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Skeletal Integrity in Patients with Nail Patella Syndrome

Division of Geriatric Medicine (A.L.T., S.L.G.), Osteoporosis Prevention and Treatment Center (C.A.C., S.L.G.), Department of Medicine, Departments of Health and Community Systems, Biostatistics, and Epidemiology, School of Nursing and Graduate School of Public Health (S.M.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213-3221; and McKusick-Nathans Institute of Genetic Medicine (I.M.), Johns Hopkins University, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Susan L. Greenspan, M.D., University of Pittsburgh, Osteoporosis Prevention and Treatment Center, Kaufmann Medical Building, Suite 1110, 3471 Fifth Avenue, Pittsburgh, Pennsylvania 15213-3221. E-mail griffithsd{at}msx.dept-med.pitt.edu.

	Abstract

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Nail patella syndrome (NPS) is a rare autosomal dominant disorder resulting from a heterogenous loss of function in the LMX1B gene. It is associated with multiple skeletal deformities, yet it is unknown whether this is associated with osteoporosis. To examine bone mass and the prevalence of fragility fractures, we assessed bone mineral density (BMD) of the spine and hip in 31 adults and 12 children with mutation-confirmed NPS and 60 healthy age- and gender-matched adult controls. For the adults with NPS, BMD was 11–20% lower at the hip sites (P 0.001) and 8% lower at the spine (P < 0.05) than that of controls. Even when adjusted for body mass index, the BMD remained significantly lower in patients with NPS in all hip regions but not in the spine. Adults with NPS also had a significantly lower Z-score (SD values from normal) at all hip sites (all P < 0.05), compared with age- and gender-matched controls in the manufacturer’s database. However, children had significantly lower Z-scores only at the femoral neck and trochanter. Participants with NPS also had a higher prevalence of fractures (odds ratio 30.9, 95% confidence interval 6.4–149.6, P < 0.001) and scoliosis (odds ratio 16.0, 95% confidence interval 3.3–78.2, P < 0.001). The majority of these fractures occurred in women before puberty and in long bones, especially the clavicle. We conclude that adults with NPS have a BMD that is 8–20% lower than controls, which is associated with an increase in the prevalence of fractures and scoliosis. Future studies are needed to determine whether bone quality, geometry, or turnover could account for these findings.

	Introduction

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NAIL PATELLA SYNDROME (NPS), a rare autosomal dominant disorder clinically diagnosed by the presence of hypoplastic or absent patella, dystrophic fingernails, iliac horns, and deformities of the elbow (1, 3, 4, 5, 6), is estimated to occur in at least one in 50,000 individuals (1, 7). NPS is the result of heterogeneous loss of function in LMX1B, a member of the LIM-homeodomain family of transcription factors (8, 9, 10). LMX1B is required for a wide range of developmental processes, including dorsoventral patterning of the limb, differentiation of dopaminergic and serotonergic neurons, patterning of the skull, and normal development of the kidney and eye (11, 12, 13, 14, 15). Changes in bone histopathology have not been reported. Osteoporosis has been reported in NPS in one published case study and anecdotal reports (16). Currently there are no published observations regarding the incidence of low bone mass or osteoporosis in this population or screening recommendations for NPS patients.

In addition to the skeletal and joint abnormalities, patients with NPS have low muscle mass and a lean body habitus. It is often difficult for them to gain weight until they reach middle age. Additional skeletal changes of lordosis, scoliosis, elbow pterygia, and talipes are frequently reported (1, 17). Glaucoma and progressive renal failure are both constituent parts of the syndrome (1). Recent studies have shown that LMX1B may regulate expression of type IV collagen during glomerular basement membrane development in the kidney (15, 19). The observation of an increased frequency of open angle glaucoma with NPS is further supported by the presence of anterior eye chamber abnormalities in LMX1B-deficient mice (12). The full extent of LMX1B’s regulation of skeletal and soft tissue development is still unknown. More than 100 mutations have been identified in patients with the clinical diagnosis of NPS, but no genotype-phenotype correlation has been observed (1, 10).

Because of the number of significant skeletal and soft tissue abnormalities, we postulated that patients with NPS would have a lower bone mineral density (BMD) with an increased prevalence of fragility fractures. To address these hypotheses, we examined BMD [assessed by dual-energy x-ray absorptiometry (DXA)], fracture history, and scoliosis in NPS patients vs. age- and gender-matched healthy controls.

	Subjects and Methods

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Subjects

Participants with previously diagnosed NPS (confirmed by mutation identification) were recruited during the Fifth International Conference on Nail Patella Syndrome (held at the University of Pittsburgh, Pittsburgh, PA, July 26–27, 2002). Age- and gender-matched adult healthy controls were recruited from the greater Pittsburgh area via advertisement. Men and women were excluded if they had diseases (hyperthyroidism, hyperparathyroidism, malabsorption, active renal disease) or took medications (glucocorticoids, anticonvulsants, excess thyroid hormone) that are known to cause bone loss. The protocol was approved by the Institutional Review Board of the University of Pittsburgh. Prospective participants were advised of the nature of the study and provided written informed consent before enrollment.

Study design

In this study, an observational case-control design was employed. Through frequency matching, adult patients with NPS were compared with healthy age- and gender-matched controls (± 5 yr of age). In addition, the BMD of adults and children with NPS was compared with that of the Hologic normative database (Hologic, Inc., Bedford, MA). All participants were seen in the Osteoporosis Prevention and Treatment Center at the University of Pittsburgh Medical Center.

Outcome variables

BMD of the hip (total hip, femoral neck, trochanter, intertrochanter) and lumbar spine (posteroanterior) was measured by DXA (QDR-4500A densitometer; Hologic, Inc.). The coefficients of variation of BMD in adults using our densitometer are 1.3% for the posteroanterior lumbar spine and 1.4% for the total hip. A questionnaire was administered, which queried participants for the occurrence of fragility fractures (nontraumatic fractures caused by a fall from standing height) and a previous clinical diagnosis of scoliosis.

Clinical characteristics

Weight was measured to the nearest kilogram, and height was measured to the nearest centimeter (Detecto scale and stadiometer; Detecto Corp., Web City, MO). Body mass index (BMI) was calculated as kilograms per square meter.

Statistical analysis

Appropriate descriptive statistics (e.g. mean, SD) were computed for each group for demographic and clinical characteristics and outcomes (raw, T-scores and Z-scores for BMD). The Z-score represents the patient’s bone density compared with the mean bone density of age- and gender-matched controls in SD units. The T-score represents the patient’s bone density compared with the mean gender-matched young adult peak bone mass in SD units. The clinical characteristics and BMD for the spine, total hip, femoral neck, trochanter, and intertrochanter regions for the adult NPS sample were compared with those for the healthy age- and gender-matched control sample using parametric and nonparametric group comparative test statistics (i.e. two-sample t test statistics for the comparison of independent groups based on a pooled or separate variance estimates and Mann-Whitney U test statistics with exact significance levels for continuous variables and ² test of independence for categorical variables). The percentage difference between the NPS and control samples relative to the control sample was also calculated to facilitate clinical interpretation of observed differences between NPS and control samples. One sample t test was used to assess whether the Z-scores and T-scores for NPS adults and children were significantly different from those of reference controls in the Hologic database.

To control for the possible confounding effects of BMI, hierarchical regression was performed, in which BMI was entered in the first block and a (0,1)-indicator variable for NPS status was entered in the second block for the adult subjects. The improvement in the model with the addition of NPS status after controlling for BMI was summarized, using the estimated regression coefficient, b, and the incremental change in the r-squared statistic or the percentage of variance explained, R_change², and tested using an incremental F test. Contingency table analysis using ² test statistics for independence, based on the exact estimation of significance levels, was used to compare the prevalence of fragility fractures and scoliosis between control adults and NPS adults and examine the relationship between fragility fractures and scoliosis for the adult sample (adults with and without NPS). The odds ratio with its 95% confidence interval was used as the measure of association when using the contingency table analysis and logistic regression. Survival analysis methods (i.e. Kaplan-Meier estimation, log-rank test, and Cox proportional hazards regression) were used to investigate the time to first fracture considering NPS status and scoliosis. The risk ratio with its 95% confidence interval was used as the measure of association when using the Cox proportional hazards regression. When conducting two-sided hypothesis testing, the level of significance was established at 0.05.

	Results

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Clinical characteristics

Participants with NPS included 31 adults (mean age 43.1 ± 12.4 yr) and 12 children (mean age 1.4 ± 1.9 yr). The adults with NPS included 16 (51.6%) premenopausal women and nine (29.0%) postmenopausal women (four of whom were on hormone replacement therapy). The adult female control group included 31 premenopausal women and 17 postmenopausal women (four of whom were on hormone replacement therapy). The mean age of the adult control group (43.9 ± 12.0 yr) (n = 60) was not statistically significantly different from the mean age of the adults with NPS. Adults with NPS had a lower weight and BMI than the healthy controls (P < 0.01; Table 1).

When adult participants with NPS were compared with the healthy age- and gender-matched adult controls from the Pittsburgh area, BMD was significantly lower at all hip sites (P 0.001, Table 1) and the posteroanterior spine (P < 0.01). In the adult control group, BMD of the spine and all hip sites was positively correlated with BMI with correlations ranging from 0.37 to 0.60 (P < 0.01 for each BMD region). By comparison, BMD in each of the regions considered was not associated with BMI in adult patients with NPS. After adjustment for BMI, BMD values remained significantly lower in participants with NPS, compared with the age- and gender-matched adult controls for the spine. Significant additional variance (all P < 0.001) for BMD values, explained by NPS, was 22.7% at the total hip, 5.5% at the femoral neck, 18.6% at the trochanter, and 24.7% at the intertrochanter.

When compared with age- and gender-matched controls from the Hologic database, the participants with NPS (n = 43) had significantly lower Z-scores at the total hip, femoral neck, trochanter, and intertrochanter (P < 0.05, Table 2). Adults with NPS (n = 31) also had a significantly lower Z-score at all hip sites (P < 0.05). There were no significant differences between the vertebral BMD of participants with NPS and that of the Hologic normative database. The adult participants with NPS had a mean T-score of –0.83 ± 1.33 SD at the spine and ranged from –1.12 ± 0.88 SD to –1.38 ± 0.89 SD at the hip sites (for all except the spine, P < 0.05, compared with zero). When children with NPS were compared with age- and gender-matched controls from the Hologic database, BMD was significantly reduced only at the femoral neck and trochanter based on Z-scores.

As reported in Table 3, adults with NPS had a significantly higher prevalence of fractures, compared with participants in the matched control group (odds ratio 30.9, 95% confidence interval 6.4–149.6, P < 0.001). The time to first fracture occurred significantly earlier in the NPS participant’s lifetime than the control subject’s lifetime (P < 0.001). The mean time to first fracture was 28.0 yr for NPS participants and 51.6 yr for control subjects. There were 16 adults who sustained 31 fractures. Most of these occurred before puberty [age 15 yr or younger (83%)], were in women (81%), and occurred in long bones, with a fracture of the clavicle occurring most often of all fractures (26%) (Table 4). In addition, half of the NPS participants fractured more than once. There were four children who sustained eight fractures, including three fractures of the clavicle.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We found that BMD of the hip was 11–20% lower in adult participants with NPS, with a similar, albeit lower, trend at the spine. Although this was statistically significant, the adults with NPS on average had a T-score only in the normal to osteopenic range by the World Health Organization criteria (20). Despite this, fragility fractures and scoliosis were significantly more common in adult participants with NPS. Furthermore, the fractures usually occurred before puberty, were often multiple, occurred in long bones (especially the clavicle), and were more common in women.

The finding of a significantly increased prevalence of fractures despite a mildly decreased BMD suggests that the increase in fractures may be secondary to factors other than decreased BMD. The vertebral BMD values in these patients could have been falsely elevated secondary to scoliosis, which can contribute to calcifications outside the vertebrae (21, 22, 23, 24). However, the majority of fragility fractures occurred in long bones, composed of predominantly cortical bone. Bone mass in NPS participants was lower in the hip, a site rich in cortical bone. This suggests that NPS participants may have a predisposition to fracture at sites rich in cortical bone. Moreover, because the majority of fractures occurred before puberty, the production of sex steroids may prevent fractures as an adult. The finding of few fractures in males may be related to androgens or differences in geometry that have been reported in men (25). Other potential causes for the increase in fractures include differences in bone quality, mineral deposition, collagen, turnover, and connectivity (26, 27, 28, 29, 30).

In other connective tissue disorders, such as Marfan syndrome, reduced BMD has been reported (31, 32, 33). However, an increased fracture history has not been reported in this unrelated autosomal dominant condition. By contrast, women with Turner’s syndrome, characterized by monosomy for the X chromosome, present with short stature and gonadal dysgenesis. These patients have low bone mass, and the prevalence of fractures is reported to be 16–45% (34, 35). However, if height and areal BMD are taken into account, bone mass may not be significantly reduced (36). In our patients with NPS, height was similar to that of controls. If patients with Turner’s syndrome are treated early with hormone replacement therapy, the prevalence of fractures may not increase (36). We enrolled 16 NPS participants who were premenopausal with normal menstrual function. Four of the nine postmenopausal women with NPS were on hormone replacement therapy. Therefore, adult women with NPS may gain fracture protection from estrogen.

It is likely that the reduced weight and BMI contributed to the decrease in bone mass in our patients. Both weight and BMI are positively associated with bone mass (37), which is in agreement with what we observed only in healthy controls. Moreover, weight loss is associated with loss of bone mass (18). However, when we adjusted for BMI, we continued to observe the reduced bone mass areas of the total hip, femoral neck, trochanter, and intertrochanter in patients with NPS, compared with healthy controls.

Study limitations included the relatively small sample size. In addition, we were unable to involve control children due to the institutional review board’s concerns about unnecessary radiation during the growing years. Furthermore, we did not do a comprehensive assessment of other potential risk factors that predispose to osteoporosis (e.g. smoking, alcohol, lack of exercise, or poor calcium intake) (2). However, we did exclude those who were on medications known to decrease bone mass or increase bone turnover (2). We do not have information on the rate of falls in these patients, which could account for an increase in the number of fractures. Finally, we were not able to collect serum or urine samples for markers of bone turnover or measures of bone mineral metabolism, which could have contributed to a better understanding of the pathophysiology.

There were also several strengths of the study. Although this is a relatively uncommon genetic disease that occurs sporadically across the country, we were able to examine a relatively large group of patients. However, because NPS may present in some patients with only minor x-ray-detected deformities, it may be more common than anticipated and could be the cause of idiopathic osteoporosis in young patients who have low bone mass or fractures. NPS should be considered in the differential diagnosis of such patients who have a negative work-up for secondary causes of low bone mass. Another strength of the study was the use of a single densitometer on which a single DXA technician performed all scans. Furthermore, this is the first study to report on the impact of NPS on bone mass of the skeleton in the context of fracture history. Finally, because some of the features of NPS are present in other diseases, we included only those who had previously been genotyped for NPS.

In summary, we found that BMD was minimally decreased in adults with NPS, and few participants had osteopenia or osteoporosis. Despite the minimal impact of NPS on BMD, there was a significantly increased prevalence of fractures, occurring mainly in long bones in prepubertal women. This suggests that sex steroids may play an important role in the prevention of fractures in these patients. Future studies are needed to assess skeletal strength, geometry, and turnover in these patients.

	Acknowledgments

 
We gratefully acknowledge the support of the Nail Patella Syndrome Worldwide and the assistance of Donna Zeminski and Jennifer Mikelonis at the Fifth International Conference on Nail Patella Syndrome.

	Footnotes

 
This work was supported by grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (to S.L.G., 1 K24 DK062895) and NIH/National Institute on Aging to the Claude D. Pepper Older Americans Independence Center, University of Pittsburgh (1 P30 AG024827-01). The Osteoporosis Prevention and Treatment Center, University of Pittsburgh, provided the department technologist and clinic coordinator time.

First Published Online December 28, 2004

Abbreviations: BMD, Bone mineral density; BMI, body mass index; DXA, dual-energy x-ray absorptiometry; NPS, nail patella syndrome.

Received May 26, 2004.

Accepted December 16, 2004.

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/4/1961    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Towers, A. L. Articles by Greenspan, S. L. Search for Related Content PubMed PubMed Citation Articles by Towers, A. L. Articles by Greenspan, S. L. Related Collections Calcium and Bone Metabolism