The leptinergic-melanocortinergic-pathway, which includes leptin (
LEP), the melanocortin 4 receptor (
MC4R), melanocortin receptor accessory protein 2 (
MRAP2) and brain derived neurotrophic factor (
BDNF)
, is involved in the regulation of both body height [
3,
5‐
9] and weight [
6,
10]. Loss-of-function mutations affecting of the components of this system lead to obese phenotypes with increased linear growth [
6,
8,
9].
The function of each of these genes provides evidence that they may be candidates for playing a causal role in SNS. (1) Rare homozygous loss-of-function mutations in the
LEP gene [
10] are associated with hypogonadism, frequent infections and severe early onset obesity [
11,
12]. A rare non-synonymous mutation located in a highly conserved
LEP position was detected in a boy with short stature and his mother. Both heterozygous carriers shared a similar phenotype of reduced appetite, pubertal delay and leanness [
13]. (2) Up to now more than 160 non-synonymous, nonsense or frameshift mutations in
MC4R resulting in reduced receptor function have been described. Carriers of these mutations are mostly (extremely) obese, hyperphagic, hyperinsulinemic and display increased linear growth [
5,
6,
14]. The minor alleles at two
MC4R polymorphisms (rs2229616 [p.Val103Ile] and rs52820871 [p.Ile251Leu]) are associated with slightly reduced body weight [
15,
16]. rs17782313, identified in GWAS of BMI/obesity [
17] and located 3′ to
MC4R, is also associated with human adult height (
p = 3.80 × 10
− 11) [
7]. Mc4r-deficient mice are obese with increased length [
18], in cavefish Mc4r mutations lead to binge eating and increased body length [
19]. An artificially induced increase in MC4R activity in the early development of zebrafish embryos causes growth retardation [
20]. (3) MRAP2 influences MC4R signalling. A mutation screen in obese children and adolescents revealed that
MRAP2 variants might contribute to human obesity [
8]. Additionally, we described an
MRAP2 mutation leading to reduced MC4R function [
21]. Animal models demonstrate the impact of Mrap2 on metabolism, growth and development [
22]. Mice with germline deletion of Mrap2 are characterized by obesity and increased linear growth [
22]. (4) BDNF regulates, mediated by the TrkB receptor, energy homeostasis downstream of MC4R [
23]. In humans, the association of a BDNF variant was described for childhood BMI, weight and height standard deviation score (SDS) [
24]. Conditional brain-specific
Bdnf knockdown resulted in increased body weight and linear growth [
9]. TrkB hypomorphic mice also showed a phenotype characterized by obesity and increased linear growth [
23].