Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics

Abstract

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.

Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency

“…The two case reports describe the frustrating diagnostic and therapeutic history of two patients with diseasecausing, compound heterozygous variants in the LEPR gene. Comparable with the previous published 88 patients with LEPR deficiency, our patients show extreme early-onset obesity, pronounced hyperphagia, and hypogonadotropic hypogonadism [9,13]. Moreover, we observed a severe psychological strain in our patients, including stigmatisation, social isolation, and severe accusations.…”

Identifying underlying medical causes of pediatric obesity: Results of a systematic diagnostic approach in a pediatric obesity center

“…Hormonal supplementation was started in case of hormonal deficiencies associated with specific genetic obesity disorders (such as growth hormone treatment in cases with leptin receptor deficiency). [49] In cases of syndromic obesity, the patients were evaluated for associated organ abnormalities or referred for disease-specific surveillance. [13,[25][26][27][28][29][30][31][32] In patients with cerebral/hypothalamic injury as cause of obesity and hyperphagia, dexamphetamine treatment was considered.…”

Two Cases With an Early Presented Proopiomelanocortin Deficiency—A Long-Term Follow-Up and Systematic Literature Review

“…Instead, in POMC deficiency, central hypothyroidism seems to be a common occurrence, and the absence of MC4R stimulation could very well be the culprit here. The diminished leptin effect on TRH stimulation is also evident in LEPR deficiency where central hypothyroidism is observed in 13% of cases ( 34 ). It would be interesting to observe whether the stimulation of MC4R with an agonist such as setmelanotide would improve central hypothyroidism to any extent, but unfortunately, there were no reports of such results in the literature to date.…”