTH) level and raised serum calcium. However, in clinical practice, increasing numbers of patients present with raised PTH but normal serum calcium, renal function and vitamin D; this is known as normocalcaemic PHPT (nPHPT). Studies investigating the clinical presentation of this condition have shown that patients may present with hypertension, nephrolithiasis, impaired glucose tolerance, osteoporosis and fragility fractures. The prevalence of such complications in nPHPT is similar to that in classical hypercalcaemic PHPT (hPHPT). Although the National Institute for Health and Care Excellence (NICE) have developed guidelines for the management of PHPT generally, a consensus is yet to be reached on the optimal management of nPHPT specifically. A review of the literature on parathyroidectomy in the treatment of nPHPT revealed that nPHPT patients were more likely to present with multi-glandular disease and significantly less nPHPT patients had an intra-operative PTH fall of >50% compared with those with hPHPT. These findings demonstrate that patients with nPHPT are more likely to receive bilateral neck explorations and require remedial surgery compared with hPHPT patients. Following surgery, improvements in bone mineral density (BMD) and renal stones are generally observed in those with nPHPT. Where surgery is not possible, medical management with alendronate has been shown to be effective in nPHPT patients. Given the higher incidence of multi-gland disease and greater possibility of remedial surgery in nPHPT, careful consideration of risks and benefits should be made on an individualised basis and surgery should be performed by surgeons experienced in four gland exploration.

Phosphaturie mesenchymal tumour, 'non-phosphaturic' variant: a case report and review of the literature

ABSTRACT BACKGROUND: Phosphaturic mesenchymal tumours are uncommon neoplasms, usually associated with tumour-induced osteomalacia, that occur in middle-aged adults but have been reported at the extremes of age. The 'non-phosphaturic' variant is even rarer METHODS: Herein, we describe the non-phosphaturic variant in a 12-year-old male who presented to the Department of Orthopaedic Surgery with a six-month history of painful progressive swelling of his right forearm in the absence of trauma. He had no other significant symptoms RESULTS: The patient had normal serum calcium and phosphate levels on biochemical analysis. An inci-sional biopsy was performed and a histopathological diagnosis of a phosphaturic mesenchymal tumour, non-phosphaturic variant, was rendered. Six weeks later, he underwent surgical excision of a 15x15 cm soft tissue mass from his right forearm. He had an uneventful postoperative period and was discharged. He has been followed up at the outpatient department and has been free of tumour recurrence for over 18 months since his surgery with no evidence of osteomalacia and no other tumours CONCLUSION: Phosphaturic mesenchymal tumours are rare mesenchymal neoplasms and their microscopically identical counterpart without phosphaturia, known as the 'non-phosphaturic' variant, is even more uncommon and may prove a greater diagnostic challenge. While the diagnosis may be confirmed by hypophosphataemia and phosphaturia secondary to the paraneoplastic phenomenon of tumour-induced osteomalacia, there may be instances, such as with our patient, where tumour-induced osteomalacia is absent. This case underscores the importance of clinicopathological correlation together with a wide differential diagnosis required to arrive at a correct diagnosis to facilitate appropriate patient management Level of evidence: Level 5 Keywords: phosphaturic mesenchymal tumours, non-phosphaturic variant

Chronic Kidney Disease –Mineral Bone Disorder (CKD- MBD) – Further Insight at the Indian patients.

The kidneys play an important role in maintaining normal serum calcium (Ca) and phosphorous (P) concentrations. Chronic kidney disease (CKD) is associated with significant disturbances in bone and mineral metabolism, leading to altered serum concentrations of Ca, P, vitamin D and parathyroid hormone (PTH)1,2,3. These changes are initially detected when the glomerular filtration rate (GFR) falls to ≤60 mL/min and are nearly uniform as GFR drops to <30ml/min2,3. This leads to a number of bone abnormalities previously called “renal osteodystrophy”, renamed as CKD-Mineral Bone Disorder (CKD-MBD) by National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) consensus group4 . CKD-MBD is a systemic disorder manifested by either one or a combination of a) abnormalities of Ca, P, PTH or vitamin D metabolism, b) abnormalities in bone turnover, mineralization, volume, linear growth or strength c) vascular or soft tissue calcification. This has over time been expanded to include left ventricular hypertrophy, hypertension, immune dysfunction and inflammation5,6.

Rare cause of pathological fracture in adults as hypophosphatemic rickets

Hypophosphatemic rickets is a disorder of defective bone minerlization due to defect in renal phosphate handling process. It is characterised by increased phosphate excretion accompanied by increased phosphatonins like fibroblast growth factor 23. It can be hereditary form of X linked, autosomal dominant, autosomal recessive type of hypophosphatemic rickets. It is associated with low serum phosphorus, normal serum calcium, inappropriately low to normal vitamin D level. Correct identification of these disorders is important for determining therapy. Early diagnosis and management prevent subsequent complication of the disease.

Autosomal Dominant Hypophosphatemic Rickets Presenting in a Phenotypically Normal Adult Female

We describe a presentation of Autosomal Dominant Hypophosphatemic Rickets (ADHR) in a 22-year-old female with normal pubertal growth and development and a negative family history in first-degree relatives. The patient presented with a 2-year history of upper and lower extremity proximal muscle pain and weakness and bilateral femoral neck and pubic bone insufficiency fractures. She had a normal serum calcium but a low phosphate as well as 25-hydroxyvitamin D (25(OH)D) levels leading initially to a diagnosis of osteomalacia. Urine phosphate reabsorption was low confirming a phosphate wasting disorder. She had an elevated Fibroblast Growth Factor 23 (FGF23) level. After Tumor-Induced Osteomalacia was ruled out by extensive imaging, she was sent for genetic testing for hereditary rickets which showed a previously reported missense variant in FGF23. Subsequently, she found out that her father’s maternal aunt and grandfather had ‘bone disorder’ and were wheelchair-bound in adulthood. After replenishment of vitamin D, treatment with calcitriol and phosphate leads to complete resolution of patient’s symptoms and laboratory abnormalities.