The aim of this study was to determine whether polymorphisms of the glucocorticoid receptor gene, influencing glucocorticoid sensitivity, are associa

Objective: Leptin receptor (LepR) deficiency is an autosomal-recessive endocrine disorder causing early-onset severe obesity, hyperphagia and pituitary hormone deficiencies. As effective pharmacological treatment has recently been developed, diagnosing LepR deficiency is urgent. However, recognition is challenging and prevalence is unknown. We aim to elucidate the clinical spectrum and to estimate the prevalence of LepR deficiency in Europe. Design: Comprehensive epidemiologic analysis and systematic literature review. Methods: We curated a list of LEPR variants described in patients and elaborately evaluated their phenotypes. Subsequently, we extracted allele frequencies from the Genome Aggregation Database (gnomAD), consisting of sequencing data of 77 165 European individuals. We then calculated the number of individuals with biallelic disease-causing LEPR variants. Results: Worldwide, 86 patients with LepR deficiency are published. We add two new patients, bringing the total of published patients to 88, of which 21 are European. All patients had early-onset obesity; 96% had hyperphagia; 34% had one or more pituitary hormone deficiencies. Our calculation results in 998 predicted patients in Europe, corresponding to a prevalence of 1.34 per 1 million people (95% CI: 0.95–1.72). Conclusions: This study shows that LepR deficiency is more prevalent in Europe (n = 998 predicted patients) than currently known (n = 21 patients), suggesting that LepR deficiency is underdiagnosed. An important cause for this could be lack of access to genetic testing. Another possible explanation is insufficient recognition, as only one-third of patients has pituitary hormone deficiencies. With novel highly effective treatment emerging, diagnosing LepR deficiency is more important than ever.

Four European Reference Networks (ERN-EYE, ERKNet, Endo-ERN, ERN-ITHACA) have teamed up to establish a consensus statement and recommendations for Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy with at least 26 genes identified to date. The clinical manifestations are pleiotropic, can be observed in utero and will progress with age. Genetic testing has progressively improved in the last years prompting for a revision of the diagnostic criteria taking into account clinical Primary and Secondary features, as well as positive or negative molecular diagnosis. This consensus statement also emphasizes on initial diagnosis, monitoring and lifelong follow-up, and symptomatic care that can be provided to patients and family members according to the involved care professionals. For paediatricians, developmental anomalies can be at the forefront for diagnosis (such as polydactyly) but can require specific care, such as for associated neuro developmental disorders. For ophthalmology, the early onset retinal degeneration requires ad hoc functional and imaging technologies and specific care for severe visual impairment. For endocrinology, among other manifestations, early onset obesity and its complications has benefited from better evaluation of eating behaviour problems, improved lifestyle programs, and from novel pharmacological therapies. Kidney and urinary track involvements warrants lifespan attention, as chronic kidney failure can occur and early management might improve outcome. This consensus recommends revised diagnostic criteria for BBS that will ensure certainty of diagnosis, giving robust grounds for genetic counselling as well as in the perspective of future trials for innovative therapies.