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PubMed1992

Report on a case of Hutchinson-Gilford progeria, with special reference to orthopedic problems.

Hutchinson-Gilford progeria is a very rare syndrome of premature aging and often features many orthopedic abnormalities. This is a case report on a young boy suffering from progeria. His orthopedic history included bilateral talus deformities of the feet, bilateral dislocated hips, pes planus, a fractured femur (which healed without complications), aseptic necrosis in the left nuclear head of the femur, bilateral fixed hip flexion deformities, bone dysplasia, osteoporosis and osteolysis.

Bone Diseases↗
PubMed1975

Heat-labile enzymes in skin fibroblasts from subjects with progeria.

To characterize further the genetic basis of progeria, thermolability studies were performed on three genetically distinct enzymes in crude extracts of cultured skin fibroblasts derived from two subjects with that syndrome. At early passage the progeric fibroblasts, as compared to controls, contained a significantly higher percentage of heat-labile glucose-6-phosphate dehydrogenase (12.83 plus or minus 1.72 vs 1.11 plus or minus 0.44 [mean plus or minus S.E.M.], p smaller than 0.001), 6-phosphogluconate dehydrogenase (9.71 plus or minus 0.68 vs. 0.67 plus or minus 0.22, p smaller than 0.001), and hypoxanthine-guanine phosphoribosyltransferase (31.41 plus or minus 1.89 vs 7.67 plus or minus 1.71, p smaller than 0.001), and the differences were maintained throughout the in vitro life-span. These data, in conjunction with previous reports of defective HL-A antigens, indicate a widespread defect in genetic expression. The most likely cause appears to be an aberration in protein synthesis or degradation, or both, although multiple somatic mutations cannot be ruled out. Increased thermolability of enzymes in cultured cells may provide a screening test for persons predisposed to progeria and other disorders of premature aging.

Adult↗
PubMed2006

Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody.

Hutchinson-Gilford progeria syndrome (HGPS; Online Mendelian Inheritance in Man accession no. 176670) is a rare disorder that is characterized by segmental premature aging and death between 7 and 20 years of age from severe premature atherosclerosis. Mutations in the LMNA gene are responsible for this syndrome. Approximately 80% of HGPS cases are caused by a G608 (GGC-->GGT) mutation within exon 11 of LMNA, which elicits a deletion of 50 aa near the C terminus of prelamin A. In this article, we present evidence that the mutant lamin A (progerin) accumulates in the nucleus in a cellular age-dependent manner. In human HGPS fibroblast cultures, we observed, concomitantly to nuclear progerin accumulation, severe nuclear envelope deformations and invaginations preventable by farnesyltransferase inhibition. Nuclear alterations affect cell-cycle progression and cell migration and elicit premature senescence. Strikingly, skin biopsy sections from a subject with HGPS showed that the truncated lamin A accumulates primarily in the nuclei of vascular cells. This finding suggests that accumulation of progerin is directly involved in vascular disease in progeria.

Age Factors↗
PubMed2006

Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome.

Children with Hutchinson-Gilford progeria syndrome (HGPS) suffer from dramatic acceleration of some symptoms associated with normal aging, most notably cardiovascular disease that eventually leads to death from myocardial infarction and/or stroke usually in their second decade of life. For the vast majority of cases, a de novo point mutation in the lamin A (LMNA) gene is the cause of HGPS. This missense mutation creates a cryptic splice donor site that produces a mutant lamin A protein, termed "progerin," which carries a 50-aa deletion near its C terminus. We have created a mouse model for progeria by generating transgenics carrying a human bacterial artificial chromosome that harbors the common HGPS mutation. These mice develop progressive loss of vascular smooth muscle cells in the medial layer of large arteries, in a pattern very similar to that seen in children with HGPS. This mouse model should prove valuable for testing experimental therapies for this devastating disorder and for exploring cardiovascular disease in general.

Animals↗
PubMedDate not supplied

Progeria: medical aspects, psychosocial perspectives, and intervention guidelines.

This article discusses progeria, a rare genetic childhood disorder that invariably results in the individual's death during early adolescence. The article begins by describing the major medical aspects of progeria. This is followed by a discussion of the psychosocial implications of the disorder with particular emphasis upon grief-triggered reactions. The article concludes with an overview of psychosocial intervention guidelines for caregivers who work with families of dying children and adolescents.

Adaptation, Psychological↗
PubMedDate not supplied

Hutchinson-Gilford progeria syndrome: a pathologic study.

Hutchinson-Gilford progeria syndrome is an extremely rare condition with features of premature and accelerated aging. The pattern of inheritance if unclear, although both autosomal recessive and autosomal dominant modes have been proposed. The children usually present in late infancy and early childhood with a characteristic phenotype of alopecia; short stature; abnormal skin, teeth, and nails; beaked nose; loss of subcutaneous fat; and failure to thrive. This condition has been reported on all inhabited continents and has been described in all major races. Laboratory findings note an increased urinary excretion of hyaluronic acid. Death results from cardiovascular abnormalities in the majority of cases and usually occurs in the second decade of life. There is no effective treatment. We report the pathologic changes noted at autopsy on a 20-year-old woman with classic features of Hutchinson-Gilford progeria syndrome.

Adult↗
PubMed2006

Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation.

LMNA-associated progeroid syndromes have been reported with both recessive and dominant inheritance. We report a 2-year-old boy with an apparently typical Hutchinson-Gilford progeria syndrome (HGPS) due to compound heterozygous missense mutations (p.T528M and p.M540T) in LMNA. Both mutations affect a conserved region within the C-terminal globular domain of A-type lamins, defining a progeria hot spot. The nuclei of the patient showed no prelamin A accumulation. In general, the nuclear phenotype did not correspond to that previously described for HGPS. Instead, honeycomb figures predominated and nuclear blebs with reduced/absent expression of B-type lamins could be detected. The healthy heterozygous parents showed similar nuclear changes, although in a smaller percentage of nuclei. Treatment with a farnesylation inhibitor resulted in accumulation of prelamin A at the nuclear periphery, in annular nuclear membrane plaques and in intra/trans-nuclear membrane invaginations. In conclusion, these findings suggest a critical role for the C-terminal globular lamin A/C region in nuclear structure and support a major contribution of abnormal assembly to the progeroid phenotype. In contrast to earlier suggestions, we show that prelamin A accumulation is not the major determinant of the progeroid phenotype.

Adult↗
PubMed1988

Increased elastin production by progeria skin fibroblasts is controlled by the steady-state levels of elastin mRNA.

Hutchinson-Gilford progeria is a unique, rare disease with markedly accelerated aging. The average lifespan of affected individuals is 12 years. Although the biochemical basis of the syndrome is unknown, its influence appears to be primarily upon mesodermal tissues. Characteristics such as the altered appearance of the skin and the extensive and fatal involvement of the cardiovascular system led us to study elastin production in cultured skin fibroblasts from three progeroid individuals. We found tropoelastin production by progeroid cells was elevated six- to nine-fold at the protein and mRNA levels, while relative collagen synthesis was similar to control strains. There was little difference between progeroid and normal cells in expression of total protein or in total cellular mRNA content. Western blot analysis of tropoelastin from progeroid fibroblasts confirmed increased production of elastin but revealed no gross changes in the molecular mass. The significant increase in tropoelastin expression lends support to the concept that progeria results from a mesenchymal dysplasia, and offers a possible biochemical marker for the phenotype.

Adolescent↗
PubMed1999

Progeria (Hutchinson-Gilford): a case report.

A new case with the typical features of progeria (Hutchinson-Gilford) occurred in India. Histopathology of the skin showed atrophic epidermis and diffuse fibrosis of dermis with loss of appendages. Roentgenographic findings were characteristic of progeria. The child also had a gangrenous ulcer over the left foot, a finding not highlighted in the literature.

Child, Preschool↗
PubMed1991

Progressive early dermatologic changes in Hutchinson-Gilford progeria syndrome.

We describe evolving dermatologic findings in a male with progeria from age 1 month to 21.5 months. At 18 months of age, irregular pigmentary changes of the abdomen, early occipital alopecia, superficial scalp veins, glyphic nasal tip, absent ear lobules, coarse hair that stands on end, crowded dentition with delayed tooth development, and dystrophic nails permitted the diagnosis of progeria. Radiographs showed evidence of resorption of the distal ends of the clavicles, attenuation of the terminal phalanges, diffuse osteopenia, and fishmouth vertebral bodies, which are typical of this syndrome. Appreciation of the evolution of early dermatologic findings may permit earlier diagnosis of this condition in infants with skin changes.

Diagnosis, Differential↗
PubMed1978

Hyaluronuria in a case of progeria. (Hutchinson-Gilford syndrome).

A classic case of progeria (Hutchinson-Gilford syndrome) in a 9-year-old Japanese boy is presented. The characteristic clinical features in this patient were similar to those reported in the literature. The total amount of acid glycosaminoglycans excreted in the urine was within the normal range, but there was an increase in hyaluronic acid excretion. The hyaluronuria was a novel finding in progeria, providing a common linkage with the hyaluronuria found in Werner's syndrome.

Child↗
PubMed1992

Hyaluronic acid in progeria and the aged phenotype?

Hyaluronic acid (HA) is implicated in functions such as vascularity, morphogenesis, repair, and the general integrity of the extracellular matrix. Hence, it is considered possible that HA is involved in the most conspicuous features of the progeroid phenotype. However, it is not known whether the increase in HA excretion seen in progeria patients is due to a primary genetic defect or is a secondary effect due to some deeper problem. The phenomenon of 'normal' aging is suggested to have a more complex etiology and phenotype than progeria and the role of HA levels is less well-defined.

Aging↗
PubMed1973

Absence of detectable HL-A antigens on cultured fibroblasts in progeria.

HL-A phenotypes were determined by a cytotoxicity assay on circulating lymphocytes of two boys with the premature aging syndrome, progeria. The antigenic phenotypes were not unusual inasmuch as they are frequently seen in the normal population. However, none of these antigens could be detected by the same assay on cultured skin fibroblasts from either individual, even when a significant mitotic potential remained before cessation of growth. Fibroblasts from normal donors were concordant with corresponding lymphocytes for HL-A antigens and maintained these antigens until mitotic division had virtually ceased. Absorption studies on fibroblasts with two HL-A2 antisera revealed that HL-A antigens are either absent or have a drastically reduced expression on progeric fibroblasts. The data are in accord with the concept of an immunological role in the pathogenesis of progeria.

Adolescent↗
PubMed1999

Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome is an extremely rare condition of premature aging. It is characterized by growth retardation and accelerated degenerative changes of cutaneous, musculoskeletal and cardiovascular systems. The pathogenesis of the disease is unknown. The patients usually appear normal at birth. Typical manifestations develop gradually and are evident by the first or second year of life. They have a remarkably similar physical appearance consisting of short stature, alopecia, craniofacial disproportion, micrognathia, hypoplastic mandible, beak-like nose, decreased subcutaneous fat, atrophic skin, sclerodermoid lesion, mottling hyperpigmentation, prominent scalp veins, prominent eyes, protruding ears with absence of earlobes, faint midfacial cyanosis, delayed closure of fontanelles and sutures, delayed dentition, horse-riding stance, thin limbs with prominent stiff joints, coxa valga, skeletal hypoplasia and dysplasia, dystrophic nails and high-pitched voice. Laboratory investigations are unremarkable. Metabolic, endocrine, serum lipid and immunologic studies show no uniform abnormalities. Typical radiographs demonstrate evidence of resorption of the distal ends of clavicles, attenuation of the terminal phalanges, diffuse osteopenia, and fishmouth vertebral bodies. In this report, a 3-year-old Thai girl with typical characteristics of Hutchinson-Gilford progeria syndrome is described.

Child, Preschool↗
PubMed1999

Lethal neonatal Hutchinson-Gilford progeria syndrome.

We report on a 35-week gestation female fetus with Hutchinson-Gilford progeria (HGP). This patient, who is the first reported with neonatal HGP in the English literature but is the fourth, counting three previous French cases, supports the existence of a more severe prenatal form of progeria. She died 7 hours after birth and presented with intrauterine growth retardation, premature aging, absence of subcutaneous fat, brachydactyly, absent nipples, hypoplastic external genitalia, and abnormal ear lobes. The child's combination of clinical and skeletal manifestations differentiates this form of HGP from other progeroid syndromes with neonatal presentation. We also report previously undescribed autopsy findings including premature loss of hair follicles, premature regression of the renal nephrogenic layer, and premature closure of the growth plates in the distal phalanges that may be related to the aging processes in this condition. We could not find any histological data to support acro-osteolysis, which is the radiographic sign of brachydactyly. The terminal phalanges in HGP seem to be underdeveloped rather than osteolytic.

Abnormalities, Multiple↗
PubMed1999

[P53-status of cells from patients with progeria and ataxia-telangiectasia exposed to ionizing irradiation].

P53 protein expression and stabilization in cell strains derived from patients suffering from progeria and ataxia-telangiectasia following gamma-irradiation have been described. A similar pattern of P53-status in healthy donor and progeria patient cells was shown using immunofluorescent cell staining. In ataxia-telangiectasia cells (strain AT2SP) the P53 protein was not detected by the same method. These data well compare with literary evidence on a disturbed P53-status at ataxia-telangiectasia.

Adult↗
PubMed2004

Hutchinson-Gilford progeria syndrome with severe calcific aortic valve stenosis and calcific mitral valve.

The case of a 12-year-old girl with clinical features of progeria with severe calcific valvar aortic stenosis is presented. The mitral valve showed the presence of calcium, and peripheral vascular disease was also present, though there was no family history of this. Aortic valve replacement was deferred because of insufficient data relating to this condition. The genetics and phenotypic mechanisms of the disease are reviewed. In view of the association of progeria with valve disease, all patients should undergo electrocardiography and echocardiography as part of their routine work-up.

Aortic Valve Stenosis↗