Endocrine Abstracts

Background: Rare genetic disorders of obesity result from an impaired central melanocortin pathway, comprised of multiple genes, including POMC, PCSK1, and LEPR. Because of their rarity and the difficulty in identifying individuals with pathogenic mutations in these genes, a complete understanding of these disorders remains unclear. We reviewed previous case reports of individuals with POMC, PCSK1, or LEPR deficiencies to understand their clinical characteristics and to identify potential features of individuals with obesity who should be genetically screened for these rare genetic disorders of obesity.

Methods: Published manuscripts and conference abstracts available in PubMed and Embase through January 1, 2019, describing the medical history of individuals with POMC, PCSK1, and LEPR deficiencies were included. Individuals were excluded if only limited information, such as age, sex, variant, and weight/BMI, were provided. The prevalence of each characteristic was calculated for each genotype by dividing the number of cases with the characteristic by the total number of cases.

Results: Fifty-eight articles and 18 abstracts were identified, describing clinical characteristics of 150 individuals. Hyperphagia was described in 68, 16, and 91%, and early-onset obesity (defined as occurring at ≤6 years of age or as described by the author) in 90, 47, and 97% of individuals with a deficiency in POMC, PCSK1, and LEPR, respectively. In individuals with a POMC deficiency (n=31), common characteristics included adrenocorticotropic hormone deficiency and hypocortisolism (68%), hypoglycemic episodes (52%), and developmental delays in childhood (39%). Only 29% had red hair, although 65% had light or pale skin for their ethnicity. In individuals with a PCSK1 deficiency (n=43), common characteristics included gastrointestinal complications in the first weeks of life (usually postnatal diarrhea; 86%), hyperproinsulinemia (65%), metabolic acidosis (53%), hypoglycemia (49%), diabetes insipidus (47%), polydipsia/polyuria (47%), hypothyroidism (44%), failure to thrive in infancy (42%), and hypocortisolism (37%). In individuals with a LEPR deficiency (n=76), common characteristics included hyperinsulinemia (49%) and delayed puberty (39%); hypogonadotropic hypogonadism and a history of frequent infection were each reported in 34%.

Conclusions: This comprehensive literature search and analysis of POMC, PCSK1, and LEPR case histories suggests potential features for identifying individuals with obesity who should be genetically screened for these rare genetic disorders. Early-onset obesity and hyperphagia are common characteristics that cause substantial disease burden in individuals with rare genetic disorders of obesity and additional burdens to families and caregivers. Standardized definitions for severe obesity and hyperphagia may also help healthcare providers identify these individuals.