Clinical Scenario:
A 2-year-old boy is referred because of progressive growth failure despite adequate nutrition. He was born at term with normal birth weight and length. Over the past year, he has developed alopecia, loss of subcutaneous fat, a pinched nose, micrognathia, and tight skin over the extremities. His developmental milestones and cognition are normal. There is no family history of a similar disorder. Genetic testing confirms Hutchinson-Gilford Progeria Syndrome (HGPS).
Which of the following molecular abnormalities is most directly responsible for the pathogenesis of this disorder?
A. Defective collagen type III synthesis
B. Expansion of CGG trinucleotide repeats
C. Failure of DNA mismatch repair
D. Persistent farnesylation of an abnormal lamin A protein
E. Telomerase deficiency causing premature telomere shortening
Correct answer & Explanation:
Correct Answer D. Persistent farnesylation of an abnormal lamin A protein
Explanation: Hutchinson-Gilford Progeria Syndrome (HGPS)
is caused by a de novo autosomal dominant mutation in the LMNA gene, most commonly c.1824C>T (p.G608G). Although this is a silent mutation, it activates a cryptic splice site, resulting in production of an abnormal lamin A protein known as progerin.
Unlike normal lamin A, progerin retains its farnesyl group because the cleavage site required for post-translational processing is absent. Persistent farnesylation causes abnormal attachment of progerin to the nuclear membrane, leading to:
Distorted nuclear architecture
Genomic instability
Impaired DNA repair
Premature cellular senescence
Progressive vascular smooth muscle cell loss
These cellular abnormalities explain the characteristic phenotype of growth failure, lipodystrophy, alopecia, skeletal abnormalities, and accelerated atherosclerosis.
Why the other options are incorrect
A. Defective collagen type III synthesis
Causes vascular Ehlers-Danlos syndrome, characterized by fragile blood vessels and hyperextensible tissues.
B. Expansion of CGG trinucleotide repeats
Causes Fragile X syndrome.
C. Failure of DNA mismatch repair
Seen in Lynch syndrome, not progeria.
E. Telomerase deficiency causing premature telomere shortening
Associated with disorders such as dyskeratosis congenita, but not the primary mechanism of HGPS.
High-Yield MRCPCH Pearls
Normal intelligence is preserved in HGPS.
Children usually appear normal at birth; clinical features become evident during the first 1–2 years.
The LMNA c.1824C>T mutation is the classic genetic defect tested in examinations.
Progerin is an abnormal farnesylated lamin A protein.
The leading cause of death is premature myocardial infarction or stroke due to accelerated atherosclerosis.
Lonafarnib, a farnesyltransferase inhibitor, is the only approved disease-modifying therapy and improves survival.
You can practice another MCQ on Aminoacidopathy.
References
- Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford Progeria Syndrome. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Updated March 13, 2025.
- Al-Haggar M, et al. Hutchinson-Gilford Progeria Syndrome: A Literature Review. J Med Life. 2022.
- 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;109:16666-16671.
