Clinical scenario: Failure to thrive | Stiffness| Aged appearance | Management
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:
The child has Hutchinson-Gilford Progeria Syndrome (HGPS), a rare premature aging syndrome caused by a de novo mutation in the LMNA gene, producing an abnormal lamin A protein called progerin.
Typical clinical features include:
- Normal appearance at birth
- Growth failure beginning during infancy
- Alopecia
- Loss of subcutaneous fat
- Characteristic “aged” facies (beaked nose, micrognathia)
- Prominent scalp veins
- Sclerodermatous skin
- Progressive joint contractures and hip abnormalities
- Normal cognitive development
The major cause of death is premature atherosclerotic cardiovascular disease, particularly myocardial infarction or stroke, usually during the second decade of life.
Lonafarnib, a farnesyltransferase inhibitor, prevents farnesylation of progerin, reducing its toxic accumulation at the nuclear membrane. Clinical studies have demonstrated:
- Improved vascular stiffness
- Better weight gain
- Improved skeletal outcomes
- Extension of survival by approximately 2.5–4 years, making it the first disease-modifying therapy for HGPS.
Why the other options are incorrect
- A. Bone marrow transplantation: No role because HGPS is a structural nuclear envelope disorder rather than a hematopoietic disease.
- B. Enzyme replacement therapy: Used for selected lysosomal storage disorders, not laminopathies.
- D. Growth hormone therapy: Does not alter disease progression or survival.
- E. Hematopoietic stem cell gene therapy: Currently not an established treatment for HGPS.
High-Yield Pearl
Children with Hutchinson-Gilford Progeria Syndrome usually die from accelerated atherosclerosis rather than from the musculoskeletal manifestations. Lonafarnib is currently the only approved disease-modifying therapy shown to improve survival.
Difficulty Level: ★★★★★ (Postgraduate – MRCPCH / FCPS-II / MD Pediatrics / American Board Pediatrics)
