Introduction: Although the majority of the cases with obesity have a multifactorial etiology, rare monogenic forms of obesity exist. Several genetic disorders have been described that lead to early onset monogenic obesity. Leptin (LEP), leptin receptor (LEPR), melanocortin 4 receptor (MC4R), proprotein converting protein subtilisin / kexin-type 1 (PCSK1) and proopiomelanocortin (POMC) are the genetic mutations that have been most frequently shown to cause monogenic forms of obesity. In this study, we aimed to present two cases who applied with early onset morbid obesity and hyperphagia in whom we detected homozygous missense and homozygous frameshift mutations in LEPR.
Case 1: A 6-month-old girl presented to our outpatient clinic with morbid obesity. In physical examination; body height was 71.1 cm (+1.61 SDS), body weight was 13.1 kg (+4.76 SDS), body mass index (BMI) was 25.9 (+4.4 SDS). Her birth weight was 3600 g. The parents were first degree cousins. She had hyperphagia and rapid weight gain at the age of 3 months. She had no red hair. In molecular analysis; C.1938G> T (p.W646C) variant and C.946C> A (p.P316T) homozygous missense mutation in the LEPR gene were detected. In the molecular analysis of the family, both parents and her sibling have been shown to be heterozygous for the same gene.
Case 2: A girl with a birth weight of 3250 g was admitted with hyperphagia and excessive weight gain at 8 months of age. There was a consanguinity (first cousin marriage) between his parents and she had a height of 73 cm (+1.21 SDS), her weight was 19.8 kg (+7.94 SDS), her BMI was 37.1 (+6.9 SDS). In molecular analysis; homozygous novel c.1220-1221insT frameshift mutation was detected in the LEPR gene. In the molecular analysis of parents; both parents were shown to be heterozygous carriers.
Conclusion: Leptin and LEPR play a key role in body weight and energy homeostasis. LEPR mutations are rare, autosomal recessive and result in hyperphagia and early onset monogenic obesity. Until now, the number of reported LEPR gene mutations is less than 60. The mutation detected in case 1 [(C.946C> A (p.P316T)] was previously reported in the literature. The mutation detected in case 2 [C.1220-1221insT ] was shown for the first time in our patient. In conclusion, we think that monogenic obesity should be kept in mind and genetic studies should be done in patients with early onset severe obesity, hyperphagia and history of consanguinity.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology