A single-centre retrospective analysis of cinacalcet therapy in primary hyperparathyroidism.

Primary hyperparathyroidism (pHPT) is a common endocrine disorder that can be cured by parathyroidectomy; patients unsuitable for surgery can be treated with cinacalcet. Availability of surgery may be reduced during COVID-19, and cinacalcet can be used as bridging therapy. In this single-centre retrospective analysis, we investigated the utility and safety of cinacalcet in patients with pHPT receiving cinacalcet between March 2019 and July 2020, including pre-parathyroidectomy bridging. We reviewed and summarised the published literature. Cinacalcet dosages were adjusted by endocrinologists to achieve target calcium < 2.70 mmol/L. Eighty-six patients were identified, with the most achieving target calcium (79.1%) with a mean dose of 39.4 mg/day (±17.1 mg/day) for a median duration of 35 weeks (1-178 weeks). Calcium was normalised in a median time of 5 weeks. The majority of patients commenced cinacalcet of 30 mg/day (78 patients) with the remainder at 60 mg/day (8 patients). Forty-seven patients commencing lower dose cinacalcet (30 mg/day) achieved target calcium without requiring 60 mg/day. Baseline PTH was significantly higher in patients requiring higher doses of cinacalcet. 18.6% of patients reported adverse reactions and 4.7% discontinued cinacalcet. Patients treated with cinacalcet pre-parathyroidectomy required a higher dose and fewer achieved target calcium compared to medical treatment with cinacalcet alone. Post-operative calcium was similar to patients who were not given pre-parathyroidectomy cinacalcet. In summary, cinacalcet at an initial dose of 30 mg/day is safe and useful for achieving target calcium in patients with symptomatic or severe hypercalcaemia in pHPT, including those treated for pre-parathyroidectomy. We propose a PTH threshold of >30 pmol/L to initiate at a higher dose of 60 mg/day.

Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort.

BACKGROUND: Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism-jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost-effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR > 0.02 presenting (i) <35 years of age, or (ii) <45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR < 0.02. AIMS AND METHODS: A retrospective review of patients referred for genetic testing over a 4 year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next-generation sequencing of the following genes; MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1 in NHS-accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort. RESULTS: A total of 121 patients were included in this study (92 female) with a mean age of 41 years (SD 17). A pathogenic germline variant was identified in 16% (n = 19). A pathogenic variant was identified in the PHPTH genes CDC73 in a single patient and MEN1 in six patients (6% of total), in the FHH genes, CASR in 11 patients and AP2S1 in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re-classification of four of the variants, with two VUS's in the CASR gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (P = .0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified CASR pathogenic variant versus those without (P = .0001) was demonstrated in this study. Thirty-three patients were aged over 50 years and the diagnostic rate of a pathogenic variant was 15.1% in those patients >50 years of age compared to 15.9% in those <50 years. Five patients >50 years and with a CCCR of <0.01, were diagnosed with a pathogenic variant in CASR. CONCLUSION: Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re-evaluating VUS's in order to inform patient management and enable appropriate genetic counselling. Finally, this study has demonstrated the need to consider genetic testing for PHPTH in patients of any age, particularly those with additional risk factors.

Management of primary hyperparathyroidism in pregnancy: a case series.

Primary hyperparathyroidism (PHPT) is characterised by the overproduction of parathyroid hormone (PTH) due to parathyroid hyperplasia, adenoma or carcinoma and results in hypercalcaemia and a raised or inappropriately normal PTH. Symptoms of hypercalcaemia occur in 20% of patients and include fatigue, nausea, constipation, depression, renal impairment and cardiac arrythmias. In the most severe cases, uraemia, coma or cardiac arrest can result. Primary hyperparathyroidism in pregnancy is rare, with a reported incidence of 1%. Maternal and fetal/neonatal complications are estimated to occur in 67 and 80% of untreated cases respectively. Maternal complications include nephrolithiasis, pancreatitis, hyperemesis gravidarum, pre-eclampsia and hypercalcemic crises. Fetal complications include intrauterine growth restriction; preterm delivery and a three to five-fold increased risk of miscarriage. There is a direct relationship between the degree of severity of hypercalcaemia and miscarriage risk, with miscarriage being more common in those patients with a serum calcium greater than 2.85 mmol/L. Neonatal complications include hypocalcemia. Herein, we present a case series of three women who were diagnosed with primary hyperparathyroidism in pregnancy. Case 1 was diagnosed with multiple endocrine neoplasia type 1 (MEN1) in pregnancy and required a bilateral neck exploration and subtotal parathyroidectomy in the second trimester of her pregnancy due to symptomatic severe hypercalcaemia. Both case 2 and case 3 were diagnosed with primary hyperparathyroidism due to a parathyroid adenoma and required a unilateral parathyroidectomy in the second trimester. This case series highlights the work-up and the tailored management approach to patients with primary hyperparathyroidism in pregnancy. Learning points: Primary hyperparathyroidism in pregnancy is associated with a high incidence of associated maternal fetal and neonatal complications directly proportionate to degree of maternal serum calcium levels. Parathyroidectomy is the definitive treatment for primary hyperparathyroidism in pregnancy and was used in the management of all three cases in this series. It is recommended when serum calcium is persistently greater than 2.75 mmol/L and or for the management of maternal or fetal complications of hypercalcaemia. Surgical management, when necessary is ideally performed in the second trimester. Primary hyperparathyroidism is genetically determined in ~10% of cases, where the likelihood is increased in those under 40 years, where there is relevant family history and those with other related endocrinopathies. Genetic testing is a useful diagnostic adjunct and can guide treatment and management options for patients diagnosed with primary hyperparathyroidism in pregnancy, as described in case 1 in this series, who was diagnosed with MEN1 syndrome. Women of reproductive age with primary hyperparathyroidism need to be informed of the risks and complications associated with primary hyperparathyroidism in pregnancy and pregnancy should be deferred and or avoided until curative surgery has been performed and calcium levels have normalised.

Disparity tuning of binocular facilitation and suppression after normal versus abnormal visual development.

PURPOSE: To study the pattern of facilitatory and suppressive binocular interactions in stereodeficient patients with strabismus and in healthy controls. METHODS: Visual evoked potentials were recorded in response to a Vernier onset/offset pattern presented to one eye, either monocularly or paired dichoptically with a straight vertical square-wave grating, which, when fused with the target in the other eye, gave rise to a percept of a series of bands appearing in depth from an otherwise uniform plane or with a grating that contained offsets that produced a standing disparity and the appearance of a constantly segmented image, portions of which moved in depth. RESULTS: Participants with normal stereopsis showed facilitative and suppressive binocular interactions that depended on which dichoptic target was presented. Patients with longstanding, constant strabismus lacked normal facilitative binocular interactions. The response to a normally facilitative stimulus was reduced below the monocular level when it was presented to the dominant eye of patients without anisometropia, consistent with classical strabismic suppression of the nondominant eye. The dominant eye of strabismic patients without anisometropia retained suppressive input from crossed but not uncrossed disparity stimuli presented to the nondominant eye. CONCLUSIONS: Abnormal disparity processing can be detected with the dichoptic VEP method we describe. Our results suggest that suppression in stereoblind, nonamblyopic observers is determined by a binocular mechanism responsive to disparity. In some cases, the sign of the disparity is important, and this suggests a mechanism that can explain diplopia in patients made exotropic after surgery for esotropia.

Releasable conjunctival suture for adjustable suture surgery.

BACKGROUND: Adjustable sutures are widely used in adult strabismus surgery, with a second procedure performed to close the conjunctiva irrespective of whether adjustment is required. We describe a technique where the conjunctiva is closed using a buried releasable suture, eliminating the second procedure if adjustment is deemed unnecessary. METHOD: The conjunctiva is closed using a 6/0 absorbable polyglactin 910 releasable suture. It is tied in a bow, like the muscle sutures, and tucked under the conjunctiva. If adjustment is not required, the eye does not need to be touched because the conjunctiva is secured by the suture. If adjustment is required, it is easy to untie the conjunctival suture, allowing good exposure to the underlying muscle sutures. RESULTS: In our prospective series of 30 patients, we found our technique effective and patient friendly. Patients had at least 3 months of follow-up with no significant complications. CONCLUSIONS: This technique is acceptable, accessible, and time saving for both surgeons and patients. It is especially useful for anxious patients and adolescents, for whom postoperative manipulation can be difficult, and for cases where the probability of adjustment is low.

A VEP measure of the binocular fusion of horizontal and vertical disparities.

PURPOSE: Because of the lateral separation of the orbits, the retinal images differ in the two eyes. These differences are reconciled into a single image through sensory and motor fusional mechanisms. This study demonstrates electrophysiologically the effects that normal horizontal and vertical fusional processes have on the processing of monocular position signals. METHODS: VEPs were recorded in 16 healthy adults in response to a vernier onset-offset target presented to one eye. The vernier offsets appeared and disappeared at 2 Hz and were introduced into bar targets that were oriented either vertically (horizontal offsets) or horizontally (vertical offsets). The magnitude of the offsets was varied over the range of 0.5 to 10 arc min. VEP amplitude was measured as a function of the size of the dynamic offset under monocular viewing conditions and in the presence of two different static targets presented to the other eye. One of the static targets matched the dynamic test, except that it had no vernier offsets. The other static target, the static pedestal, matched the dynamic test, but contained a set of static vernier offsets in locations corresponding to the locations of the dynamic offsets presented to the other eye. RESULTS: VEP amplitude was a monotonically increasing function of vernier offset size under monocular viewing conditions. The addition of the static target without offsets in the other eye resulted in an increased amplitude VEP response. The addition of the static target with vernier offsets resulted in a decrease in VEP amplitude for both horizontal and vertical disparities. CONCLUSIONS: The normal process of fusion results in a single visual direction. To obtain a single visual direction, the visual system must synthesize a binocular visual direction that differs from the monocular components. One of the conditions (the static pedestal with offsets) produces binocular visual direction shifts that degrade the appearance of vernier onset-offset, and reduce VEP amplitude for both horizontal and vertical disparities. This characteristic evoked response marker is a promising tool for measuring binocular fusion objectively in patients with strabismus.

Comparison of proximal and distal rotational femoral osteotomy in children with cerebral palsy.

This study compares the complication rates and results of 27 proximal (intertrochanteric) and 51 distal femoral rotational osteotomies in 48 patients with static encephalopathy. There was no significant difference between the 14% rate of orthopaedic complications in the intertrochanteric osteotomy (ITO) group and the 10% rate in the distal osteotomy (DO) group. Loss of fixation occurred in three of 51 limbs (6%) in the DO group and in none of 27 limbs in the ITO group. If the results of one surgeon are excluded, fixation loss occurred in one of the 49 remaining DO cases (2%). There was one delayed union in the study population (1/27 limbs [4%] in the ITO group). Of the 33 limbs studied with postoperative gait analysis, overcorrection was present in two limbs (6%): one of 10 limbs (10%) in the ITO group and one of 23 (4%) in the DO group. Static and dynamic measures of femoral rotation improved in both groups, and no statistically significant differences were present between the two groups. Though variable, the mean change in dynamic and static measurements postoperatively was approximately 40% less than the amount of derotation reported at surgery.