Clinical Scenario:
A 4-year-old boy is brought to the pediatric genetics clinic because of poor weight gain, progressive stiffness of joints, and an aged appearance. He was born at term with a normal birth weight and developed normally during infancy. Examination reveals severe growth failure, alopecia, loss of subcutaneous fat, prominent scalp veins, micrognathia, beaked nose, sclerodermatous skin changes, and coxa valga. His intelligence is normal. Echocardiography is currently normal.
Which of the following is the most appropriate long-term management strategy that has been shown to improve survival in this condition?
A. Bone marrow transplantation
B. Enzyme replacement therapy
C. Farnesyltransferase inhibitor therapy
D. Growth hormone therapy
E. Hematopoietic stem cell gene therapy
Correct answer & Explanation:
Correct Answer: C. Farnesyltransferase inhibitor therapy
Explanation: Hutchinson-Gilford Progeria Syndrome (HGPS)
The child has Hutchinson-Gilford Progeria Syndrome (HGPS), a rare premature-aging disorder caused by a usually de novo pathogenic variant in the LMNA gene, resulting in production of an abnormal lamin A protein called progerin.
Typical clinical features include:
- Normal appearance at birth or in early infancy
- Severe postnatal growth failure
- Alopecia
- Loss of subcutaneous fat
- Characteristic aged facies, including a narrow nasal ridge, small mouth, and micrognathia
- Prominent superficial veins
- Sclerodermatous skin changes
- Progressive joint contractures and skeletal abnormalities
- Normal intellectual development
HGPS is associated with severe, accelerated cardiovascular and cerebrovascular disease. More than 80% of deaths are related to heart failure and/or myocardial infarction, with cerebrovascular disease also contributing substantially.
Lonafarnib, a farnesyltransferase inhibitor, is the targeted therapy for HGPS. It inhibits the post-translational farnesylation of progerin, reducing its abnormal accumulation at the nuclear envelope. Clinical studies have demonstrated improvements in vascular parameters and other disease manifestations, with an average lifespan extension of approximately 4.2 years. Current GeneReviews data report an average lifespan of approximately 14.5 years without lonafarnib and approximately 18.7 years with treatment.
Why the other options are incorrect
- A. Bone marrow transplantation: Has no role in HGPS, which results from an LMNA-related nuclear-envelope abnormality rather than a hematopoietic disorder.
- B. Enzyme replacement therapy: Used for selected lysosomal storage disorders and is not applicable to HGPS.
- D. Growth hormone therapy: May not correct the underlying molecular defect or the progressive cardiovascular disease of HGPS.
- E. Hematopoietic stem cell gene therapy: Not an established treatment for HGPS.
High-Yield Pearl
HGPS is caused by abnormal progerin production due to an LMNA defect. Lonafarnib inhibits progerin farnesylation and is the FDA-approved targeted therapy for HGPS. Premature cardiovascular and cerebrovascular disease is the major cause of mortality.
Difficulty Level: ★★★★★ (Postgraduate – MRCPCH / FCPS-II / MD Pediatrics / American Board Pediatrics)
You can practice another MCQ on Progeria.
References
- Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford Progeria Syndrome. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; updated March 13, 2025.
- Gordon LB, Shappell H, Massaro J, et al. Association of lonafarnib treatment vs no treatment with mortality rate in patients with Hutchinson-Gilford progeria syndrome. JAMA. 2018;319(16):1687-1695.
- Gordon LB, Kleinman ME, Miller DT, et al. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2012;109(43):16666-16671
