Phenotype and course of Hutchinson-Gilford progeria syndrome

Abstract

Background: Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription.

Methods: We enrolled 15 children between 1 and 17 years of age, representing nearly half of the world's known patients with Hutchinson-Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006.

Results: Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle-brachial indexes, and adventitial thickening.

Conclusions: Establishing the detailed phenotype of Hutchinson-Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00094393.)

Figure 1. Physical Findings in Children with Hutchinson–Gilford Progeria Syndrome

Panel A shows short stature in Patient 2 at 21 months of age. Panel B shows alopecia in Patient 5 at 4 years of age. Panel C shows progressive aging in Patient 9 at 7 years of age. Panel D shows prominent veins, knee joints, and contractures under maximal passive extension in Patient 12. Panel E shows tufting of fingers in Patient 13. Panel F shows phalangeal joint contractures in Patient 14. Panel G shows dimpling in the left leg of Patient 4. Panel H shows areas of hypopigmented skin in Patient 2. Panel I shows abdominal outpouching and reticulated hyperpigmented skin interspersed with hypopigmented skin in Patient 8. Panel J shows circumoral cyanosis in Patient 5.

Figure 2. Weight, Height, Bone Density, and Percent of Body Fat as a Function of Age in 15 Children with Hutchinson–Gilford Progeria Syndrome

Panel A shows weight plotted according to age. Red squares represent the normal third percentile for both boys and girls, which is approximately 2 SD below the mean. Blue diamonds and I bars represent means (±SD) for patients with Hutchinson–Gilford progeria syndrome. Points are centered for each time period. For example, all values between 0 and 4 months are averaged and plotted at 2 months. The numbers of patients with Hutchinson–Gilford progeria syndrome for whom data were available are given below each point. Data obtained while patients were receiving growth hormone treatment were excluded. Panel B shows height plotted according to age, as in Panel A. Data obtained during growth hormone treatment were excluded. Panel C shows bone density as a function of age. Each z-score unit represents 1 SD from the normal mean for age. Panel D shows body fat as a function of age. Circles represent girls, and diamonds represent boys. Open symbols represent normal values, with bars for 1 SD; closed symbols represent values for children with Hutchinson–Gilford progeria syndrome.

Figure 3. Vascular, Bone, Dental, and Auditory Findings in Children with Hutchinson–Gilford Progeria Syndrome

In Panel A, the markers show the borders of plaque in the common carotid artery in Patient 15. Panel B shows the vascular lesion (arrow) in the carotid artery in Patient 15. Panel C shows acro-osteolysis in Patient 14 at 12 years of age. Distal phalanges show resorption to tufts. Panel D shows clavicular resorption and the conical chest in Patient 13 at 10 years of age. Panel E shows the coxa valga in Patient 13. The angle of the acetabulum with respect to the femur is reduced. The left hip joint is characterized by destruction and displacement. Panel F shows high-grade stenosis (arrows) at the level of the carotid siphons bilaterally in Patient 14. Panel G shows the ogival palate in Patient 9. Panel H shows the composite audiogram of the right ear, indicating low-frequency hearing loss in 11 patients with Hutchinson–Gilford progeria syndrome. The black line indicates the mean air-conduction threshold for the right ear, and the orange line indicates the bone-conduction threshold for the right ear.