INTRODUCTION:

HGPS, a rare premature aging condition, provides a unique window into the aging process at both cellular and organismal levels, as affected children display accelerated aging phenotypes¹. Hutchinson described the condition in 1886, but its features were not well-defined at the time².

According to the Progeria Research Foundation, around 350-400 children globally are affected by progeria, with no apparent bias towards sex or ethnicity. Progeria is an extremely rare condition, occurring roughly 1 out of every 20 million individuals³.

Based on the different features disease progression is marked by reduced subcutaneous fat and vascular narrowing, treatment options include lonafarnib a farnesyltransferase inhibitor. HGPS is a debilitating condition with no cure, leading to a poor quality of life for affected children. Treatment options are limited, and the disease's rapid progression remains a significant challenge⁵. HGPS patients exhibit clinical characteristics of premature aging, including alopecia, aberrant pigmentation, loss of subcutaneous fat and die in their teens because of atherosclerosis and cardiovascular complications.⁶

Definition:–

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare disorder characterized by accelerated aging in children, leading to premature aging symptoms and reduced lifespan.¹⁴

Aetiology:

· Continuous point mutation “C.1824C >T” this represents about the genetic mutation C- refers to the coding DNA sequence (cDNA).

· LMNA gene.

Table 1: A Comparison between a Progeria Cell with A Normal Cell.¹³

Stages in a normal cell	Steps in the progerian cell
The LAMN gene codes for a protein called prelamin A.	The LAMN gene codes for a protein called prelamin A.
relamin A has a farnesyl group at the end.	Prelamin A has a farnesyl group at the end.
he farnesyl group is removed from preamine A.	The farnesyl group is attached to prelamin A.
he normal form is called prelamin A.	An abnormal form of prelamin a called progeria.
relamin A is not anchored to the nuclear periphery.	Progeria is anchored in the nucleus.
he normal state of the kernel.	Abnormally shaped nucleus.

Epidemiology:

Hutchinson-Gilford Progeria Syndrome is an exceptionally rare genetic condition, occurring in approximately 1 in 4-8 million births globally. HGPS impacts boys and girls equally, with no apparent ethnic or geographic bias in its occurrence. The rarity of HGPS makes it challenging to study and understand the full scope of its epidemiology. Despite its rarity, research into HGPS provides valuable insights into the aging process and potential therapeutic strategies for related conditions.⁷

Pathophysiology:

Hutchinson-Gilford Progeria Syndrome is commonly caused by spontaneous mutations in the LMNA gene, specifically at codon 608 in exon 11, leading to autosomal dominant inheritance.⁸

· The LMNA gene produces key components of nuclear lamina, specifically Lamin A and Lamin C, which are integral to the nuclear membrane's structure.

· The nuclear lamina plays a crucial role in various cellular processes, including cell division, chromatin organization, DNA replication, nuclear shape maintenance, and transcriptional regulation.

· The LMNA mutation in HGPS typically involves C-T nucleotide substitution at position 1824, creating a cryptic splice site that leads to a truncated mRNA lacking 150 nucleotides, ultimately affecting protein production. Additionally, it influences the basic principles that govern nuclear structure and functionality.

· Progerin disrupts nuclear function in cells that express Lamin A, leading to adverse effects on various cellular processes, including cell division, DNA replication, and gene transcription.

· The CAAX sequence is defined by a cysteine, followed by two aliphatic amino acids, and ending with any amino acid represented by "X".

· In prelamin A, the CSSIM sequence within the CAAX motif facilitates farnesylation, where a farnesyl lipid group is added by farnesyltransferase, impacting protein function and localization.

· Prelamin A bounded with a nuclear membrane is farnesylation and equally CAAX signaling modification. After farnesylation, the protein undergoes further processing, where the three C-terminal amino acids are cleaved.

· After a second nuclear cleavage, the farnesylated cysteine and 15C- terminal amino acids are removed from Prelamin A, allowing it to integrate into the nuclear lamina.

· In HGPS, preprogerin undergoes farnesylation but lacks the internal region (amino acids 606 – 656) which is necessary for the final cleavage step, preventing removal of the farnesyl group.

· Mutations in ZMPSTE24, a gene crucial for prelamin A processing, can cause severe mandibuloacral dysostosis, highlighting the importance of proper lamin processing in disease pathology.

· ZMPSTE24, the human homolog of yeast STE24, plays a crucial role in the final cleavage step of prelamin A to mature lamin A.

· The accumulation of progerin in Hutchinson-Gilford Progeria Syndrome (HGPS) results in nuclear envelope defects, including inward blebbing and changes in nuclear morphology.

Clinical Manifestations:

Children’s with HGPS are usually normal at the time of birth and also during early infancy. The classic and non-classic genotype of HGPS (Hutchinson – Gilford Progeria Syndrome) are characterized by different factors as listed below¹¹

Early Symptoms (Within the first 12 months):

a) Growth failure

b) Alopecia

c) Skin changes: Skin may appear tight, wrinkled, and with spots, or it may have areas of loose, outpouching skin.

d) Characteristic appearance: large head, beaked nose, prominent eyes, thin lips, small jaw, and small ears.

e) Loss of subcutaneous fat

f) Tooth development issues manifest as delayed eruption and abnormal morphology.

g) Skeletal abnormalities: Thin, fragile bones, thin ribs, and a narrow chest may be present.

h) Hearing loss: Low-frequency conductive hearing loss is a common finding.

Later Manifestations (beyond the first year of life):

a) Cardiovascular problems: HGPS patients develop severe atherosclerosis at a young age, leading to heart attacks and strokes.

b) Joint stiffness and contractures: Joint problems, including hip dislocations, are common.

c) Osteoporosis and osteolysis: Bone thinning and resorption are present.

Diagnostic Evaluation:

Hutchinson-Gilford Progeria Syndrome (HGPS) investigations are multi-faceted approach including clinical evaluation, imaging, and genetic testing.¹²

Physical Examination:

· Growth failure, skin changes, loss of fat tissue, hair loss, and distinctive facial features.

· Growth and Development

· Assess for any hearing or vision problems.

Imaging Studies:

· X-rays and CT scans: To assess the musculoskeletal abnormalities like hip dislocation, bone density, and joint issues.

· Echocardiogram: To evaluate valve abnormalities, diastolic dysfunction, and ventricular hypertrophy.

· MRI: To detect potential stroke or other neurological problems.

Genetic Testing:

· LMNA Gene Analysis: To identify the presence of the pathogenic variant in the LMNA gene, particularly the c. 1824C>T mutation (also known as G608G).

Management:

1. Targeted Therapy:

· Lonafarnib therapy used for HGPS benefits such as increased lifespan, slowed cardiovascular disease progression, improved arterial wall stiffness, enhanced carotid – femoral pulse wave velocity, improved low – tone hearing, potential reduction in headache frequency.⁹

· Side-effects – Gastrointestinal issues (varying severity and duration)

2. Supportive Care:

· General care: Nutritional support (frequent small meals, multivitamins), medication dosing based on weight or body surface area, foot care (shoe pads), school adaptations for short stature.

· Medical management: includes cautious anesthesia and intubation (preferably fiberoptic), sun protection measures, regular dental care, and hip dislocation management through physical therapy, bracing, and potential surgery.

· Therapeutic approaches: include physical and occupational therapy to maintain joint mobility and flexibility, hormonal management (e.g., oral contraceptives for excessive bleeding), and cardiovascular care (low-dose aspirin and anti-congestive therapy).¹³

· Surgical Interventions: Modified valve replacement procedures for critical aortic stenosis.

· Additional care: Includes social work support, hearing aids for hearing loss, and eye lubrication for ocular health.

· Lifestyle Modifications: Healthy diet and regular physical activity, optimal hydration, exercise and diet modification for hyperlipidemia.

3. Surveillance:

Surveillance is a plan which helps to track disease progression and to identify potential complications early, enabling timely interventions like:-

· Frequency –based Assessments:

- Every 6 -12 month – blood pressure, Echocardiogram, carotid scan.

- Annual monitoring includes dental check-ups with radiographs, assessments by physical and occupational therapists, lipid profile testing, eye exams, and neurological evaluations with head and neck imaging (MRI/MRA).

- Ongoing Monitoring – Assessing the growth and caloric intake, skin manifestations, and family needs and support.

4. Agents to Avoid:

· Certain activities pose risks, including crowded settings with taller individuals, trampolines, and bouncy houses, which may increase the likelihood of hip dislocation.

· Calcium supplementation (extra skeletal calcium deposits).

5. Genetic Counseling:

· HGPS is an Autosomal dominant disorder.

· De Novo Mutations -In roughly 98% of cases, the condition arises from new mutations rather than inherited genetic factors.

· Gonadal Mosaicism – 2% of cases may result from inheritance from an unaffected parent with mosaicism.

· Sibling recurrence risk is low due to de novo mutations, but parental gonadal mosaicism may elevate this risk.

· Genetic testing options are available prenatally or preimplantation once the specific LMNA mutation is identified.

Complications:

Early detection and Management can help to mitigate these complications¹⁵

1. Cardiovascular:

· Atherosclerosis

· Cardiac Disease

· Stroke

· Hypertension

2. Musculoskeletal:

· Joint dislocations (hip)

· Osteolysis

· Limited mobility

3. Other:

· Growth delays

· Skin changes (eg- thinning, wrinkling)

· Dental abnormalities

· Hearing loss

· Vision Problems (eg- exposure keratopathy)

CONCLUSION:

HGPS is a rare genetic disorder that causes segmental premature aging in children, offering valuable insights into the aging process at both cellular and organismal levels. Despite significant progress in understanding the disease, much remains to be discovered, ongoing research continues to reveal new aspects of aging. The study of HGPS provides a unique model of understanding the roles of LaminA, LaminC and progerin in cells. Research has led to promising treatment possibilities, with a focus on assessing cardiovascular effects, as it is the primary cause of premature death in HGPS patients. Further studies are needed to uncover the treatment efficacies of current and emerging management modalities and to improve our understanding of disease ultimately identifying new therapeutic targets and outcome metrics. By exploring HGPS, scientists can gain a deeper understanding of the disease and develop effective treatments to improve the lives of affected children.

REFERENCES:

1. Ulrich NJ, Gordon LB. Hutchinson-Gilford progeria syndrome. Handb Clin Neurol. 2015; 132:249–264.

2. Brune T, Bonne G, Denecke J, et al. Progeria: a new kind of Laminopathy-- report of the First European Symposium on Progeria and creation of EURO-Progeria, a European Consortium on Progeria and related disorders. Pediatric Endocrinol Rev. 2004; 2: 39–45.

3. Progeria 101/ FAQ. August. [Sep; 2019]. 2019. https://www.progeriaresearch.org/progeria-101faq/ https://www.progeriaresearch.org/progeria-101faq/ [Ref list]

4. MXR Foo, PF Ong, O. Dreesen. Premature aging syndromes: From patients to mechanism J Dermatol Sci. 2019; 96: 58-65.

5. J K Sinha, S Ghosh, M. Raghunath. Progeria: a rare genetic premature ageing disorder. Indian J Med Res. 2014; 139: 667-674

6. Foo MXR, Ong PF, Dreesen O. Premature aging syndromes: From patients to mechanism. J Dermatol Sci. 2019 Nov; 96(2): 58-65. doi: 10.1016/j.jdermsci.2019.10.003.

7. Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford Progeria Syndrome. Seattle, WA: Gene Reviews; 1993. Hutchinson-Gilford Progeria Syndrome.

8. Kara N Shah, M. (2020, December 28. Hutchinson-Gilford Progeria Workup. [Dec; 2020]. 2020.

9. Dhillon, S. Lonafarnib: First Approval. Drugs. 2021; 81: 283–289 https://doi.org/10.1007/s40265-020-01464-z

10. Eriksson M, Brown WT, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003 May 15; 423 (6937): 293-8. doi: 10.1038/nature01629. Epub 2003 Apr 2511.

11. De Sandre-Giovannoli A, Bernard R, Cau P, et al. Lamin a truncation in Hutchinson-Gilford progeria. Science. 2003; 300: 2055

12. Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford Progeria Syndrome. 2003 Dec 12 [Updated 2025 Mar 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

13. Goldman RD, Gruenbaum Y, Moir RD, Shumaker DK, Spann TP. Nuclear Lamins: building blocks of nuclear architecture. Genes Dev. 2002; 16:533–547

14. Mahek D., Pooja K., Shital F. An Overview of Hutchinson- Gilford Progeria Syndrome. Research Journal of Pharmacology and Pharmacodynamics. 2025; 17(2): 137-3. doi: 10.52711/2321-5836.2025.00022

15. Gruenbaum Y, Margalit A, Goldman RD, Shumaker DK, Wilson KL. The nuclear lamina comes of age. Nat Rev Mol Cell Biol. 2005; 6:21–31

16. Goldman RD, Shumaker DK, Erdos MR, et al Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2004; 101

Received on 28.04.2025 Revised on 10.06.2025

Accepted on 12.07.2025 Published on 16.08.2025

Available online from August 25, 2025

Int. J. Nursing Education and Research. 2025;13(3):204-208.

DOI: 10.52711/2454-2660.2025.00042

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