Genetic Evaluation for Monogenic Disorders of Low Bone Mass and Increased Bone Fragility: What Clinicians Need to Know.

PURPOSE OF REVIEW: The purpose of this review is to outline the principles of clinical genetic testing and to provide practical guidance to clinicians in navigating genetic testing for patients with suspected monogenic forms of osteoporosis. RECENT FINDINGS: Heritability assessments and genome-wide association studies have clearly shown the significant contributions of genetic variations to the pathogenesis of osteoporosis. Currently, over 50 monogenic disorders that present primarily with low bone mass and increased risk of fractures have been described. The widespread availability of clinical genetic testing offers a valuable opportunity to correctly diagnose individuals with monogenic forms of osteoporosis, thus instituting appropriate surveillance and treatment. Clinical genetic testing may identify the appropriate diagnosis in a subset of patients with low bone mass, multiple or unusual fractures, and severe or early-onset osteoporosis, and thus clinicians should be aware of how to incorporate such testing into their clinical practices.

Improving access to exome sequencing in a medically underserved population through the Texome Project.

PURPOSE: Genomic medicine can end diagnostic odysseys for patients with complex phenotypes; however, limitations in insurance coverage and other systemic barriers preclude individuals from accessing comprehensive genetics evaluation and testing. METHODS: The Texome Project is a 4-year study that reduces barriers to genomic testing for individuals from underserved and underrepresented populations. Participants with undiagnosed, rare diseases who have financial barriers to obtaining exome sequencing (ES) clinically are enrolled in the Texome Project. RESULTS: We highlight the Texome Project process and describe the outcomes of the first 60 ES results for study participants. Participants received a genetic evaluation, ES, and return of results at no cost. We summarize the psychosocial or medical implications of these genetic diagnoses. Thus far, ES provided molecular diagnoses for 18 out of 60 (30%) of Texome participants. Plus, in 11 out of 60 (18%) participants, a partial or probable diagnosis was identified. Overall, 5 participants had a change in medical management. CONCLUSION: To date, the Texome Project has recruited a racially, ethnically, and socioeconomically diverse cohort. The diagnostic rate and medical impact in this cohort support the need for expanded access to genetic testing and services. The Texome Project will continue reducing barriers to genomic care throughout the future study years.

Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders.

OBJECTIVE: Liver transplantation (LTx) is an intervention when medical management is not sufficiently preventing individuals with urea cycle disorders (UCDs) from the occurrence of hyperammonemic events. Supplementation with L-citrulline/arginine is regularly performed prior to LTx to support ureagenesis and is often continued after the intervention. However, systematic studies assessing the impact of long-term L-citrulline/arginine supplementation in individuals who have undergone LTx is lacking to date. METHODS: Using longitudinal data collected systematically, a comparative analysis was carried out by studying the effects of long-term L-citrulline/arginine supplementation vs. no supplementation on health-related outcome parameters (i.e., anthropometric, neurological, and cognitive outcomes) in individuals with UCDs who have undergone LTx. Altogether, 52 individuals with male ornithine transcarbamylase deficiency, citrullinemia type 1 and argininosuccinic aciduria and a pre-transplant "severe" disease course who have undergone LTx were investigated by using recently established and validated genotype-specific in vitro enzyme activities. RESULTS: Long-term supplementation of individuals with L-citrulline/arginine who have undergone LTx (n = 16) does neither appear to alter anthropometric nor neurocognitive endpoints when compared to their severity-adjusted counterparts that were not supplemented (n = 36) after LTx with mean observation periods between four to five years. Moreover, supplementation with L-citrulline/arginine was not associated with an increase of disease-specific plasma arithmetic mean values for the respective amino acids when compared to the non-supplemented control cohort. CONCLUSION: Although supplementation with L-citrulline/arginine is often continued after LTx, this pilot study does neither identify altered long-term anthropometric or neurocognitive health-related outcomes nor does it find an adequate biochemical response as reflected by the unaltered plasma arithmetic mean values for L-citrulline or L-arginine. Further prospective analyses in larger samples and even longer observation periods will provide more insight into the usefulness of long-term supplementation with L-citrulline/arginine for individuals with UCDs who have undergone LTx.

Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders.

PURPOSE: Liver transplantation (LTx) is performed in individuals with urea cycle disorders when medical management (MM) insufficiently prevents the occurrence of hyperammonemic events. However, there is a paucity of systematic analyses on the effects of LTx on health-related outcome parameters compared to individuals with comparable severity who are medically managed. METHODS: We investigated the effects of LTx and MM on validated health-related outcome parameters, including the metabolic disease course, linear growth, and neurocognitive outcomes. Individuals were stratified into "severe" and "attenuated" categories based on the genotype-specific and validated in vitro enzyme activity. RESULTS: LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. However, neurocognitive outcome in individuals with LTx did not differ from the medically managed counterparts as reflected by the frequency of motor abnormality and cognitive standard deviation score at last observation. CONCLUSION: Whereas LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy and was associated with a more favorable growth outcome, LTx-as currently performed-was not associated with improved neurocognitive outcomes compared with long-term MM in the investigated urea cycle disorders.

Monitoring the treatment of urea cycle disorders using phenylbutyrate metabolite analyses: Still many lessons to learn.

Medications that elicit an alternate pathway for nitrogen excretion such as oral sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB) and intravenous sodium phenylacetate (NaPAA) are important for the management of urea cycle disorders (UCDs). Plasma concentrations of their primary metabolite, phenylacetate (PAA), as well as the ratio of PAA to phenylacetylglutamine (PAGN) are useful for guiding dosing and detecting toxicity. However, the frequency of toxic elevations of metabolites and associated clinical covariates is relatively unknown. A retrospective analysis was conducted on 1255 plasma phenylbutyrate metabolite measurements from 387 individuals. An additional analysis was also conducted on a subset of 68 individuals in whom detailed clinical information was available. In the course of these analyses, abnormally elevated plasma PAA and PAA:PAGN were identified in 39 individuals (4.15% of samples) and 42 individuals (4.30% of samples), respectively. Abnormally elevated PAA and PAA:PAGN values were more likely to occur in younger individuals and associate positively with dose of NAPBA and negatively with plasma glutamine and glycine levels. These results demonstrate that during routine clinical management, the majority of patients have PAA levels that are deemed safe. As age is negatively associated with PAA levels however, children undergoing treatment with NaPBA may need close monitoring of their phenylbutyrate metabolite levels.

Health-related quality of life in a systematically assessed cohort of children and adults with urea cycle disorders.

PURPOSE: Individuals with urea cycle disorders (UCDs) may develop recurrent hyperammonemia, episodic encephalopathy, and neurological sequelae which can impact Health-related Quality of Life (HRQoL). To date, there have been no systematic studies of HRQoL in people with UCDs. METHODS: We reviewed HRQoL and clinical data for 190 children and 203 adults enrolled in a multicenter UCD natural history study. Physical and psychosocial HRQoL in people with UCDs were compared to HRQoL in healthy people and people with phenylketonuria (PKU) and diabetes mellitus. We assessed relationships between HRQoL, UCD diagnosis, and disease severity. Finally, we calculated sample sizes required to detect changes in these HRQoL measures. RESULTS: Individuals with UCDs demonstrated worse physical and psychosocial HRQoL than their healthy peers and peers with PKU and diabetes. In children, HRQoL scores did not differ by diagnosis or severity. In adults, individuals with decreased severity had worse psychosocial HRQoL. Finally, we show that a large number of individuals would be required in clinical trials to detect differences in HRQoL in UCDs. CONCLUSION: Individuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.

Approach to the Patient: Pharmacological Therapies for Fracture Risk Reduction in Adults With Osteogenesis Imperfecta.

CONTEXT: Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. The effectiveness of medications used for fracture reduction in adults with OI is understudied and practice recommendations are not well established. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis. Oral and intravenous bisphosphonates have been shown to improve bone mineral density (BMD) in adults with OI and are commonly used; however, conclusive data confirming fracture protection are lacking. Similarly, teriparatide appears to increase BMD, an effect that seems to be limited to individuals with type I OI. The role of denosumab, abaloparatide, romosozumab, and estradiol/testosterone in adult OI have not been systematically studied. Anti-sclerostin agents and transforming growth factor-beta antagonists are under investigation in clinical trials. OBJECTIVE: This review summarizes current knowledge on pharmacologic treatment options for reducing fracture risk in adults with OI. METHODS: A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in June 2022. Articles screened were restricted to adults. Additional sources were identified through manual searches of reference lists. CONCLUSION: Fracture rates are elevated in adults with OI. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving BMD. Further research is needed to develop medications for adults with OI that will lead to definite fracture rate reduction.

A multicenter study to evaluate pain characteristics in osteogenesis imperfecta.

The objective was to describe pain characteristics and treatments used in individuals with varying severity of osteogenesis imperfecta (OI) and investigate pain-associated variables. This work was derived from a multicenter, longitudinal, observational, natural history study of OI conducted at 12 clinical sites of the NIH Rare Diseases Clinical Research Network's Brittle Bone Disorders Consortium. Children and adults with a clinical, biochemical, or molecular diagnosis of OI were enrolled in the study. We did a cross-sectional analysis of chronic pain prevalence, characteristics, and treatments used for pain relief and longitudinal analysis to find the predictors of chronic pain. We included 861 individuals with OI, in 41.8% chronic pain was present, with similar frequency across OI types. Back pain was the most frequent location. Nonsteroidal anti-inflammatory drugs followed by bisphosphonates were the most common treatment used. Participants with chronic pain missed more days from school or work/year and performed worse in all mobility metrics than participants without chronic pain. The variables more significantly associated with chronic pain were age, sex, positive history of rodding surgery, scoliosis, other medical problems, assistive devices, lower standardized height, and higher body mass index. The predictors of chronic pain for all OI types were age, use of a wheelchair, and the number of fractures/year. Chronic pain is prevalent in OI across all OI types, affects mobility, and interferes with participation. Multiple covariates were associated with chronic pain.

Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency.

OBJECTIVE: Ornithine transcarbamylase deficiency (OTC-D) is an X-linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity-adjusted classification system based on in vitro residual enzymatic OTC activity. METHODS: Applying a cell-based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC-D (mOTC-D) as reported in the UCDC and E-IMD registries. RESULTS: Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC-D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. INTERPRETATION: Residual enzymatic OTC activity reliably predicts the disease severity in mOTC-D and could thus serve as a tool for severity-adjusted evaluation of therapeutic strategies and counselling patients and parents.

A GMR-based assay for quantification of the human response to influenza.

Detecting and quantifying the host transcriptional response to influenza virus infection can serve as a real-time diagnostic tool for clinical management. We have employed the multiplexing capabilities of GMR sensors to develop a novel assay based on the influenza metasignature (IMS), which can classify influenza infection based on transcript levels. We show that the assay can reliably detect ten IMS transcripts and distinguish subjects with naturally acquired influenza infection from those with other symptomatic viral infections (AUC 0.93, 95% CI: 0.82-1.00). Separately, we validated that the gene IFI27, not included in the IMS panel, has very high single-biomarker accuracy (AUC 0.95, 95% CI: 0.90-0.99) in stratifying patients with influenza. We demonstrate that a portable GMR biosensor can be used as a tool to diagnose influenza infection by measuring the host response, simultaneously highlighting the power of immune system metrics and advancing the field of gene expression-based diagnostics.

ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype.

Argininosuccinate lyase (ASL) is essential for the NO-dependent regulation of tyrosine hydroxylase (TH) and thus for catecholamine production. Using a conditional mouse model with loss of ASL in catecholamine neurons, we demonstrate that ASL is expressed in dopaminergic neurons in the substantia nigra pars compacta, including the ALDH1A1 + subpopulation that is pivotal for the pathogenesis of Parkinson disease (PD). Neuronal loss of ASL results in catecholamine deficiency, in accumulation and formation of tyrosine aggregates, in elevation of α-synuclein, and phenotypically in motor and cognitive deficits. NO supplementation rescues the formation of aggregates as well as the motor deficiencies. Our data point to a potential metabolic link between accumulations of tyrosine and seeding of pathological aggregates in neurons as initiators for the pathological processes involved in neurodegeneration. Hence, interventions in tyrosine metabolism via regulation of NO levels may be therapeutic beneficial for the treatment of catecholamine-related neurodegenerative disorders.

Alterations of a serum marker of collagen X in growing children with osteogenesis imperfecta.

Abnormalities in the structure and/or processing of type I collagen cause osteogenesis imperfecta and result in bone fragility, abnormal bone growth and short stature. Type I collagen is expressed in the growth plate but the mechanisms by which abnormalities in collagen I contribute to growth plate dysfunction and growth retardation are unknown. The non-collagenous domain (NC1) of type X collagen (CXM) is released from the hypertrophic zone of active growth plates and is a marker for new endochondral bone formation. Serum CXM levels are strongly correlated with the rate of growth in healthy children. We hypothesized that CXM levels in children with OI would be abnormal when compared to normally growing children. Using participants from the Brittle Bone Disease Consortium Natural History Study we analyzed the distribution of CXM over the ages of 8 months to 40 years in 187 subjects with OI (89 type I and 98 types III/IV) as well as analyzed the relationship between growth velocity and CXM levels in a subset of 100 children <16 years old with OI (44 type I and 56 types III/IV). CXM levels in both control and OI children demonstrated a similar pattern of variation by age with higher levels in early life and puberty followed by a post-pubertal drop. However, there was greater variability within the OI cohort and the relationship with growth velocity was weaker. The ratio of CXM level to growth velocity was elevated in children with type III/IV OI compared to controls. These results suggest that the relationship between hypertrophic zone function and the end point of skeletal growth is disrupted in OI.

Biomarkers for liver disease in urea cycle disorders.

BACKGROUND: Urea cycle disorders (UCDs) are among the most common inborn errors of liver metabolism. As therapies for hyperammonemia associated with urea cycle dysfunction have improved, chronic complications, such as liver disease, have become increasingly apparent in individuals with UCDs. Liver disease in UCDs may be associated with hepatic inflammation, hepatic fibrosis, portal hypertension, liver cancer and even liver failure. However, except for monitoring serum aminotransferases, there are no clear guidelines for screening and/or monitoring individuals with UCDs for liver disease. Thus, we systematically evaluated the potential utility of several non-invasive biomarkers for liver fibrosis in UCDs. METHODS: We evaluated grey-scale ultrasonography, liver stiffness obtained from shear wave elastography (SWE), and various serum biomarkers for hepatic fibrosis and necroinflammation, in a cohort of 28 children and adults with various UCDs. RESULTS: Overall, we demonstrate a high burden of liver disease in our participants with 46% of participants having abnormal grey-scale ultrasound pattern of the liver parenchyma, and 52% of individuals having increased liver stiffness. The analysis of serum biomarkers revealed that 32% of participants had elevated FibroTest™ score, a marker for hepatic fibrosis, and 25% of participants had increased ActiTest™ score, a marker for necroinflammation. Interestingly, liver stiffness did not correlate with ultrasound appearance or FibroTest™. CONCLUSION: Overall, our results demonstrate the high overall burden of liver disease in UCDs and highlights the need for further studies exploring new tools for identifying and monitoring individuals with UCDs who are at risk for this complication. TRIAL REGISTRATION: This study has been registered in ClinicalTrials.gov (NCT03721367).

Pregnancy in women with osteogenesis imperfecta: pregnancy characteristics, maternal, and neonatal outcomes.

BACKGROUND: Women with rare diseases, such as osteogenesis imperfecta, may consider pregnancy, although data regarding outcomes, specific risks, and management strategies are lacking. OBJECTIVE: The Brittle Bone Disorders Consortium of the National Institute of Health Rare Diseases Clinical Research Network established an Osteogenesis Imperfecta Pregnancy Registry to collect and evaluate pregnancy, maternal, and neonatal outcomes in women with osteogenesis imperfecta. STUDY DESIGN: This was a cross-sectional, survey-based study. Appropriate participants of the Brittle Bone Disorders Consortium Contact Registry were invited to participate in the study. Self-reported information regarding pregnancy characteristics and maternal and neonatal outcomes of women with osteogenesis imperfecta was compared with that of the general population, referenced by literature-based standards. Furthermore, compared with the general population, cohorts of women and fetuses with osteogenesis imperfecta were evaluated to determine whether the presence of osteogenesis imperfecta conveyed an increase in antepartum, intrapartum, and postpartum complications and an increase in adverse neonatal outcomes. RESULTS: Here, a total 132 participants completed the survey. Compared with the general population, women with osteogenesis imperfecta had higher rates of diabetes in pregnancy (13.3% vs 7%; 95% confidence interval, 7.0-19.6; P=.049), cesarean delivery (68.5% vs 32.7%; 95% confidence interval, 59.9-77.1; P<.001), need for blood transfusion (8.3% vs 1.5%; 95% confidence interval, 3.9-12.8; P=.019), and antepartum and postpartum fractures (relative risk, 221; 95% confidence interval, 59.3-823; P<.001). Maternal hospitalization and cesarean delivery rates were higher in individuals with moderate or severe osteogenesis imperfecta than women who reported mild osteogenesis imperfecta. Neonates born to women with osteogenesis imperfecta had higher risk of being low (26.2% vs 6.8%; P<.001) or very low birthweight (13.8% vs 1.4%; P<.001) infants than the general population. Neonates born to women with osteogenesis imperfecta had a higher rate of neonatal intensive care unit admissions (19% vs 5.68%; P<.001) and higher neonatal mortality at 28 days of life (4.8% vs 0.4%; P=.026), regardless of neonatal osteogenesis imperfecta status. CONCLUSION: Pregnancies for women with osteogenesis imperfecta are at an increased risk of complications, including hemorrhage, fractures, diabetes mellitus, and increased neonatal morbidity.

Health-related quality of life in adults with osteogenesis imperfecta.

Patient-reported outcome measures (PROMs) are increasingly utilized as endpoints in clinical trials. The Short Form Health Survey-12 (SF-12v2) is a generic PROM for adults. We sought to evaluate the validity of SF-12v2 in adults with osteogenesis imperfecta (OI). Physical and mental health-related quality of life (HRQoL) were assessed in a large cohort of adults in a multicenter, observational, natural history study. Physical HRQoL scores were correlated with the Gillette Functional Assessment Questionnaire (GFAQ). We calculated sample sizes required in clinical trials with crossover and parallel-group designs to detect clinically meaningful changes in physical HRQoL. Three hundred and two adults with OI types I, III, and IV were enrolled. Physical HRQoL scores in the study population were lower than population norms. Physical HRQoL scores moderately correlated with GFAQ for OI types I and IV. We found no correlations between mental and physical HRQoL. From a clinical trial readiness perspective, we show that SF-12v2 reliably measures physical function in adults with OI and can be utilized in crossover trials to detect meaningful physical HRQoL changes with small sample sizes. This study shows that SF-12v2 can be used to measure changes in physical HRQoL in response to interventions in OI.

A deep intronic variant is a common cause of OTC deficiency in individuals with previously negative genetic testing.

Pathogenic variants in non-coding regions of genes encoding enzymes or transporters of the urea cycle can lead to urea cycle disorders (UCDs). However, not all commercially available testing platforms interrogate these regions. Here, we used a gene panel based on massively parallel sequencing (MPS) in 10 individuals with clinical or pedigree-based evidence of a proximal UCD but without a molecular confirmation of the diagnosis. We identified causal variant(s) in 5 of 10 individuals, including in 3 of 7 individuals in whom prior molecular testing was unrevealing. We show that a deep-intronic pathogenic variant in OTC, c.540+265G>A, is an important cause of ornithine transcarbamylase (OTC) deficiency.

Widespread disturbance in extracellular matrix collagen biomarker responses to teriparatide therapy in osteogenesis imperfecta.

Osteogenesis imperfecta (OI), a heritable disorder caused by abnormalities in synthesis or processing of type I collagen, is characterized by skeletal fragility. Type I collagen interacts with multiple components of the extracellular matrix (ECM) including other collagens types. Thus, alterations in structure or quantity may broadly affect ECM homeostasis. In fact, while OI is clinically categorized by severity of bone disease, patients can also present with extra-skeletal manifestations, including the pulmonary, muscle and cardiovascular systems. Parathyroid hormone (PTH) is a regulator of skeletal homeostasis but the receptor for PTH/PTH1R is expressed in a variety of other tissues. Given interactions between type I collagen with other collagens in the ECM and the potential for PTH action on tissues beyond the skeleton, we explored whether serum levels of non-type I collagens are altered in response to teriparatide (human parathyroid hormone 1-34). We measured biomarkers of collagens II, III, IV, V, and VI in serum from individuals with type I and types III/IV OI in response to an 18 month course of teriparatide or placebo. These results were compared to similar biomarker measures in postmenopausal (PM) women without OI treated with teriparatide. In type I OI, teriparatide therapy increased concentrations of biomarkers of collagens II, III, IV, V, and VI. In individuals with types III/IV OI these biomarker changes in response to teriparatide were blunted, as we previously reported with collagen I biomarkers during teriparatide therapy. In contrast to OI, in PM women there were no effects of teriparatide on the collagen biomarkers we assessed (II, V, and VI). These findings suggest that in OI teriparatide therapy has abnormal effects on the homeostasis of many ECM collagens likely derived from skeletal as well as extra-skeletal tissues.

Severity-adjusted evaluation of newborn screening on the metabolic disease course in individuals with cytosolic urea cycle disorders.

OBJECTIVE: The implementation of newborn screening (NBS) programs for citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) is subject to controversial debate. The aim of this study was to assess the impact of NBS on the metabolic disease course and clinical outcome of affected individuals. METHODS: In 115 individuals with CTLN1 and ASA, we compared the severity of the initial hyperammonemic episode (HAE) and the frequency of (subsequent) HAEs with the mode of diagnosis. Based on a recently established functional disease prediction model, individuals were stratified according to their predicted severe or attenuated phenotype. RESULTS: Individuals with predicted attenuated forms of CTLN1 and ASA were overrepresented in the NBS group, while those with a predicted severe phenotype were underrepresented compared to individuals identified after the manifestation of symptoms (SX). Identification by NBS was associated with reduced severity of the initial HAE both in individuals with predicted severe and attenuated phenotypes, while it was not associated with lower frequency of (subsequent) HAEs. Similar results were obtained when including some patients diagnosed presymptomatically (i.e. prenatal testing, and high-risk family screening) in this analysis. CONCLUSION: Since one of the major challenges of NBS outcome studies is the potential overrepresentation of individuals with predicted attenuated phenotypes in NBS cohorts, severity-adjusted evaluation of screened and unscreened individuals is important to avoid overestimation of the NBS effect. NBS enables the attenuation of the initial HAE but does not affect the frequency of subsequent metabolic decompensations in individuals with CTLN1 and ASA. Future long-term studies will need to evaluate the clinical impact of this finding, especially with regard to mortality, as well as cognitive outcome and quality of life of survivors.

A Multicenter Study of Intramedullary Rodding in Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI), a heritable connective tissue disorder with wide clinical variability, predisposes to recurrent fractures and bone deformity. Management requires a multidisciplinary approach in which intramedullary rodding plays an important role, especially for moderate and severe forms. We investigated the patterns of surgical procedures in OI in order to establish the benefits of rodding. The main hypothesis that guided this study was that rodded participants with moderate and severe OI would have lower fracture rates and better mobility. METHODS: With data from the Linked Clinical Research Centers, we analyzed rodding status in 558 individuals. Mobility and fracture data in OI Types III and IV were compared between rodded and non-rodded groups. Univariate regression analyses were used to test the association of mobility outcomes with various covariates pertinent to rodding. RESULTS: Of the individuals with OI, 42.1% had undergone rodding (10.7% of those with Type I, 66.4% with Type III, and 67.3% with Type IV). Rodding was performed more frequently and at a younger age in femora compared with tibiae. Expanding intramedullary rods were used more frequently in femora. In Type III, the rate of fractures per year was significantly lower (p ≤ 0.05) for rodded bones. In Type III, the mean scores on the Gillette Functional Assessment Questionnaire (GFAQ) and Brief Assessment of Motor Function (BAMF) were higher in the rodded group. However, Type-IV non-rodded subjects had higher mean scores in nearly all mobility outcomes. OI type, the use of expanding rods in tibiae, and anthropometric measurements were associated with mobility outcomes scores. CONCLUSIONS: Current practice in 5 orthopaedic centers with extensive experience treating OI demonstrates that most individuals with moderate and severe types of OI undergo rodding procedures. Individuals with severe OI have improved mobility outcomes and lower fracture rates compared with their non-rodded peers, which suggests that early bilateral rodding benefits OI Type III. Our analysis showed a change in practice patterns in the final years of the study in the severe forms, with earlier and more simultaneous rodding procedures performed. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.