Purpose To evaluate genotype-phenotype associations in individuals carrying germline variants of TMEM127, a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL) Design Data collected from a registry of probands with TMEM127 variants, published reports and public databases Main outcome analysis clinical, genetic and functional associations Results The cohort comprised 110 index patients (111 variants) with a mean age of 45 (range, 21-84 years). Females were predominant (76 vs. 34, P<0.001). Most patients had PHEO (n=94; 85.5%), although PGL (n=10; 9%) and renal cell carcinoma (RCC, n=6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n=63) occurred only once and 13 were recurrent (2-12 times). Although non-truncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEOs vs. 69% other, P<0.0001) and clustered disproportionately within transmembrane regions (P<0.01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into four groups based on mutation type, localization and predicted disruption. Conclusions Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.

Many patients with type 2 diabetes will ultimately require the inclusion of basal insulin in their treatment regimen. Since most people with type 2 diabetes are managed in the community, it is important that primary care providers understand and correctly manage the initiation and titration of basal insulins, and help patients to self-manage insulin injections. Newer, long-acting basal insulins provide greater stability and flexibility than older preparations and improved delivery systems. Basal insulin is usually initiated at a conservative dose of 10 units/day or 0.1–0.2 units/kg/day, then titrated thereafter over several weeks or months, based on patients’ self-measured fasting plasma glucose, to achieve an individualized target (usually 80–130 mg/dL). Through a shared decision-making process, confirmation of appropriate goals and titration methods should be established, including provisions for events that might alter scheduled titration (e.g. travel, dietary change, illness, hospitalization, etc.). Although switching between basal insulins is usually easily accomplished, pharmacokinetic and pharmacodynamic differences between formulations require clinicians to provide explicit guidance to patients. Basal insulin is effective long-term, but overbasalization (continuing to escalate dose without a meaningful reduction in fasting plasma glucose) should be avoided. Key messages Primary care providers often initiate basal insulin for people with type 2 diabetes. Basal insulin is recommended to be initiated at 10 units/day or 0.1–0.2 units/kg/day, and doses must be titrated to agreed fasting plasma glucose goals, usually 80–130 mg/dL. A simple rule is to gradually increase the initial dose by 1 unit per day (NPH, insulin detemir, and glargine 100 units/mL) or 2–4 units once or twice per week (NPH, insulin detemir, glargine 100 and 300 units/mL, and degludec) until FPG levels remain consistently within the target range. If warranted, switching between basal insulins can be done using simple regimens. The dose of basal insulin should be increased as required up to approximately 0.5–1.0 units/kg/day in some cases. Overbasalization (continuing to escalate dose without a meaningful reduction in fasting plasma glucose) is not recommended; rather re-evaluation of individual therapy, including consideration of more concentrated basal insulin preparations and/or short-acting prandial insulin as well as other glucose-lowering therapies, is suggested.

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