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

Kleinendorst L1, Abawi O2, van der Kamp HJ3, Alders M4, Meijers-Heijboer HEJ5, van Rossum EFC6, van den Akker E7, van Haelst MM8.

Author information

1: L Kleinendorst, Clinical Genetics, Amsterdam UMC - Locatie AMC, Amsterdam, Netherlands.
2: O Abawi, Obesity Center CGG, Erasmus MC, Rotterdam, Netherlands.
3: H van der Kamp, Pediatrics, div. of Endocrinology, UMC Utrecht - Locatie WKZ, Utrecht, Netherlands.
4: M Alders, Clinical Genetics, Amsterdam UMC - Locatie AMC, Amsterdam, Netherlands.
5: H Meijers-Heijboer, Clinical Genetics, Amsterdam UMC - Locatie AMC, Amsterdam, Netherlands.
6: E van Rossum, Obesity Center CGG, Erasmus MC, Rotterdam, Netherlands.
7: E van den Akker, Obesity Center CGG, Erasmus MC, Rotterdam, Netherlands.
8: M van Haelst, Clinical Genetics, Amsterdam UMC - Locatie AMC, Amsterdam, Netherlands.

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 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.