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Jane J Tellam Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
University of Queensland, Herston, Queensland, Australia

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Ghusoon Abdulrasool Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
University of Queensland, Herston, Queensland, Australia
Pathology Queensland, Australia

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Louise C H Ciin Gold Coast University Hospital, Southport, Queensland, Australia
Griffith University, Southport, Queensland, Australia

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Summary

Distinguishing primary hyperparathyroidism (PHPT) from familial hypocalciuric hypercalcaemia (FHH) can be challenging. Currently, 24-h urinary calcium is used to differentiate between the two conditions in vitamin D replete patients, with urinary calcium creatinine clearance ratio (UCCR) <0.01 suggestive of FHH and >0.02 supportive of PHPT. A 26-year-old Caucasian gentleman presented with recurrent mild hypercalcaemia and inappropriately normal parathyroid hormone (PTH) following previous parathyroidectomy 3 years prior. He had symptoms of fatigue and light-headedness. He did not have any other symptoms of hypercalcaemia. His previous evaluation appeared to be consistent with PHPT as evidenced by hypercalcaemia with inappropriately normal PTH and UCCR of 0.0118 (borderline low using guidelines of >0.01 consistent with PHPT). He underwent parathyroidectomy and three parathyroid glands were removed. His calcium briefly normalised after surgery, but rose again to pre-surgery levels within 3 months. Subsequently, he presented to our centre and repeated investigations showed 24-h urinary calcium of 4.6 mmol/day and UCCR of 0.0081 which prompted assessment for FHH. His calcium-sensing receptor (CASR) gene was sequenced and a rare inactivating variant was detected. This variant was described once previously in the literature. His mother was also confirmed to have mild hypercalcaemia with hypocalciuria and, on further enquiry, had the same CASR variant. The CASR variant was classified as likely pathogenic and is consistent with the diagnosis of FHH. This case highlights the challenges in differentiating FHH from PHPT. Accurate diagnosis is vital to prevent unnecessary surgical intervention in the FHH population and is not always straightforward.

Learning points:

  • Distinguishing FHH from PHPT with co-existing vitamin D deficiency is difficult as this can mimic FHH. Therefore, ensure patients are vitamin D replete prior to performing 24-h urinary calcium collection.

  • Individuals with borderline UCCR could have either FHH or PHPT. Consider performing CASR gene sequencing for UCCR between 0.01 and 0.02.

  • Parathyroid imaging is not required for making the diagnosis of PHPT. It is performed when surgery is considered after confirming the diagnosis of PHPT.

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Daniela Gallo Department of Medicine and Surgery, Endocrine Unit, University of Insubria, Varese, Italy

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Sara Rosetti Department of Medicine and Surgery, Endocrine Unit, University of Insubria, Varese, Italy

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Ilaria Marcon Department of Oncology, ASST dei Sette Laghi, Varese, Italy

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Elisabetta Armiraglio Pathology Unit, ASST Gaetano Pini, Centro Specialistico Ortopedico Traumatologico, Gaetano Pini-CTO, Milano, Italy

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Antonina Parafioriti Pathology Unit, ASST Gaetano Pini, Centro Specialistico Ortopedico Traumatologico, Gaetano Pini-CTO, Milano, Italy

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Graziella Pinotti Department of Oncology, ASST dei Sette Laghi, Varese, Italy

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Giuseppe Perrucchini I.R.C.C.S Istituto Ortopedico Galeazzi, Milano, Italy

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Bohdan Patera Department of Medicine and Surgery, Endocrine Unit, University of Insubria, Varese, Italy

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Linda Gentile Department of Medicine and Surgery, Endocrine Unit, University of Insubria, Varese, Italy

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Maria Laura Tanda Department of Medicine and Surgery, Endocrine Unit, University of Insubria, Varese, Italy

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Luigi Bartalena Department of Medicine and Surgery, Endocrine Unit, University of Insubria, Varese, Italy

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Eliana Piantanida Department of Medicine and Surgery, Endocrine Unit, University of Insubria, Varese, Italy

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Summary

Brown tumors are osteoclastic, benign lesions characterized by fibrotic stroma, intense vascularization and multinucleated giant cells. They are the terminal expression of the bone remodelling process occurring in advanced hyperparathyroidism. Nowadays, due to earlier diagnosis, primary hyperparathyroidism keeps few of the classical manifestations and brown tumors are definitely unexpected. Thus, it may happen that they are misdiagnosed as primary or metastatic bone cancer. Besides bone imaging, endocrine evaluation including measurement of serum parathyroid hormone and calcium (Ca) levels supports the pathologist to address the diagnosis. Herein, a case of multiple large brown tumors misdiagnosed as a non-treatable osteosarcoma is described, with special regards to diagnostic work-up. After selective parathyroidectomy, treatment with denosumab was initiated and a regular follow-up was established. The central role of multidisciplinary approach involving pathologist, endocrinologist and oncologist in the diagnostic and therapeutic work-up is reported. In our opinion, the discussion of this case would be functional especially for clinicians and pathologists not used to the differential diagnosis in uncommon bone disorders.

Learning points:

  • Brown tumors develop during the remodelling process of bone in advanced and long-lasting primary or secondary hyperparathyroidism.

  • Although rare, they should be considered during the challenging diagnostic work-up of giant cell lesions.

  • Coexistence of high parathyroid hormone levels and hypercalcemia in primary hyperparathyroidism is crucial for the diagnosis.

  • A detailed imaging study includes bone X-ray, bone scintiscan and total body CT; to rule out bone malignancy, evaluation of bone lesion biopsy should include immunostaining for neoplastic markers as H3G34W and Ki67 index.

  • If primary hyperparathyroidism is confirmed, selective parathyroidectomy is the first-line treatment.

  • In advanced bone disease, treatment with denosumab should be considered, ensuring a strict control of Ca levels.

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Carmina Teresa Fuss Division of Endocrinology and Diabetology, Department of Medicine I, University Hospital Würzburg, Würzburg, Germany

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Stephanie Burger-Stritt Division of Endocrinology and Diabetology, Department of Medicine I, University Hospital Würzburg, Würzburg, Germany

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Silke Horn Division of Endocrinology and Diabetology, Department of Medicine I, University Hospital Würzburg, Würzburg, Germany

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Ann-Cathrin Koschker Division of Endocrinology and Diabetology, Department of Medicine I, University Hospital Würzburg, Würzburg, Germany

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Kathrin Frey Division of Endocrinology and Diabetology, Department of Medicine I, University Hospital Würzburg, Würzburg, Germany

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Almuth Meyer Division of Endocrinology and Diabetology, Department of Internal Medicine, Helios Klinikum Erfurt, Erfurt, Germany

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Stefanie Hahner Division of Endocrinology and Diabetology, Department of Medicine I, University Hospital Würzburg, Würzburg, Germany

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Summary

Standard treatment of hypoparathyroidism consists of supplementation of calcium and vitamin D analogues, which does not fully restore calcium homeostasis. In some patients, hypoparathyroidism is refractory to standard treatment with persistent low serum calcium levels and associated clinical complications. Here, we report on three patients (58-year-old male, 52-year-old female, and 48-year-old female) suffering from severe treatment-refractory postsurgical hypoparathyroidism. Two patients had persistent hypocalcemia despite oral treatment with up to 4 µg calcitriol and up to 4 g calcium per day necessitating additional i.v. administration of calcium gluconate 2–3 times per week, whereas the third patient presented with high frequencies of hypocalcemic and treatment-associated hypercalcemic episodes. S.c. administration of rhPTH (1–34) twice daily (40 µg/day) or rhPTH (1–84) (100 µg/day) only temporarily increased serum calcium levels but did not lead to long-term stabilization. In all three cases, treatment with rhPTH (1–34) as continuous s.c. infusion via insulin pump was initiated. Normalization of serum calcium and serum phosphate levels was observed within 1 week at daily 1–34 parathyroid hormone doses of 15 µg to 29.4 µg. Oral vitamin D and calcium treatment could be stopped or reduced and regular i.v. calcium administration was no more necessary. Ongoing efficacy of this treatment has been documented for up to 7 years so far. Therefore, we conclude that hypoparathyroidism that is refractory to both conventional treatment and s.c. parathyroid hormone (single or twice daily) may be successfully treated with continuous parathyroid hormone administration via insulin pump.

Learning points:

  • Standard treatment of hypoparathyroidism still consists of administration of calcium and active vitamin D.

  • Very few patients with hypoparathyroidism also do not respond sufficiently to standard treatment or administration of s.c. parathyroid hormone once or twice daily.

  • In those cases, continuous s.c. administration of parathyroid hormone via insulin pump may represent a successful treatment alternative.

Open access
Lorena Arnez St Mary’s Hospital, Isle of Wight NHS Trust, Newport, UK

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Victor Lawrence St Mary’s Hospital, Isle of Wight NHS Trust, Newport, UK

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Summary

A 40-year-old woman was hospitalised at 25-week gestation following a diagnosis of severe symptomatic hypercalcaemia (adjusted serum calcium 3.02 mmol/L). A diagnosis of primary hyperparathyroidism (PHP) was made on the basis of elevated parathyroid hormone (PTH) 11.2 pmol/L (reference range 1.5–6.9) and exclusion of familial hypocalciuric hypercalcaemia. Ultrasound examination of the neck did not convincingly demonstrate an abnormal or enlarged parathyroid gland and parathyroid scintigraphy was not performed due to maternal choice relating to perceived radiation risk to the foetus. At neck exploration during the 28th week of pregnancy a right lower pole parathyroid lesion was excised together with two abnormal lymph nodes (largest 1.6 cm). Histology confirmed a parathyroid adenoma and also papillary thyroid carcinoma deposits in the two resected lymph nodes. Post-operatively, levels of adjusted serum calcium normalised and pregnancy progressed uneventfully to term. Total thyroidectomy was performed 2 weeks after delivery revealing two small foci of papillary micro-carcinoma (largest 2.3 mm, one in each thyroid lobe) with no evidence of further metastatic tumour in lymph nodes removed during functional neck dissection. Radioiodine remnant ablation (RRA) was performed 2 months post thyroidectomy to allow for breast involution. The patient remains in full clinical and biochemical remission 9 years later. We present and review the difficult management decisions faced in relation to the investigation and treatment of PHP in pregnancy, further complicated by incidentally discovered locally metastatic pT1aN1aM0 papillary thyroid carcinoma.

Learning points:

  • PHP may have serious consequences during pregnancy and usually requires surgical management during pregnancy to reduce the risk of maternal and foetal complications. The indications for and optimal timing of surgical management are discussed.

  • Localisation by parathyroid scintigraphy is controversial during pregnancy: modified dose regimes may be considered in preference as an alternative to unguided neck exploration.

  • Breastfeeding is contraindicated for 6–8 weeks before radioactive-iodine remnant ablation (RRA) to prevent increased breast uptake. Breastfeeding is further contra-indicated until after a subsequent pregnancy.

  • Incidentally discovered differentiated thyroid carcinoma (DTC) in cervical lymph nodes in some cases may be managed expectantly because in one quarter of thyroidectomies the primary tumour remains occult.

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Florence Gunawan Barwon Health, Geelong University Hospital, Geelong, Victoria, Australia

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Elizabeth George Barwon Health, Geelong University Hospital, Geelong, Victoria, Australia

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Mark Kotowicz Barwon Health, Geelong University Hospital, Geelong, Victoria, Australia

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Summary

Denosumab is a fully human MAB that acts as a potent anti-resorptive by inhibiting activation of osteoclasts by inhibiting the receptor activator of nuclear factor-kappa B (RANK) ligand. Hypocalcaemia has been reported as one of the serious adverse sequelae of use of denosumab. We present a case of refractory hypocalcaemia following administration of a single dose of denosumab in a patient with metastatic castrate-resistant prostate cancer. The patient’s serum calcium and vitamin D concentrations and renal function were normal prior to denosumab administration. Serum alkaline phosphatase (ALP) level was however elevated pre-morbidly consistent with known bone metastases. The patient was treated with high-dose oral and IV calcium without any appreciable response in serum calcium. During his 30-day hospital admission, he demonstrated disease progression with development of new liver metastases and bone marrow involvement. Normocalcaemia was not achieved despite 1 month of aggressive therapy. Given the patient was asymptomatic and prognosis guarded, he was eventually discharged for ongoing supportive care under the palliative care team.

Learning points:

  • Denosumab is a potent anti-resorptive therapy and hypocalcaemia is one of the known adverse effects.

  • Serum calcium and vitamin D concentrations must be replete prior to administration of denosumab to reduce the risk of hypocalcaemia.

  • Denosumab has been proven to be more effective than zoledronic acid in preventing skeletal-related adverse effects in patients with metastatic castrate-resistant prostate cancer.

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Nirusha Arnold Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia

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Victor O’Toole Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia

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Tien Huynh Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia

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Howard C Smith Westmead Teaching Hospital, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Catherine Luxford Kolling Institute of Medical Research, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Roderick Clifton-Bligh Kolling Institute of Medical Research, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Creswell J Eastman Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia
Westmead Teaching Hospital, Royal North Shore Teaching Hospital, The University of Sydney, Sydney, New South Wales, Australia

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Summary

Parathyroid-independent hypercalcaemia of pregnancy, due to biallelic loss of function of the P450 enzyme CYP24A1, the principal inactivator of 1,25(OH)2D results in hypervitaminosis D, hypercalcaemia and hypercalciuria. We report two cases of this disorder, with intractable hypercalcaemia, one occurring during gestation and into the postpartum, and the other in the postpartum period. Case 1, a 47-year-old woman with a twin pregnancy conceived by embryo transfer, presented with hypercalcaemia at 23 weeks gestation with subnormal serum parathyroid hormone (PTH) and normal serum 25-OH D levels. She was admitted to hospital at 31 weeks gestation with pregnancy-induced hypertension, gestational diabetes and increasing hypercalcaemia. Caesarean section at 34 weeks gestation delivered two healthy females weighing 2.13 kg and 2.51 kg. At delivery, the patient’s serum calcium level was 2.90 mmol/L. Postpartum severe hypercalcaemia was treated successfully with Denosumab 60 mg SCI, given on two occasions. CYP24A1 testing revealed she was compound heterozygous for pathogenic variants c.427_429delGAA, (p.Glu143del) and c.1186C>T, (p.Arg396Trp). Case 2, a 36-year-old woman presented 4 days after the delivery of healthy twins with dyspnoea, bradycardia, severe headaches, hypertension and generalized tonic-clonic seizures after an uneventful pregnancy. She was hypercalcaemic with a suppressed PTH, normal 25(OH)D, and elevated 1,25(OH)2D levels. Her symptoms partially responded to i.v. saline and corticosteroids in the short term but bisphosphonates such as Pamidronate and Zoledronic acid did not result in sustained improvement. Denosumab 120 mg SCI successfully treated the hypercalcaemia which resolved completely 2 months post-partum. CYP24A1 testing revealed she was homozygous for the pathogenic variant c.427_429delGAA, (p.Glu143del).

Learning points:

  • Hypercalcaemia in pregnancy can be associated with considerable morbidity with few options available for management.

  • In non-PTH-related hypercalcaemia the diagnosis of CYP24A1 deficiency should be considered.

  • Making a definitive diagnosis of CYP24A1 deficiency by genetic testing delays the diagnosis, while the availability of serum 24,25-dihydroxyvitamin D (24,25(OH)2D) will expedite a diagnosis.

  • In pregnant women with CYP24A1 deficiency hypercalcaemia can worsen in the post-partum period and is more likely to occur with twin pregnancies but generally resolves within 2–3 months.

  • Therapeutic alternatives are limited in pregnancy and their effectiveness is short-lived and mostly ineffective. Denosumab used in both our patients after delivery was the most effective agent normalizing calcium and may have benefit as a long-term therapeutic agent in preventing complications in patients with CYP24A1 deficiency.

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Andrew R Tang Division of Endocrinology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada

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Laura E Hinz Division of Endocrinology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada

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Aneal Khan Department of Medical Genetics and Pediatrics, University of Calgary, Alberta Children’s Hospital Research Institute, Calgary, Alberta, Canada

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Gregory A Kline Division of Endocrinology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada

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Summary

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare, autosomal recessive disorder caused by mutations in the SLC34A3 gene that encodes the renal sodium-dependent phosphate cotransporter 2c (NaPi-IIc). It may present as intermittent mild hypercalcemia which may attract initial diagnostic attention but appreciation of concomitant hypophosphatemia is critical for consideration of the necessary diagnostic approach. A 21-year-old woman was assessed by adult endocrinology for low bone mass. She initially presented age two with short stature, nephrocalcinosis and mild intermittent hypercalcemia with hypercalciuria. She had no evidence of medullary sponge kidney or Fanconi syndrome and no bone deformities, pain or fractures. She had recurrent episodes of nephrolithiasis. In childhood, she was treated with hydrochlorothiazide to reduce urinary calcium. Upon review of prior investigations, she had persistent hypophosphatemia with phosphaturia, low PTH and a high-normal calcitriol. A diagnosis of HHRH was suspected and genetic testing confirmed a homozygous c.1483G>A (p.G495R) missense mutation of the SLC34A3 gene. She was started on oral phosphate replacement which normalized her serum phosphate, serum calcium and urine calcium levels over the subsequent 5 years. HHRH is an autosomal recessive condition that causes decreased renal reabsorption of phosphate, leading to hyperphosphaturia, hypophosphatemia and PTH-independent hypercalcemia due to the physiologic increase in calcitriol which also promotes hypercalciuria. Classically, patients present in childhood with bone pain, vitamin D-independent rickets and growth delay. This case of a SLC34A3 mutation illustrates the importance of investigating chronic hypophosphatemia even in the presence of other more common electrolyte abnormalities.

Learning points:

  • Hypophosphatemia is an important diagnostic clue that should not be ignored, even in the face of more common electrolyte disorders.

  • HHRH is a cause of PTH-independent hypophosphatemia that may also show hypercalcemia.

  • HHRH is a cause of hypophosphatemic nephrocalcinosis that should not be treated with calcitriol, unlike other congenital phosphate wasting syndromes.

  • Some congenital phosphate wasting disorders may not present until adolescence or early adulthood.

Open access
Peter Novodvorsky Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK

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Ziad Hussein Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Muhammad Fahad Arshad Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Ahmed Iqbal Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Malee Fernando Department of Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Alia Munir Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK

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Sabapathy P Balasubramanian Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Department of General Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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Summary

Spontaneous remission of primary hyperparathyroidism (PHPT) due to necrosis and haemorrhage of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’ is a very rare, but previously described phenomenon. Patients usually undergo parathyroidectomy or remain under close clinical and biochemical surveillance. We report two cases of parathyroid auto-infarction diagnosed in the same tertiary centre; one managed surgically and the other conservatively up to the present time. Case #1 was a 51-year old man with PHPT (adjusted (adj.) calcium: 3.11 mmol/L (reference range (RR): 2.20–2.60 mmol/L), parathyroid hormone (PTH) 26.9 pmol/L (RR: 1.6–6.9 pmol/L) and urine calcium excretion consistent with PHPT) referred for parathyroidectomy. Repeat biochemistry 4 weeks later at the surgical clinic showed normal adj. calcium (2.43 mmol/L) and reduced PTH. Serial ultrasound imaging demonstrated reduction in size of the parathyroid lesion from 33 to 17 mm. Twenty months later, following recurrence of hypercalcaemia, he underwent neck exploration and resection of an enlarged right inferior parathyroid gland. Histology revealed increased fibrosis and haemosiderin deposits in the parathyroid lesion in keeping with auto-infarction. Case #2 was a 54-year-old lady admitted with severe hypercalcaemia (adj. calcium: 4.58 mmol/L, PTH 51.6 pmol/L (RR: 1.6–6.9 pmol/L)) and severe vitamin D deficiency. She was treated with intravenous fluids and pamidronate and 8 days later developed symptomatic hypocalcaemia (1.88 mmol/L) with dramatic decrease of PTH (17.6 pmol/L). MRI of the neck showed a 44 mm large cystic parathyroid lesion. To date, (18 months later), she has remained normocalcaemic.

Learning points:

  • Primary hyperparathyroidism (PHPT) is characterised by excess parathyroid hormone (PTH) secretion arising mostly from one or more autonomously functioning parathyroid adenomas (up to 85%), diffuse parathyroid hyperplasia (<15%) and in 1–2% of cases from parathyroid carcinoma.

  • PHPT and hypercalcaemia of malignancy, account for the majority of clinical presentations of hypercalcaemia.

  • Spontaneous remission of PHPT due to necrosis, haemorrhage and infarction of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’, ‘auto-parathyroidectomy’ or ‘parathyroid apoplexy’ is a very rare in clinical practice but has been previously reported in the literature.

  • In most cases, patients with parathyroid auto-infarction undergo parathyroidectomy. Those who are managed conservatively need to remain under close clinical and biochemical surveillance long-term as in most cases PHPT recurs, sometimes several years after auto-infarction.

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Maria P Yavropoulou 1st Propaedeutic Department of Internal Medicine, LAIKO General Hospital of Athens

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Efstathios Chronopoulos 2nd Orthopaedic Department, Konstantopouleio General Hospital

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George Trovas Laboratory for Research of the Musculoskeletal System, Th Garofalidis, National and Kapodistrian University of Athens, Athens, Greece

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Emmanouil Avramidis 2nd Orthopaedic Department, Konstantopouleio General Hospital

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Francesca Marta Elli Endocrinology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

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Giovanna Mantovani Endocrinology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

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Pantelis Zebekakis 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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John G Yovos 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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Summary

Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the parathyroid hormone. Type 1A (PHP1A), which is the most common variant, also include developmental and skeletal defects named as Albright hereditary osteodystrophy (AHO). We present two cases, a 54- and a 33-year-old male diagnosed with PHP who were referred to us for persistently high levels of serum calcitonin. AHO and multinodular goitre were present in the 54-year-old male, while the second patient was free of skeletal deformities and his thyroid gland was of normal size and without nodular appearance. We performed GNAS molecular analysis (methylation status and copy number analysis by MS-MLPA) in genomic DNA samples for both patients. The analysis revealed a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1, in the patient with the clinical diagnosis of PHP1A. This amino acid change appears to be in accordance with the clinical diagnosis of the patient. The genomic DNA analysis of the second patient revealed the presence of the recurrent 3-kb deletion affecting the imprinting control region localised in the STX16 region associated with the loss of methylation (LOM) at the GNAS A/B differentially methylated region and consistent with the diagnosis of an autosomal dominant form of PHP type 1B (PHP1B). In conclusion, hypercalcitoninaemia may be encountered in PHP1A and PHP1B even in the absence of thyroid pathology.

Learning points:

  • We describe a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1 as the cause of PHP1A.

  • Hypercalcitoninaemia in PHP1A is considered an associated resistance to calcitonin, as suggested by the generalised impairment of Gsα-mediated hormone signalling.

  • GNAS methylation defects, as in type PHP1B, without thyroid pathology can also present with hypercalcitoninaemia.

Open access
Alejandro García-Castaño Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Barakaldo, Spain

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Leire Madariaga Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Barakaldo, Spain
Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain

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Sharona Azriel Hospital Infanta Sofia, Madrid, Spain

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Gustavo Pérez de Nanclares Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Barakaldo, Spain
Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain

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Idoia Martínez de LaPiscina Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Barakaldo, Spain

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Rosa Martínez Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Barakaldo, Spain

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Inés Urrutia Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Barakaldo, Spain

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Aníbal Aguayo Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Barakaldo, Spain
Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain

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Sonia Gaztambide Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Barakaldo, Spain
Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain

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Luis Castaño Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Barakaldo, Spain
Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain

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Summary

Familial hypocalciuric hypercalcemia type I is an autosomal dominant disorder caused by heterozygous loss-of-function mutations in the CASR gene and is characterized by moderately elevated serum calcium concentrations, low urinary calcium excretion and inappropriately normal or mildly elevated parathyroid hormone (PTH) concentrations. We performed a clinical and genetic characterization of one patient suspected of familial hypocalciuric hypercalcemia type I. Patient presented persistent hypercalcemia with normal PTH and 25-hydroxyvitamin D levels. The CASR was screened for mutations by PCR followed by direct Sanger sequencing and, in order to detect large deletions or duplications, multiplex ligation-dependent probe amplification (MLPA) was used. One large deletion of 973 nucleotides in heterozygous state (c.1733-255_2450del) was detected. This is the first large deletion detected by the MLPA technique in the CASR gene.

Learning points:

  • Molecular studies are important to confirm the differential diagnosis of FHH from primary hyperparathyroidism.

  • Large deletions or duplications in the CASR gene can be detected by the MLPA technique.

  • Understanding the functional impact of the mutations is critical for leading pharmacological research and could facilitate the therapy of patients.

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