**2.3. SH2B1 deficiency**

However, recently the first cases of functional leptin deficiency have been described [23, 24]. This entity is characterized by detectable immunoreactive levels of circulating leptin, but

So, serum leptin may be a useful marker in patients with severe early‐onset obesity as an undetectable serum leptin is highly suggestive of a diagnosis of congenital leptin deficiency due to homozygous loss of function mutations in the *LEP* gene [12]. Leptin‐deficient subjects are born of normal birth weight but exhibit rapid weight gain in the first few months of life

Leptin deficiency causes the loss of appetite control, so it is associated with hyperphagia, increased energy intake and aggressive behavior when food is denied. Other phenotypic features include hypothalamic hypothyroidism, hypogonadotropic hypogonadism (because leptin stimulates hypothalamic gonadotropin‐releasing hormone [GnRH] production), elevated plasma insulin, T‐cell abnormalities (because leptin also stimulates the inflammatory response and proliferation of T cells and cytokines Th1 mediated), and advanced bone age [26].

Leptin deficiency is entirely treatable with daily subcutaneous injections of recombinant human leptin with beneficial effects on the degree of hyperphagia, reversal of the immune defects and infection risk and permissive effects on the development of puberty [25]. The major effect of leptin administration is the normalization of hyperphagia and enhanced satiety

In 1998 (1 year after the discovery of the congenital leptin deficiency), patients with similar phenotypic characteristic of leptin deficiency, but with a high blood level of leptin, were reported [28]. In these patients, a mutation in the leptin receptor (*LEPR*, OMIM \*601007),

One subsequent study has demonstrated that 3% of a group of patients with severe, early‐ onset obesity had a pathogenic *LEPR* mutation, but blood levels of leptin were not very high, suggesting that blood leptin levels cannot be used as a marker for leptin‐receptor deficiency

In literature, many mutations of the leptin receptor are described. Most recently, three novel mutations have been reported in the *LEPR* in two unrelated affected obese girls when latest genetic analysis techniques like whole‐exome sequencing and targeted sequencing have been

The clinical phenotypes associated with congenital leptin‐receptor deficiency are similar to those of leptin deficiency, with severe obesity from the first few months of the life, hypothala‐

On the contrary, in these patients, because of a non‐functional LEPR, leptin treatment is ineffective. Other factors could possibly bypass normal leptin delivery systems, but these are

bioinactivity of the hormone due to defective receptor binding [23, 24].

Currently, the prevalence of mutations in leptin is about 1% [12].

**2.2. Congenital leptin‐receptor deficiency (OMIM #614963)**

mapped at 1p31.3, has been described [28].

used for the mutational analysis in this gene [30, 31].

mic hypothyroidism and hypogonadotropic hypogonadism [12, 26].

not yet currently available for the treatment of these patients [32].

resulting in severe obesity [25].

218 Adiposity - Omics and Molecular Understanding

[25, 27].

[29].

The Src‐homology‐2 B adaptor protein 1 (*SH2B1*, OMIM \*608937) is a key intermediary in leptin signaling, promoting the activation of the leptin signaling pathway downstream of Janus kinase 2 (*JAK2*, OMIM \*147796) [15]. So, leptin‐stimulated activation of hypothalamic JAK2 is dramatically attenuated in *SH2B1* knockout mice [33].

In 2010, it was described that the 220‐kb 16p11.2 deletion (28.73–28.95 Mb) seen in three patients co‐segregated with severe early‐onset obesity alone [14]. This deletion includes a small number of genes, one of which was *SH2B1*, known to be involved in leptin and insulin signaling [12]. However, several mutations in the *SH2B1* gene have also been reported in association with early‐onset obesity, severe insulin resistance and behavioral abnormalities in some patients [34].

The phenotype of the children with *SH2B1*‐containing deletions is characterized by extreme hyperphagia and fasting insulin levels disproportionately elevated compared to age and obesity‐matched controls [15]. As expected, obese *SH2B1* KO mice develop hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance and NIDDM [35]. Interestingly, central and peripheral SH2B1 seem to regulate insulin sensitivity and glucose metabolism independently of its action on body weight in man and mice [36].

In these patients, there is no specific treatment, but care must be taken in starting a specific follow‐up on the hyperphagia, obesity and alteration of gluco‐insulinemic metabolism.
