What Is Progeria?

  • Deepika Rana Bachelor of Dental Surgery(BDS), Dentistry , H.P.Government Dental College, IGMC Shimla.Himachal Pradesh
  • Rajni Sarma MBBS, MD from North-Eastern Hill University, India
  • Regina Lopes Junior Editor, Centre of Excellence, Health and Social Care, The Open University

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Introduction

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, segmental "premature ageing" disease that is invariably fatal. It is commonly known as progeria. A genetic mutation is the disease's aetiology. Signs of ageing include wrinkles and baldness caused by progeria.

Are you intrigued by the mysterious world of progeria? Explore the genetics, current research causes and treatment. Continue reading for a thorough knowledge of this unusual ailment and its impact on those affected.

Children with HGPS display characteristics that could provide an understanding of the ageing process at both the cellular and organismal levels. Early childhood presentations generally vary by growth and dermatological findings. Atherosclerotic cardiovascular disease and strokes account for the majority of morbidity and death in children with HGPS, with deaths occurring at an average age of 14.6 years. 

Progeria, Hutchinson-Gilford syndrome, and progeria of childhood are other names for HGPS.1 Drs. Hastings Gilford and Jonathan Hutchinson initially described HGPS in 1897 and 1886, respectively (Gilford, 1904; Hutchinson, 1886). Its cause remained a medical mystery for over a century. 

Gilford categorised the illness as a premature ageing syndrome because of the patients' general ageing-related characteristics and the presence of age-related symptoms such as hair loss, joint contractures, absence of subcutaneous fat, atherosclerosis-like cardiovascular disease, and childhood heart attacks and stroke deaths (Merideth et al., 2008).

According to research on disease gene mapping, a mutation in LMNA causes HGPS, an autosomal dominant, sporadic disease (De Sandre-Giovannoli et al., 2003; Eriksson et al., 2003). The proteins lamins A and C, which are essential structural components of eukaryotic nucleus cells, are produced by this gene. HGPS belongs to a class of disorders known as laminopathies, caused by mutations in different regions of the LMNA gene that cause a broad range of overlapping illnesses.2

How often does progeria occur? 

With an incidence of 1 in 8 million births, HGPS is a rare condition. However, because many cases probably go undetected or are misdiagnosed, the exact rate has been estimated to be closer to 1 in 4 million births

Race

97% of patients reported are White. This racial discrepancy's cause is uncertain.

Sex

HGPS has a 1.5:1 assigned male at birth (AMAB)-to-assigned female at birth (AFAB) ratio, with a slight AMAB bias.

Age

While many affected children come with sclerodermatous skin abnormalities, clinical signs of HGPS may not be identified or apparent at birth. It may take until the child is 6–12 months old or older to see the distinctive facial features' cutaneous and musculoskeletal manifestations.3,4

Clinical features

The clinical aspects are listed in the graphic below, along with comprehensive details as follows. Clinical characteristics that emerge in childhood and reflect certain aspects of accelerated ageing define classic and non-classic genotype HGPS. Progeria children appear normal at birth and in the first few months of life. Clinical features include:6

Created by: Deepika Rana (Created with BioRender.com)

Affected partClinical features
Growth deficiency- Short stature (<3rd percentile)
- Poor weight gain (<3rd percentile)
- Weight low for height
- Diminished subcutaneous body fat
Face- A large head for the face
- Long, narrow nose
- Thin vermilion of the upper and lower lips
- Retro and micrognathia
Ectodermal- Steeple-shaped palatal vault
- About 50% of individuals affected have a short, thick lingual frenulum that restricts tongue movement
- A high-pitched voice develops from rigid laryngeal tissues and a narrow airway
Dental- Delaying first tooth loss and delayed eruption
- Crowding of teeth 
- Partial secondary tooth eruption
Skin- Areas characterised as taut, thickened, fibrotic, indurated, or rippling are examples of "sclerodermatous" skin alterations.
- Skin outpouchings over the lower belly and proximal thighs
- Abnormal pigmentation
Hair- Complete alopecia develops from partial alopecia
- The occiput may have a few downy hairs
- Certain people lose their eyelashes and eyebrows
Nails- Dystrophic nails
Endocrine- Affected people never reach sexual maturity
- Serum leptin concentrations are below the limit of detection 
- 50% of individuals have insulin resistance
Cardiovascular- Severe atherosclerosis
- Ventricular hypertrophy is a sign of cardiovascular decline, accompanied by decreased heart muscle relaxation
- Aortic and mitral valve anomalies, such as regurgitation, stenosis, and calcification, appear in the second decade of life
- Angina, exertion-related dyspnoea and overt heart failure manifest as late findings in the course of the illness
- As early as age four, people have experienced transient ischaemic episodes (TIA), and silent and symptomatic strokes
- Plaque accumulation can result in partial and total blockages of the carotid arteries Few people with the condition experience the Raynaud phenomenon in their fingers
Eyes- Nocturnal lagophthalmos 
- Corneal dryness and clouding
- Corneal ulceration
Hearing- Low-frequency conductive hearing loss
Musculoskeletal- Coxa valga with a broad, shuffling gait followed by avascular necrosis of the femoral head
- Osteolysis of the distal phalanges
- Short clavicles with distal resorption
- Pear-shaped thorax6

Diagnosis

Several screening techniques serve to diagnose HGPS. Here is a synopsis of the steps involved:3,4

Physical examination

Together with a comprehensive clinical evaluation, a meticulous physical examination determines the distinctive characteristics of HGPS.

Genetic testing

Phenotype recognition combined with a progerin-producing mutation in the LMNA gene, either at the exon 11 intronic border (atypical form) or within exon 11 (classic type), is the diagnostic criteria for HGPS.

Imaging studies

Findings from radiography typically appear in the first or second year of life and are related to the thorax, phalanges, skull, and long bones. 

Computed tomography (CT) and magnetic resonance imaging (MRI) revealed many craniofacial structural bone and soft tissue abnormalities. Brain magnetic resonance angiography (MRA) establishes cerebrovascular occlusive disease. Checking for coronary artery disease and congestive heart failure should be done using serial electrocardiography (ECG) and echocardiography.

Biopsy findings

Scleroderma features emerge from skin biopsy specimens from firm, sclerotic regions.3,4

Treatment and management

HGPS treatment and management entail a multidisciplinary approach. 

Pharmacological treatment

  • Protein farnesyltransferase inhibitors (FTIs) are the most often utilised therapeutic medicines among various pharmacological techniques. Progeria symptoms and nuclear scaffolding breakdown improve by blocking protein farnesylation
  • The finding that lonafarnib therapy enhances the bone structure, auditory status, and neurologic function of children with HGPS lends credibility to this
  • Given the potential for cardiotoxicity and safety issues associated with long-term FTI usage, a clinical trial conducted over the past ten years has investigated the use of lonafarnib in combination with pravastatin and zoledronic acid
  • Of the patients, 71% have completed the primary result after receiving the triple therapy. Patients benefit from increased bone mineral density due to the triple therapy.

Nucleic acid therapy

  • Over 40% of the examined publications that reported preclinical and clinical trials used nucleic acid therapy as an option for treating HGPS 
  • Neonatal genetic modification, antisense oligonucleotide (ASO) treatment, CRISPR/Cas9-based therapy, and ex vivo genetic manipulation are the documented strategies to carry out the procedure. It is necessary to administer the intervention before birth

Cardiovascular management

  • It's vital to monitor for cardiovascular and cerebrovascular diseases. Individuals must take low doses of aspirin to avoid atherosclerotic brain and heart disease.

Physical and occupational therapy

Medical experts' assistance

  • Children with HGPS require coordinated assistance from many professionals, such as paediatric dentists, cardiologists, gastroenterologists, physical and occupational therapists, dermatologists, geneticists, and nutritionists. 

Psychosocial support

  • Progeria patients and their families benefit from psychological services like counselling and support groups. Providing coping mechanisms and attending to mental health are essential components of encompassing care

Diet

  • Children and infants with HGPS struggle to eat and may not develop. Age-appropriate nutritional supplements are advisable.3,9

Prognosis

Patients diagnosed with HGPS typically live 13 years, although they can range in age from 7 to 27. Based on a median follow-up of 5.3 years from therapy beginning, data from the largest cohort of HGPS patients showed a mean survival of 14.6 years, with enhanced mean survival of 1.6 years in patients treated with a protein farnesylation inhibitor.3

Recent developments

Future discoveries and advancements in the knowledge and treatment of HGPS are anticipated due to continued research and participation in clinical trials. Pictured below is a list of a few of them.10,11,12

PPMO, splicing, statins, and amino bisphosphonates

Created by: Deepika Rana (Canva)10,11,12

Summary

Progeria is a rare and challenging genetic illness that needs constant attention, understanding, and assistance. A multidisciplinary approach to care, coping mechanisms, and medical experts' guidance all help to improve the quality of life for affected individuals. Enhanced support for impacted individuals and their families could be possible as medical science advances and therapies become more effective. 

References

  1. Ullrich NJ, Gordon LB. Chapter 18 - Hutchinson–Gilford progeria syndrome. In: Islam MP, Roach ES, editors. Handbook of Clinical Neurology [Internet]. Elsevier; 2015 [cited 2023 Nov 14]. p. 249–64. (Neurocutaneous Syndromes; vol. 132). Available from: https://www.sciencedirect.com/science/article/pii/B9780444627025000184
  2. Gordon LB, Rothman FG, López-Otín C, Misteli T. Progeria: a paradigm for translational medicine. Cell [Internet]. 2014 Jan 30 [cited 2023 Nov 14];156(3):400–7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318797/
  3. Hutchinson-Gilford Progeria: practice essentials, background, pathophysiology. 2023 Jun 30 [cited 2023 Nov 14]; Available from: https://emedicine.medscape.com/article/1117344-overview#showall
  4. Progeria - an overview | Sciencedirect topics [Internet]. [cited 2023 Nov 14]. Available from: https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/progeria
  5. Sinha JK, Ghosh S, Raghunath M. Progeria: A rare genetic premature ageing disorder. Indian J Med Res [Internet]. 2014 May [cited 2023 Nov 14];139(5):667–74. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140030/
  6. Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford progeria syndrome. In: Adam MP, Feldman J, Mirza GM, Pagon RA, Wallace SE, Bean LJ, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2023 Nov 14]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1121/
  7. Sowmiya R, Prabhavathy D, Jayakumar S. Progeria in siblings: a rare case report. Indian J Dermatol [Internet]. 2011 [cited 2023 Nov 15];56(5):581–2. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221230/
  8. Corcoy R, Aris A, De Leiva A. Case report: fertility in a case of progeria. The American Journal of the Medical Sciences [Internet]. 1989 Jun 1 [cited 2023 Nov 15];297(6):383–4. Available from: https://www.sciencedirect.com/science/article/pii/S000296291536300X
  9. Lai W, Wong W. Progress and trends in the development of therapies for Hutchinson–Gilford progeria syndrome. Ageing Cell [Internet]. 2020 Jul [cited 2023 Nov 15];19(7):e13175. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370734/
  10. Puttaraju M, Jackson M, Klein S, Shilo A, Bennett CF, Gordon L, et al. Systematic screening identifies therapeutic antisense oligonucleotides for Hutchinson–Gilford progeria syndrome. Nat Med [Internet]. 2021 Mar [cited 2023 Nov 16];27(3):526–35. Available from: https://www.nature.com/articles/s41591-021-01262-4
  11. Erdos MR, Cabral WA, Tavarez UL, Cao K, Gvozdenovic-Jeremic J, Narisu N, et al. A targeted antisense therapeutic approach for Hutchinson–Gilford progeria syndrome. Nat Med [Internet]. 2021 Mar [cited 2023 Nov 16];27(3):536–45. Available from: https://www.nature.com/articles/s41591-021-01274-0
  12. Varela I, Pereira S, Ugalde AP, Navarro CL, Suárez MF, Cau P, et al. Combined treatment with statins and amino bisphosphonates extends longevity in a mouse model of human premature ageing. Nat Med [Internet]. 2008 Jul [cited 2023 Nov 16];14(7):767–72. Available from: https://www.nature.com/articles/nm1786

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Deepika Rana

Bachelor of Dental Surgery(BDS), Dentistry , H.P.Government Dental College, IGMC Shimla.Himachal Pradesh

Hi, I am Deepika Rana Dentist by profession finished my Clinical Research Certification Programme from Duke NUS Medical school, Singapore in 2022. I joined Klarity’s internship because of my ongoing desire to learn and educate others about medicine through Writing. I enjoy producing articles that give readers detailed information about a variety of ailments that can be accessed through the Health Library created by Klarity.

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