Clinical utility of comprehensive gene panel testing for common and rare causes of skeletal dysplasia and other skeletal disorders: Results from the largest cohort to date.

Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019-April 2022). Median (range) age was 8 (0-90) years, 70.5% had short stature and/or disproportionate growth, 27.4% had a positive molecular diagnosis (MDx), and 30 individuals received two MDx. Genes most commonly contributing to MDx were FGFR3 (16.9%), ALPL (13.0%), and COL1A1 (10.3%). Most of the 112 genes associated with ≥1 MDx were primarily involved in signal transduction (n = 35), metabolism (n = 23), or extracellular matrix organization (n = 17). There were implications associated with specific care/treatment options for 84.4% (1158/1372) of MDx-positive individuals; >50% were linked to conditions with targeted therapy approved or in clinical development, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and mucopolysaccharidosis. Forty individuals with initially inconclusive results became MDx-positive following family testing. Follow-up mucopolysaccharidosis enzyme activity testing was positive in 14 individuals (10 of these were not MDx-positive). Our findings showed that inclusion of metabolic genes associated with SD increased the clinical utility of a gene panel and confirmed that integrated use of comprehensive gene panel testing with orthogonal testing reduced the burden of inconclusive results.

Complications and Revisions After Spine Surgery in Patients With Skeletal Dysplasia: Have We Improved?

STUDY DESIGN: Retrospective case series. OBJECTIVE: To report contemporary rates of complications and subsequent surgery after spinal surgery in patients with skeletal dysplasia. METHODS: A case series of 25 consecutive patients who underwent spinal surgery between 2007 and 2017 were identified from a single institution's skeletal dysplasia registry. Patient demographics, medical history, surgical indication, complications, and subsequent surgeries (revisions, extension to adjacent levels, or for pathology at a non-contiguous level) were collected. Charlson comorbidity indices were calculated as a composite measure of overall health. RESULTS: Achondroplasia was the most common skeletal dysplasia (76%) followed by spondyloepiphyseal dysplasia (20%); 1 patient had diastrophic dysplasia (4%). Average patient age was 53.2 ± 14.7 years and most patients were in excellent cardiovascular health (88% Charlson Comorbidity Index 0-4). Mean follow up after the index procedure was 57.4 ± 39.2 months (range). Indications for surgery were mostly for neurologic symptoms. The most commonly performed surgery was a multilevel thoracolumbar decompression without fusion (57%). Complications included durotomy (36%), neurologic complication (12%), and infection requiring irrigation and debridement (8%). Nine patients (36%) underwent a subsequent surgery. Three patients (12%) underwent a procedure at a non-contiguous anatomic zone, 3 (12%) underwent a revision of the previous surgery, and another 3 (12%) required extension of their previous decompression or fusion. CONCLUSIONS: Surgical complication rates remain high after spine surgery in patients with skeletal dysplasia, likely attributable to inherent characteristics of the disease. Patients should be counseled on their risk for complication and subsequent surgery.

Patient-reported prevalence of gastrointestinal issues in the adult skeletal dysplasia population with a concentration on osteogenesis imperfecta.

Patient-reported concerns indicate that gastrointestinal (GI) manifestations affect the skeletal dysplasia population, but quantitative information regarding prevalence and severity of GI issues is limited. We examined the frequency and characteristics of GI symptoms in adults with skeletal dysplasias by reviewing 101 responses to the Gastrointestinal Symptom Rating Scale (GSRS). Participant demographics, medication history, and ambulatory status were collected from medical records. Compared to published GSRS reference data, our cohort scored higher on reflux, diarrhea, and total scores, and lower on abdominal pain and indigestion scores; none of these differences were statistically significant. Although osteogenesis imperfecta respondents had more severe symptoms across all domains, only reflux reached significance (p = 0.009). Scores in patients with achondroplasia were higher for indigestion, constipation, diarrhea, and total scores and lower on abdominal pain and reflux scores than the general population; only the diarrhea score was significant (p = 0.034). There were no statistically significant differences in any of the domain or total GSRS scores across ambulatory status groups. Increased height correlated with worse abdominal pain domain score (p = 0.033). The number of medications positively correlated with total GSRS score (p = 0.013). Future studies should include larger numbers of individuals to allow a more in-depth analysis of patient-reported symptoms and signs within this population.

International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia.

Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life.

Orthopedic considerations and surgical outcomes in Ehlers-Danlos syndromes.

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of connective tissue disorders with varying physical manifestations. There are no clear guidelines for addressing orthopedic concerns or reporting surgical outcomes in this population. This article reviews the literature, reports on a new study, and offers considerations prior to surgical intervention. The new study seeks to determine the effectiveness of surgical intervention in individuals with EDS. It is a retrospective chart review of 154 individuals clinically diagnosed with EDS who had orthopedic surgery >2 years ago at Hospital for Special Surgery. A total of 120 individuals were included in the study. One hundred eleven females and 9 males underwent a total of 320 orthopedic surgeries, of which 204 surgeries had available post-operative follow-up. The average age at surgery was 38.2 years (range: 7.6-83.3). Multiple post-operative complications (290) were reported in 91% of cases. Common complications were persistent pain/discomfort (45), continued subluxation/dislocation (20), instability (19), pain/discomfort from hardware (17), and infection (16). Our results suggest that surgical outcomes are worse for individuals with EDS compared to the general population, a finding which is similar to other studies. Complications occurred more frequently in the EDS population than the average population, suggesting that surgery should be undertaken by a multidisciplinary team of clinicians with careful pre-operative planning and full knowledge of the risks and benefits. Guidelines for the care of this unique population must be established.

TLE4 Is a Critical Mediator of Osteoblast and Runx2-Dependent Bone Development.

Healthy bone homeostasis hinges upon a delicate balance and regulation of multiple processes that contribute to bone development and metabolism. While examining hematopoietic regulation by Tle4, we have uncovered a previously unappreciated role of Tle4 on bone calcification using a novel Tle4 null mouse model. Given the significance of osteoblasts in both hematopoiesis and bone development, this study investigated how loss of Tle4 affects osteoblast function. We used dynamic bone formation parameters and microCT to characterize the adverse effects of Tle4 loss on bone development. We further demonstrated loss of Tle4 impacts expression of several key osteoblastogenic genes, including Runx2, Oc, and Ap, pointing toward a potential novel mechanism for Tle4-dependent regulation of mammalian bone development in collaboration with the RUNX family members.

Lifetime impact of achondroplasia: Current evidence and perspectives on the natural history.

Achondroplasia, the most common form of disproportionate short stature, is caused by a variant in the fibroblast growth factor receptor 3 (FGFR3) gene. Advances in drug treatment for achondroplasia have underscored the need to better understand the natural history of this condition. This article provides a critical review and discussion of the natural history of achondroplasia based on current literature evidence and the perspectives of clinicians with extensive knowledge and practical experience in managing individuals with this diagnosis. This review draws evidence from recent and ongoing longitudinal natural history studies, supplemented with relevant cross-sectional studies where longitudinal research is lacking, to summarize the current knowledge on the nature, incidence, chronology, and interrelationships of achondroplasia-related comorbidities across the lifespan. When possible, data related to adults are presented separately from data specific to children and adolescents. Gaps in knowledge regarding clinical care are identified and areas for future research are recommended and discussed.

Best practice guidelines in managing the craniofacial aspects of skeletal dysplasia.

BACKGROUND: Recognition and appropriate management of the craniofacial manifestations of patients with skeletal dysplasia are challenging, due to the rarity of these conditions, and dearth of literature to support evidence-based clinical decision making. METHODS: Using the Delphi method, an international, multi-disciplinary group of individuals, with significant experience in the care of patients with skeletal dysplasia, convened to develop multi-disciplinary, best practice guidelines in the management of craniofacial aspects of these patients. RESULTS: After a comprehensive literature review, 23 initial statements were generated and critically discussed, with subsequent development of a list of 22 best practice guidelines after a second round voting. CONCLUSIONS: The guidelines are presented and discussed to provide context and assistance for clinicians in their decision making in this important and challenging component of care for patients with skeletal dysplasia, in order standardize care and improve outcomes.

Quality of life in adults with achondroplasia in the United States.

Studies examining quality of life (QoL) in adults with achondroplasia are limited. We report on QoL and psychiatric illness diagnoses in a modern cohort of adults with achondroplasia. SF-36 Health Survey scores from adults with achondroplasia were compared to general population scores. Demographics, physical measurements, and psychiatric illness diagnoses were recorded from medical records. The achondroplasia population had lower scores than the general population in all categories. Most people with achondroplasia (56%) had a diagnosed psychiatric illness. Those with a diagnosed psychiatric illness had lower scores in physical functioning, role limitations due to physical and emotional health, and mental health. Pain, energy/fatigue, and general health scale scores were roughly equivalent (<2 points difference). Social functioning was >15 points higher in individuals with psychiatric illness diagnoses. Adults with achondroplasia report significantly lower physical and mental well-being and had nearly 3× the rate of psychiatric illness diagnosis than the general population, highlighting the importance of total care for this population. Healthcare providers must understand the physical and mental comorbidities of achondroplasia, beyond short stature and orthopedic issues, so they can proactively improve QoL across the lifespan for patients and families.

Best practice guidelines for management of spinal disorders in skeletal dysplasia.

BACKGROUND: Disorders of the spine present a common and difficult management concern in patients with skeletal dysplasia. Due to the rarity of these conditions however, the literature, largely consisting of small, single institution case series, is sparse in regard to well-designed studies to support clinical decision making in these situations. METHODS: Using the Delphi method, an international, multi-disciplinary group of individuals, with significant experience in the care of patients with skeletal dysplasia, convened to develop multi-disciplinary, "best practice" guidelines in the care of spinal disorders in patients with skeletal dysplasia. RESULTS: Starting with 33 statements, the group a developed a list of 31 "best practice" guidelines. CONCLUSIONS: The guidelines are presented and discussed to provide context for clinicians in their decision making in this often-challenging realm of care.

Joint Replacements in Individuals With Skeletal Dysplasias: One Institution's Experience and Response to Operative Complications.

BACKGROUND: Skeletal dysplasias are a heterogeneous group of >400 genetic disorders characterized by abnormal bone growth. Many individuals experience joint pain and limitation, coming to require joint replacement much earlier than the average-statured population. In addition, prosthesis survival rate is less in the dysplastic population. The purpose of this study is to identify risk factors for surgery and provide recommendations to improve surgical outcomes. METHODS: This a retrospective review of 29 individuals with a skeletal dysplasia who had 64 joint replacements between April 1985 and January 2019 at a single institution. We collected demographics, physical examination, medical history, imaging studies, surgical indication, and complications. RESULTS: Spondyloepiphyseal dysplasia was the most common skeletal dysplasia (7), followed by pseudoachondroplasia (4) and multiple epiphyseal dysplasia (4). Average age of the cohort was 40.6 years (range 14-64). Hip arthroplasty (34) was the most commonly performed surgery. The majority of arthroplasties (75%) required custom components. Complication rate was 37.3%, most commonly pulmonary embolism (3) and pneumonia (3). Most complications (81.8%) occurred in individuals with either a pre-existing cardiopulmonary comorbidity or lumbar/sacral deformity. Body mass index did not correlate with complication severity (R = -0.042, P = .752) or rate (R = 0.006, P = .963). CONCLUSION: Surgical complications are highest in patients with pre-existing cardiopulmonary conditions. Body mass index does not predict complications in this cohort. Preoperative evaluations for individuals with skeletal dysplasias should include comprehensive work-up of spine issues and extraskeletal systems that present an operative risk. Intraoperative protocol should include special consideration for placement on the table, airway maintenance, and spinal cord monitoring in select cases.

Blood pressure in adults with short stature skeletal dysplasias.

Hypertension, compounded by obesity, contributes to cardiovascular disease and mortality. Data describing hypertension prevalence in adults with short stature skeletal dysplasias are lacking, perhaps due to poor fit of typical adult blood pressure cuffs on rhizomelic or contracted upper extremities. Through health screening research, blood pressure was measured in short stature adults attending support group meetings and skeletal dysplasia clinics. Blood pressure was measured with a commercially available, narrower adult cuff on the upper and/or lower segment of the arm. Height, weight, age, gender, diagnosis, exercise, and medications were collected. Subjects were classified as normotensive, prehypertensive, or hypertensive for group analysis; no individual clinical diagnoses were made. In 403 short stature adults, 42% were hypertensive (systolic >140, diastolic >90 OR taking antihypertensive medications). For every BMI unit and 1 kg weight increase in males, there was a 9% and an 8% increase, respectively, in the odds of hypertension versus normotension. In females, the increase was 10% and 6%, respectively. In those with achondroplasia, the most common short stature dysplasia, males (n = 106) had 10% greater odds of hypertension versus normotension for every BMI unit and kilogram increase. In females with achondroplasia (n = 128), the odds of hypertension versus normotension was 8% greater for each BMI unit and 7% for each additional kilogram. These data suggest a high population prevalence of hypertension among short stature adults. Blood pressure must be monitored as part of routine medical care, and measuring at the forearm may be the only viable clinical option in rhizomelic short stature adults with elbow contractures.

Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders.

PURPOSE: Skeletal dysplasias comprise a heterogeneous group of inherited disorders of development, growth, and maintenance of the human skeleton. Because of their relative rarity and wide phenotypic variability, patients should be accurately identified, uniformly assessed, and managed by clinicians who are aware of their potential complications and possess the knowledge and resources to treat them effectively. This study presents expert guidelines developed to improve the diagnosis and management of patients with type II collagen skeletal disorders to optimize clinical outcomes. METHODS: A panel of 11 multidisciplinary international experts in the field of skeletal dysplasia participated in a Delphi process, which comprised analysis of a thorough literature review with subsequent generation of 26 diagnosis and care recommendations, followed by two rounds of anonymous voting with an intervening face-to-face meeting. Those recommendations with more than 80% agreement were considered as consensual. RESULTS: After the first voting round, consensus was reached to support 12 of 26 (46%) statements. After the panel discussion, the group reached consensus on 22 of 24 revised statements (92%). CONCLUSIONS: Consensus-based, expert best practice guidelines developed as a standard of care to assist accurate diagnosis, minimize associated health risks, and improve clinical outcomes for patients with type II collagen skeletal dysplasias.

Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia.

BACKGROUND: Skeletal dysplasia comprises a heterogeneous and collectively common group of inherited disorders of development, growth, and maintenance of the human skeleton. There is potential for increased perinatal morbidity and mortality in pregnant women who themselves have skeletal dysplasia, and for affected fetuses where skeletal dysplasia is suspected in utero. OBJECTIVE: We sought to establish guidelines for perinatal health care professionals who should be aware of these risks, to optimize maternal and child health pregnancy outcomes through best prenatal and delivery management practices. STUDY DESIGN: A panel of 13 multidisciplinary international experts participated in a Delphi process, which comprised consideration of thorough literature review and a list of 54 possible care recommendations subject to 2 rounds of anonymous voting and a face-to-face meeting. Those recommendations with >80% agreement were considered as consensual. RESULTS: During the first round, consensus was reached to support 30 out of the 54 statements. After the panel discussion, the group reached consensus on 40 statements. These statements include guidelines for the evaluation and treatment of pregnant women with skeletal dysplasia and for the unborn child with or suspected to have skeletal dysplasia. CONCLUSION: Consensus-based best practice guidelines are provided as a minimum of standard care to minimize associated health risks, and improve clinical outcomes for patients with skeletal dysplasia.

Best practices in peri-operative management of patients with skeletal dysplasias.

Patients with skeletal dysplasia frequently require surgery. This patient population has an increased risk for peri-operative complications related to the anatomy of their upper airway, abnormalities of tracheal-bronchial morphology and function; deformity of their chest wall; abnormal mobility of their upper cervical spine; and associated issues with general health and body habitus. Utilizing evidence analysis and expert opinion, this study aims to describe best practices regarding the peri-operative management of patients with skeletal dysplasia. A panel of 13 multidisciplinary international experts participated in a Delphi process that included a thorough literature review; a list of 22 possible care recommendations; two rounds of anonymous voting; and a face to face meeting. Those recommendations with more than 80% agreement were considered as consensual. Consensus was reached to support 19 recommendations for best pre-operative management of patients with skeletal dysplasia. These recommendations include pre-operative pulmonary, polysomnography; cardiac, and neurological evaluations; imaging of the cervical spine; and anesthetic management of patients with a difficult airway for intubation and extubation. The goals of this consensus based best practice guideline are to provide a minimum of standardized care, reduce perioperative complications, and improve clinical outcomes for patients with skeletal dysplasia.

Bone robusticity in two distinct skeletal dysplasias diverges from established patterns.

Achondroplasia (ACH) is a heritable disorder of endochondral bone formation characterized by disproportionate short stature. Osteogenesis imperfecta (OI) is a heritable bone and connective tissue disorder characterized by bone fragility. To investigate bone morphology of these groups, we retrospectively reviewed 169 de-identified bone age films from 20 individuals with ACH, 39 individuals with OI and 37 age- and sex-matched controls (matched to historical measurements from the Bolton-Brush Collection). We calculated robustness (Tt.Ar/Le) and relative cortical area (Ct.Ar/Tt.Ar) from measurements of the second metacarpal, which reflect overall bone health. Relative cortical area (RCA) is a significant predictor of fracture risk and correlates with robustness at other sites. Individuals with OI had RCH values above and robustness values below that of the control population. Bisphosphonate treatment did not significantly impact either robustness or RCA. In contrast to that reported in the unaffected population, there was no sexual dimorphism found in OI robustness or relative cortical area. We suggest that the underlying collagen abnormalities in OI override sex-specific effects. Individuals with ACH had robustness values above and RCA values below that of the control population. Sexual dimorphism was found in ACH robustness and RCH values. CLINICAL SIGNIFICANCE: Identifies morphologic trends in two distinct skeletal dysplasia populations (OI and ACH) to better understand development of bone robusticity and slenderness in humans. Understanding these patterns of bone morphology is important to predict how individuals will respond to treatment and to increase treatment effect. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2392-2396, 2017.

Multiparametric Classification of Skin from Osteogenesis Imperfecta Patients and Controls by Quantitative Magnetic Resonance Microimaging.

The purpose of this study is to evaluate the ability of quantitative magnetic resonance imaging (MRI) to discriminate between skin biopsies from individuals with osteogenesis imperfecta (OI) and skin biopsies from individuals without OI. Skin biopsies from nine controls (unaffected) and nine OI patients were imaged to generate maps of five separate MR parameters, T1, T2, km, MTR and ADC. Parameter values were calculated over the dermal region and used for univariate and multiparametric classification analysis. A substantial degree of overlap of individual MR parameters was observed between control and OI groups, which limited the sensitivity and specificity of univariate classification. Classification accuracies ranging between 39% and 67% were found depending on the variable of investigation, with T2 yielding the best accuracy of 67%. When several MR parameters were considered simultaneously in a multivariate analysis, the classification accuracies improved up to 89% for specific combinations, including the combination of T2 and km. These results indicate that multiparametric classification by quantitative MRI is able to detect differences between the skin of OI patients and of unaffected individuals, which motivates further study of quantitative MRI for the clinical diagnosis of OI.

Non-Lethal Type VIII Osteogenesis Imperfecta Has Elevated Bone Matrix Mineralization.

CONTEXT: Type VIII osteogenesis imperfecta (OI; OMIM 601915) is a recessive form of lethal or severe OI caused by null mutations in P3H1, which encodes prolyl 3-hydroxylase 1. OBJECTIVES: Clinical and bone material description of non-lethal type VIII OI. DESIGN: Natural history study of type VIII OI. SETTING: Pediatric academic research centers. PATIENTS: Five patients with non-lethal type VIII OI, and one patient with lethal type VIII OI. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Clinical examinations included bone mineral density, radiographs, and serum and urinary metabolites. Bone biopsy samples were analyzed for histomorphometry and bone mineral density distribution by quantitative backscattered electron imaging microscopy. Collagen biochemistry was examined by mass spectrometry, and collagen fibrils were examined by transmission electron microscopy. RESULTS: Type VIII OI patients have extreme growth deficiency, an L1-L4 areal bone mineral density Z-score of -5 to -6, and normal bone formation markers. Collagen from bone and skin tissue and cultured osteoblasts and fibroblasts have nearly absent 3-hydroxylation (1-4%). Collagen fibrils showed abnormal diameters and irregular borders. Bone histomorphometry revealed decreased cortical width and very thin trabeculae with patches of increased osteoid, although the overall osteoid surface was normal. Quantitative backscattered electron imaging showed increased matrix mineralization of cortical and trabecular bone, typical of other OI types. However, the proportion of bone with low mineralization was increased in type VIII OI bone, compared to type VII OI. CONCLUSIONS: P3H1 is the unique enzyme responsible for collagen 3-hydroxylation in skin and bone. Bone from non-lethal type VIII OI children is similar to type VII, especially bone matrix hypermineralization, but it has distinctive features including extremely thin trabeculae, focal osteoid accumulation, and an increased proportion of low mineralized bone.

Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy.

Achondroplasia is the most common inherited disorder of bone growth (skeletal dysplasia). Despite this fact, consistent and evidence-based management approaches to recognized, life-threatening complications, such as foramen magnum stenosis, are lacking. This study aims to outline best practice, based on evidence and expert consensus, regarding the diagnosis, assessment, and management of foramen magnum stenosis in achondroplasia during infancy. A panel of 11 multidisciplinary international experts on skeletal dysplasia was invited to participate in a Delphi process. They were: 1) presented with a list of 26 indications and a thorough literature review, 2) given the opportunity to anonymously rate the indications and discuss in face to face discussion; 3) edit the list and rate it in a second round. Those indications with more than 80% agreement were considered as consensual. After two rounds of rating and a face-to-face meeting, consensus was reached to support 22 recommendations for the evaluation and treatment of foramen magnum stenosis in infants with achondroplasia. These recommendations include indications for surgical decompression, ventriculomegaly, and hydrocephalus, sleep-disordered breathing, physical exams and the use of polysomnography and imaging in this condition. We present a consensus-based best practice guidelines consisting of 22 recommendations. It is hoped that these guidelines will lead to more uniform and structured evaluation, standardizing care pathways, and improving mortality and morbidity outcomes for this cohort.