Rare Presentation of Heterozygous PCSK1 Deficiency in an Adolescent Male

Proprotein convertase subtilisin/kexin type 1 (PCSK1) is an enzyme involved in processing prohormones into active peptides. PCSK1 deficiency is a rare genetic condition in which the homozygous presentation has been documented to cause diarrhea during infancy, as well as childhood obesity, high levels of proinsulin, and diverse endocrine abnormalities.

An eleven-year-old male was evaluated in the pediatric cardiology clinic for hypertriglyceridemia and rapid weight gain. He had recently been diagnosed with heterozygous PCSK1 deficiency, defined as c.661A > G, which is predicted to result in the amino acid substitution p.Asn221Asp. The patient reported regular hyperphagia to the point of nausea, with a diet of processed and sugary foods. Past medical history included obstructive sleep apnea and migraines. Physical examination was unremarkable aside from severe obesity (BMI 39.7 kg/m²) and elevated blood pressure. His fasting lipid panel showed elevated triglycerides (330 mg/dL), low HDL (38 mg/dL), normal LDL (71 mg/dL), elevated total cholesterol (175 mg/dL), and normal HbA1c (5.0%). The patient was counseled on lifestyle modifications with the weight management clinic and began a structured weight loss program along with discussions of possible GLP-1 agonist initiation. Follow-up lipid monitoring was planned in 3 months after the cardiology clinic visit.

This case of a heterozygous PCSK1 variant may demonstrate an association between this variant and the patient's clinical presentation, possibly expanding the known clinical spectrum of the disorder beyond the previously reported presentations in homozygous cases. Our case may show how heterozygous presentations with this variant of PCSK1 deficiency demonstrate a different presentation from the homozygous phenotype in younger patients. This patient shows that PCSK1 abnormalities could have an association with individuals who have hyperphagia and significant obesity, but normal HbA1c and LDL levels. Additional studies could be considered to evaluate prevalence in the population, long-term outcomes, and targeted therapies.