Novel Leptin Receptor Mutations Identified in Two Girls with Severe Obesity Are Associated with Increased Bone Mineral Density

<b><i>Background:</i></b> Recessive mutations in the leptin receptor <i>(LEPR)</i> are a rare cause of hyperphagia and severe early-onset obesity. To date, the phenotype has only been described in 25 obese children, some of whom also had altered immune function, hypogonadotropic hypogonadism, reduced growth hormone secretion, hypothalamic hypothyroidism or reduced adult height. We provide a detailed description of the phenotype of 2 affected girls to add to this knowledge. <b><i>Methods:</i></b> Whole-exome sequencing and targeted sequencing were used to detect the <i>LEPR</i> mutations. RNA analysis was performed to assess the effect of splice-site mutations. <b><i>Results:</i></b> In 2 unrelated girls with severe obesity, three novel <i>LEPR</i> mutations were detected. Longitudinal growth data show normal childhood growth, and in the older girl, a normal adult height despite hypogonadotropic hypogonadism and the lack of an obvious pubertal growth spurt. Bone age is remarkably advanced in the younger (prepubertal) girl, and bone mineral density (BMD) is high in both girls, which might be directly or indirectly related to leptin resistance. <b><i>Conclusion:</i></b> The spectrum of clinical features of LEPR deficiency may be expanded with increased BMD. Future observations in LEPR-deficient subjects should help further unravel the role of leptin in human bone biology.