Evaluation of genotype-phenotype relationships in patients referred for endocrine assessment in suspected Pendred syndrome.

DESIGN: Patients with Pendred syndrome have genotypic and phenotypic variability, leading to challenges in definitive diagnosis. Deaf children with enlarged vestibular aqueducts are often subjected to repeated investigations when tests for mutations in SLC26A4 are abnormal. This study provides genotype and phenotype information from patients with suspected Pendred syndrome referred to a single clinical endocrinology unit. METHODS: A retrospective analysis of 50 patients with suspected Pendred syndrome to investigate the correlation between genetic, perchlorate discharge test (PDT) and endocrine status. RESULTS: Eight patients with monoallelic SLC26A4 mutations had normal PDT. Of the 33 patients with biallelic mutations, ten of 12 patients with >30% discharge developed hypothyroidism. In our cohort, c.626G>T and c.3-2A>G result in milder clinical presentations with lower median perchlorate discharge of 9.3% (interquartile range 4-15%) compared with 40% (interquartile range 21-60%) for the remaining mutations. Eight novel mutations were detected. All patients with PDT <30% remained euthyroid to date, although the majority are still under the age of 30. There was a significant correlation between PDT and goitre size (R=0.61, P=0.0009) and the age of onset of hypothyroidism (R=-0.62, P=0.0297). In our population, the hazard of becoming hypothyroid increased by 7% per percentage point increase in PDT (P<0.001). CONCLUSION: There is a correlation between SLC26A4 genotype and thyroid phenotype. If results hold true for larger patient numbers and longer follow-up, then for patients with monoallelic mutations, PDT could be unnecessary. Patients with biallelic mutations and PDT discharge >30% have a high risk of developing goitre and hypothyroidism, and should have lifelong monitoring.

Diagnosing unilateral primary aldosteronism - comparison of a clinical prediction score, computed tomography and adrenal venous sampling.

CONTEXT: In patients with primary aldosteronism (PA), adrenalectomy is potentially curative for those correctly identified as having unilateral excessive aldosterone production. It has been suggested that a recently developed and published clinical prediction score (CPS) may correctly identify some patients as having unilateral disease, without recourse to adrenal venous sampling. OBJECTIVE: We have applied the CPS to a large cohort of PA patients with defined and documented outcomes. We also incorporated a minor modification to the CPS and a radiological grading score (RGS) into our analysis to assess whether its performance could be augmented. RESULTS: A total of 75 patients with a robust diagnosis following bilateral adrenal venous cannulation and/or strictly defined surgical outcome were analysed. Applying the CPS to this group of patients produced a sensitivity of 38·8% and a specificity of 88·5% of correctly identifying unilateral aldosterone production. Using a suggested modification to the CPS, in which different levels of hypokalaemia were given different weightings, the sensitivity rose to 40·8%, with an identical specificity. Using the RGS alone improved sensitivity to 91·7%, but specificity was reduced to 62·5%. CONCLUSION: Applying the recently developed CPS to this cohort of patients, it was not possible to reproduce the 100% specificity reported in the original publication. Using the modified score or incorporating the RGS did not improve its performance. In this cohort, we were unable to show superiority of the CPS over an imaging-based strategy. CPS may have a role in guiding clinical decision-making, especially in those whose adrenal venous sampling (AVS) has been unsuccessful.

Etomidate in the emergency management of hypercortisolemia.

We describe a protocol for etomidate infusion for the emergency management of hypercortisolemia. Etomidate is commenced at 2.5 mg/h and titrated subsequently according to cortisol levels. It is well tolerated without any sedative effects and can be administered safely via peripheral access for use in the general ward setting.