Progeria refers specifically to Hutchinson-Gilford Progeria syndrome. Hutchinson-Gilford Progeria syndrome is an extremely rare condition in which physical aspects of aging are greatly accelerated, and few affected children live past age 13. About 1 in 8 million babies are born with this condition.
Progeria Authors: Doctors Laurence Faivre1 and Valérie Cormier-Daire Creation Date: July 2001 Updated: May 2003 March 2005 Scientific Editor: Doctor Valérie Cormier-Daire 1 Consultation de génétique, CHU Hôpital du Bocage, 2 Boulevard Maréchal de Lattre de Tassigny, 21034 Dijon Cedex, France. firstname.lastname@example.org Abstract Keywords Disease name and synonyms Prevalence Diagnosis criteria / Definition Clinical description Differential diagnosis Diagnostic methods Etiology Genetic counseling Antenatal diagnosis Management including treatment Unresolved questions References Abstract 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. Keywords 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 Prevalence The estimated birth prevalence is one in four million births. Faivre L., Cormier-Daire V. Progeria. Orphanet encyclopedia. March 2005. http://www.orpha.net/data/patho/GB/uk-progeria05.pdf 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. http://www.orpha.net/data/patho/GB/uk-progeria05.pdf 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. http://www.orpha.net/data/patho/GB/uk-progeria05.pdf 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. http://www.orpha.net/data/patho/GB/uk-progeria05.pdf 4
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