Progeria

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Hutchinson-Gilford progeria syndrome or progeria was first discovered by DeBusk and the name was given by Hastings Gilford. Dyck et al reported a patient who had progeria and underwent coronary artery bypass surgery and percutaneous transluminal angioplasty.De Paula Rodrigues et al described the involvement of bones and joints in progeria patients. The word progeria is of greek origin which means prematurely old.

Progeria may be classified according to genotype into two groups: Classic progeria and atypical progeria.

It is thought that Hutchinson-Gilford progeria is due to mutation in LMNA gene.

The most common cause of Hutchinson-Gilford progeria syndrome (HGPS) is mutation in LMNA gene.

Hutchinson-Gilford progeria syndrome (HGPS) must be differentiated from other diseases such as Atypical progeria syndromes, Restrictive dermopathy, Familial partial lipodystrophy (FPLD), Wiedemann-Rautenstrauch syndrome, Congenital generalized lipodystrophy, Cockayne syndrome, Mandibuloacral dysplasia and Petty-Laxova-Wiedemann progeroid syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare hereditary disease. The incidence of Hutchinson-Gilford progeria syndrome (HGPS) is very rare. The usual age of diagnosis for Hutchinson-Gilford progeria syndrome(HGPS) ia around two to three years of age. Approximately 100 cases of Hutchinson-Gilford progeria syndrome (HGPS) have been reported in the literature till now worldwide.

The most potent risk factor in the development of Hutchinson-Gilford progeria syndrome is mutation in LMNA gene.

There is insufficient evidence to recommend routine screening for Hutchinson-Gilford progeria syndrome (HGPS).

The symptoms of Hutchinson-Gilford progeria syndrome (HGPS) usually develop in the first decade of life, complications of Hutchinson-Gilford progeria syndrome (HGPS) include progressive atherosclerosis and myocardial infarction. Prognosis is generally poor, in patients with Hutchinson-Gilford progeria syndrome (HGPS).

There is no single diagnostic study of choice for the diagnosis of Hutchinson-Gilford progeria syndrome (HGPS).

The majority of patients with Hutchinson-Gilford progeria syndrome (HGPS) are growth issues, cardiac issues, ophthalmologic problems, hearing problems, failure to thrive, poor weight gain and prominent scalp veins.

Common physical examination findings of Hutchinson-Gilford progeria syndrome (HGPS) include skin changes, hair changes, eye problems and musculoskeletal abnormalities.

Some patients with Hutchinson-Gilford progeria syndrome (HGPS) may have elevated platelet counts, serum phosphorus levels and decreased leptin levels and bone density.

There are no ECG findings associated with Hutchinson-Gilford progeria syndrome (HGPS).

An x-ray may be helpful in the diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) and findings are acroosteolysis and clavicular resorption.

There are no echocardiography/ultrasound findings associated with Hutchinson-Gilford progeria syndrome (HGPS).

CT scan findings associated with Hutchinson-Gilford progeria syndrome (HGPS) include calcification and stenosis of internal carotid artery.

Head MRI may be helpful in the diagnosis of craniofacial abnormalities in patients with Hutchinson-Gilford Progeria syndrome(HGPS).

There are no other imaging findings associated with Hutchinson-Gilford progeria syndrome (HGPS).

There are no other diagnostic studies associated with Hutchinson-Gilford progeria syndrome (HGPS).

There is no treatment for Hutchinson-Gilford progeria syndrome (HGPS); the mainstay of therapy is supportive care. But the good news is that there are new investigational therapies for Hutchinson-Gilford progeria syndrome (HGPS) patients which include lonafarnib and everolimus.

Surgery is not the first-line treatment option for patients with Hutchinson-Gilford progeria syndrome (HGPS). Surgery is usually reserved for patients with hip dislocation.

There are no established measures for the primary prevention of Hutchinson-Gilford progeria syndrome (HGPS).

Effective measures for the secondary prevention of Hutchinson-Gilford progeria syndrome (HGPS) include nutritional assessment, assessment of the cardiac and neurologicstatus of the patient, musculoskeletal issues assessment, dental evaluation, ophthalmology evaluation, and audiology evaluation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Hutchinson-Gilford progeria syndrome or progeria was first discovered by DeBusk and the name was given by Hastings Gilford. Dyck et al reported a patient who had progeria and underwent coronary artery bypass surgery and percutaneous transluminal angioplasty.De Paula Rodrigues et al described the involvement of bones and joints in progeria patients. The word progeria is of greek origin which means prematurely old.

• In 1886, Hutchinson is the to first to described the syndrome progeria.^{[1][2][3][4][5]}
• In 1972, progeria was renamed to “Hutchinson-Gilford progeria syndrome” by DeBusk.
• In 1904, the name to the disease as progeria was given by Hastings Gilford.
• Jonathan Hutchinson previously mention the disease progeria disorder and written about progeria.
• Paterson reported 2 cases of progeria in 2 brothers whose parents had a consanguineous marriage.

• In 1986, Ogihara et al reported a case in Japan who might have progeria and survived till 45 years which is unusually long life span for the disease.
• In 1987, Dyck et al reported a patient who had progeria and underwent coronary artery bypass surgery and percutaneous transluminal angioplasty.
• In 1987, De Martinville et al reported 3 cases of neonatal Hutchinson-Gilford progeria syndrome in France.
• In 1990, Parkash et al noticed mandibuloacral dysplasia in a patient who is suffering with progeria.
• In 1990, Fatunde et al reported progeria in 3 out of 6 siblings in a family.
• In 2002, De Paula Rodrigues et al described the involvement of bones and joints in progeria patients.
• In 2006, Hennekam described the phenotypes of Hutchinson-Gilford progeria syndrome.
• In 2008, Merideth et al studied 15 patients who are suffering with Hutchinson-Gilford progeria syndrome very comprehensively about the features of the disease and well documented.

The following are a few famous cases of progeria:

1. Sam: Sam passed away on January 10, 2014. He was 17 years old.
   • “Life According to Sam” is a famous documentary about Sam condition
2. Meghan Waldron: She is a senior in high school and lives with her family in Massachusetts.
3. Megan: She is currently enrolled in the Lonafarnib Trial Extension/Expansion.
4. Sammy: Sammy is 23 years old and is from Italy, In 2014 Sammy was featured in an Italian National Geographic Series, Il Viaggio Di Sammy.
5. Adalia: She’s from Texas, this 12-year-old is widely known for her funny videos and special relationship with her mom, Natalia – her 14 million Facebook followers are proof of that.
6. Brennan: Ten-year-old boy from New York. In July 2014, Brennen had his first Progeria Clinical Trial visit in Boston.
7. Zoey: In July 2013 Zoey began taking lonafarnib as part of the Trial Expansion.
8. Beandri: Beandri is 13 years old and from South Africa.
9. Enzo: Enzo is a seven-year-old boy from Australia.
10. Cameron: Cameron is from Pittsburgh, Pennsylvania.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Progeria may be classified according to genotype into two groups: Classic progeria and atypical progeria.

• Progeria may be classified according to genotype into two groups:^[1]

Group	Classification of Hutchinson-Gilford Progeria Syndrome	Cause
Group 1	Classic Hutchinson-Gilford progeria syndrome	Due to nucleotide substitution in the lamin A/C gene LMNA(c.1824C>T [p.Gly608Gly])
Group 2	Atypical Hutchinson-Gilford progeria syndrome	Due to a variety of pathogenic variants in intron 11 of the LMNA gene

• Other Non-progeroid laminopathies associated with LMNA gene mutations which produces atypical or truncated protein A lamin:^{[2][3][4][5][6][7][8]}
  • Emery-Dreifuss muscular dystrophy(Autosomal dominant)
  • Emery-Dreifuss muscular dystrophy(Autosomal recessive)
  • Familial dilated cardiomyopathy(Autosomal dominant)
  • Dilated cardiomyopathy and hypergonadotropic hypogonadism
  • Dilated cardiomyopathy with apical left ventricular aneurysm(Autosomal dominant)
  • Mandibuloacral dysplasia(Autosomal recessive)^[9]
  • Heart-hand syndrome, Slovenian type
  • Petty-Laxova-Wiedemann progeroid syndrome^[10]
  • Charcot-Marie-Tooth type 2B1
  • Restrictive dermopathy^[11][12]
  • Familial partial lipodystrophy type 2
  • Dunnigan-type familial partial lipodystrophy (FPLD), (Autosomal dominant)
  • Limb-girdle muscular dystrophy^[13]
  • Malouf syndrome with hypergonadotropic hypogonadism and cardiomyopathy^[14]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

It is thought that Hutchinson-Gilford progeria is the result due to mutation in LMNA gene.

• It is understood that Hutchinson-Gilford progeria is the result due to mutation in LMNA gene.^[1]

Genes involved in the pathogenesis of Hutchinson-Gilford progeria syndrome (HGPS) include:^[2]

LMNA Gene

Classic Hutchinson-Gilford progeria syndrome

• The location of the Hutchinson-Gilford progeria syndrome (HGPS) gene was at chromosome 1q.^[3][4]
• A single nucleotide substitution in the lamin A/C gene LMNA(c.1824C>T [p.Gly608Gly]) results in classic HGPS.^[5][6][7]
• The mutation does not change the position of glycine at 608 in protein chain.
• De novo dominant mutation in the LMNA gene causes classic HGPS.
• A single de novo dominant mutation at C to T pathogenic variant which is located at exon 11, C1824T of the LMNA gene results in activation of a cryptic splice donor site.^[8]
• Now at cryptic splice donor site there is formation of a messenger RNA with a 150-nucleotide internal deletion near the C-terminus of the chain.
• The resultant of the mutation leads to formation of short lamin A protein which is called progerin.
• Progerin has a 50-amino acid internal deletion along with CAAX box farnesylation site due to de novo dominant mutation.
• Now the progerin which has 50-amino acid misses the cleave site, due to internal deletion which results in continuous farnesylation which in turn results in progerin anchored to the nuclear envelope.^[9]
• This continuous farnesylation thought be the cause of the disease and results in following changes:
  • Nuclear blebbing
  • Disorganized heterochromatin
  • Dysregulated gene transcription
• This whole unexpected sequences in the cell leads to genomic instability and may leads to premature aging and disease in Hutchinson-Gilford progeria syndrome.^[10]
• And it is also thought that in Hutchinson-Gilford progeria syndrome telomere length is decreased gradually.^[11]

• The cause of atypical progeria syndromes is almost similar to Classic Hutchinson-Gilford progeria syndrome except the mutations are mostly occurs in intron 11 of the LMNA gene where as in Classic Hutchinson-Gilford progeria the mutations occurs in c.1824C>T [p.Gly608Gly].^[12][13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

The most common cause of Hutchinson-Gilford progeria syndrome (HGPS) is mutation in LMNA gene.

Common causes of Hutchinson-Gilford progeria syndrome (HGPS) may include:^[1][2][3][4]

• Mutation in LMNA gene which results in production of abnormal protein laminin A which is also called progerin
• LMNA gene plays a very crucial role in the following:
  • Membrane which surrounds the cell’s nucleus and stabilizes the nuclear membrane.
• The location of the LMNA gene is on chromosome 1.

Less common causes of Hutchinson-Gilford progeria syndrome (HGPS) include:

• ZMPSTE24 gene mutation^[5]

• Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in the LMNA gene.

Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	Mutation in LMNA gene
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	No underlying causes
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	LMNA gene mutation
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Hutchinson-Gilford progeria syndrome (HGPS) must be differentiated from other diseases such as Atypical progeria syndromes, Restrictive dermopathy, Familial partial lipodystrophy (FPLD), Wiedemann-Rautenstrauch syndrome, Congenital generalized lipodystrophy, Cockayne syndrome, Mandibuloacral dysplasia and Petty-Laxova-Wiedemann progeroid syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) must be differentiated from the following:^[1]

• Atypical progeria syndromes
• Restrictive dermopathy^[2]
• Familial partial lipodystrophy (FPLD)
• Wiedemann-Rautenstrauch syndrome^[3]
• Congenital generalized lipodystrophy^[4]
• Cockayne syndrome
• Mandibuloacral dysplasia^[5]
• Petty-Laxova-Wiedemann progeroid syndrome^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare hereditary disease. The incidence of Hutchinson-Gilford progeria syndrome (HGPS) is very rare. The usual age of diagnosis for Hutchinson-Gilford progeria syndrome (HGPS) ia around two to three years of age. Approximately 100 cases of Hutchinson-Gilford progeria syndrome (HGPS) have been reported in the literature till now worldwide.

• The incidence of Hutchinson-Gilford progeria syndrome (HGPS) is approximately one in four to eight million births worldwide.^[1][2]
• The incidence of Hutchinson-Gilford progeria syndrome (HGPS) in Netherlands is 1:4,000,000.^[3]

• The prevalence of Hutchinson-Gilford progeria syndrome (HGPS) is approximately 1 in 20 million individuals worldwide.

• Hutchinson-Gilford progeria syndrome (HGPS) commonly affects individuals of very younger age rather than older age.
• The median age at diagnosis is 2.9 years overall.^[4]

• Hutchinson-Gilford progeria syndrome (HGPS) usually affects individuals of the white race.

• Hutchinson-Gilford progeria syndrome (HGPS) affects men and women equally but males are little more commonly affected by Hutchinson-Gilford progeria syndrome than females.
• The male to female ratio is approximately 1.5:1.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

The most potent risk factor in the development of Hutchinson-Gilford progeria syndrome is mutation in LMNA gene.

• The most potent risk factor in the development of Hutchinson-Gilford progeria syndrome is mutation in LMNA gene.^[1][2][3][4]
• Other than genetic there are no other risk factors mentioned

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

There is insufficient evidence to recommend routine screening for Hutchinson-Gilford progeria syndrome (HGPS).

There is insufficient evidence to recommend routine screening for Hutchinson-Gilford progeria syndrome (HGPS).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

The symptoms of Hutchinson-Gilford progeria syndrome (HGPS) usually develop in the first decade of life, complications of Hutchinson-Gilford progeria syndrome (HGPS) include progressive atherosclerosis and myocardial infarction. Prognosis is generally poor, in patients with Hutchinson-Gilford progeria syndrome (HGPS).

• The symptoms of Hutchinson-Gilford progeria syndrome (HGPS) usually develop in the first decade of life, and start with symptoms as follows:^[1][2]
  • Failure to thrive
  • Loss of subcutaneous fat
  • Poor weight gain
    • Weight increase of only 0.44 kg/year
  • Short stature
    • Decreased linear weight gain
  • Alopecia

• Common complications of Hutchinson-Gilford progeria syndrome (HGPS) include:^[3][4][5]
  • Progressive atherosclerosis
  • Myocardial infarction
  • Transient ischemic attack (TIA)
  • Stroke
  • Exposure keratopathy
  • Conductive hearing loss

• Prognosis is generally poor, in patients with Hutchinson-Gilford progeria syndrome (HGPS).^[6]
• The presence of progressive atherosclerosis is associated with a particularly poor prognosis among patients with Hutchinson-Gilford progeria syndrome (HGPS).
• The average lifespan of patients with Hutchinson-Gilford progeria syndrome (HGPS) is about 15 years.^[7][8]

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