BabyScreen+ newborn screening

Gene: PCSK9

Green List (high evidence)

Rated as 'strong actionability' in paediatric patients by ClinGen.

The clinical features of HoFH are characterized by extensive xanthomas, premature and progressive cardiovascular disease (CVD), and total cholesterol >500 mg/dL.

HoFH commonly presents as physical manifestations in infancy and early childhood, consisting primarily of fleshy cutaneous and tendinous xanthomata, most marked in the Achilles tendon. Clinical CVD events begin as early as the first decade of life, but usually manifest by the second decade, consisting primarily of coronary ostial stenoses and occlusions, aortic valve thickening with stenosis and/or regurgitation, and extensive atherosclerosis of the aortic root. Untreated, most individuals with HoFH develop severe CAD and aortic stenosis before age 20 and die before age 30. Children as young as 4 years of age have suffered sudden death due to acute MI. The rate of either death or coronary bypass surgery by the teenage years is high.

The initial treatment for individuals with FH, irrespective of their calculated cardiovascular risk, should be a high intensity statin. Statin therapy is recommended to be initiated by 8-12 years of age; however, HoFH patients under the age of 8-10 years with high-risk family history, high-risk conditions, or multiple risk factors might be considered for medication initiation at a younger age. Target serum LDL-C concentrations have not been established for children, but in adults, the goal should be a reduction of at least 50% in LDL-C concentration from baseline. Statin treatment is lifelong.

Ezetimibe, as a monotherapy or in combination with statin therapy, is recommended as an option for treating HoFH in patients in whom initial statin therapy is contraindicated or not tolerated or when LDL-C levels are not controlled by statins alone.

LDL-C apheresis should be offered for treatment of HoFH with initiation based on response to lipid-lowering therapy (LLT), the presence of CHD, and child weight (>15kg). For children, treatment can be performed as early as technically feasible (before age 5 and at least by age 8).

Dietary modifications may be started after 2 years of age and should be under the supervision of a dietician or nutritionist for children and young adults.

Created: 29 Dec 2022, 10:04 p.m. | Last Modified: 29 Dec 2022, 10:04 p.m.

Panel Version: 0.1750

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypercholesterolemia, familial, 3, MIM# 603776