PEDIATRICS Vol. 120 No. 4 October 2007, pp. 824-833 (doi:10.1542/10.1542/peds.2007-1357)
ARTICLE |
Disease Progression in Hutchinson-Gilford Progeria Syndrome: Impact on Growth and Development
a Departments of Pediatrics
c Diagnostic Imaging
f Biostatistics, Rhode Island Hospital, Providence, Rhode Island
b Departments of Pediatrics
d Radiology, Warren J. Alpert Medical School at Brown University, Providence, Rhode Island
e Biostatistics and Computational Biology
h Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts
g Department of Gerontology, Brown University, Providence, Rhode Island
i Department of Pediatric Hematology and Oncology, Children's Hospital Boston, Boston, Massachusetts
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
OBJECTIVES. Hutchinson-Gilford progeria syndrome is a rare and uniformly fatal segmental "premature aging" disease that affects a variety of organ systems. We sought to more clearly define the bone and weight abnormalities in patients with progeria as potential outcome parameters for prospective clinical trials.
PATIENTS AND METHODS. We collected and analyzed longitudinal medical information, both retrospectively and prospectively, from a total of 41 children with Hutchinson-Gilford progeria syndrome spanning 14 countries, from the Progeria Research Foundation Medical and Research Database at the Brown University Center for Gerontology.
RESULTS. In addition to a number of previously well-defined phenotypic findings in children with progeria, this study identified abnormalities in the eruption of secondary incisors lingually and palatally in the mandible and maxilla, respectively. Although bony structures appeared normal in early infancy, clavicular resorption, coxa valga, avascular necrosis of the femoral head, modeling abnormalities of long bones with slender diaphyses, flared metaphyses, and overgrown epiphyses developed. Long bones showed normal cortical thickness centrally and progressive focal demineralization peripherally. The most striking finding identified 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.
Key Words: progeria • Hutchinson-Gilford progeria syndrome • developmental dysplasia • osteoporosis • clinical trial
Abbreviations: HGPS—Hutchinson-Gilford progeria syndrome • CI—confidence interval
Hutchinson-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, progerin.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 ischemic 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 recently 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, Wiedemann-Rautenstrauch syndrome and restrictive dermopathy).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 patients) 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 associated with HGPS and might guide therapeutic strategies.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 efficacy 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 patterns in growth and development were identified, including reduced linear weight gain that remains stable over a patient's life span, which will serve as the primary clinical outcome parameter in a clinical trial for HGPS.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
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 Excel (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 confirmed LMNA G608G mutational analysis performed by the Progeria Research Foundation Diagnostics Program (Peabody, MA) or confirmed genetic analysis from medical 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. Families weighed children once per week, 3 times, before breakfast in undergarments or pajamas only and reported 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 examined 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 sample. 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 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% confidence 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 |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
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 longitudinally for children with multiple radiographs over time and cross-sectionally, with increasing age. Acroosteolysis was the earliest abnormal finding. Three children provided 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. Six other patients provided a single study, all with abnormal findings. In total, 30 hand studies in 14 of 14 patients between ages 9.3 months and 11.7 years demonstrated 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 findings was observed, however, with infants as young as 6 months demonstrating some radiographic changes. Children went on to develop progressive abnormalities, as described below.
Figure 2 demonstrates progressive mandibular maldevelopment, clavicular resorption, and thinning and tapering of ribs. Mandibular maldevelopment, where the mandible is small with an increased obtuse angle to its shape, was evident in 5 patients who provided radiograph 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 obtained, between the ages of 4.0 months and 15.8 years, and exhibited progressive clavicular resorption with increasing 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 radiographs 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 narrowing at the apex. Clavicular resorption was evident significantly 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 normal 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 abnormal radiographs of the pelvis, the average ages of transition were 22.0 ± 19.7 months and 44.2 ± 20.6 months, respectively. The onset of knee or ankle contracture 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 adductor tightness. One patient developed hip subluxations. Another patient in our series had prophylactic iliac osteotomies to prevent this complication. Two adolescent patients also show remodeling of the posterior patella 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 metaphysis 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 demonstrated a marked constriction in all of the patients (9 of 9 patients showed normal humeral and radial structure before age 3.3 years). Femoral necks were broadened; 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. The diaphyses were much more slender than usual for age. The epiphyses were similarly large and broadened.
|
Long bones also demonstrated atypical demineralization. We found that, in 19 of 19 patients, diaphyseal cortical bone was of normal width and mineralization, whereas the metaphyses and epiphyses were qualitatively 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 basketball), 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 newborn 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 osteoarthritis was found (Fig 5). In all of the children, 3 elements crucial for diagnosis of arthritis were missing. Joint spaces were of normal width, there were no periarticular 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).
|
Anthropometric Analyses
Weight Analysis: Birth to 24 Months
Twenty five of 29 children were born at term (
37 weeks' gestation). Longitudinal weight data were available 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, beginning 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 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 average follow-up than girls (boys: 8.1 months; girls: 4.4 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 prospective 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 prospective data sets were not significantly different. Both demonstrated dramatic impairment compared with weight gain in normal age- and gender-matched children.
Linear Growth
Clinical charts indicate that 30 of 30 children developed knee flexion contractures. Of 19 with information supplied 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 contractures 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 recorded 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 children with height recorded for ages 34 months and beyond were below the third percentile of normal.
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
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 similar, 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 abnormalities 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 disease characteristics that can be used as primary parameters for treatment efficacy during clinical trials.
HGPS is classically known as a disease of premature aging, as its name and clinical appearances imply. Indeed, 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 evidence 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 defect, the way in which progerin production is dramatically increased in HGPS and translates into clinical disease 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 hypervascularity in adults and children,34 bone loss may also occur as a consequence of ischemia related to vascular disease (reviewed by Rajzbaum and Bezie35). The nonclassical, regional demineralization found at the distal 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 absorptiometry or peripheral quantitative computed tomography is warranted in future studies.
A common perception in the literature has been that children with HGPS develop arthritis, likely because joints are prominent and contracted.16 Although juxta-articular osteopenia is commonly associated with arthritis, we found no evidence of either rheumatoid or osteoarthritis, conditions that would be characterized by neovascularization rather than a lack of vascular supply,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, particularly 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 infancy, and progressing to abnormality within several years.
One of the earliest clinical findings in HGPS, in addition 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 maldevelopment because of dental crowding and small jaw bones.
We hypothesize that microvascular insufficiency and matrix abnormalities contribute to the bony maldevelopment 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 subjects 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 growth in HGPS, which is mediated by the growth plates, could also be because of undervascularization. Avascular necrosis of the femoral head is another significant 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 progressive microvascular disease process in HGPS. We further 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 primary dysplastic changes.
HGPS is best known as a large vessel disease, which has previously been well characterized as being primarily responsible for the cardiac sequelae and death. However, this study of growth and development supports the involvement of microvascular insufficiency and extracellular 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 premature 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 disease 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 linearity of weight gain over time that is significantly below age- and gender-matched normal weight gain. The estimates 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 studying 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 observed 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 number, 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 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 parameters 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. Fortunately, 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 markedly similar between patients, it was necessary to collect and objectively analyze a large quantity of clinical information 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 biomarkers, are important characteristics to examine as well.
|
CONCLUSIONS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Using the largest cohort of patient records in existence, we defined a number of growth characteristics important 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. Acroosteolysis was the earliest abnormal finding, and joint contracture preceded the development of coxa valga. We found atypical demineralization of long bones, with decreased mineralization toward the metaphyses and normal 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 parameter 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 National 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.
|
FOOTNOTES |
|---|
Accepted Jun 26, 2007.
Address correspondence to Leslie B. Gordon, MD, PhD, Hasbro Children's Hospital, Department of Pediatrics, 593 Eddy St, Providence, RI 02903. E-mail: leslie_gordon{at}brown.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
- Brown W, Zebrower M, Kieras F. Progeria, a model disease for the study of accelerated aging. Basic Life Sci. 1985;35 :375 –396[Medline]
- DeBusk FL. The Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the literature. J Pediatr. 1972;80 :697 –724[CrossRef][Web of Science][Medline]
- Hennekam RC. Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A. 2006;140 :2603 –2624[Medline]
- Cao H, Hegele RA. LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J Hum Genet. 2003;48 :271 –274[CrossRef][Web of Science][Medline]
- De Sandre-Giovannoli A, Bernard R, Cau P, et al. Lamin a truncation in Hutchinson-Gilford progeria.
Science. 2003;300
:2055
[Free Full Text] - Eriksson M, Brown WT, Gordon LB, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423 :293 –298[CrossRef][Medline]
- Goldman RD, Shumaker DK, Erdos MR, et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome.
Proc Natl Acad Sci USA. 2004;101
:8963
–8968
[Abstract/Free Full Text] - Csoka AB, Cao H, Sammak PJ, Constantinescu D, Schatten GP, Hegele RA. Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes.
J Med Genet. 2004;41
:304
–308
[Free Full Text] - Fernandez-Palazzi F, McLaren AT, Slowie DF. Report on a case of Hutchinson-Gilford progeria, with special reference to orthopedic problems. Eur J Pediatr Surg. 1992;2 :378 –382[Web of Science][Medline]
- Green LN. Progeria with carotid artery aneurysms: report of a case.
Arch Neurol. 1981;38
:659
–661
[Abstract/Free Full Text] - Moen C. Orthopaedic aspects of progeria.
J Bone Joint Surg Am. 1982;64
:542
–546
[Free Full Text] - Gamble JG. Hip disease in Hutchinson-Gilford progeria syndrome. J Pediatr Orthop. 1984;4 :585 –589[Web of Science][Medline]
- Hasty MF, Vann J. Progeria in a pediatric dental patient: literature review and case report. Pediatr Dent. 1988;10 :314 –319[Medline]
- Reichel W, Bailey JA 2nd, Zigel S, Garcia-Bunuel R, Knox G. Radiological findings in progeria. J Am Geriatr Soc. 1971;19 :657 –674[Web of Science][Medline]
- Sood S, Rao RC, Ragav B, Berry M. Progeria syndrome with characteristic deformation of proximal radius observed on CT. Acta Radiol. 1991;32 :67 –68[Web of Science][Medline]
- Gupte S, Pal M, Sharma Y, Kohli U. Progeria with osteoarthritis in a four-year-old girl. A case report. Indian J Pediatr. 1976;43 :319 –320[Medline]
- Capell BC, Erdos MR, Madigan JP, et al. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome.
Proc Natl Acad Sci USA. 2005;102
:12879
–12884
[Abstract/Free Full Text] - Fong LG, Frost D, Meta M, et al. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria.
Science. 2006;311
:1621
–1623
[Abstract/Free Full Text] - Glynn MW, Glover TW. Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition.
Hum Mol Genet. 2005;14
:2959
–2969
[Abstract/Free Full Text] - Toth JI, Yang SH, Qiao X, et al. Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes.
Proc Natl Acad Sci USA. 2005;102
:12873
–12878
[Abstract/Free Full Text] - Yang SH, Bergo MO, Toth JI, et al. Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation.
Proc Natl Acad Sci USA. 2005;102
:10291
–10296
[Abstract/Free Full Text] - Yang SH, Meta M, Qiao X, et al. A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. J Clin Invest. 2006;116 :2115 –2121[CrossRef][Web of Science][Medline]
- Columbaro M, Capanni C, Mattioli E, et al. Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment. Cell Mol Life Sci. 2005;62 :2669 –2678[CrossRef][Web of Science][Medline]
- Huang S, Chen L, Libina N, et al. Correction of cellular phenotypes of Hutchinson-Gilford progeria cells by RNA interference. Hum Genet. 2005;118 :444 –450[CrossRef][Web of Science][Medline]
- Scaffidi P, Misteli T. Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat Med. 2005;11 :440 –445[CrossRef][Web of Science][Medline]
- Abdenur JE, Brown WT, Friedman S, Smith M, Lifshitz F. Response to nutritional and growth hormone treatment in progeria. Metabolism. 1997;46 :851 –856[CrossRef][Web of Science][Medline]
- Bridger JM, Kill IR. Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis. Exp Gerontol. 2004;39 :717 –724[CrossRef][Web of Science][Medline]
- Danes BS. Progeria: a cell culture study on aging. J Clin Invest. 1971;50 :2000 –2003[Web of Science][Medline]
- Goldstein S. Lifespan of cultured cells in progeria. Lancet. 1969;1(7591) :424
- Goldstein S. Studies on age-related diseases in cultured skin fibroblasts. J Invest Dermatol. 1979;73 :19 –23[CrossRef][Web of Science][Medline]
- Scaffidi P, Misteli T. Lamin A-dependent nuclear defects in human aging.
Science. 2006;312
:1059
–1063
[Abstract/Free Full Text] - Hamer L, Kaplan F, Fallon M. The musculoskeletal manifestations of progeria: a literature review. Orthopedics. 1988;11 :763 –769[Web of Science][Medline]
- Llorens R. A review of osteoporosis: diagnosis and treatment. Mo Med. 2006;103 :612 –615; quiz 615–616[Medline]
- Resnick D. Diagnosis of Bone and Joint Disorders . 4th ed. Philadelphia, PA: WB Saunders; 2002
- Rajzbaum G, Bezie Y. Postmenopausal osteoporosis and atheroma. Joint Bone Spine. 2006;73 :661 –666[CrossRef][Web of Science][Medline]
- Goldring S, Gravallese E. Pathogenesis of bone erosions in rheumatoid arthritis. Curr Opin Rheumatol. 2000;12 :195 –199[CrossRef][Web of Science][Medline]
- Hall JW 3rd, Denneny JC 3rd. Audiologic and otolaryngologic findings in progeria: case report. J Am Acad Audiol. 1993;4 :116 –121[Medline]
- O'Meara W. Ectopic eruption pattern in selected permanent teeth.
J Dent Res. 1962;41
:607
–616
[Free Full Text] - Ash M, Nelson S. Wheeler's Dental Anatomy, Physiology and Occlusion . 7th ed. Philadelphia, PA: WB Saunders; 1993
- Csoka AB, English SB, Simkevich CP, et al. Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging Cell. 2004;3 :235 –243[CrossRef][Web of Science][Medline]
- Delahunt B, Stehbens WE, Gilbert-Barness E, Shozawa T, Ruger BM. Progeria kidney has abnormal mesangial collagen distribution. Pediatr Nephrol. 2000;15 :279 –285[CrossRef][Web of Science][Medline]
- Lemire JM, Patis C, Gordon LB, Sandy JD, Toole BP, Weiss AS. Aggrecan expression is substantially and abnormally upregulated in Hutchinson-Gilford progeria syndrome dermal fibroblasts. Mech Ageing Dev. 2006;127 :660 –669[CrossRef][Web of Science][Medline]
- Varga R, Eriksson M, Erdos MR, et al. Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome.
Proc Natl Acad Sci USA. 2006;103
:3250
–3255
[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  B. C. Capell, M. Olive, M. R. Erdos, K. Cao, D. A. Faddah, U. L. Tavarez, K. N. Conneely, X. Qu, H. San, S. K. Ganesh, et al. A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model PNAS, October 14, 2008; 105(41): 15902 - 15907. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Gordon, C. J. Harling-Berg, and F. G. Rothman Highlights of the 2007 Progeria Research Foundation Scientific Workshop: Progress in Translational Science J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2008; 63(8): 777 - 787. [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Merideth, L. B. Gordon, S. Clauss, V. Sachdev, A. C.M. Smith, M. B. Perry, C. C. Brewer, C. Zalewski, H. J. Kim, B. Solomon, et al. Phenotype and Course of Hutchinson-Gilford Progeria Syndrome N. Engl. J. Med., February 7, 2008; 358(6): 592 - 604. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
