A patient with ROHHAD syndrome and leptin-melanocortin pathway gene variations. Correlation or just a coincidence? Case report

In cases of early onset, severe obesity, especially when in the presence of additional clinical manifestations, genetic investigation to exclude syndromic or monogenic obesity is indicated. ROHHAD syndrome is one of the rarest syndromes associated with obesity. Genetic analysis has not to date identified responsible genes; therefore, its diagnosis is based on clinical criteria. Monogenic obesity is mainly caused by variants in genes involved in the leptin-melanocortin pathway, the satiety pathway. We present a patient with severe obesity from the age of 3 years, endocrinopathies (central diabetes insipidus, central hypothyroidism, precocious puberty, and growth hormone deficiency), hypoventilation, cold extremities, psychomotor retardation, behavioral disorders, strabismus, fatty liver infiltration, and syndromic facial features. Based on the clinical features, ROHHAD syndrome was diagnosed. The patient underwent genetic testing of 80 genes involved in the leptin-melanocortin pathway. He was found to be heterozygous in the PLXNA3 gene for a sequence variant designated c.3640 C > T, which is predicted to result in the amino acid substitution p.Arg1214Trp. This variant has not been reported in the literature and is of unknown clinical significance. The patient was also heterozygous in the PCSK1 gene for a sequence variant designated c.661 A > G, which is predicted to result in the amino acid substitution p.Asn221Asp and is classified as a risk factor for obesity. We present the first reported patient with ROHHAD syndrome and variants in two genes involved in the leptin-melanocortin pathway. The possibility of the coexistence of two rare types of obesity, syndromic and monogenic, makes this case particularly exceptional and raises questions about the potential association between the two entities.