ESPE Abstracts

Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare condition (estimated incidence 1:4–8 million), caused by mutations in LMNA gene, which leads to premature aging. Median life expectancy is shortened to 13 years due to vascular complications such as stroke or myocardial infarction. We present below the history of a child born with a pathogenic LMNA variant c.433G>A (p.Glu145Lys). A male patient was referred due to failure to thrive and low growth velocity at age 18 months. He was born SGA (39th GW, BW 3270 g, BL 46 cm), had feeding problems and runny stools since early life. His motor development was slightly delayed. He underwent detailed paediatric check-up that failed to elucidate the underlying condition. Due to severe short stature (height −2.38 S.D.) and low IGF-I (39 ug/l; −1.45 S.D.) he was tested and finally diagnosed with growth hormone (GH) deficiency (peak GH 2.43 ug/l after clonidine stimulation). The subsequent MR revealed partial empty sella. GH therapy was initiated when 23 months old. Unfortunately, GH failed to improve growth velocity, despite a transient increase of IGF-I to 135 ug/l (−0.15 S.D.). The treatment was stopped at age 4.4 years (height −3.93 S.D.). His phenotype became suggestive of progeria when 2.5 years old, with partial hair loss, visible veins on his forehead, pinched nose and small recessed jaw. HGPS was confirmed by genetic testing. His first ischemic complication manifested via transient hemiparesis at age 4.2 years. MRI revealed severe ischemia of basal ganglia, subcortical ischemic changes in the right frontal lobe and severely reduced flow in the right internal carotid artery. Several subsequent episodes of transitory ischemic attacks developed despite combined anticoagulation and antiplatelet therapy. When 7 years old, he presented with seizures and unconsciousness due to a massive haemorrhagic stroke which led to a fatal outcome. LMNA provides instructions for making intermediate filament proteins known as lamin A and C. Their role is to support and provide stability to the nuclear membrane. The c.433G>A (p.Glu145Lys) variant is known to disable lamins to form dimers and higher structures. No causal therapy is available, however some data in animal models proposed a positive effect of IGF-I administration (Ugalde AP et al. Aging, 2010;2:1017–1022). Our single-case observation revealed failure of GH therapy, not only to improve growth, but to prevent or postpone vascular complications in HGPS as well, despite increased IGF-I levels.

Supported by grant AZV of Czech Ministry of Health No. 18-07-00283.