**2. Monogenic obesity**

A "monogene" is by textbook definition, a gene with a strong effect on the phenotype (Men‐ delian traits or Mendelian—single gene conditions), giving rise to a one‐on‐one relationship between genotype and phenotype.

So, monogenic and not syndromic obesity is caused by a single mutation of a gene.

This form of obesity occurs in infancy and is often associated with additional behavior, developmental or endocrinological disabilities, such as hyperphagia and hypogonadism; however, significant developmental delays are not visible, and the obesity is often not associated with other clinical manifestations [3, 6, 8, 13–17].


The types of monogenic obesity are summarized in **Table 1** [10–12, 18].

**Table 1.** Main features of monogenic not syndromic obesity.

These types of monogenic obesity are caused by mutations in leptin–melanocortin hypothala‐ mic pathway genes. These genes regulate the sense of appetite and hunger (**Figure 1**).

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach http://dx.doi.org/10.5772/66128 217

**Figure 1.** Appetite regulation: inhibitory (‐) and favoring (+) mechanisms. Adapted with permission from Perrone et al. [11].

#### **2.1. Congenital leptin deficiency (OMIM #614962)**

Rare genetic forms of obesity are important to be detected clinically because it allows to progress in understanding the physiopathology of obesity. On the other hand, there is a specific management of these forms of obesity provided by specialized and multidisciplinary teams.

A "monogene" is by textbook definition, a gene with a strong effect on the phenotype (Men‐ delian traits or Mendelian—single gene conditions), giving rise to a one‐on‐one relationship

This form of obesity occurs in infancy and is often associated with additional behavior, developmental or endocrinological disabilities, such as hyperphagia and hypogonadism; however, significant developmental delays are not visible, and the obesity is often not

LEP deficiency *LEP* Hypogonadism, absent or delayed puberty, frequent infections, undetectable serum

SH2B2 deficiency *SH2B1* Severe insulin resistance and disproportionate to degree of obesity; in rare cases

POMC deficiency *POMC* Hypogonadism, absent or delayed puberty, hair and cute hypopigmentation, isolated

PCSK1 deficiency *PCSK1* Hypogonadism, absent or delayed puberty, postprandial hypoglycemia, elevated

These types of monogenic obesity are caused by mutations in leptin–melanocortin hypothala‐ mic pathway genes. These genes regulate the sense of appetite and hunger (**Figure 1**).

plasma proinsulin, severe malabsorption in the neonatal period

Developmental delay, hyperactivity, impaired memory, impaired pain sensation

presence of developmental delay

So, monogenic and not syndromic obesity is caused by a single mutation of a gene.

associated with other clinical manifestations [3, 6, 8, 13–17].

leptin LEPR deficiency *LEPR* Hypogonadism, absent or delayed puberty

The types of monogenic obesity are summarized in **Table 1** [10–12, 18].

**Monogenic obesity Gene name Main distinguishing features in addition to obesity**

ACTH deficiency

MC4‐R deficiency *MC4‐R* Accelerated growth, increased final height

SIM1 deficiency *SIM 1* Spectrum of developmental delay

Adapted with permission from Ramachandrappa and Farooqi [19].

*BDNF o NTRK2*

CART deficiency *CART* Anxiety and depression

**Table 1.** Main features of monogenic not syndromic obesity.

BDNF/trkB deficiency

**2. Monogenic obesity**

216 Adiposity - Omics and Molecular Understanding

between genotype and phenotype.

In 1997, two severely obese cousins (an 8‐year‐old female child with a weight of 86 kg and a 2‐year‐old male child with a weight of 29 kg) were reported from a highly consanguineous family of Pakistani origin [20]. Despite their severe obesity, both children had undetectable levels of serum leptin and a mutation in the gene encoding leptin mapped at 7q32.1. The disease is caused by mutations in the *LEP* gene (OMIM \*164160) typically leading to defects in protein synthesis or secretion, and therefore to the absence or very low blood levels of this hormone [21–23].

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

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 resulting in severe obesity [25].

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

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 [25, 27].

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

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

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 [29].

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

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‐ mic hypothyroidism and hypogonadotropic hypogonadism [12, 26].

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