IRIDA Phenotype in TMPRSS6 Monoallelic-Affected Patients: Toward a Better Understanding of the Pathophysiology.

Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive inherited form of iron deficiency anemia characterized by discrepantly high hepcidin levels relative to body iron status. However, patients with monoallelic exonic TMPRSS6 variants have also been reported to express the IRIDA phenotype. The pathogenesis of an IRIDA phenotype in these patients is unknown and causes diagnostic uncertainty. Therefore, we retrospectively summarized the data of 16 patients (4 men, 12 women) who expressed the IRIDA phenotype in the presence of only a monoallelic TMPRSS6 variant. Eight unaffected relatives with identical exonic TMPRSS6 variants were used as controls. Haplotype analysis was performed to assess the (intra)genetic differences between patients and relatives. The expression and severity of the IRIDA phenotype were highly variable. Compared with their relatives, patients showed lower Hb, MCV, and TSAT/hepcidin ratios and inherited a different wild-type allele. We conclude that IRIDA in monoallelic TMPRSS6-affected patients is a phenotypically and genotypically heterogeneous disease that is more common in female patients. We hypothesize that allelic imbalance, polygenetic inheritance, or modulating environmental factors and their complex interplay are possible causes. This explorative study is the first step toward improved insights into the pathophysiology and improved diagnostic accuracy for patients presenting with IRIDA and a monoallelic exonic TMPRSS6 variant.

The Effect of Eighteen-Month Metformin Treatment in Obese Adolescents: Comparison of Results Obtained in Daily Practice with Results from a Clinical Trial.

Background. In a recent randomized controlled trial (RCT) in obese adolescents, 18 month-treatment with metformin versus placebo was reported to lead to stabilisation of the BMI. This study aimed to compare the effect of metformin on BMI in obese adolescents in daily practice versus results obtained in an RCT. Methods. Obese adolescents treated off label with metformin in daily practice in an outpatient clinic with a follow-up of ≥18 months were identified. Anthropometric and biochemical data were collected at baseline and at 18 months. Patients treated with metformin for 18 months in an RCT were used for comparison. BMI was compared between the two groups. Results. Nineteen patients (median age 14.3 (interquartile range 11.7-15.7) years, BMI 31.3 (28.8-33.8) kg/m2) treated in daily practice were compared to 23 patients receiving metformin in the RCT (age 13.6 (12.6-15.3) years, BMI 29.8 (28.1-34.5) kg/m2). BMI change after 18 months was -0.36 (-2.10-1.58) versus +0.22 (-2.87-1.27) kg/m2 for the two groups, respectively. In the multivariable model, BMI change was not statistically significantly different between the two groups (p = 0.61). Conclusion. Treatment with metformin in obese adolescents in daily practice resulted in a comparable change in BMI as observed in an RCT. This trial is registered with ClinicalTrials.gov number: NCT01487993.