Professional Documents
Culture Documents
Progeria
Progeria
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://www.pediatrics.org/cgi/content/full/120/4/824
Departments of aPediatrics, cDiagnostic Imaging, and fBiostatistics, Rhode Island Hospital, Providence, Rhode Island; Departments of bPediatrics and dRadiology, Warren
J. Alpert Medical School at Brown University, Providence, Rhode Island; Departments of eBiostatistics and Computational Biology and hPediatric Oncology, Dana Farber
Cancer Institute, Boston, Massachusetts; gDepartment of Gerontology, Brown University, Providence, Rhode Island; iDepartment of Pediatric Hematology and Oncology,
Children’s Hospital Boston, Boston, Massachusetts
The authors have indicated they have no financial relationships relevant to this article to disclose.
ABSTRACT
OBJECTIVES. Hutchinson-Gilford progeria syndrome is a rare and uniformly fatal
segmental “premature aging” disease that affects a variety of organ systems. We
www.pediatrics.org/cgi/doi/10.1542/
sought to more clearly define the bone and weight abnormalities in patients with peds.2007-1357
progeria as potential outcome parameters for prospective clinical trials. doi:10.1542/peds.2007-1357
PATIENTS AND METHODS. We collected and analyzed longitudinal medical information, both Key Words
progeria, Hutchinson-Gilford progeria
retrospectively and prospectively, from a total of 41 children with Hutchinson-Gilford syndrome, developmental dysplasia,
progeria syndrome spanning 14 countries, from the Progeria Research Foundation osteoporosis, clinical trial
Medical and Research Database at the Brown University Center for Gerontology. Abbreviations
HGPS—Hutchinson-Gilford progeria
RESULTS. In addition to a number of previously well-defined phenotypic findings in syndrome
CI— confidence interval
children with progeria, this study identified abnormalities in the eruption of
Accepted for publication Jun 26, 2007
secondary incisors lingually and palatally in the mandible and maxilla, respec-
Address correspondence to Leslie B. Gordon,
tively. Although bony structures appeared normal in early infancy, clavicular MD, PhD, Hasbro Children’s Hospital,
resorption, coxa valga, avascular necrosis of the femoral head, modeling abnor- Department of Pediatrics, 593 Eddy St,
Providence, RI 02903. E-mail: leslie㛭gordon@
malities of long bones with slender diaphyses, flared metaphyses, and overgrown brown.edu
epiphyses developed. Long bones showed normal cortical thickness centrally and PEDIATRICS (ISSN Numbers: Print, 0031-4005;
progressive focal demineralization peripherally. The most striking finding identi- Online, 1098-4275). Copyright © 2007 by the
American Academy of Pediatrics
fied in the retrospective data set of 35 children was an average weight increase of
only 0.44 kg/year, beginning at ⬃24 months of age and persisting through life,
with remarkable intrapatient linearity. This rate is ⬎2 SD below normal weight
gain for any corresponding age and sharply contrasts with the parabolic growth
pattern for normal age- and gender-matched children. This finding was also
confirmed prospectively.
CONCLUSIONS. Our analysis shows evidence of a newly identified abnormal growth
pattern for children with Hutchinson-Gilford progeria syndrome. The skeletal and
dental findings are suggestive of a developmental dysplasia rather than a classical
aging process. The presence of decreased and linear weight gain, maintained in all
of the patients after the age of 2 years, provides the ideal parameter on which
altered disease status can be assessed in clinical trials.
824 GORDON et al
Downloaded from www.pediatrics.org. Provided by Pakistan:AAP Sponsored on July 1, 2010
H UTCHINSON-GILFORD PROGERIA SYNDROME (HGPS)
is a rare (frequency 1 in 4 million) and uniformly
fatal segmental “premature aging” disease that affects a
over a patient’s life span, which will serve as the primary
clinical outcome parameter in a clinical trial for HGPS.
FIGURE 1
Permanent teeth form and erupt palatally and lingually (arrows)
to the primary teeth as demonstrated here in 4 different children:
A, 8-month-old girl (MRI); B, 10.5-year-old boy (MRI); C, 10.5-year-
old boy (photograph); D, 10-year-old boy (photograph).
826 GORDON et al
Downloaded from www.pediatrics.org. Provided by Pakistan:AAP Sponsored on July 1, 2010
and exhibited progressive clavicular resorption with in-
creasing age. Thinning and tapering of ribs was evident
in a total of 14 of 17 patients who provided radiographs
between the ages of 2.0 months and 18.1 years. Three
patients did not exhibit abnormal ribs at ages 3.4, 5.8,
and 6.7 years. Eleven patients contributed longitudinal
radiographs showing normal ribs that later progressed to
thin, tapered ribs. Three patients contributed radio-
graphs only at later ages (10.5, 13.1, and 16.0 years of
age), all of whom showed the abnormal pattern. The
thorax developed a pyramidal configuration, with the
ribs having a “drooped” appearance resulting in narrow-
ing at the apex. Clavicular resorption was evident signif-
icantly earlier than rib abnormality (18.4 ⫾ 9.9 months
versus 4.4 ⫾ 2.2 years, respectively).
The diaphyses were much more slender than usual for Anthropometric Analyses
age. The epiphyses were similarly large and broadened.
Weight Analysis: Birth to 24 Months
Long bones also demonstrated atypical demineraliza-
Twenty five of 29 children were born at term (ⱖ37
tion. We found that, in 19 of 19 patients, diaphyseal
weeks’ gestation). Longitudinal weight data were avail-
cortical bone was of normal width and mineralization,
able for 27 children in the data set (11 girls and 16 boys).
whereas the metaphyses and epiphyses were qualita-
The average weight at birth for the children was 2.91 kg
tively more demineralized, indicating that decreased
(95% CI: 2.69 to 3.13). The average weight of the girls
mineralization is localized to the ends of the bones (Fig was 0.14 kg greater than that of the boys, but this
4). Only 1 patient experienced a bone breakage and difference was not statistically significant (P ⫽ .35). For
healed normally (as a result of a fall while playing bas- the birth-to-24-month age group, weight was related to
ketball), indicating no increase above normal in fracture the square of age in months and resulted in a rate of
risk in HGPS. weight gain that decreased as the children aged from
birth to 24 months (Fig 6A).
Normal Radiologic Findings Weight Analysis of Retrospective and Prospective Data Sets
Bone ages and growth plates were normal. Bone ages for Ages Beyond 24 Months
derived from hand radiographs in 14 children, ages new- There were data for 35 children in the retrospective data
born to 11.7 years, were within normal limits, and set (15 girls and 20 boys; Table 1). The children had an
growth plates of all 22 of the children’s joint films were average of 75 months of follow-up, starting at any time
open, similar to age-matched normal control subjects, at point beyond 2 years of age (median: 74 months), with
newborn to 18.1 years of age. In the 10 children who boys having longer average follow-up than girls (boys:
provided skull films between the ages of 2.9 months and 96 months; girls: 48 months). When there were multiple
8.5 years, we found no evidence of widened cranial weight recordings on a given day, they were averaged to
sutures, a finding described previously as being part of give a daily weight measurement. The data set had an
this disorder by DeBusk.2 average of 22 weight measurements per child, with boys
Arthritis was not a feature of HGPS. Radiograph films having a larger number of measurements than girls
from 21 children, ages newborn to 14.6 years, were (boys: 26 measurements; girls: 16 measurements). The
assessed for arthritis in wrists, ankles, hips, knees, and rate of weight gain was constant over time, rather than
elbows. No evidence of either rheumatoid or osteoar- varying, with an average increase of 0.44 kg/year, be-
thritis was found (Fig 5). In all of the children, 3 ele- ginning at ⬃2 years of age (Table 2 and Fig 6B). Girls
ments crucial for diagnosis of arthritis were missing. were 0.87 kg lighter, on average, than boys (P ⫽ .03;
Joint spaces were of normal width, there were no peri- 95% CI: ⫺1.3 to ⫺ 0.4). Although interpatient rates of
articular erosions, and there were no proliferative weight gain varied, for age ranges 2 to 16 years, the rate
changes (no osteophyte formation). Most impressively, of weight gain for each child was constant and closely
1 child with long-standing and severe avascular necrosis predicted by the statistical model developed (Fig 6C).
of the hip did not exhibit traumatic arthritis that would There were data for 25 children in the prospective data
typically evolve in a nonprogeroid patient (Fig 3C). set, 24 of whom are also included in the retrospective
828 GORDON et al
Downloaded from www.pediatrics.org. Provided by Pakistan:AAP Sponsored on July 1, 2010
months). When there were multiple weight recordings
on a given day, weights were averaged to result in a daily
weight measurement. The data set had an average of 18
weight measurements per child, with boys having a
larger number of measurements than girls (boys: 19
measurements; girls: 17 measurements). The prospec-
tive data also showed that the rate of weight gain was
constant over time, and, in this case, increased at a rate
of 0.524 kg/year (Table 2). From this model, girls were
0.85 kg lighter (95% CI: ⫺1.6 to ⫺0.1), on average, than
boys (P ⫽ .03).
Linear weight gain in both the retrospective and pro-
spective data sets were not significantly different. Both
demonstrated dramatic impairment compared with
weight gain in normal age- and gender-matched chil-
dren.
Linear Growth
Clinical charts indicate that 30 of 30 children developed
knee flexion contractures. Of 19 with information sup-
plied in the first 6 years of life, the average age of noted
contracture was 14.6 months (range: birth to 50.0
months). Therefore, unlike weight evaluation, recorded
heights are underestimates as a result of knee contrac-
tures that uniformly affect this patient population.
Recorded lengths and heights on 38 children were
analyzed (20 boys and 18 girls). Birth lengths were
recorded for 24 children. Of those, 23 fell between the
13.0th and 99.6th percentiles (mean: 48.6 ⫾ 24.7
months), and 1 was significantly decreased (0.0008th
percentile). For 26 children whose clinical charts re-
corded length and height data within the first year and
thereafter, measures fell below the third percentile of
normal for age between birth and 34.0 months (mean:
16.2 ⫾ 10.6 months) and stayed ⬎2 SD below normal
thereafter. All of the values for 12 of 12 additional chil-
dren with height recorded for ages 34 months and be-
yond were below the third percentile of normal.
DISCUSSION
Children with HGPS look so similar that they could all be
mistaken for siblings. There is variability in onset and
rate of progression of disease among children, although
FIGURE 4
Long-bone abnormalities and juxta-articular demineralization in HGPS: A, 6-year-old the final phenotype in these patients is remarkably sim-
lower leg with HGPS shows normal diaphyseal width and cortical thickness (see insets) ilar, underscoring the identical common mutation that
and flaring and demineralization of the proximal and distal metaphyses (arrows) com-
leads downstream to similar pathobiology. However, the
pared with a normal age-matched control (B). C, An 8.5-year-old elbow with HGPS shows
normally mineralized humeral diaphyses, constricted radial neck, and overgrowth and rarity of HGPS (frequency: 1 in 4 million live births1–3)
demineralization of the capitellum of the distal humerus compared with a normal age- makes it extremely difficult to amass sufficient clinical
matched control (D). Note here, as in the wrist, that there is no evidence of joint cartilage
information to delineate the nature of growth abnormal-
loss with HGPS.
ities and the underlying disease process in HGPS. We
have collected and analyzed the largest set of clinical
weight data set (13 girls and 12 boys; Table 1). The data for HGPS to date and used the data set not only to
children had an average of 6 months of prospective compare and contrast features of HGPS with what is
follow-up, starting at any time point beyond 2 years of documented in the literature but also to search out dis-
age (median: 5.3 months), with boys having longer av- ease characteristics that can be used as primary param-
erage follow-up than girls (boys: 8.1 months; girls: 4.4 eters for treatment efficacy during clinical trials.
HGPS is classically known as a disease of premature joints are prominent and contracted.16 Although juxta-
aging, as its name and clinical appearances imply. In- articular osteopenia is commonly associated with arthri-
deed, there is cellular evidence for the shortened life tis, we found no evidence of either rheumatoid or os-
span of HGPS fibroblasts in vitro,27–30 and this is likely teoarthritis, conditions that would be characterized by
caused because progerin, the protein product of the neovascularization rather than a lack of vascular sup-
HGPS genetic mutation, builds in cellular concentration ply,36 even in the presence of joint malalignment and
with successive cell passages.7 Importantly, there is evi- demineralization that is usual for HGPS.
dence that progerin is produced at very low levels in However, we did find extensive evidence for skeletal
normal fibroblasts,31 suggesting that this molecule may dysplasia in HGPS. Most of the bone pathology of the
also play some role in normal human aging. In addition upper and lower extremities was noted distally, partic-
to other factors downstream of the primary genetic de- ularly in the fingers, all of the long bones, thinning and
fect, the way in which progerin production is dramati- tapering of ribs distally, and clavicular tissue that was
cally increased in HGPS and translates into clinical dis- resorbed from the lateral margin in toward the midline.
ease warrants careful comparison with the diseases of We show definitively that these features are progressive,
normal aging. starting with normal-looking clavicular structures in in-
In our analysis, the bony sequelae in HGPS presented fancy, and progressing to abnormality within several
as a progressive skeletal dysplasia and varied from the years.
typical aging phenomena. Bone age and growth plate One of the earliest clinical findings in HGPS, in addi-
closure rates remained normal; demineralization was tion to growth delay, is delayed dentition.13,37 Classically
focal rather than global; and arthritis was not identified in HGPS there is severely delayed tooth eruption, and
in any patients. teeth are crowded and irregularly positioned. We now
Osteoporosis and arthritis are common sequelae of show, for the first time, that, in addition to delayed
normal aging. Classically, HGPS has been associated with dentition, the permanent incisors erupt lingually. This
global osteoporosis.3,9,32 However, our analysis showed novel finding is not identified in other disease processes.
focal and nonclassical demineralization rather than the Although ectopic eruption of molars can be associated
global demineralization seen in osteoporosis of normal with small-sized mandible and maxilla,38 children with
aging33 and without the increased fracture risk. Unlike HGPS have normally sized skulls at 8 months of age (Fig
generalized cortical thinning of osteoporosis of aging, the 1 A and B), when secondary teeth are beginning to form
cortical thickness in the diaphyseal regions was normal within the mandible and maxilla.39 Thus, the data point
and became more thinned as it extended toward the to a primary abnormality and not simply maldevelop-
metaphysis. Although osteopenia is associated with hy- ment because of dental crowding and small jaw bones.
pervascularity in adults and children,34 bone loss may We hypothesize that microvascular insufficiency and
also occur as a consequence of ischemia related to vas- matrix abnormalities contribute to the bony maldevel-
cular disease (reviewed by Rajzbaum and Bezie35). The opment in HGPS. Both in vitro and in vivo pathologic
nonclassical, regional demineralization found at the dis- studies support a role for microvasculature abnormalities
tal end of all long bones in HGPS may be a sign of in HGPS.40–42 We found abnormally narrow femoral and
vascular insufficiency. A more quantitative analysis of humoral shafts, as well as abnormally broad metaphyses
bone mineralization using dual energy radiograph ab- and epiphyses, compared with age-matched control sub-
sorptiometry or peripheral quantitative computed to- jects with resultant abnormal shaft/metaphysis diameter
mography is warranted in future studies. ratios. The physes themselves do not have a direct blood
A common perception in the literature has been that supply but are indirectly supplied above and below by
children with HGPS develop arthritis, likely because vessels at the epiphysis and the metaphysis. Slowed bone
830 GORDON et al
Downloaded from www.pediatrics.org. Provided by Pakistan:AAP Sponsored on July 1, 2010
TABLE 1 Characteristics of Data Sets Beyond 24 Months of Age
Variables Mean SD Median Minimum Maximum
Retrospective data set
(N ⫽ 35)
Months of follow-
up per child
Girls 48.3 33.9 51.9 3.4 120.2
Boys 95.7 54.6 98.6 0.23 184.7
Overall 75.4 52.0 74.0 0.23 184.7
Weight readings
per child
Girls 16.0 14.0 14.0 2.0 52.0
Boys 26.0 24.0 21.5 2.0 88.0
Overall 22.0 21.0 19.0 2.0 88.0
Prospective data set
(N ⫽ 25)
Months of follow-
up per child
Girls 4.4 2.1 5.3 0.7 6.7
Boys 8.1 10.4 5.3 3.7 40.9
Overall 6.2 7.4 5.3 0.7 40.9
Weight readings
per child
Girls 17.0 9.0 19.0 5.0 30.0
Boys 19.0 5.0 19.5 7.0 25.0
Overall 18.0 7.0 19.0 5.0 30.0
832 GORDON et al
Downloaded from www.pediatrics.org. Provided by Pakistan:AAP Sponsored on July 1, 2010
Heather Hardie, MD; Monica Kleinman, MD; and Kyra transferase improves nuclear blebbing in mouse fibroblasts
Johnson. with a targeted Hutchinson-Gilford progeria syndrome muta-
tion. Proc Natl Acad Sci U S A. 2005;102:10291–10296
22. Yang SH, Meta M, Qiao X, et al. A farnesyltransferase inhibitor
REFERENCES improves disease phenotypes in mice with a Hutchinson-
1. Brown W, Zebrower M, Kieras F. Progeria, a model disease for Gilford progeria syndrome mutation. J Clin Invest. 2006;116:
the study of accelerated aging. Basic Life Sci. 1985;35:375–396 2115–2121
2. DeBusk FL. The Hutchinson-Gilford progeria syndrome. Re-
23. Columbaro M, Capanni C, Mattioli E, et al. Rescue of hetero-
port of 4 cases and review of the literature. J Pediatr. 1972;80:
chromatin organization in Hutchinson-Gilford progeria by
697–724
drug treatment. Cell Mol Life Sci. 2005;62:2669 –2678
3. Hennekam RC. Hutchinson-Gilford progeria syndrome: review
24. Huang S, Chen L, Libina N, et al. Correction of cellular phe-
of the phenotype. Am J Med Genet A. 2006;140:2603–2624
notypes of Hutchinson-Gilford progeria cells by RNA interfer-
4. Cao H, Hegele RA. LMNA is mutated in Hutchinson-Gilford
ence. Hum Genet. 2005;118:444 – 450
progeria (MIM 176670) but not in Wiedemann-Rautenstrauch
25. Scaffidi P, Misteli T. Reversal of the cellular phenotype in the
progeroid syndrome (MIM 264090). J Hum Genet. 2003;48:
271–274 premature aging disease Hutchinson-Gilford progeria syn-
5. De Sandre-Giovannoli A, Bernard R, Cau P, et al. Lamin a drome. Nat Med. 2005;11:440 – 445
truncation in Hutchinson-Gilford progeria. Science. 2003;300: 26. Abdenur JE, Brown WT, Friedman S, Smith M, Lifshitz F.
2055 Response to nutritional and growth hormone treatment in
6. Eriksson M, Brown WT, Gordon LB, et al. Recurrent de novo progeria. Metabolism. 1997;46:851– 856
point mutations in lamin A cause Hutchinson-Gilford progeria 27. Bridger JM, Kill IR. Aging of Hutchinson-Gilford progeria syn-
syndrome. Nature. 2003;423:293–298 drome fibroblasts is characterised by hyperproliferation and
7. Goldman RD, Shumaker DK, Erdos MR, et al. Accumulation of increased apoptosis. Exp Gerontol. 2004;39:717–724
mutant lamin A causes progressive changes in nuclear archi- 28. Danes BS. Progeria: a cell culture study on aging. J Clin Invest.
tecture in Hutchinson-Gilford progeria syndrome. Proc Natl 1971;50:2000 –2003
Acad Sci U S A. 2004;101:8963– 8968 29. Goldstein S. Lifespan of cultured cells in progeria. Lancet. 1969;
8. Csoka AB, Cao H, Sammak PJ, Constantinescu D, Schatten GP, 1(7591):424
Hegele RA. Novel lamin A/C gene (LMNA) mutations in atyp- 30. Goldstein S. Studies on age-related diseases in cultured skin
ical progeroid syndromes. J Med Genet. 2004;41:304 –308 fibroblasts. J Invest Dermatol. 1979;73:19 –23
9. Fernandez-Palazzi F, McLaren AT, Slowie DF. Report on a case 31. Scaffidi P, Misteli T. Lamin A-dependent nuclear defects in
of Hutchinson-Gilford progeria, with special reference to or- human aging. Science. 2006;312:1059 –1063
thopedic problems. Eur J Pediatr Surg. 1992;2:378 –382 32. Hamer L, Kaplan F, Fallon M. The musculoskeletal manifestations
10. Green LN. Progeria with carotid artery aneurysms: report of a of progeria: a literature review. Orthopedics. 1988;11:763–769
case. Arch Neurol. 1981;38:659 – 661 33. Llorens R. A review of osteoporosis: diagnosis and treatment.
11. Moen C. Orthopaedic aspects of progeria. J Bone Joint Surg Am. Mo Med. 2006;103:612– 615; quiz 615– 616
1982;64:542–546 34. Resnick D. Diagnosis of Bone and Joint Disorders. 4th ed. Phila-
12. Gamble JG. Hip disease in Hutchinson-Gilford progeria syn- delphia, PA: WB Saunders; 2002
drome. J Pediatr Orthop. 1984;4:585–589 35. Rajzbaum G, Bezie Y. Postmenopausal osteoporosis and ather-
13. Hasty MF, Vann J. Progeria in a pediatric dental patient: liter- oma. Joint Bone Spine. 2006;73:661– 666
ature review and case report. Pediatr Dent. 1988;10:314 –319 36. Goldring S, Gravallese E. Pathogenesis of bone erosions in
14. Reichel W, Bailey JA 2nd, Zigel S, Garcia-Bunuel R, Knox G. rheumatoid arthritis. Curr Opin Rheumatol. 2000;12:195–199
Radiological findings in progeria. J Am Geriatr Soc. 1971;19: 37. Hall JW 3rd, Denneny JC 3rd. Audiologic and otolaryngologic
657– 674
findings in progeria: case report. J Am Acad Audiol. 1993;4:
15. Sood S, Rao RC, Ragav B, Berry M. Progeria syndrome with
116 –121
characteristic deformation of proximal radius observed on CT.
38. O’Meara W. Ectopic eruption pattern in selected permanent
Acta Radiol. 1991;32:67– 68
teeth. J Dent Res. 1962;41:607– 616
16. Gupte S, Pal M, Sharma Y, Kohli U. Progeria with osteoarthritis
39. Ash M, Nelson S. Wheeler’s Dental Anatomy, Physiology and Oc-
in a four-year-old girl. A case report. Indian J Pediatr. 1976;43:
clusion. 7th ed. Philadelphia, PA: WB Saunders; 1993
319 –320
40. Csoka AB, English SB, Simkevich CP, et al. Genome-scale
17. Capell BC, Erdos MR, Madigan JP, et al. Inhibiting farnesyla-
tion of progerin prevents the characteristic nuclear blebbing of expression profiling of Hutchinson-Gilford progeria syndrome
Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci reveals widespread transcriptional misregulation leading to
U S A. 2005;102:12879 –12884 mesodermal/mesenchymal defects and accelerated atheroscle-
18. Fong LG, Frost D, Meta M, et al. A protein farnesyltransferase rosis. Aging Cell. 2004;3:235–243
inhibitor ameliorates disease in a mouse model of progeria. 41. Delahunt B, Stehbens WE, Gilbert-Barness E, Shozawa T,
Science. 2006;311:1621–1623 Ruger BM. Progeria kidney has abnormal mesangial collagen
19. Glynn MW, Glover TW. Incomplete processing of mutant distribution. Pediatr Nephrol. 2000;15:279 –285
lamin A in Hutchinson-Gilford progeria leads to nuclear ab- 42. Lemire JM, Patis C, Gordon LB, Sandy JD, Toole BP, Weiss AS.
normalities, which are reversed by farnesyltransferase inhibi- Aggrecan expression is substantially and abnormally upregu-
tion. Hum Mol Genet. 2005;14:2959 –2969 lated in Hutchinson-Gilford progeria syndrome dermal fibro-
20. Toth JI, Yang SH, Qiao X, et al. Blocking protein farnesyltrans- blasts. Mech Ageing Dev. 2006;127:660 – 669
ferase improves nuclear shape in fibroblasts from humans with 43. Varga R, Eriksson M, Erdos MR, et al. Progressive vascular
progeroid syndromes. Proc Natl Acad Sci U S A. 2005;102: smooth muscle cell defects in a mouse model of Hutchinson-
12873–12878 Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2006;103:
21. Yang SH, Bergo MO, Toth JI, et al. Blocking protein farnesyl- 3250 –3255