Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder

Impact on cardiovascular risk follow-up from a shift to the CKD-EPI formula for eGFR reporting: a cross-sectional population-based primary care study

OBJECTIVE: To assess the impact on cardiovascular risk factor management in primary care by the introduction of chronic kidney disease epidemiological collaboration (CKD-EPI) for estimated-glomerular filtration rate (eGFR) reporting. DESIGN AND SETTING: Cross-sectional study of routine healthcare provision in 47 primary care practices in The Netherlands with Modification of Diet and Renal Disease Study eGFR reporting. METHODS: eGFR values were recalculated using CKD-EPI in patients with available creatine tests. Patients reclassified from CKD stage 3a to CKD stage 2 eGFR range were compared to those who remained in stage 3a for differences in demographic variables, blood pressure, comorbidity, medication usage and laboratory results. RESULTS: Among the 60 673 adult patients (37% of adult population) with creatine values, applying the CKD-EPI equation resulted in a 16% net reduction in patients with CKD stage 3 or worse. Patients reclassified from stage 3a to 2 had lower systolic blood pressure (139.7 vs 143.3 mm Hg p<0.0001), higher diastolic blood pressure (81.5 vs 78.4 mm Hg p<0.0001) and higher cholesterol (5.4 vs 5.1 mmol/L p<0.0001) compared to those who remained in stage 3a. Of those reclassified out of a CKD diagnosis 463 (32%) had no comorbidities that would qualify for annual CVD risk factor assessment and 20 (12% of those with sufficient data) had a EuroSCORE CVD risk >20% within 10 years. CONCLUSIONS: Use of the CKD-EPI equation will result in many patients being removed from CKD registers and the associated follow-up. Current risk factor assessment in this group may be lacking from routine data and some patients within this group are at an increased risk for cardiovascular events

Insulin therapy in poorly controlled type 2 diabetic patients: does it affect quality of life?

BACKGROUND: Strict glycaemic control in type 2 diabetic patients is recommended in a number of treatment protocols. However, although better glycaemic control prevents or postpones chronic diabetic complications, it remains uncertain how this affects quality of life in the short and long term. AIM: To study the impact of insulin therapy on glycaemic control and quality of life in type 2 diabetic patients, with secondary failure on maximal oral medication. DESIGN OF STUDY: Two separate sets of analyses were performed: a longitudinal analysis of those patients converted to insulin therapy and a comparison of 12-week outcomes between the two randomisation groups. SETTING: Ten general practices, participating in the Nijmegen Monitoring Project. METHOD: Patients, poorly controlled on maximal oral therapy, were stratified with respect to age and sex, and randomly allocated to insulin therapy in two different schedules: (a) after a 12-week period with enhanced compliance to diet and oral therapy: or (b) as soon as secondary failure was established. Patients were referred to a diabetologist to start insulin therapy and were referred back to their general practitioner (GP) as soon as glycaemic control was stable. We assessed fasting blood glucose, HbA1c functional health, and quality of life (Sickness Impact Profile, COOP/WONCA charts, Diabetes Symptom Checklist) at baseline, after the patient was referred back to the GP, and nine months later. RESULTS: Of the 38 included patients, three patients dropped out and seven patients were not switched over to insulin therapy. In patients starting insulin therapy, mean HbA1c and fasting blood glucose level decreased from 9.5% to 7.6%, and from 12.0 mmol to 8.4 mmol, respectively (P < 0.001). The better control was accompanied by a decrease in hyperglycaemic complaints (P = 0.01). No increase in hypoglycaemic complaints was found. There were no statistically significant changes in quality-of-life parameters. After 12 weeks, patients directly referred to insulin therapy showed a statistically significant improvement in HbA1c and fasting glucose level, in contrast to patients with enhanced compliance. Quality-of-life scores did not significantly differ statistically. CONCLUSION: Insulin therapy in poorly controlled type 2 diabetic patients from general practice resulted in a significant clinical improvement of glycaemic control, accompanied by a reduction of hyperglycaemic complaints, without an increase in hypoglycaemic complaints or an adverse influence on quality of life