Progeria - PDF by neophyte


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Authors: Doctors Laurence Faivre1 and Valérie Cormier-Daire
Creation Date: July 2001
Updated: May 2003
         March 2005

Scientific Editor: Doctor Valérie Cormier-Daire
Consultation de génétique, CHU Hôpital du Bocage, 2 Boulevard Maréchal de Lattre de Tassigny, 21034
Dijon Cedex, France.

Disease name and synonyms
Diagnosis criteria / Definition
Clinical description
Differential diagnosis
Diagnostic methods
Genetic counseling
Antenatal diagnosis
Management including treatment
Unresolved questions

Hutchinson-Gilford progeria syndrome is an extremely rare disorder characterized by premature aging of
postnatal onset. The main clinical and radiological features include alopecia, thin skin, hypoplasia of nails,
loss of subcutaneous fat, stiffness of joints and osteolysis. Intelligence is not impaired. Early death is
caused by atherosclerosis or cerebrovascular disease, and failure to thrive. Most cases are sporadic,
caused by a de novo dominant recurrent truncating mutation within the lamin A gene. Numerous
progeroid syndromes represent differential diagnoses for this entity.

Hutchinson-Gilford syndrome, premature aging, lamin A gene mutation

Disease name and synonyms                                           Diagnosis criteria / Definition
- Progeria                                                          Association of:
- Hutchinson-Gilford progeria syndrome (HGPS)                       - Prematurely aged phenotype of postnatal onset
Progeria is a term recognized by many                               - Rapidly progressive growth failure
physicians as applying to individuals who appear                    - Characteristic facies, alopecia, loss of
prematurely aged. Misdiagnosis of HGPS is                           subcutaneous fat, hypotrichosis, thin, wrinkled
frequently made in patients presenting with                         skin with prominent superficial veins
some of the features of the syndrome, i.e.                          - Stiffness of joints, osteolysis
alopecia and skin with an aged appearance.                          -    Early     death     by    atherosclerosis or
                                                                    cerebrovascular disease
The estimated birth prevalence is one in four
million births.

Faivre L., Cormier-Daire V. Progeria. Orphanet encyclopedia. March 2005.                                                              1
Clinical description                                                be hypoplastic and the fontanels and sutures
Clinical manifestations are evident by the first or                 remain open longer than expected. Wormian
second year of life. The failure to grow and to                     bones are common. Thinning and resorption of
gain weight at a normal rate usually appears                        the distal clavicles is the most consistent
abruptly during the first year of life and can recur                abnormality to be found in the thorax. Narrowing
later at times of illness. Linear growth tends to                   of the posterior ribs is frequent. The long bones
be about half the normal rate, and shows no                         are slender with thin cortices. Severe coxa vara
rapid increase at prepubertal or pubertal ages.                     is a consistent finding, and moderate genu
The weight deficit is greater than the height                       valgum is frequently present. The progressive
deficit. By the time growth failure can be noticed,                 bone loss from the distal phalanxes of the
the patients usually have a cranium which                           fingers and/or toes is one of the hallmarks of the
appears to be large in comparison with the face                     disease.
and body. Intelligence and brain development is
not impaired. The mean age of death is 14                           Etiology
years. This death is often secondary to coronary                    The etiopathogenesis of progeria has been slow
artery disease.                                                     to emerge. Extensive metabolic investigations
Consistent clinical features include lower weight                   have failed to detect the defect in HGPS. Growth
and less subcutaneous fat, craniofacial                             hormone (GH) responses are normal, elevated
disproportion, micrognathia, prominent scalp                        GH level is frequent, with an elevated metabolic
veins, alopecia, "plucked-bird" appearance,                         rate. No abnormality of thyroid, parathyroid,
abnormal teeth, pyriform thorax, short clavicles,                   pituitary or adrenal gland function has been
"horse-riding" stance, wide-based gait, coxa                        reported.      There      is    a     degree     of
valga, thin limbs, prominent and stiff joints, and                  insulinoresistance.     Abnormalities    of    skin
distal osteolysis.                                                  collagen and elastin have been described, with
Other     anomalies      frequently     present   in                markedly elevated elastin and collagen type IV
Hutchinson-Gilford progeria are thin, wrinkled,                     production. Skin cultures are sometimes difficult
sclerodermatous and brown-spotted skin,                             because of early cell death. Hyperlipidemia has
hypotrichosis, absence of eyebrows and                              never been very high or marked. Some authors
eyelashes, patent fontanels and sutures, beaked                     suggested defective vitamin E metabolism,
nose, circumoral cyanosis, thin lips, protruding                    others demonstrated increased fraction of heat-
ears with absent lobes, and dystrophic nails with                   labile enzymes and other altered proteins. One
short terminal phalanges.                                           patient had an inverted insertion in the long arm
Autopsy reports have described varying degrees                      of chromosome 1 in 70% of cells, which
of generalized atherosclerosis, mainly involving                    suggested that a gene for progeria may be
the larger arteries. Coronary occlusions with                       located on chromosome 1. Studies of aneuploidy
myocardial infarctions were found more                              in skin fibroblasts of patients with HGPS showed
frequently than cerebral vascular lesions.                          that the rate was significantly higher than in
Nephrosclerosis was sometimes described.                            controls, but without a significant pattern of
                                                                    chromosome-specific aneuploidy. Studies of the
Differential diagnosis                                              DNA maintenance indicate faithful transcription
Many other premature aging syndromes, which                         in HGPS. Another study showed reduced DNA
are called progeroid syndromes and which also                       repair in progeria cells.
mimic senescence, need to be distinguished                          In 2003, mutations in LMNA, the gene encoding
from progeria. Neonatal progeroid syndromes                         Lamin A (1q21.2), have been evidenced. It is to
are evident at birth and include Wiedemann-                         date the only gene associated with HGPS, and
Rautenstrauch     syndrome,    Hallerman-Streiff                    point mutations are found in 90% of individuals.
syndrome and De Barsy syndrome. Others,                             A recurrent de novo point mutation within exon
including Mandibuloacral dysplasia or Cockayne                      G608G is found in most of the individuals,
syndrome are diagnosed later in life, although                      leading to abnormal splicing truncated protein.
they may have a neonatal onset. Werner                              Individuals with the common mutation G608G
syndrome and acrogeria can be also mistaken                         present a remarkably similar phenotype,
with HGPS.                                                          whereas patients with other point mutations have
                                                                    unusual phenotypes. Other individuals with
Diagnostic methods                                                  HGPS have been found to have uniparental
Diagnosis currently depends upon recognition of                     isodisomy of chromosome 1 and a deletion of
clinical and radiographic findings. The finding of                  the LMNA gene.
the common LMNA truncating mutation could                           The protein product of this gene coats and
also be helpful in the diagnosis.                                   organizes the interior surface of the nuclear
The characteristic radiological abnormalities are                   envelope. Immunofluorescence of HGPS
to be found in the skull, thoracic cage, long                       fibroblasts with antibodies directed against lamin
bones and phalanxes. The cranial bones tend to                      A reveals that 40-50% of the cells show irregular

Faivre L., Cormier-Daire V. Progeria. Orphanet encyclopedia. March 2005.                                                                2
shape of the nuclear envelope. The common                           lowered the basal metabolism rate. Since
mutation appears to act as a dominant negative                      delayed loss of primary teeth is common,
mutation      affecting    nuclear    morphology.                   extractions may be required to avoid crowding or
Interestingly, mutations in LMNA have also been                     development of two rows of teeth.
reported     in     other    conditions,  named
laminopathies, including autosomal dominant                         Unresolved questions
and     recessive      Emery-Dreiffus    muscular                   A unique consanguineous family with autosomal
dystrophy, autosomal recessive restrictive                          recessive HGPS and homozygous mutation
dermopathy, autosomal dominant dilated                              within the Lamin A gene has been reported, with
cardiomyopathy with conduction system defects,                      overlapping features with mandibuloacral
autosomal dominant Dunningam-type partial                           dysplasia. Further reports should confirm the
lipodystophy, autosomal dominant limb-girdle                        existence of an autosomal recessive entity in
muscular dystrophy 1B, autosomal recessive                          HGPS.
Charcot-Marie-Tooth type 2B1, autosomal                             A patient was reported to have a neonatal form
recessive mandibuloacral dysplasia and atypical                     of HGPS, but this diagnosis is discussed since
Werner syndrome.                                                    the postnatal character of the premature aging is
                                                                    part of the definition of HGPS.
Genetic counseling                                                  Although patients with HGPS have an aged
De novo dominant mutations have been                                appearance, they usually do not demonstrate
evidenced in HGPS. Most cases are sporadic                          senile cataracts, senile presbycusis, presbyopia,
and mean paternal age is increased. The risk for                    arcus     senilis,    osteoarthritis, or   senile
the sibs of a proband is small, limited to the                      personalities. This syndrome may only mimic
possibility of germinal mosaicism. Nevertheless,                    certain aspects of the aging process.
genetic counseling requires clinical expertise in
order to rule out other differential diagnosis and                  References
therefore different mode of inheritance.                            Abdenur JE, Brown WT, Friedman S, Smith M,
Molecular analysis of the LMNA gene could be                        Lifshitz F. Response to nutritional and growth
helpful in some cases. Parent to child                              hormone treatment in progeria. Metabolism
transmission has never been observed since                          1997; 46: 851-856.
patients with HGPS do not reproduce.                                Arboleda H, Quintero L, Yunis E. Wiedemann-
                                                                    Rautenstrauch neonatal progeroid syndrome:
Antenatal diagnosis                                                 report of three new patients. J Med Genet 1997;
Antenatal early molecular diagnosis is available                    34: 433-437.
if the mutation has been identified in the                          Baker PB, Baba N, Boesel CP. Cardiovascular
proband, although the risk of recurrence is small,                  abnormalities in progeria. Case report and
limited to the unlikely possibility of germline                     review of the literature. Arch Pathol Lab Med
mosaicism in one of the parents. Careful                            1981; 105: 384-386.
ultrasound monitoring searching for intrauterine                    Cao H, Hegele RA. LMNA is mutated in
growth retardation could also be proposed, but                      Hutchinson-Gilford progeria (MIM 176670) but
normal growth cannot rule out the diagnosis with                    not in Wiedemann-Rautenstrauch progeroid
certainty since birth weight varies from 1 to 3.8                   syndrome (MIM 264090). J Hum Genet 2003;
kg.                                                                 48: 271-274.
                                                                    DeBusk FL. The Hutchinson-Gilford progeria
Management including treatment                                      syndrome. Report of 4 cases and review of the
No effective therapy is currently available to cure                 literature. J Pediatr 1972; 80: 697-724.
the     disease.    Nevertheless,    symptomatic                    De Sandre-Giovannoli A, Bernard R, Cau P,
treatment should be proposed for all its                            Navarro C, Amiel J, Boccaccio I, Lyonnet S,
complication, including orthopedic complications.                   Stewart CL, Munnich A, Le Merrer M, Levy N.
The main complication of progeria is coronary                       Lamin A truncation in Hutchinson-Gilford
artery disease, and monitoring for cardiovascular                   progeria. Science. 2003 27;300(5628):2055.
disease should be obtained at least annually.                       Eriksson M, Brown WT, Gordon LB, Glynn MW,
The possibility of coronary artery bypass surgery                   Singer J, Scott L, Erdos MR, Robbins CM,
or percutaneous transluminal angioplasty has                        Moses TY, Berglund P, Dutra A, Pak E, Durkin
been reported. Low doses of aspirin could be                        S, Csoka AB, Boehnke M, Glover TW, Collins
discussed in the prevention of heart attacks or                     FS. Recurrent de novo point mutations in lamin
stokes. Anesthetics should be used with                             A cause Hutchinson-Gilford progeria syndrome.
particular caution. Non aggressive nutritional                      Nature 2003;423:293-298.
therapy was proposed in a study and slightly                        Fossel M. Human aging and progeria. J Pediatr
improved weight gain and growth. Combined                           Endocrinol Metab 2000; 13 Suppl 6:1477-1481.
nutritional therapy and GH treatment improved                       Mukherjee AB, Costello C. Aneuploidy analysis
growth velocity, levels of growth factors and                       in fibroblasts of human premature aging

Faivre L., Cormier-Daire V. Progeria. Orphanet encyclopedia. March 2005.                                                              3
syndromes by FISH during in vitro cellular aging.                   Rodriguez JI, Perez-Alonso P, Funes R, et al.
Mech Ageing Dev 1998; 103:209-222.                                  Lethal neonatal Hutchinson-Gilford Progeria
O'Brien ME, Jensen S, Weiss AS. Hutchinson-                         syndrome. Am J Med Genet 1999; 82: 242-248.
Gilford progeria: faithful DNA maintenance,                         Wang SM, Nishigori C, Yagi T, Takebe H.
inheritance and allelic transcription of beta(1-4)                  Reduced DNA repair in progeria cells and effects
galactosyltransferase.    Mech      Ageing    Dev                   of gamma-ray irradiation on UV-induced
1998;101:43-56.                                                     unscheduled DNA synthesis in normal and
Parkash H, Sidhu SS, Raghavan R, et al.                             progeria cells. Mutat Res. 1991; 256:59-66.
Hutchinson-Gilford progeria: familial occurrence.
Am J Med Genet 1990; 36: 431-433.

Faivre L., Cormier-Daire V. Progeria. Orphanet encyclopedia. March 2005.                                                             4

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