The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca2+o) homeostasis. To elucidate the role of AP2σ2 in Ca2+o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype–phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype–phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

These are the first UK case reports of Type 2 diabetes in children. Paediatricians need to be aware of the risk of Type 2 diabetes developing in childhood in high-risk ethnic groups, particularly in association with obesity and a positive family history.

Ethnic differences in insulin sensitivity are associated with ethnic differences in body fat. South Asian adolescents are more insulin resistant, with more body fat than white European adolescents, which may contribute to their increased risk of developing type 2 diabetes.

Study Type – Therapy (case series)Level of Evidence 4What's known on the subject? and What does the study add?Approximately 200 cases of persistent Müllerian duct syndrome have been reported over the last 50 years and most authors suggest leaving the Müllerian remnant in situ because of the difficulty in dissection and the presumed absence of risk of malignancy. However, with increasing reports of Müllerian malignancies emerging, we report our 10‐year experience of managing patients with persistent Müllerian duct syndrome, with removal of müllerian remnants.This case series shows that there is an increased risk of Müllerian malignancy that was previously unknown. With the laparoscopic approach, orchidopexy with simultaneous removal of Müllerian remnants could be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future. This is a new technique that has not been previously performed. Considering the current evidence of malignancy in the Müllerian remnant, surgeons would need to discuss with families about removal of remnants or long‐term monitoring.OBJECTIVES To describe the presentation and management of eight patients with persistent Müllerian duct syndrome (PMDS) seen over a 10‐year period at our tertiary centre. To review the literature of Müllerian malignancies reported in PMDS. PATIENTS AND METHODS The hospital records of eight patients with PMDS were retrospectively reviewed between 2001 and 2011. Extensive PubMed searches for PMDS and Müllerian malignancy were performed. RESULTS Eleven cases with PMDS and malignancy of the Müllerian remnants were identified. From our own PMDS series: five males presented with bilateral undescended testes and three had unilateral undescended testis. We found that the Müllerian remnants could be removed by laparoscopy and three patients had simultaneous laparoscopic removal of the Müllerian structures and laparoscopic orchidopexy. CONCLUSIONS The principle aim of orchidopexy with simultaneous laparoscopic removal of the Müllerian structures can be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future. Surgeons should consider excision of the Müllerian remnants where possible.

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