Case Presentation: Functional Assessment of a CASR Variant Identified in a Patient with Hypercalcaemia Confirms Familial Hypocalciuric Hypercalcaemia in the Patient and a Sister Previously Misdiagnosed with Primary Hyperparathyroidism.

Background: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH) are common causes of hypercalcaemia. Patients are mostly asymptomatic in the case of FHH and often so in the case of PHPT. In addition, biochemical parameters show considerable overlap, making differential diagnosis difficult. Genetic screening for inactivating variants in the calcium-sensing receptor (CASR) gene that are causative of FHH assists with the diagnosis since such variants are not generally associated with PHPT. However, novel CASR variants must undergo functional assessment before they can be definitively assigned a causative role in FHH. Case Presentations. We describe a 73-year-old female (patient A) who presented with mild parathyroid hormone (PTH)-dependent hypercalcaemia and a history of osteoporosis. Family history revealed that her sister (patient B) had presented a decade earlier with symptoms of PHPT including a history of mild hypercalcaemia and multiple renal calculi, prompting parathyroid surgery. However, a subtotal parathyroidectomy did not resolve her hypercalcaemia long term. On this basis, genetic screening was performed on patient A. This identified a heterozygous variant in the CASR, NM_000388.4:c.T101C: p.Leu34Pro (L34P). Functional analysis showed that the L34P variant was unable to produce mature, dimerized receptor and did not respond to Ca++ ions. Adopting American College of Medical Genetics-based guidelines, the variant was classified as 'Pathogenic (II)'. Patient B was subsequently found to carry the L34P variant heterozygously, confirming a diagnosis of FHH, not PHPT. Conclusion: This study shows the importance of examining patient's family history in providing clues to the diagnosis in isolated cases of hypercalcaemia. In this case, history of a sister's unsuccessful parathyroidectomy prompted genetic screening in a patient who might otherwise have undergone inappropriate parathyroid surgery. Screening detected an inactivating CASR variant, firming up a diagnosis of FHH. These studies reaffirm the requirement for functionally assessing novel CASR variants prior to assigning causality to FHH.

Osteolytic lesions: osteitis fibrosa cystica in the setting of severe primary hyperparathyroidism.

A 58-year-old female patient presented with several weeks history of significant bilateral knee pain. Initial knee radiographs demonstrated lucencies of the bony cortex while extensive osteolytic lesions on a routine chest radiograph were suggestive of multiple myeloma or bony metastases. Biochemical investigation revealed primary hyperparathyroidism with renal insufficiency. A parathyroid adenoma was demonstrated on a neck ultrasound and sestamibi scan and subsequently confirmed by histology. We illustrate a case of primary hyperparathyroidism with osteitis fibrosa cystica and brown tumours which were initially mistaken for malignant disease.

How good is a morning cortisol in predicting an adequate response to intramuscular synacthen stimulation?

CONTEXT: Previous studies have demonstrated that a morning serum cortisol of <100 nmol/l makes further dynamic testing such as the Synacthen stimulation test (SST) unnecessary to confirm adrenal insufficiency. The morning cortisol level that reliably predicts adrenal sufficiency (AS) is less well established, and values ranging from 300 to 500 nmol/l have been proposed. OBJECTIVE: The aim of this study was to determine the ambulatory morning cortisol level that predicts adrenal sufficiency, as defined by an adequate response to SST, using a receiver operating characteristics (ROC) curve. DESIGN: Observational retrospective cross-sectional study. METHOD & SUBJECTS: We conducted a retrospective audit of SST performed at PathWest Laboratory QEII from January 2006 to August 2008. A total of 761 results were obtained. Patients who were acutely ill or in intensive care, on glucocorticoid therapy, and those with inadequate data or multiple records were excluded from the analysis leaving 505 available for analysis. Baseline serum was obtained prior to intramuscular injection of 250 mcg Synacthen, and a second sample was obtained 30 min post-Synacthen. AS was defined as a 30-min post-Synacthen cortisol of >550 nmol/l; values ≤550 nmol/l were considered inadequate. RESULTS: Based on SST criteria, of the 505 patients included in the study, 350 patients (69%) were adrenal sufficient and 155 (31%) had adrenal insufficiency. Using the minimum ROC distance criterion, a basal cortisol value of >236 nmol/l was identified to predict AS with sensitivity 84% and specificity 71%. However, to increase the specificity to 95%, we recommend a basal cortisol cut-off of >375 nmol/l. For patients with known pituitary disease (n = 152), basal cortisol of >214 nmol/l (sensitivity 85% and specificity 71%) may obviate the need for SST in the appropriate clinical context, although 330 nmol/l gives a specificity of 95%. CONCLUSION: Basal morning cortisol is a viable first step in the evaluation of patients with suspected adrenal insufficiency.

The effect of midday moderate-intensity exercise on postexercise hypoglycemia risk in individuals with type 1 diabetes.

CONTEXT: Exercise increases the risk of hypoglycemia in type 1 diabetes. OBJECTIVE: Recently we reported a biphasic increase in glucose requirements to maintain euglycemia after late-afternoon exercise, suggesting a unique pattern of delayed risk for nocturnal hypoglycemia. This study examined whether this pattern of glucose requirements occurs if exercise is performed earlier in the day. DESIGN, PARTICIPANTS, AND INTERVENTION: Ten adolescents with type 1 diabetes underwent a hyperinsulinemic euglycemic glucose clamp on 2 different occasions during which they either rested or performed 45 minutes of moderate-intensity exercise at midday. Glucose was infused to maintain euglycemia for 17 hours after exercise. MAIN OUTCOME MEASURES: The glucose infusion rate (GIR) to maintain euglycemia, glucose rates of appearance and disappearance, and levels of counterregulatory hormones were compared between conditions. RESULTS: GIRs to maintain euglycemia were not significantly different between groups at baseline (9.8 ± 1.4 and 9.5 ± 1.6 g/h before the exercise and rest conditions, respectively) and did not change in the rest condition throughout the study. In contrast, GIR increased more than 3-fold during exercise (from 9.8 ± 1.4 to 30.6 ± 4.7 g/h), fell within the first hour of recovery, but remained elevated until 11 hours after exercise before returning to baseline levels. CONCLUSIONS: The pattern of glucose requirements to maintain euglycemia in response to moderate-intensity exercise performed at midday suggests that the risk of exercise-mediated hypoglycemia increases during and for several hours after moderate-intensity exercise, with no evidence of a biphasic pattern of postexercise risk of hypoglycemia.

Pamidronate improves pain, wellbeing, fracture rate and bone density in 14 children and adolescents with chronic neurological conditions.

OBJECTIVE: To investigate if intravenous pamidronate improves bone density in a cohort of patients with chronic neurological conditions and low bone density, in whom fractures and bone pain are impacting on care. METHODS: Fourteen participants (M:F = 7:7, average age 12.4 years) were enrolled in a prospective uncontrolled study in which pamidronate was infused every 6-8 weeks over a 2 year period, the average dose received was 12.5 mg kg(-1). RESULTS: Bone mineral density z-score improved at all sites measured over the 2 years; whole body -4.84 to -3.14 (p = 0.01), lumbar spine -2.92 to -1.1 (p = 0.02) and femoral neck -4.6 to -3.58 (p = 0.04). Of the eight patients with pain at baseline, seven reported decreased pain after 12 months of pamidronate. Of the 11 patients who answered the general wellbeing part of the questionnaire, eight patients reported an improvement in general wellbeing and three reported no change. There was a downward trend in the average annualized fracture rate from 0.42 to 0.14 fractures per year (p = 0.09). CONCLUSION: Pamidronate improves bone density and reduces pain in children and adolescents with chronic neurological conditions.