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Hutchinson-Gilford progeria syndrome
1st described in 1886.
Epidemiology:
- rare, 100 cases reported worldwide [3]
- 1 in 4,000.000 births [6]
Pathology:
1) accelerated atherosclerosis
2) premature aging
3) alopecia
4) atrophy of subcutaneous fat
5) skeletal hypoplasia
a) stiff joints
b) hip dislocations
6) progerin (protein protein product of mutant LMNA gene) disrupts nuclear membrane, alters transcription
Genetics:
1) point mutations in the LMNA gene
a) mutations not found in parents, this NOT inherited
b) point mutation C->T in exon 11 of the LMNA gene in 25 patients
1] results in a silent Gly-Gly change at codon 608
2] apparently occurs at cryptic splice site
3] results in protein with deleted C-terminus (50 amino acid residues)
4] C-terminus contains endoproteolytic cleavage site for normal synthesis of lamin A
5] result is abnormalities in nuclear membrane
c) other point mutations in exon 11 the LMNA gene have been reported
2) 3 patients described without LMNA gene mutations
Clinical manifestations:
1) normal development during the 1st year of life
2) growth retardation beginning in the 2nd year of life
3) mean age of diagnosis is 19 months
4) senile appearance
a) dry, wrinkled, sclerotic skin
b) alopecia
c) bird-like facies
d) joint contractures
e) decreased body fat
5) farsightedness
6) low-frequency conductive hearing loss
7) speech deficits
8) dental abnormalities
Laboratory:
- prolonged prothrombin time [4]
- thrombocytosis
- increased serum phosphorus
Special laboratory:
- echocardiography may be useful in clinical trials [3]
Complications:
1) atherosclerosis
a) myocardial infarction
b) TIA, stroke
2) LV diastolic dysfunction most common cardiac abnormality [3]
- prevalence increases with age
- LV systolic dysfunction & valvular heart disease less common
3) seizures
Management:
- lonafarnib may delay mortality [6]
- pravastatin adds no cardiovascular benefit [7]
- zoledronate may improve bone mineral density
- prognosis
- most patients die by the age of 13
General
progeroid syndrome
Database Correlations
OMIM 176670
References
- Harrison's Principles of Internal Medicine, 13th ed.
Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1038
- Stedman's Medical Dictionary 26th ed, Williams &
Wilkins, Baltimore, 1995
- Novelli G & D'Apice MR, Trends in Mol Med 9(9):370, 2003
- Merideth MA et al,
Phenotype and course of Hutchinson-Gilford progeria syndrome.
N Engl J Med 2008, 358:592
PMID: 18256394
- Prakash A, Gordon LB, Kleinman ME et al
Cardiac Abnormalities in Patients With Hutchinson-Gilford
Progeria Syndrome.
JAMA Cardiol. Published online February 21, 2018
PMID: 29466530
https://jamanetwork.com/journals/jamacardiology/article-abstract/2672949
- Gordon LB, Shappell H, Massaro J et al
Association of Lonafarnib Treatment vs No Treatment With
Mortality Rate in Patients With Hutchinson-Gilford Progeria
Syndrome.
JAMA. 2018;319(16):1687-1695
PMID: 29710166
https://jamanetwork.com/journals/jama/fullarticle/2679278?
- Hisama FM, Oshima J.
Precision Medicine and Progress in the Treatment of
Hutchinson-Gilford Progeria Syndrome.
JAMA. 2018;319(16):1663-1664.
PMID: 29710145
https://jamanetwork.com/journals/jama/fullarticle/2679255
- Gordon LB, Kleinman ME, Massaro J et al
Clinical Trial of the Protein Farnesylation Inhibitors
Lonafarnib, Pravastatin, and Zoledronic Acid in Children With
Hutchinson-Gilford Progeria Syndrome.
Circulation. 2016 Jul 12;134(2):114-25.
PMID: 27400896 Free PMC Article