Disease Progression in Hutchinson-Gilford Progeria Syndrome: Impact on

Growth and Development

Leslie B. Gordon, Kathleen M. McCarten, Anita Giobbie-Hurder, Jason T. Machan,
Susan E. Campbell, Scott D. Berns and Mark W. Kieran
Pediatrics 2007;120;824-833
DOI: 10.1542/peds.2007-1357

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

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
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rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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ARTICLE

Disease Progression in Hutchinson-Gilford Progeria

Syndrome: Impact on Growth and Development
Leslie B. Gordon, MD, PhDa,b, Kathleen M. McCarten, MDc,d, Anita Giobbie-Hurder, MSe, Jason T. Machan, PhDf, Susan E. Campbell, MAg,
Scott D. Berns, MD, MPHa,b, Mark W. Kieran, MD, PhDh,i

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
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H UTCHINSON-GILFORD PROGERIA SYNDROME (HGPS)
is a rare (frequency 1 in 4 million) and uniformly
fatal segmental “premature aging” disease that affects a
variety of organ systems.1–3 Classical HGPS is caused by a
single base mutation in LMNA, which results in the
production of a mutant lamin A protein product, pro-
gerin.4–6 Progerin, like its normal lamin A counterpart,
likely resides in the nuclear membrane and nucleoplasm
of most differentiated cell types.7 Progerin results in
complex downstream organ system disruption that is
strikingly similar between patients.2 Death in HGPS is
caused primarily by heart attacks between ages 7 and 21
years as a result of rapidly progressive arteriosclerosis.3
Death is often preceded by hypertension, transient isch-
emic attacks, and strokes.
Because there are only an estimated 40 identified
cases worldwide at any one time, most of the clinical
information supplied in the literature is based on case
reports (reviewed by Hennekam3). Because the gene
mutation responsible for HGPS was uncovered only re-
cently in 2003,4–6 and a genetic test for HGPS was not
available until that time, some of the case reports on
which HGPS was clinically characterized likely involved
misdiagnoses, especially because other diseases may
phenotypically mimic HGPS early in life (ie, Wiede-
mann-Rautenstrauch syndrome and restrictive dermop-
athy).8 For example, studies by Fernandez-Palazzi et al9
and Green10 reported on patients with full heads of hair
at the ages of 6 and 22 years, respectively, and Moen11
reported on a surviving 25-year-old woman, all findings
not characteristic of HGPS. Radiologic, orthopedic, and
dental studies have been largely case studies with review
of the literature,9,11–15 and little longitudinal data were
available. The 2 largest case studies by DeBusk2 (4 pa-
tients) and recently by Hennekam3 (10 patients) were
written ⬎30 years apart. The lack of a large body of
longitudinal data, and the possibility that some of the
case studies are misdiagnosed, have made it difficult to
assess some of the characteristics that are classically as-
sociated with HGPS and might guide therapeutic strate-
gies.16
The discovery of the mutation responsible for HGPS
and its protein product gave rise to studies supporting
the pursuit of both chemical17–23 and genetic24,25 therapies
for HGPS. With the exception of a pilot trial of human
growth hormone,26 there has never been a treatment
trial for HGPS, and sufficiently sensitive and specific
pretreatment benchmarks for assessing treatment effi-
cacy have been difficult to identify.
For this study, we collected and analyzed longitudinal
medical information from 41 children with confirmed
HGPS spanning 14 countries, from the Progeria Research
Foundation Medical and Research Database at the
Brown University Center for Gerontology. Novel pat-
terns in growth and development were identified, in-
cluding reduced linear weight gain that remains stable
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over a patient’s life span, which will serve as the primary
clinical outcome parameter in a clinical trial for HGPS.
METHODS
Patients and Data
Data were collected between June 2000 and February
2007. A total of 408 radiograph studies from 22 children,
at ages ranging from newborn to 16.7 years, and MRIs of
heart, brain, and cerebral vessels in children at ages
ranging from 4 months to 11.7 years were reviewed
retrospectively by a single pediatric radiologist at Hasbro
Children’s Hospital (Providence, RI). Medical charts and
self-reported weight data from 41 children diagnosed
with HGPS in 14 countries were also reviewed. All 22 of
the children with radiology data are included in the set
of 41 children reporting weight data. Radiology and
vitals data sets were constructed by using Microsoft Ex-
cel (Redmond, WA).
This study was approved by the institutional review
boards of Rhode Island Hospital and Brown University.
All of the patients had been diagnosed with HGPS on the
basis of phenotypic expression of the disease and con-
firmed LMNA G608G mutational analysis performed by
the Progeria Research Foundation Diagnostics Program
(Peabody, MA) or confirmed genetic analysis from med-
ical charts. Informed consent was obtained from all of
the patients and/or legal guardians. When appropriate,
translators were used during the consenting process.
Longitudinal Growth Assessment
Retrospective growth data were abstracted from clinical
charts between June 2000 and May 2006. In addition,
weight data were collected prospectively between June
2006 and February 2007. A digital scale with a sensitivity
of 0.045 kg (model UC-321PL Precision personal health
scale; A & D Medical, Milpitas, CA), log book, and 2.3-kg
weighing disk were shipped to participating families
along with instructions in the language of origin. Fami-
lies weighed children once per week, 3 times, before
breakfast in undergarments or pajamas only and re-
ported those weights along with the weekly weight of
the disk to ensure consistency of the scale.
Statistical Methodology
Descriptive statistics, such as mean, median, and range,
were used to characterize the amount and length of
follow-up in the vitals data sets. Statistical models ex-
amined weight in kilograms as a function of gender and
age of each child and used random-effects maximum
likelihood regression. This regression technique models
the weight of each child and aggregates the individual
estimates to derive weight estimates for the entire sam-
ple. Using this approach, the weight growth curve for
each child is counted equally in the calculation of overall
effects. To allow for the possibility of a nonconstant rate
PEDIATRICS Volume 120, Number 4, October 2007 825
of weight gain, models were developed that included
linear and quadratic terms for age in years as predictors.
Estimates from the models are presented with 95% con-
fidence intervals. Data analyses were performed by using
SAS 8.2 (SAS Institute, Cary, NC). All of the statistical
tests are 2-sided with an ␣ value of .05.
RESULTS
Radiologic Findings
Primary Dental Abnormality
In 7 of 7 children who provided MRI studies between the
ages of 8 months and 11.3 years, we found that the
secondary incisors were located lingually and palatally in
the mandible and maxilla, respectively, rather than
erupting in place of the primary incisors, as seen in
normal children (Fig 1). All of the children also exhibited
dental crowding and delayed tooth eruption of both
primary and secondary teeth, including both upper and
lower sets.
Progressive Bone Remodeling
To understand the progressive nature of bony findings in
HGPS, we analyzed radiographs provided both longitu-
dinally for children with multiple radiographs over time
and cross-sectionally, with increasing age. Acroosteolysis
was the earliest abnormal finding. Three children pro-
vided radiographs of the hands in infancy at ages 2.9,
9.3, and 12 months. Of these, only 1 hand study was
normal, at age 2.9 months. Eight of 8 patients (these 3
children and 5 additional children with studies beyond
13 months) provided longitudinal studies demonstrating
progressively severe acroosteolysis with increasing age.
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
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Six other patients provided a single study, all with ab-
normal findings. In total, 30 hand studies in 14 of 14
patients between ages 9.3 months and 11.7 years dem-
onstrated acroosteolysis in some or all phalanges.
We next analyzed a set of 6 children, each of whom
had radiograph studies of the bony skeleton and skull
performed in both infancy (ages 0 –13 months) and at
older ages. Detailed studies of all of the structures, except
the hands and feet, were evaluable in each. Importantly,
all of the bony structures were initially normal in the 6
infants. Significant variability in onset of abnormal find-
ings was observed, however, with infants as young as 6
months demonstrating some radiographic changes. Chil-
dren went on to develop progressive abnormalities, as
described below.
Figure 2 demonstrates progressive mandibular malde-
velopment, clavicular resorption, and thinning and ta-
pering of ribs. Mandibular maldevelopment, where the
mandible is small with an increased obtuse angle to its
shape, was evident in 5 patients who provided radio-
graph films and 5 patients who provided MRIs between
the ages of 19 months and 10.5 years. Eight patients
exhibited normal mandibular anatomy between 3 and
22 months of age, 4 of whom provided longitudinal films
demonstrating progression to abnormality.
Clavicular resorption was evident in 15 of 17 patients
who provided clavicle films. Two patients did not exhibit
abnormal clavicles by 19.1 and 21.0 months of age. Five
patients progressed from normal (ages: newborn to 19
months) to abnormal anatomy between the ages of 8.9
and 40.0 months. Ten patients provided longitudinal
studies with abnormal clavicles in the earliest films ob-
tained, between the ages of 4.0 months and 15.8 years,

FIGURE 2
Bones begin normally and progress with age to abnormal findings in HGPS. Each series
originates from a single child: mandible at 9 months (normal) (A) and 3 years (B) showing
receding mandible with abnormal angle (white arrows); clavicles at 2 months (normal)
(C), 11 months (D), 16 months (E), and 4.5 years (F) showing progressive resorption
(yellow outlines the clavicle, and blue outlines theoretical normal clavicular morphology
at each age); ribs at 11.6 months (G) show normal morphology and mineralization. Com-
pare the fifth and sixth ribs (black arrows) to the same child at 6.2 years of age (H) when
the ribs are thinned and irregularly tapered (arrow), and the entire rib cage is pyriform.
Note the clavicular resorption.
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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).
Long-Bone Remodeling Developed After Joint Contracture
Coxa valga is a straightening of the femoral head-neck
axis to ⬎125°. Although the bony pelvis remained nor-
mal in configuration at all of the ages, we found that
coxa valga was evident between the ages of 9.0 months
and 14.5 years in 19 of 19 patients who provided hip
films (Fig 3). Knee or ankle contracture was noted in 19
of 19 patients with joint assessment. Abnormal joint
extension contracture was noted between newborn and
50.4 months of age (average: 15.3 ⫾ 15.9 months). In 5
of 5 patients with both documented development of
knee contracture and transitions from normal to abnor-
mal radiographs of the pelvis, the average ages of tran-
sition were 22.0 ⫾ 19.7 months and 44.2 ⫾ 20.6
months, respectively. The onset of knee or ankle con-
tracture preceded the development of coxa valga by an
average of 22.3 ⫾ 6.5 months (95% confidence interval
[CI]: 14.2 to 30.4). The coxa valga deformity is distinct
from that seen in neuromuscular diseases, which show
hypertrophy of the lesser trochanter secondary to ad-
ductor tightness. One patient developed hip subluxa-
tions. Another patient in our series had prophylactic iliac
osteotomies to prevent this complication. Two adoles-
cent patients also show remodeling of the posterior pa-
tella secondary to chronic flexion contracture at the
knee.
Other long-bone modeling abnormalities developed
concurrently with coxa valga in all of the children (Fig
4). In the upper extremity, the proximal humeral me-
taphysis was flared. At the elbow, after age 4.8 years, the
capitellum of the distal humerus was enlarged relative to
surrounding bony structures, and the radial neck dem-
onstrated a marked constriction in all of the patients (9
of 9 patients showed normal humeral and radial struc-
ture before age 3.3 years). Femoral necks were broad-
ened; femoral heads were correspondingly broad and
decreased in height. At the knee, the distal femoral
metaphyses and epiphyses, as well as the proximal tibial
metaphyses and epiphyses, were dramatically flared.
PEDIATRICS Volume 120, Number 4, October 2007 827
FIGURE 3
Coxa valga in HGPS compared with normal bone anatomy and
neuromuscular disease. Black lines show the shaft-neck axes, and
the arrows show femoral heads. A, Normal 8-year-old femur with
a head-neck axis of 125°; B, 8-year-old child with HGPS with
broadened femoral neck, hypoplastic lesser trochanter, flattened
femoral epiphysis (arrow), and a head-neck axis of 152°; C, 7-year-
old with HGPS and avascular necrosis, with broadened femoral
neck, absent lesser trochanter, flattened and fragmented femoral
epiphysis (arrow), and a head-neck axis of 155°. D, Neuromuscular
disease in an 8-year-old, showing a head-neck axis of 155° but
large lesser trochanter and normal femoral head.
The diaphyses were much more slender than usual for
age. The epiphyses were similarly large and broadened.
Long bones also demonstrated atypical demineraliza-
tion. We found that, in 19 of 19 patients, diaphyseal
cortical bone was of normal width and mineralization,
whereas the metaphyses and epiphyses were qualita-
tively more demineralized, indicating that decreased
mineralization is localized to the ends of the bones (Fig
4). Only 1 patient experienced a bone breakage and
healed normally (as a result of a fall while playing bas-
ketball), indicating no increase above normal in fracture
risk in HGPS.
Normal Radiologic Findings
Bone ages and growth plates were normal. Bone ages
derived from hand radiographs in 14 children, ages new-
born to 11.7 years, were within normal limits, and
growth plates of all 22 of the children’s joint films were
open, similar to age-matched normal control subjects, at
newborn to 18.1 years of age. In the 10 children who
provided skull films between the ages of 2.9 months and
8.5 years, we found no evidence of widened cranial
sutures, a finding described previously as being part of
this disorder by DeBusk.2
Arthritis was not a feature of HGPS. Radiograph films
from 21 children, ages newborn to 14.6 years, were
assessed for arthritis in wrists, ankles, hips, knees, and
elbows. No evidence of either rheumatoid or osteoar-
thritis was found (Fig 5). In all of the children, 3 ele-
ments crucial for diagnosis of arthritis were missing.
Joint spaces were of normal width, there were no peri-
articular erosions, and there were no proliferative
changes (no osteophyte formation). Most impressively,
1 child with long-standing and severe avascular necrosis
of the hip did not exhibit traumatic arthritis that would
typically evolve in a nonprogeroid patient (Fig 3C).
828 GORDON et al
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Anthropometric Analyses
Weight Analysis: Birth to 24 Months
Twenty five of 29 children were born at term (ⱖ37
weeks’ gestation). Longitudinal weight data were avail-
able for 27 children in the data set (11 girls and 16 boys).
The average weight at birth for the children was 2.91 kg
(95% CI: 2.69 to 3.13). The average weight of the girls
was 0.14 kg greater than that of the boys, but this
difference was not statistically significant (P ⫽ .35). For
the birth-to-24-month age group, weight was related to
the square of age in months and resulted in a rate of
weight gain that decreased as the children aged from
birth to 24 months (Fig 6A).
Weight Analysis of Retrospective and Prospective Data Sets
for Ages Beyond 24 Months
There were data for 35 children in the retrospective data
set (15 girls and 20 boys; Table 1). The children had an
average of 75 months of follow-up, starting at any time
point beyond 2 years of age (median: 74 months), with
boys having longer average follow-up than girls (boys:
96 months; girls: 48 months). When there were multiple
weight recordings on a given day, they were averaged to
give a daily weight measurement. The data set had an
average of 22 weight measurements per child, with boys
having a larger number of measurements than girls
(boys: 26 measurements; girls: 16 measurements). The
rate of weight gain was constant over time, rather than
varying, with an average increase of 0.44 kg/year, be-
ginning at ⬃2 years of age (Table 2 and Fig 6B). Girls
were 0.87 kg lighter, on average, than boys (P ⫽ .03;
95% CI: ⫺1.3 to ⫺ 0.4). Although interpatient rates of
weight gain varied, for age ranges 2 to 16 years, the rate
of weight gain for each child was constant and closely
predicted by the statistical model developed (Fig 6C).
There were data for 25 children in the prospective data
set, 24 of whom are also included in the retrospective

FIGURE 4
Long-bone abnormalities and juxta-articular demineralization in HGPS: A, 6-year-old
lower leg with HGPS shows normal diaphyseal width and cortical thickness (see insets)
and flaring and demineralization of the proximal and distal metaphyses (arrows) com-
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
demineralization of the capitellum of the distal humerus compared with a normal age-
matched control (D). Note here, as in the wrist, that there is no evidence of joint cartilage
loss with HGPS.
weight data set (13 girls and 12 boys; Table 1). The
children had an average of 6 months of prospective
follow-up, starting at any time point beyond 2 years of
age (median: 5.3 months), with boys having longer av-
erage follow-up than girls (boys: 8.1 months; girls: 4.4
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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
the final phenotype in these patients is remarkably sim-
ilar, underscoring the identical common mutation that
leads downstream to similar pathobiology. However, the
rarity of HGPS (frequency: 1 in 4 million live births1–3)
makes it extremely difficult to amass sufficient clinical
information to delineate the nature of growth abnormal-
ities and the underlying disease process in HGPS. We
have collected and analyzed the largest set of clinical
data for HGPS to date and used the data set not only to
compare and contrast features of HGPS with what is
documented in the literature but also to search out dis-
ease characteristics that can be used as primary param-
eters for treatment efficacy during clinical trials.
PEDIATRICS Volume 120, Number 4, October 2007 829
FIGURE 5
Wrist radiographs with normal bone age, joint cartilage, and ra-
diocarpal and intercarpal joint spaces (arrow) in a normal 9-year-
old (A) and a 9-year-old with HGPS (B), in contrast to an 11-year-
old with juvenile rheumatoid arthritis showing total loss of
radiocarpal and intercarpal joint spaces (arrow) and mild erosions
(C).
HGPS is classically known as a disease of premature
aging, as its name and clinical appearances imply. In-
deed, there is cellular evidence for the shortened life
span of HGPS fibroblasts in vitro,27–30 and this is likely
caused because progerin, the protein product of the
HGPS genetic mutation, builds in cellular concentration
with successive cell passages.7 Importantly, there is evi-
dence that progerin is produced at very low levels in
normal fibroblasts,31 suggesting that this molecule may
also play some role in normal human aging. In addition
to other factors downstream of the primary genetic de-
fect, the way in which progerin production is dramati-
cally increased in HGPS and translates into clinical dis-
ease warrants careful comparison with the diseases of
normal aging.
In our analysis, the bony sequelae in HGPS presented
as a progressive skeletal dysplasia and varied from the
typical aging phenomena. Bone age and growth plate
closure rates remained normal; demineralization was
focal rather than global; and arthritis was not identified
in any patients.
Osteoporosis and arthritis are common sequelae of
normal aging. Classically, HGPS has been associated with
global osteoporosis.3,9,32 However, our analysis showed
focal and nonclassical demineralization rather than the
global demineralization seen in osteoporosis of normal
aging33 and without the increased fracture risk. Unlike
generalized cortical thinning of osteoporosis of aging, the
cortical thickness in the diaphyseal regions was normal
and became more thinned as it extended toward the
metaphysis. Although osteopenia is associated with hy-
pervascularity in adults and children,34 bone loss may
also occur as a consequence of ischemia related to vas-
cular disease (reviewed by Rajzbaum and Bezie35). The
nonclassical, regional demineralization found at the dis-
tal end of all long bones in HGPS may be a sign of
vascular insufficiency. A more quantitative analysis of
bone mineralization using dual energy radiograph ab-
sorptiometry or peripheral quantitative computed to-
mography is warranted in future studies.
A common perception in the literature has been that
children with HGPS develop arthritis, likely because
830 GORDON et al
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joints are prominent and contracted.16 Although juxta-
articular osteopenia is commonly associated with arthri-
tis, we found no evidence of either rheumatoid or os-
teoarthritis, conditions that would be characterized by
neovascularization rather than a lack of vascular sup-
ply,36 even in the presence of joint malalignment and
demineralization that is usual for HGPS.
However, we did find extensive evidence for skeletal
dysplasia in HGPS. Most of the bone pathology of the
upper and lower extremities was noted distally, partic-
ularly in the fingers, all of the long bones, thinning and
tapering of ribs distally, and clavicular tissue that was
resorbed from the lateral margin in toward the midline.
We show definitively that these features are progressive,
starting with normal-looking clavicular structures in in-
fancy, and progressing to abnormality within several
years.
One of the earliest clinical findings in HGPS, in addi-
tion to growth delay, is delayed dentition.13,37 Classically
in HGPS there is severely delayed tooth eruption, and
teeth are crowded and irregularly positioned. We now
show, for the first time, that, in addition to delayed
dentition, the permanent incisors erupt lingually. This
novel finding is not identified in other disease processes.
Although ectopic eruption of molars can be associated
with small-sized mandible and maxilla,38 children with
HGPS have normally sized skulls at 8 months of age (Fig
1 A and B), when secondary teeth are beginning to form
within the mandible and maxilla.39 Thus, the data point
to a primary abnormality and not simply maldevelop-
ment because of dental crowding and small jaw bones.
We hypothesize that microvascular insufficiency and
matrix abnormalities contribute to the bony maldevel-
opment in HGPS. Both in vitro and in vivo pathologic
studies support a role for microvasculature abnormalities
in HGPS.40–42 We found abnormally narrow femoral and
humoral shafts, as well as abnormally broad metaphyses
and epiphyses, compared with age-matched control sub-
jects with resultant abnormal shaft/metaphysis diameter
ratios. The physes themselves do not have a direct blood
supply but are indirectly supplied above and below by
vessels at the epiphysis and the metaphysis. Slowed bone
 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

TABLE 2 Statistical Models of Weight, Gender, and Age Beyond 24

Months of Age
Variables Mean, kg SE 95% CI P
Retrospective data set (N ⫽ 35)
Intercepta 8.154 0.169 7.810 to 8.490 ⬍.001
Girls ⫺0.866 0.239 ⫺1.340 to ⫺0.389 ⬍.001
Boys 0.000 — — —
Age, yb 0.438 0.104 0.227 to 0.649 ⬍.001
Prospective data set (N ⫽ 25)
Intercepta 7.170 0.357 6.450 to 7.880 ⬍.001
Girls ⫺0.847 0.373 ⫺1.600 to ⫺0.100 .028
Boys 0.000 — — —
Age, yb 0.524 0.0670 0.380 to 0.660 ⬍.001
— indicates no data.
a Intercept is the average weight for all of the children at 24 months.
b If female, weight in kilograms ⫽ (8.154 ⫺ 0.866) ⫹ (0.438 ⫻ age in years); if male, weight in

FIGURE 6 kilograms ⫽ 8.154 ⫹ (0.438 ⫻ age in years).

Growth characteristics of HGPS with age show normal birth weight followed by failure to
thrive. Shown is the average weight for age for 10 boys from birth to 12 months (A) and
2 to 8 years (B). The CV is ⬍6% for each data point. The data for girls are not significantly
different from those for boys (P ⬍ .05; data not shown). C, Weight versus age for 1 male
child. Circles represent the actual weight measurements, and crosses show weights as
predicted by the statistical model developed for age ranges 2 to 16 years. P indicates
percentile. The growth charts were adapted from those developed by the National Cen-
ter for Health Statistics in collaboration with the National Center for Chronic Disease and
Health Promotion (see www.cdc.gov/growthcharts).
growth in HGPS, which is mediated by the growth
plates, could also be because of undervascularization.
Avascular necrosis of the femoral head is another signif-
icant complication. This can vary from mild sclerosis of
the femoral head to fragmentation. We demonstrated
the gradual development of coxa valga and avascular
necrosis of the femoral head, which does not seem to be
a consequence of arthritis. These findings, in addition to
clavicular resorption and acroosteolysis, point to a pro-
gressive microvascular disease process in HGPS. We fur-
ther hypothesize that extracellular matrix abnormality,
leading to progressive joint contractures, contributes to
progressive bone remodeling. Coxa valga is a well-
known and pathognomonic characteristic of HGPS. We
found that the femoral neck is normal early in life and
develops coxa valga several years after the appearance of
joint contractures in the knees and ankles. This indicates
that the remodeling that results in coxa valga is likely
influenced by joint contractures and possibly also pri-
mary dysplastic changes.
HGPS is best known as a large vessel disease, which
has previously been well characterized as being primar-
ily responsible for the cardiac sequelae and death. How-

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ever, this study of growth and development supports the
involvement of microvascular insufficiency and extra-
cellular matrix defects as major contributors to skeletal
dysplasia in HGPS. This evidence is inferential and does
not rule out a role for stem cell depletion and/or prema-
ture cell death affecting not only cells of the vasculature
but other cell types, such as osteoblasts and osteoclasts,
that are responsible for bone remodeling. Several HGPS
mouse models have recently been created and mimic
some aspects of human disease, such as small size, bony
abnormalities, and large vessel disease.21,43 Future studies
using these models will be important in further assessing
the influences of these various components to the dis-
ease process.
Use of Weight Data as a Primary Clinical Parameter for Clinical
Trials
Analyses of both retrospective and prospective data for
ages beyond 24 months demonstrate the predictable lin-
earity of weight gain over time that is significantly below
age- and gender-matched normal weight gain. The esti-
mates of annual weight gain were consistent between
the 2 data sets, with each estimate contained in the 95%
CI of the other. Although the reproducibility of the
limited linear weight gain is striking, investigation into
the biological bases for this finding is needed. Based on
the limited data from patients on growth hormone,
where similar weight deficiencies were noted despite
this therapy, this pathway is not likely to be responsible
for this problem. More detailed analysis of caloric intake,
energy expenditure, and other physiologic parameters of
growth and development are needed to provide insight
into this finding. Previous reports have not indicated a
primary defect in gastrointestinal function as the cause.
Based on the analysis of weight data in the retrospective
patient group that demonstrated linearity and reliability
of the rate of weight gain over time in HGPS, weight gain
would be an ideal primary clinical parameter for study-
ing therapeutic interventions in this disease. Unlike the
bony, dental, and cardiovascular manifestations of
HGPS, which may become fixed and irreversible,
changes in body weight may be much more easily ob-
served in response to therapeutic interventions. The
finding of linear, stable, and reproducible abnormalities
in weight for this patient population was, therefore, of
significant importance.
There are several limitations to consider in our study.
The films available for each child varied widely in num-
ber, type, and ages performed. Inherently, retrospective
chart review is hampered by frequency, availability, and
quality of primary care and subspecialty services for each
child. Because HGPS is a rare disease, many physicians
are not familiar with features that should be assessed. In
addition, HGPS is underrecognized early in life (average
age at diagnosis is 2.9 years3), and many children did not
receive testing in the first 2 years of life. This likely
832 GORDON et al
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contributed to the broad age ranges at which many of
the clinical tests, such as skeletal surveys, were initiated.
However, because we collected data from a relatively
large cohort of patients, radiologic clinical assessments
were conducted in some of the children in the normal
course of care, and we were able to assess many param-
eters early in life. Still, outliers for each finding (such as
the child whose ribs were still normal at 80 months of
age) may not be identified with this size cohort. Fortu-
nately, anthropometric data are collected routinely in
children, and this allowed for a large body of growth
data that was key to arriving at an acceptably consistent
primary outcome measure for clinical trials. For HGPS,
although it is well known that the phenotype is mark-
edly similar between patients, it was necessary to collect
and objectively analyze a large quantity of clinical infor-
mation to determine that the rate of weight gain would
be a consistent and analyzable abnormality that is valid
for the wide cross-section of patient ages and disease
severities. Still, rate of weight gain is a global measure of
disease, and additional, potentially modifiable outcome
measures, such as bone abnormalities, cardiovascular
status, body composition, insulin resistance, and biomar-
kers, are important characteristics to examine as well.
CONCLUSIONS
Using the largest cohort of patient records in existence,
we defined a number of growth characteristics impor-
tant for both understanding the biology of HGPS and for
defining outcome parameters essential to clinical trials in
HGPS. Secondary incisors were located lingually and
palatally in the mandible and maxilla, respectively,
which is a feature not found in other disease processes.
Skeletal abnormalities were progressive. Most children
had normal radiologic findings during early infancy. Ac-
roosteolysis was the earliest abnormal finding, and joint
contracture preceded the development of coxa valga. We
found atypical demineralization of long bones, with de-
creased mineralization toward the metaphyses and nor-
mal disphyseal cortical bone. Bone age and growth
plates were normal, and arthritis was not present. After
age 24 months, the intrapatient rate of weight gain in
HGPS was dramatically impaired, linear, and constant
over time. This finding provides an ideal outcome pa-
rameter for treatment trials in HGPS.
ACKNOWLEDGMENTS
This research was funded by the Progeria Research
Foundation, the National Institute on Aging (National
Institutes of Health 1 R21 AG021902-01), and the Na-
tional Heart, Lung, and Blood Institute.
We gratefully acknowledge the children with HGPS
and their families for participating in this study, as well
as the following people for technical assistance and/or
article review: Nancy L. Wolf-Jensen, MSW; Nancy C.
Grossman; Lori E. Gordon, DVM; Tammy Harling, DMD;
Heather Hardie, MD; Monica Kleinman, MD; and Kyra
Johnson.
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PEDIATRICS Volume 120, Number 4, October 2007 833
 Disease Progression in Hutchinson-Gilford Progeria Syndrome: Impact on
Growth and Development
Leslie B. Gordon, Kathleen M. McCarten, Anita Giobbie-Hurder, Jason T. Machan,
Susan E. Campbell, Scott D. Berns and Mark W. Kieran
Pediatrics 2007;120;824-833
DOI: 10.1542/peds.2007-1357
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